Inhibitors of receptor-interacting protein kinase 1

Mutual reference to related applications This application was filed under US Patent Law Article 119 (e), US Provisional Patent Application No. 62 / 292,202, filed February 5, 2016, May 24, 2016. No. 62 / 341,019, No. 62 / 363,775 submitted on July 18, 2016, No. 62 / 385,217 submitted on September 8, 2016, and No. 3 November 2016. Claim the priority of the submitted No. 62 / 417,219. The entire contents of these applications are incorporated into this application by reference.

Fields The present disclosure generally relates to inhibitors of kinases, their therapeutic uses, and their manufacture.

Inflammation can be a defense mechanism that responds to harmful stimuli such as pathogen invasion and tissue damage, whereas chronic inflammation is associated with many humans such as neurodegeneration, rheumatoid arthritis, autoimmune and inflammatory diseases, and cancer. It is an important fundamental factor in the disease of. Similarly, activation of cell death pathways such as necrosis and apoptosis, which are useful in eliminating infected or damaged cells, is also an important underlying mechanism for human disease, including acute and chronic neurodegenerative diseases. be.

Receptor-interacting protein kinase 1 is a crucial regulator of inflammation, apoptosis and necroptosis. Receptor-interacting protein kinase 1 plays an important role in regulating the inflammatory response mediated by the nuclear factor kappa light chain enhancer of activated B cells (NF-κB). Most recent studies have shown that its kinase activity regulates the necroptosis of the form of necrotic cell death that was traditionally thought to be passive and disordered, and is characterized by a unique morphology. It is shown. In addition, the receptor-interacting protein kinase 1 is part of a pro-apoptotic complex that is active in regulating apoptosis.

Receptor-interacting protein kinases 1 are subject to complex and complex regulatory mechanisms including ubiquitination, deubiquitination and phosphorylation. These regulatory events comprehensively determine whether cells survive and activate an inflammatory response or death through apoptosis or necroptosis. Abnormal regulation of receptor-interacting protein kinase 1 signaling can lead to excessive inflammation or cell death, and in contrast, studies have shown that inhibition of receptor-interacting protein kinase 1 causes inflammation or cell death. It has been shown that it can be an effective therapy for diseases associated with.

<p> Provided herein are compounds useful as inhibitors of receptor-interacting protein kinase 1. The disclosure also provides a composition comprising a pharmaceutical composition, a kit comprising the compound, and methods of using (or administering) and producing the compound. The present disclosure further provides compounds or compositions thereof for use in methods of treating a disease, disorder or condition mediated by a receptor-interacting protein kinase 1. The present disclosure also discloses the above compounds or compositions thereof in the manufacture of agents for the treatment of diseases, disorders or conditions mediated by (or at least partially mediated by) the receptor-interacting protein kinase 1. Provide use.</p>

In certain embodiments, the compounds of formula I are provided. In certain embodiments, compounds of formula IIc are provided. In certain embodiments, compounds of formula IIe are provided. In certain embodiments, compounds of formula IIf are provided. In certain embodiments, the compounds of formula V are provided. In certain embodiments, compounds of formula Va are provided. In certain embodiments, the compounds of formula VI are provided. In certain embodiments, the compounds as shown in Table 1 or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or mixtures of stereoisomers are provided. In certain embodiments, the compounds as shown in Table 2 or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or mixtures of stereoisomers are provided. In certain embodiments, the compounds as shown in Table 3 or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or mixtures of stereoisomers are provided. In certain embodiments, the compounds as shown in Table 4 or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or mixtures of stereoisomers are provided.

Provided herein are pharmaceutical compositions comprising a compound comprising any of the formulas described herein and an excipient.

Compounds and compositions for use in pharmaceuticals are provided herein. In certain embodiments, the compounds and compositions are for use in the treatment of receptor-interacting protein kinase 1-mediated diseases or disorders.

Receptor Interaction Protein Kinase 1 A method of treating an intervening disease or disorder, comprising administering a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein to a subject in need thereof. , The above method is provided herein.

In certain embodiments, the disease or disorder is inflammatory bowel disease, Crohn's disease, ulcerative colonitis, psoriasis, retinal detachment, retinal pigment degeneration, luteal degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis. , Gout, SoJIA, systemic erythematosus, Schegren syndrome, systemic dermatosis, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic fatty hepatitis, alcoholic fatty hepatitis, autoimmune hepatitis, self Immune hepatobiliary disease, primary sclerosing cholangitis, nephritis, Celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, septicemia, systemic inflammatory reaction syndrome, cerebrovascular disorder, myocardium Infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic disease, asthma, atopic dermatitis, multiple sclerosis, type I diabetes, Wegner's granulomatosis, pulmonary sarcoidosis, Bechet's disease, interleukin-1 converting enzyme-related fever Syndrome, chronic obstructive pulmonary disease, tumor necrotizing factor receptor-related periodic syndrome, or periodontitis. In certain embodiments, the disease or disorder is trauma, ischemia, stroke, myocardial infarction, infection, lysosome accumulation, Gauche's disease, Clave's disease, Niemannpic's disease, septicemia, Parkinson's disease, Alzheimer's disease, muscle atrophy. Side cord sclerosis (ALS / Lou Gehrig's disease), Huntington's disease, HIV-related dementia, retinal degenerative disease, glaucoma, age-related luteal degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease. In certain embodiments, the disease or disorder is Alzheimer's disease, ALS, Friedreich's ataxia, Huntington's disease, Levy's body disease, Parkinson's disease, or spinal muscular atrophy. In certain embodiments, the disease or disorder is brain injury, spinal cord injury, dementia, stroke, Alzheimer's disease, ALS, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyGlutamine (polyQ) disease. , Stroke, Farr's disease, Menquez's disease, Wilson's disease, cerebral ischemia, or prion's disease.

1. Definitions The following detailed description describes exemplary embodiments of the present technology. However, it should be appreciated that such detailed description is not intended as a limitation to the scope of the present disclosure, but instead is provided as a detailed description of exemplary embodiments.

As used herein, the following words, phrases, and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise. Will be done.

A dash sign ("-") that is not between two letters or symbols is used to indicate the point of attachment for a substituent. For example, -C (O) NH₂Is bonded through the carbon atom. The dash symbol before or at the end of the chemical group is for convenience; the chemical group may be displayed by or without one or more dash symbols without losing its usual meaning. Wavy lines drawn through the lines in the structure indicate the bonding points of the groups. Directional or stereochemistry is not implied or implied by the order in which the chemical groups are listed or named, unless chemically or structurally required.

Prefix "C_uv"Indicates that the following groups have u ~ v carbon atoms. For example, "C_1-6"Alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

References to "about" a value or parameter include (and describe) embodiments in which the value or parameter itself is of interest. In certain embodiments, the term "about" comprises ± 10% of the indicated amount. In certain embodiments, the term "about" comprises ± 5% of the indicated amount. In certain embodiments, the term "about" comprises ± 1% of the indicated amount. Further, the term "about X" includes a description of "X". Also, the singular forms "a" and "the" include plural references unless the context explicitly indicates otherwise. Thus, for example, a reference to a "compound" comprises a plurality of such compounds, and a reference to an "assay" includes a reference to one or more assays and their equivalents known to those of skill in the art.

"Alkyl" refers to unbranched or branched saturated hydrocarbon chains. As used herein, alkyl has 1 to 20 carbon atoms (ie, C)._1-20Alkyl), with 1-8 carbon atoms (ie C)_1-8Alkyl), with 1-6 carbon atoms (ie C)_1-6Alkyl), or has 1 to 4 carbon atoms (ie, C)_1-4Alkyl). In certain embodiments, the alkyl has 1-12 carbon atoms (ie, C)._1-12Alkyl). Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, And 3-methylpentyl. When an alkyl residue having a specific carbon number is named by a chemical name or identified by a molecular formula, all position isomers having that carbon number may be included; thus, for example, "butyl". As n-butyl (ie-(CH)₂)₃CH₃), sec-Butyl (ie-CH (CH)₃) CH₂CH₃), Isobutyl (ie-CH₂CH (CH)₃)₂) And tert-butyl (ie -C (CH)₃)₃) Is mentioned; as "propyl", n-propyl (ie-(CH)₂)₂CH₃) And isopropyl (ie-CH (CH)₃)₂).

An "alkenyl" is an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (ie, C)._2-20Alkyl), an alkyl group with 2-8 carbon atoms (ie C)_2-8Alkyl), an alkyl group with 2-6 carbon atoms (ie C)_2-6Alkyl), or an alkyl group with 2-4 carbon atoms (ie, C)_2-4Refers to alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

An "alkynyl" is an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (ie, C)._2-20Alkynyl), an alkyl group with 2-8 carbon atoms (ie C)_2-8Alkynyl), an alkyl group with 2-6 carbon atoms (ie C)_2-6Alkynyl), or an alkyl group with 2-4 carbon atoms (ie, C)_2-4Alkyne). The term "alkynyl" also includes these groups having a triple bond of 1 and a double bond of 1.

"Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

"Alkylthio" refers to the group "alkyl-S-".

"Acyl" refers to the group-C (O) R, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; these are, respectively. It may be optionally substituted as defined herein. Examples of acyls include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

"Amid" is a group-C (O) NR^{y y}R^{z z}"C-amide" group and group-NR pointing to^{y y}C (O) R^{z z}Refers to both of the "N-amide" groups, where R^{y y}And R^{z z}Are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each may be optionally substituted.

"Amino" is a group-NR^{y y}R^{z z}Point to, where R^{y y}And R^{z z}Are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, haloalkyl, aryl, or heteroaryl; each may be optionally substituted.

"Amidino" is -C (NH) (NH)₂). In certain embodiments, "amidino" is -C (NR) (NR).₂), Where each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; these are each defined herein. As such, it may be optionally replaced.

"Aryl" refers to an aromatic carbocyclic group having a single ring (eg, monocyclic) or multiple rings (eg, bicyclic or tricyclic) including a condensation system. As used herein, aryl has 6 to 20 ring carbon atoms (ie, C)._6-20Aryl), with 6-12 carbon ring atoms (ie C)_6-12Aryl), or having 6-10 carbon ring atoms (ie, C)_6-10Aryl). In certain embodiments, aryl has 6-18 carbon ring atoms (ie, C)._6-18Aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not include or overlap any of the heteroaryls defined below. When one or more aryl groups are fused with heteroaryl, the resulting ring system is heteroaryl. When one or more aryl groups are fused with heterocyclyl, the resulting ring system is heterocyclyl.

"Azide" is -N₃Point to.

"Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-".

"Carbamic acid" is a group-OC (O) NR^{y y}R^{z z}"O-carbamoyl" group and group-NR pointing to^{y y}C (O) OR^{z z}Refers to both of the "N-carbamoyl" groups, where R^{y y}And R^{z z}Are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each may be optionally substituted.

"Carboxy" refers to -C (O) OH.

"Carboxy ester" or "ester" refers to both -OC (O) R and -C (O) OR, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, hetero. They can be alkyl or heteroaryl; each of these may be optionally substituted as defined herein.

"Cyano" or "carbonitrile" refers to the group -CN.

"Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including condensation, cross-linking, and spiro ring systems. The term "cycloalkyl" comprises a cycloalkenyl group (ie, the cyclic group has at least one double bond). As used herein, cycloalkyl has 3 to 20 ring carbon atoms (ie, C)._3-20Cycloalkyl), with 3-12 ring carbon atoms (ie, C)_3-12Cycloalkyl), with 3-10 ring carbon atoms (ie, C)_3-10Cycloalkyl), with 3-8 ring carbon atoms (ie C)_3-8Cycloalkyl), or has 3 to 6 ring carbon atoms (ie, C)_3-6Cycloalkyl). In certain embodiments, the cycloalkyl has 3 to 15 ring carbon atoms (ie, C)._3-15Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Furthermore, the term cycloalkyl is intended to include any non-aromatic ring that can be condensed into an aryl ring, regardless of binding to the rest of the molecule.

In certain embodiments, cycloalkyl also includes "spirocycloalkyl" when there are two positions for substitution on the same carbon atom. Examples of monocyclic radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of polycyclic radicals include adamantyl, norbornyl, decalynyl, 7,7-dimethyl-bicyclo [2.2.1] heptanyl and the like.

"Guanidine" is-NHC (NH) (NH)₂). In certain embodiments, "guanidine" is -NRC (NR) (NR).₂), Where each R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; these are, respectively, as defined herein. It may be optionally replaced.

"Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-".

"Hydrazino" is-NHNH₂Point to.

"Imino" refers to the group-C (NR) R, where each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; Each of these may be optionally substituted as defined herein.

"Imid" refers to the group-C (O) NRC (O) R, where each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or hetero. Aryl; each of these may be optionally substituted as defined herein.

Examples of "halogen" or "halo" include fluoro, chloro, bromo, and iodine.

"Haloalkyl" refers to the non-branched or branched alkyl group as defined above, where one or more hydrogen atoms are replaced by halogen. For example, when a residue is substituted with more than 1 halogen, the residue can be referred to by using a prefix corresponding to the number of associated halogen sites. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two ("di") or three ("tri") halo groups, which may be, but are not necessarily the same, the same halogen. As an example of haloalkyl, difluoromethyl (-CHF)₂) And trifluoromethyl (-CF)₃). In certain embodiments, examples of haloalkyl are difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, Examples include 2-dibromoethyl.

"Haloalkoxy" refers to the alkoxy group as defined above, where one or more hydrogen atoms are replaced by halogen.

"Hydroxyalkyl" refers to an alkyl group as defined above, where one or more hydrogen atoms are replaced by hydroxy groups.

"Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any bonded hydrogen atom) are independently replaced by the same or different heteroatom groups. The term "heteroalkyl" includes non-branched or branched saturated chains with carbon and heteroatoms. As an example, one, two or three carbon atoms may be independently replaced by the same or different heteroatoms. Heteroatomic groups, but not limited to -NR-, -O-, -S-, -S (O)-, -S (O)₂-Etc., where R is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. As an example of a heteroalkyl group, -OCH₃, -CH₂OCH₃, -SCH₃, -CH₂SCH₃,-NRCH₃, And -CH₂NRCH₃Where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. In certain embodiments, as an example of a heteroalkyl group, -CH₂OCH₃, -CH₂SCH₃, And -CH₂NRCH₃Where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; these are, respectively, as defined herein. It may be optionally replaced. As used herein, as heteroalkyl, 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to Contains 2 heteroatoms or 1 heteroatom. In certain embodiments, the term "heteroalkyl" requires that the point of attachment to the rest of the molecule is through a carbon atom.

"Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryls are 1 to 20 ring carbon atoms (ie, C)._1-20Heteroaryl), 3-12 ring carbon atoms (ie C)_3-12Heteroaryl), or 3-8 carbon ring atoms (ie, C)_3-8Heteroaryl) and; 1-5 heteroatoms, 1-4 heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur Includes an atom, or one ring heteroatom. In certain embodiments, the term "heteroaryl" refers to a 5- to 14-membered ring system. In certain embodiments, the heteroaryl contains 1 to 13 ring carbon atoms (ie, C)._3-12Heteroaryl). In certain embodiments, the heteroaryl comprises 1-6 heteroatoms. Examples of heteroaryl groups include pyrimidinyl, prynyl, pyridyl, pyridadinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings are, but are not limited to, benzo [d] thiazolyl, quinolinyl, isoquinolinyl, benzo [b] thiophenyl, indazolyl, benzo [d] imidazolyl, pyrazolo [1,5-a] pyridinyl, and imidazole [1]. , 5-a] Pyrazinyl, where the heteroaryl may be attached via any ring of the condensation system. In certain embodiments, examples of heteroaryl groups include azepinyl, acridinyl, benzoimidazolyl, benzothiazolyl, benzindrill, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiasiazolyl, benzo [b] [. 1,4] Dioxepynyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxynyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiol) Phenyl), benzotriazolyl, benzo [4,6] imidazole [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindrill, indolinyl, isoindolinyl, isoquinolyl, indridinyl, isooxazolyl, naphthyldinyl, oxadiazolyl, 2-a Oxoazepinyl, oxazolyl, oxylanyl, 1-oxide pyridinyl, 1-oxide pyrimidinyl, 1-oxide pyrazinenyl, 1-oxide pyridadinyl, 1-phenyl-1H-pyrrolill, phenazinyl, phenothiazine, phenoxadinyl, phthalazinyl, Pteridinyl, prynyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thiophenyl (ie, thienyl). .. Any aromatic ring with a single or multiple fused rings containing at least one heteroatom is said to be heteroaryl regardless of binding to the rest of the molecule (ie, any of the fused rings). Through one). Heteroaryl does not include or overlap any of the aryls defined above.

"Heteroarylalkyl" refers to the group "heteroaryl-alkyl-".

"Heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term "heterocyclyl" includes a heterocycloalkenyl group (ie, a heterocyclyl group has at least one double bond), a crosslinked-heterocyclyl group, a condensed heterocyclyl group, and a spiro-heterocyclyl group. The heterocyclyl may be a single ring or a plurality of rings, and the plurality of rings may be a condensation, a crosslink, or a spiro. In certain embodiments, the heterocyclyl may comprise one or more oxo (C = O) or N-oxide (NO-) sites. Any non-aromatic ring containing at least one heteroatom is considered heterocyclyl, regardless of bond (ie, can be bonded through a carbon atom or heteroatom). Further, the term heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom, which ring is fused to an aryl or heteroaryl ring regardless of binding to the rest of the molecule. You can do it. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (ie, C)._2-20Heterocyclyl), with 2-12 ring carbon atoms (ie, C)_2-12Heterocyclyl), has 2 to 10 ring carbon atoms (ie, C)_2-10Heterocyclyl), with 2-8 ring carbon atoms (ie, C)_2-8Heterocyclyl), with 3-12 ring carbon atoms (ie, C)_3-12Heterocyclyl), with 3-8 ring carbon atoms (ie, C)_3-8Heterocyclyl), or has 3 to 6 ring carbon atoms (ie, C)_3-6Heterocyclyl); 1-5 ring heteroatoms independently selected from nitrogen, sulfur or oxygen, 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms , Or has one ring heteroatom. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. In certain embodiments, examples of heterocyclyl groups include dioxolanyl, thienyl [1,3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isooxazolidinyl, morpholinyl, octahydroindrill. , Octahydroisoindrill, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolydinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithienyl , Tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. As used herein, the term "spiro-heterocyclyl" refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, wherein one or more additional rings. Is a 3-10 membered cycloalkyl or 3-10 membered heterocyclyl, and a single atom of one or more additional rings is also an atom of the 3-10 membered heterocyclyl. Examples of spiro-heterocyclyl rings are bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro [3.5] nonanyl, 2-oxa-6-azaspiro [3.4] octanyl, and 6-oxa-1. -Azaspiro [3.3] heptanyl is mentioned. Examples of fused heterocyclyl rings are, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno [2,

"Hydroxy" or "hydroxyl" refers to the group -OH.

"Oxo" refers to a group (= O) or (O).

"Nitro" is a group-NO₂Point to.

"Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

"Oxime" refers to the group-CR (= NOH), where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; these are the books, respectively. It may be optionally substituted as defined herein.

"Sulfonyl" is a group-S (O)₂Refers to R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyls are methyl sulfonyl, ethyl sulfonyl, phenyl sulfonyl, and toluene sulfonyl.

"Sulfinyl" refers to the group -S (O) R, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; these are the books, respectively. It may be optionally substituted as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

"Sulfonamide" is a group-SO₂NRR and -NRSO₂Refers to R, where each R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; these are each defined herein. As such, it may be optionally replaced.

"Alkylsulfonyl" is a group-S (O)₂Refers to R, where R is alkyl.

"Alkyl sulfinyl" refers to the group -S (O) R, where R is alkyl.

"Iothiocyanate" refers to the group-SCN.

"Thiol" refers to the group-SH.

"Thioxo" or "thione" refers to a group (= S) or (S).

In certain embodiments of any of the terms defined above, R^{y y}And R^{z z}Are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of these is optionally substituted as defined herein. May be done.

In certain embodiments of any of the terms defined above, R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; these are the books, respectively. It may be optionally substituted as defined herein. Certain commonly used alternative chemical names may be used. For example, a divalent group, such as a divalent "alkyl" group, a divalent "aryl" group, etc., may also be referred to as an "alkylene" or "alkylenyl" group, an "allylen" group or an "allylenyl" group, respectively. good. Also, unless explicitly stated otherwise, when a group combination is referred to herein as one site, eg arylalkyl, the last mentioned group contains an atom and by this atom. , The site is bound to the rest of the molecule.

The term "arbitrarily" or "arbitrarily" means that the event or situation described subsequently may or may not occur, and that the description is an example in which the event or situation occurs. And it means that it contains examples that do not occur. Also, the term "arbitrarily substituted" means that any one or more hydrogen atoms in the indicated atom or group may or may not be replaced by a non-hydrogen site. Point to good things.

The term "replaced" means that any one or more hydrogen atoms in the indicated atom or group have been replaced by one or more substituents other than hydrogen, provided that they are notated. The condition is that the normal valence of the atom is not exceeded. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azido, carbamoyl, carboxy, carboxyester, cyano, guanidino, halo, haloalkyl, haloalkoxy, Examples include heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiosianate, thiol, thion, or combinations thereof.

In certain embodiments, the term "substituted" as used herein refers to the above groups (ie, alkyl, alkoxy, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl). , Heteroaryl, and / or heteroalkyl), where at least one hydrogen atom is a non-hydrogen atom, eg, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amide, amino, amidino. Aryl, Aralkyl, Azido, Carbamoyl, Carboxy, Carboxylester, Cyano, Cycloalkyl, Cycloalkylalkyl, Guanadino, Halo, Haloalkyl, Haloalkoxy, Hydroxyalkyl, Heteroalkyl, Heteroaryl, Heteroarylalkyl, Heterocyclyl, Heterocyclylalkyl, Hydrazin , Hydrazone, imino, imide, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfic acid, sulfonic acid, sulfonic acid, thiol, thioxo, N-oxide, or -Si (R)¹⁰⁰)₃: Here, each R¹⁰⁰Means any of the above groups independently substituted by a bond to hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;

In certain embodiments, the term "substituted" as used herein refers to the above groups (ie, alkyl, alkylene, alkoxy, haloalkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyl, heteroaryl, In any of hydroxyalkyl and / or alkoxyalkyl), at least one hydrogen atom is a non-hydrogen atom, eg, but not limited to: an alkyl group, a haloalkyl group, a halogen atom, eg, F, Cl, Br, and I; Oxygen atoms in groups such as alkenyl, haloalkenyl group, alkynyl group, haloalkynyl group, aryl, heteroaryl, cycloalkyl or heterocyclyl group, hydroxy group, alkoxy group, and ester group; thiol group, thioalkyl group. , Sulfur atoms in groups such as thiohaloalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines, etc. Replaced by a bond to a nitrogen atom in a group; a silicon atom in a group such as a trialkylsilyl group, a dialkylarylsilyl group, an alkyldiarylsilyl group, and a triarylsilyl group; and other heteroatoms in various other groups; Means one of the above groups. "Substituted" also means that one or more hydrogen atoms are heteroatoms, such as oxygen at oxo, carbonyl, formyl, carboxy, carbonate, and ester groups; and groups such as imine, oxime, hydrazone, and nitrile. It also means any of the above groups that have been replaced by higher order bonds (eg, double or triple bonds) to nitrogen in.

In certain embodiments, "substituted" means that one or more hydrogen atoms are independently deuterium, halo, cyano, nitro, azide, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl. , Heterocyclyl, aryl, heteroaryl, -NR^gR^h, -NR^gC (= O) R^h, -NR^gC (= O) NR^gR^h, -NR^gC (= O) OR^h, -NR^gS (= O)_1-2R^h, -C (= O) R^g, -C (= O) OR^g, -OC (= O) OR^g, -OC (= O) R^g, -C (= O) NR^gR^h, -OC (= O) NR^gR^h, -OR^g, -SR^g, -S (= O) R^g, -S (= O)₂R^g, -OS (= O)_1-2R^g, -S (= O)_1-2OR^g, -NR^gS (= O)_1-2NR^gR^h, = NSO₂R^g, = NOR^g, -S (= O)_1-2NR^gR^h,-SCIENCE FICTION₅, -SCF₃Or-OCF₃Includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups that have been replaced by. In certain embodiments, "substituted" means that one or more hydrogen atoms are -C (= O) R.^g, -C (= O) OR^g, -C (= O) NR^gR^h, -CH₂SO₂R^g, -CH₂SO₂NR^gR^hIt also means any of the above groups that have been replaced by. In certain embodiments, "substituted" means that one or more hydrogen atoms are -NR.^gS (O)_1-2NR^gR^h, -CH₂S (O) R^g, -CH₂S (O) NR^gR^h, -OC (= O) OR^g,-SCIENCE FICTION₅, -SCF₃Or-OCF₃Further includes any of the above groups, which have been replaced by. In certain embodiments, "substituted" means that one or more hydrogen atoms are amino, cyano, hydroxy, imino, nitro, oxo, tioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, Further comprising any of the above groups, which have been replaced by a bond to an aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl group. In the above, R^gAnd R^hAnd RⁱAre the same or different and independently, hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or. Heteroarylalkyl, or R^gAnd R^hAnd RⁱTwo of them, together with the atoms to which they are attached, are optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxy or alkoxy. It forms a heterocyclyl ring. In embodiments, the alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl are independent of each other. It is optionally substituted with one or more oxo, alkyl, halo, amino, hydroxy or alkoxy. Further, each of the above-mentioned substituents may be optionally substituted with one or more of the above-mentioned substituents.

Reached by defining a substituent with an endlessly added substituent (eg, a substituted aryl having a substituted alkyl such as itself substituted by a substituted aryl group, further substituted by a substituted heteroalkyl group). Polymers or similar indefinite structures are not intended to be included herein. Unless otherwise stated, the maximum number of substitutions in a series of compounds described herein is 3. For example, a series of substituted substituted aryl groups having two other substituted aryl groups is limited to ((substituted aryl) substituted aryl) substituted aryls. Similarly, the above definition is not intended to include an unacceptable substitution pattern (eg, methyl substituted with 5 fluorines, or a heteroaryl group with 2 adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those of skill in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups as defined herein. Unless otherwise specified, when a group is described as optionally substituted, any substituent of the group is unsubstituted in itself. For example, in certain embodiments, the term "substituted alkyl" is an alkyl group having one or more substituents, including hydroxy, halo, alkoxy, acyl, oxo, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Point to. In other embodiments, the one or more substituents may be further substituted with halos, alkyls, haloalkyls, hydroxys, alkoxys, cycloalkyls, heterocyclyls, aryls, or heteroaryls, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

It is intended that any compound or formula given herein also represents an unlabeled form and isotope label of the compound. The isotope-labeled compound has the structure represented by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. .. Examples of isotopes that can be incorporated into the compounds of the present disclosure include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine.²H (deuterium, D),³H (tritium),¹¹C,¹³C,¹⁴C,¹⁵N,¹⁸F,³¹P,³²P,³⁵S,³⁶Cl and¹²⁵I can be mentioned. Various isotope-labeled compounds of the present disclosure, such as radioisotopes, eg,³H,¹³C and¹⁴These compounds in which C is incorporated. Such isotope-labeled compounds can be used in metabolic studies, reaction rate theory studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays. Or it may be useful in patient radiotherapy.

The disclosure also includes a "deuterated analog" of a compound of formula I in which 1 to n hydrogens attached to a carbon atom are replaced by deuterium, where n is hydrogen in the molecule. Is the number of. Such compounds exhibit increased metabolic resistance and are therefore useful for increasing the half-life of any compound of formula I when administered to mammals, especially humans. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5 (12): 524-527 (1984). Such compounds are synthesized by means well known in the art, for example by using a starting material in which one or more hydrogens are replaced by deuterium.

The deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism dynamics) properties with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes, such as deuterium, provides certain therapeutic benefits from higher metabolic stability, such as increased in vivo half-life, reduced required doses and / or improved therapeutic index. Can be.¹⁸F,³H,¹¹C-labeled compounds may be useful for PET or SPECT or other imaging studies. The isotope-labeled compounds and prodrugs thereof of the present disclosure are disclosed in the scheme or described below by substituting readily available isotope-labeled reagents for non-isotope-labeled reagents. It can be generally prepared by performing the procedures in the examples and preparations. It is understood that deuterium in this context is considered a substituent in the compound of formula I.

The concentration of such heavier isotopes, specifically deuterium, can be defined by isotope enrichers. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", it is understood that the position has hydrogen in its natural abundant isotopic composition. Will be done. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

In many cases, the compounds of this disclosure are capable of forming acids and / or base salts in the presence of amino and / or carboxy groups or similar groups.

Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomers, stereoisomers, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" is a compound, salt, composition, agent useful for preparing a pharmaceutical composition suitable for veterinary or human pharmaceutical applications. Refers to shapes and other materials.

The term "pharmaceutically acceptable salt" for a given compound retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. Refers to salt. Examples of the "pharmaceutically acceptable salt" or "physiologically acceptable salt" include salts with inorganic acids and salts with organic acids. Also, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acid salt. In contrast, when the product is a free base, the addition salt, especially the pharmaceutically acceptable addition salt, is free base in a suitable organic solvent according to the conventional procedure for preparing an acid addition salt from a base compound. Can be purified by dissolving the solution and treating the solution with an acid. Those of skill in the art will recognize various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartrate acid, citric acid, benzoic acid, cinnamic acid, Includes mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amines such as alkylamines (ie, NH).₂(Alkyl)), dialkylamine (ie, HN (alkyl))₂), Trialkylamine (ie, N (alkyl))₃), Substituted alkylamines (ie NH₂(Substituted alkyl)), di (substituted alkyl) amine (ie, HN (substituted alkyl))₂), Tri (substituted alkyl) amine (ie, N (substituted alkyl))₃), Alkenylamine (ie NH₂(Alkenyl)), dialkenylamine (ie, HN (alkenyl))₂), Trialkenylamine (ie, N (alkenyl)₃), Substituted alkenylamine (ie NH₂(Substituted alkenyl)), di (substituted alkenyl) amine (ie, HN (substituted alkenyl))₂), Tri (substituted alkenyl) amine (ie, N (substituted alkenyl)₃, Mono-, di- or tri-cycloalkylamines (ie NH₂(Cycloalkyl), HN (Cycloalkyl)₂, N (cycloalkyl)₃), Mono-, di- or tri-arylamine (ie NH₂(Aryl), HN (Aryl)₂, N (aryl)₃), Or a salt of a mixed amine, and the like. Specific examples of suitable amines are simply, by way of example, isopropylamine, trimethylamine, diethylamine, tri (iso-propyl) amine, tri (n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperazine, morpholin, Examples include N-ethylpiperidine.

The term "hydrate" refers to a complex formed by combining a compound of formula I and water.

"Solvate" refers to an aggregate or complex of one or more solvent molecules and compounds of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

Some of the compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, the amide-containing compound may be present in equilibrium with the imic acid tautomer. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between the tautomers, the compound may contain tautomers of both amides and imic acids to those of skill in the art. Understood. Therefore, it is understood that the amide-containing compound contains an imide acid tautomer. Similarly, it is understood that the imide acid-containing compound contains an amide tautomer.

The compounds disclosed herein, or pharmaceutically acceptable salts thereof, contain asymmetric centers and therefore, for amino acids, as (R)-or (S)-, or (D)-or ( As L)-, it can give rise to enantiomers, diastereomers and other stereoisomers that can be defined in terms of absolute stereochemistry. The present disclosure is intended to include all such possible isomers, as well as racemic and optically pure forms. Optically active (+) and (-), (R)-and (S)-, or (D)-and (L) -isomers may be prepared using chiral synthons or chiral reagents, or It may be divided using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers are chiral synthesis from suitable optically pure precursors, or, for example, racemic compounds (or salts or salts or using chiral fast liquid chromatography (HPLC)). Includes division of the derivative racemic compound). When the compounds described herein contain an olefinic double bond, or other center of geometric asymmetry, the compound comprises both E and Z geometric isomers, unless otherwise specified. Is intended. Similarly, it is also intended to include all tautomeric types.

A "stereoisomer" is an isomer that differs only in the state in which the atoms are arranged in space, and includes enantiomers and diastereomers. In certain embodiments, a "trait isomer" refers to a compound that is composed of the same atoms bonded by the same bond but has different three-dimensional structures that are incompatible. The present disclosure contemplates various character isomers and mixtures thereof, and includes "enantiomers" which refer to two character isomers that are mirror images of molecules that cannot be superimposed on each other.

An "enantiomer" is a character pair that is a mirror image that cannot be superimposed on each other. The 1: 1 mixture of enantiomer pairs is a "racemic" mixture.

"Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

Absolute stereochemistry is specified according to the Cahn Ingold Prelog RS system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. The split compound whose absolute configuration is unknown is designated as (+) or (-) depending on the direction (right-handed or left-handed) of rotation of the plane of polarization at the wavelength of the sodium D line.

"Prodrug" means any compound that releases the active parent drug according to formula I or any other formula described herein in vivo when the prodrug is administered to a mammalian subject. do. Prodrugs of formula I or any other formula compound described herein modify a functional group present in formula I or any other formula compound described herein. In, the modification is prepared by modifying it so that it can be cleaved in vivo to release the parent compound. The prodrug may be prepared by modifying the functional groups present in the compound so that the modification is cleaved either by conventional manipulation or in vivo to become the parent compound. Prodrugs are in the hydroxy, amino, carboxy or sulfhydryl groups in Formula I or any other formula compound described herein. Includes compounds of formula I or any other formula described herein that are attached to any group that can be cleaved in vivo to regenerate a free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters of hydroxy functional groups in compounds of formula I or any other formula described herein (eg, acetates, formates and benzoate derivatives), amides, guanidines, carboxamides. (For example, N, N-dimethylaminocarbonyl) and the like. The preparation, selection and use of prodrugs is described by T.Higuchi and V.Stella, "Pro-drugs as Novel Delivery Systems," Vol.14 of the ACSSymposium Series; "Design of Prodrugs", ed.H.Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, ed. Edward B.Roche, American Pharmaceutical Considered in the Association and Pergamon Press, 1987, each of these is incorporated herein by reference in its entirety.

As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" or "excipient" is any solvent, dispersion medium, coating, etc. Includes antibacterial and antifungal agents, isotonic agents and absorption retarders. The use of such vehicles and agents for pharmaceutically active substances is well known in the art. Any conventional vehicle or agent is intended for use in a therapeutic composition, unless it is incompatible with the active ingredient. Supplemental active ingredients can also be incorporated into the composition.<tables num="A-1"><img file="JP6974331B2_D0001.tif" /></tables><tables num="A-2"><img file="JP6974331B2_D0002.tif" /></tables>

3. Compounds Provided herein are compounds that are useful as inhibitors of receptor-interacting protein kinase 1. In certain embodiments, Equation I:<chemistry num="1"><img file="JP6974331B2_D0003.tif" /></chemistry>During the ceremony Y¹Is O or NR²Is; X¹And X²Are independently nitrogen or carbon, and X¹And X²Together, they include cycloalkyls that are optionally substituted, heterocyclyls that are optionally substituted, aryls that are optionally substituted, or heteroaryls that are optionally substituted. Forming and also R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl or Y¹Is NR²When is R²And R¹Together with the nitrogen atoms to which they are attached form an arbitrarily substituted heterocyclyl or an optionally substituted heteroaryl ring, or X.¹And R¹Together with the atoms to which they are attached form a heterocyclyl that is optionally substituted or a heteroaryl ring that is optionally substituted, and also X.²Is -CH₂-Is either; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; however, the site.<chemistry num="2"><img file="JP6974331B2_D0004.tif" /></chemistry>But<chemistry num="3"><img file="JP6974331B2_D0005.tif" /></chemistry>And the aromatic ring is optionally substituted, and at least one of the following occurs: (1) L is absent or -C (R).⁸)₂-And each R⁸Is optionally replaced by C₁-C₆Alkyl or halo, or two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) Y²Is -C (R⁶)₂-And at least one R⁶Is other than hydrogen; (3) Y²Is -O- and A is substituted with halo or cyano, or A is thiazolyl or 3- or 4-membered ring; (4) Y²Is -S-, -S (O)-or -S (O)₂-And A is other than isoxazole and phenyl, or Y²Is -S (O) (NH)-; (5) Y²Is -NR⁵-And A is other than isoxazole, pyrazole and triazole; (6) the carbonyl moiety and L are substituted with other than 1,3- in ring A; or (7) R.⁹Is a substituted cycloalkyl, a substituted heterocyclyl, a substituted aryl or a substituted heteroaryl, where at least one substituent is a cyano; (8) R.¹Is optionally substituted with halo, hydroxy or cyano C₂-C₆Alkyl; or (9) X¹And X²But the part<chemistry num="4"><img file="JP6974331B2_D0006.tif" /></chemistry>When forming a phenyl ring that is optionally substituted as in, at least one substituent is at the 1- or 4-position, and (a) at the 1-position is other than fluoro, chloro or methyl. And / or (b) at position 4 other than fluoro or methyl; in addition, the site<chemistry num="5"><img file="JP6974331B2_D0007.tif" /></chemistry>But<chemistry num="6"><img file="JP6974331B2_D0008.tif" /></chemistry>Here, the nitrogen-containing aromatic ring is optionally substituted; provided that; In addition, the compound is: 5- (difluoro (phenyl) methyl) -N- (4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) isooxazole. -3-Carboxamide; 5- (difluoro (phenyl) methyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) Isoxazole-3-carboxamide; 2- (4-bromobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl ) Thiazole-4-carboxamide; 2-benzyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) thiazole-4- Carboxamide; 4- (1,4-dihydro-2-oxo-3 (2H) -quinazolinyl) -N- [2,3,4,5-tetrahydro-1- (1-methylethyl) -2-oxo-1H -1-benzazepine-3-yl] -1-piperidincarboxamide; 4- (2-amino-7-chloro-4-quinolinyl) -N-[(3S) -2,3,4,5-tetrahydro-2- Oxo-1H-1-benzazepine-3-yl] -1-piperazincarboxamide; or 4- (2-amino (aino) -7-chloro-4-quinolinyl) -N-[(3S) -2,3,4 , 5-Tetrahydro-1-methyl-2-oxo-1H-1-benzazepine-3-yl] -1-piperazin Carboxamide; a compound thereof, or a pharmaceutically acceptable salt thereof, a prodrug. , Mutual variants, steric isomers or mixtures of steric isomers are provided.

In certain embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, a prodrug, a tautomer, a stereoisomer or a mixture of stereoisomers is provided: Y in formula.¹Is O or NR²Is; X¹And X²Are independently nitrogen or carbon, and X¹And X²Together, they include cycloalkyls that are optionally substituted, heterocyclyls that are optionally substituted, aryls that are optionally substituted, or heteroaryls that are optionally substituted. Forming and also R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl or Y¹Is NR²When is R²And R¹Together with the nitrogen atoms to which they are attached form an arbitrarily substituted heterocyclyl or an optionally substituted heteroaryl ring, or X.¹And R¹Together with the atoms to which they are attached form a heterocyclyl that is optionally substituted or a heteroaryl ring that is optionally substituted, and also X.²Is -CH₂-Is either; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; however, the site.<chemistry num="7"><img file="JP6974331B2_D0009.tif" /></chemistry>But<chemistry num="8"><img file="JP6974331B2_D0010.tif" /></chemistry>And the aromatic ring is optionally substituted, and at least one of the following occurs: (1) L is absent or -C (R).⁸)₂-And each R⁸Is optionally replaced by C₁-C₆Alkyl or halo, or two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) Y²Is -C (R⁶)₂-And at least one R⁶Is other than hydrogen; (3) Y²Is -O- and A is substituted with halo or cyano, or A is thiazolyl or 3- or 4-membered ring; (4) Y²Is -S-, -S (O)-or -S (O)₂-And A is other than isoxazole and phenyl, or Y²Is -S (O) (NH)-; (5) Y²Is -NR⁵-And A is other than isoxazole, pyrazole and triazole; or (6) the carbonyl moiety and L are substituted with other than 1,3- in ring A; (7) R.¹Is optionally substituted with halo, hydroxy or cyano C₂-C₆Alkyl; or (8) X¹And X²But the part<chemistry num="9"><img file="JP6974331B2_D0011.tif" /></chemistry>When forming a phenyl ring that is optionally substituted as in, at least one substituent is at the 1- or 4-position, and (a) at the 1-position is other than fluoro, chloro or methyl. And / or (b) at position 4 other than fluoro or methyl; in addition, the site<chemistry num="10"><img file="JP6974331B2_D0012.tif" /></chemistry>But<chemistry num="11"><img file="JP6974331B2_D0013.tif" /></chemistry>Here, the nitrogen-containing aromatic ring is optionally substituted; provided that; In addition, the compound is: 5- (difluoro (phenyl) methyl) -N- (4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) isooxazole. -3-Carboxamide; 5- (difluoro (phenyl) methyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) Isoxazole-3-carboxamide; 2- (4-bromobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl ) Thiazole-4-carboxamide; 2-benzyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) thiazole-4- Carboxamide; 4- (1,4-dihydro-2-oxo-3 (2H) -quinazolinyl) -N- [2,3,4,5-tetrahydro-1- (1-methylethyl) -2-oxo-1H -1-benzazepine-3-yl] -1-piperidincarboxamide; 4- (2-amino-7-chloro-4-quinolinyl) -N-[(3S) -2,3,4,5-tetrahydro-2- Oxo-1H-1-benzazepine-3-yl] -1-piperazincarboxamide; or 4- (2-amino-7-chloro-4-quinolinyl) -N-[(3S) -2,3,4,5- Tetrahydro-1-methyl-2-oxo-1H-1-benzazepine-3-yl] -1-It is a condition that it is not piperidine carboxamide.

In certain embodiments, R³And R⁴At least one of the halos, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring.

In certain embodiments, L is absent or -C (R).⁸)₂-And each R⁸Is optionally replaced by C₁-C₆Alkyl or halo, or two Rs⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring.

In certain embodiments, Y¹Is NR²Is.

In certain embodiments, X¹And X²Are independently substituted nitrogen or carbon, together, 5-membered arbitrarily substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted. It forms aryls, or heteroaryls that are optionally substituted.

In certain embodiments, X¹And R¹Together with the atoms to which they are attached form a 5- or 6-membered optionally substituted heterocyclyl or optionally substituted heteroaryl ring;²Is -CH₂-.

In certain embodiments, Y²Is -C (R⁶)₂-And; one R⁶Is replaced with hydrogen, halo, or optionally C₁-C₆Alkyl and the other R⁶Is halo or optionally replaced with C₁-C₆Alkyl; or two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yls form optionally substituted cycloalkyl or optionally substituted heterocyclyl rings.

In certain embodiments, Y²Is -O-, where A is substituted with halo or cyano; or A is thiazolyl or a 3- or 4-membered ring.

In certain embodiments, Y²Is -S-, -S (O)-or-S (O)₂-And A is other than isoxazole and phenyl, or Y²Is -S (O) N (H)-.

In certain embodiments, Y²Is -NR⁵-And; X¹And X²Together form a optionally substituted phenyl, where A is other than isoxazole, pyrazole and triazole; X¹And X²Together form a pyridyl that is optionally substituted; A is other than triazole; or X¹And X²Is an optional substituted pyrimidyl and A is other than pyrazole and triazole.

In certain embodiments, the carbonyl moiety and L are substituted at the ring A other than at the 1st and 3rd positions.

In certain embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof, a prodrug, a tautomer, a stereoisomer or a mixture of stereoisomers is provided;¹Is O or NR²Is; X¹And X²Are independently nitrogen or carbon, and X¹And X²Together, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. Forming and also R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl or Y¹Is NR²When is R²And R¹Together with the nitrogen atoms to which they are attached form an arbitrarily substituted heterocyclyl or an optionally substituted heteroaryl ring, or X.¹And R¹Together with the atoms to which they are attached form a heterocyclyl that is optionally substituted or a heteroaryl ring that is optionally substituted, and also X.²Is -CH₂-Is either; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; however, Provided that at least one of them occurs: (1) R³And R⁴At least one of the halos, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And each R⁸Is optionally replaced by C₁-C₆Alkyl or halo, or two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (3) Y¹Is NR²Is; (4) X¹And X²Are independently substituted nitrogen or carbon, together, 5-membered arbitrarily substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted. Forming aryl, or optionally substituted heteroaryl; (5) X¹And R¹Together with the atoms to which they are attached form a 5- or 6-membered optionally substituted heterocyclyl or optionally substituted heteroaryl ring;²Is -CH₂-Is; (6) Y²Is -C (R⁶)₂-And; one R⁶Is replaced with hydrogen, halo, or optionally C₁-C₆Alkyl and the other R⁶Is halo or optionally replaced with C₁-C₆Alkyl; or two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (7) Y²Is -O-; A is substituted with halo or cyano; or A is thiazolyl or 3- or 4-membered ring; (8) Y²Is -S-, -S (O)-or-S (O)₂-And A is other than isoxazole and phenyl, or Y²Is -S (O) N (H)-; (9) Y²Is -NR⁵-And; X¹And X²Together form a optionally substituted phenyl, where A is other than isoxazole, pyrazole and triazole; X¹And X²Together form a pyridyl that is optionally substituted; A is other than triazole; or X¹And X²Is optionally substituted pyrimidyl, where A is other than pyrazole and triazole; (10) the carbonyl moiety and L are substituted at the ring A other than at the 1,3 position; (11). Y²Is -O-; X¹And X²Together form a pyridyl that is optionally substituted; A is other than isoxazole; (12) R¹Is optionally substituted with halo, hydroxy or cyano C₂-C₆Alkyl; or (13) X¹And X²But the part<chemistry num="12"><img file="JP6974331B2_D0014.tif" /></chemistry>When forming a phenyl ring that is optionally substituted as in, at least one substituent is at the 1- or 4-position, and (a) at the 1-position is other than fluoro, chloro or methyl. And / or (b) at position 4 other than fluoro or methyl; In addition, the compound is: 5- (difluoro (phenyl) methyl) -N- (4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) isooxazole. -3-Carboxamide; 5- (difluoro (phenyl) methyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) Isoxazole-3-carboxamide; 2- (4-bromobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl ) Thiazole-4-carboxamide; 2-benzyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) thiazole-4- Carboxamide; 4- (1,4-dihydro-2-oxo-3 (2H) -quinazolinyl) -N- [2,3,4,5-tetrahydro-1- (1-methylethyl) -2-oxo-1H -1-benzazepine-3-yl] -1-piperidincarboxamide; 4- (2-amino-7-chloro-4-quinolinyl) -N-[(3S) -2,3,4,5-tetrahydro-2- Oxo-1H-1-benzazepine-3-yl] -1-piperazincarboxamide; or 4- (2-amino-7-chloro-4-quinolinyl) -N-[(3S) -2,3,4,5- Tetrahydro-1-methyl-2-oxo-1H-1-benzazepine-3-yl] -1-It is a condition that it is not piperidine carboxamide.

In certain embodiments, the compound is 5- (difluorophenylmethyl) -N-[(3S) -2,3,4,5-tetrahydro-5-methyl-4-oxo-1,5-benzoxazole. Pin-3-yl] -3-isoxazolecarboxamide or 5- (difluorophenylmethyl) -N-[(3S) -2,3,4,5-tetrahydro-4-oxo-1,5-benzoxazepine -3-Il] -3-Isoxazole Carboxamide is not.

Compounds that are useful as inhibitors of receptor-interacting protein kinase 1 are also provided herein. In certain embodiments, the compound of formula I: R in the formula.¹Is H or C which is optionally replaced₁-C₆Alkyl; (a) X¹And X²Are independently nitrogen or carbon and together are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or It forms a heteroaryl that is optionally substituted; or (b) X¹And R¹Together with the atoms to which they are attached form a heterocyclyl that is optionally substituted or a heteroaryl ring that is optionally substituted;²Is -CH₂-And; Y¹Is O or NR²And here, R²And R¹Together with the nitrogen atoms to which they are attached form a heterocyclyl that is optionally substituted or a heteroaryl ring that is optionally substituted; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Are independently replaced by H, halo, and optionally C₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; L is absent, -O-, -S-, -S (O). )-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; however, Provided that at least one of them occurs: (1) R³And R⁴At least one of the halos, or optionally C₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And each R⁸Is optionally replaced by C₁-C₆Alkyl or halo, provided that the compound is 5- (difluoro (phenyl) methyl) -N- (4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl ) Not isoxazole-3-carboxamide, or 5- (difluoro (phenyl) methyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4) ] Oxazepine-3-yl) Isoxazole-3-carboxamide, provided that it is not, or two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (3) Y¹Is NR²Is; (4) X¹And X²Are independently substituted nitrogen or carbon, together, 5-membered arbitrarily substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted. Forming aryl, or optionally substituted heteroaryl; (5) X¹And R¹Together with the atoms to which they are attached form a 5- or 6-membered optionally substituted heterocyclyl or optionally substituted heteroaryl ring;²Is -CH₂-Is; (6) Y²Is -C (R⁶)₂-And; one R⁶Is replaced with hydrogen, halo, or optionally C₁-C₆Alkyl and the other R⁶Is halo or optionally replaced with C₁-C₆Alkyl; or two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (7) Y²Is -O-; A is substituted with halo or cyano; or A is thiazolyl or 3- or 4-membered ring; where the compound is 2- (4-bromobenzyl)-. N- (5-Methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) thiazole-4-carboxamide or 2-benzyl-N- (5-) Methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) thiazole-4-carboxamide, provided that it is not; (8) Y²Is -S-, -S (O)-or-S (O)₂-And; A is other than 1,3-isoxazole, or Y²Is -S (O) N (H)-; (9) Y²Is -NR⁵-And; X¹And X²Together form a optionally substituted phenyl, where A is other than isoxazole, pyrazole and triazole; X¹And X²Together form a pyridyl that is optionally substituted; A is other than triazole; or X¹And X²Is an optionally substituted pyrimidyl, where A is other than pyrazole and triazole; or (10) the carbonyl moiety and L are substituted at the ring A other than at the 1,3 position; or its. Provided are pharmaceutically acceptable salts, prodrugs, tautomers, stereoisomers or mixtures of stereoisomers.

In certain embodiments, R¹Is C₁-C₆It is alkyl. In certain embodiments, R¹Is methyl.

In certain embodiments, site:<chemistry num="13"><img file="JP6974331B2_D0015.tif" /></chemistry>teeth,<chemistry num="14"><img file="JP6974331B2_D0016.tif" /></chemistry><chemistry num="15"><img file="JP6974331B2_D0017.tif" /></chemistry>And in the formula X³, X⁴And X⁵Are S, O, N, NH, or CH, respectively; X⁶, X⁷, X⁸And X⁹Are N or CH, respectively; q is 0, 1 or 2; each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl or -S (O)₂-C₁-C₆It is alkyl.

In certain embodiments, site:<chemistry num="16"><img file="JP6974331B2_D0018.tif" /></chemistry>teeth,<chemistry num="17"><img file="JP6974331B2_D0019.tif" /></chemistry><chemistry num="18"><img file="JP6974331B2_D0020.tif" /></chemistry>And in the formula X³, X⁴And X⁵Are S, O, N, NH, or CH, respectively; X⁶, X⁷, X⁸And X⁹Are N or CH, respectively; q is 0, 1 or 2; each R¹⁰Is an independently substituted cyano, halo or optionally substituted alkyl.

In certain embodiments, site:<chemistry num="19"><img file="JP6974331B2_D0021.tif" /></chemistry>teeth,<chemistry num="20"><img file="JP6974331B2_D0022.tif" /></chemistry>And in the formula X³, X⁴And X⁵Are S, O, N, NH, or CH, respectively; X⁶, X⁷, X⁸And X⁹Are N or CH, respectively; q is 0, 1 or 2; each R¹⁰Is an independently substituted halo or optionally substituted alkyl.

In certain embodiments, site:<chemistry num="21"><img file="JP6974331B2_D0023.tif" /></chemistry>teeth,<chemistry num="22"><img file="JP6974331B2_D0024.tif" /></chemistry>Is.

In certain embodiments, sites<chemistry num="23"><img file="JP6974331B2_D0025.tif" /></chemistry>teeth,<chemistry num="24"><img file="JP6974331B2_D0026.tif" /></chemistry>Is.

In certain embodiments, sites<chemistry num="25"><img file="JP6974331B2_D0027.tif" /></chemistry>teeth,<chemistry num="26"><img file="JP6974331B2_D0028.tif" /></chemistry>Is.

In certain embodiments, sites<chemistry num="27"><img file="JP6974331B2_D0029.tif" /></chemistry>teeth,<chemistry num="28"><img file="JP6974331B2_D0030.tif" /></chemistry>Is.

In certain embodiments, Y¹Is O.

In certain embodiments, R¹Is methyl. In certain embodiments, R¹Is ethyl.

In certain embodiments, Y²teeth<chemistry num="29"><img file="JP6974331B2_D0031.tif" /></chemistry>Where n is 1, 2, 3 or 4;<chemistry num="30"><img file="JP6974331B2_D0032.tif" /></chemistry>Is.

In certain embodiments, Y²Is -O-; A is substituted with halo or cyano; or A is a thiazolyl or 3- or 4-membered cycloalkyl or 3- or 4-membered heterocycloalkyl ring.

In certain embodiments, R³And R⁴Both are fluoro, or R³Or R⁴One of which is fluoro and the other is hydrogen, or R³And R⁴Is forming cyclopropyl, or R³Is R⁶To form cyclopropyl. In certain embodiments, R³Or R⁴Is methyl.

In certain embodiments, A is phenyl, phenylbenzo [d] thiazolyl, isooxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo [1,2-b] pyrazolyl, pyrrolyl, thiazolyl, imidazolyl. , Thiasiazolyl, cyclobutyl, cyclopropyl, or azetidinyl.

In certain embodiments, A is oxazolyl, oxazolyl, pyrazolyl, triazolyl, 5,6-dihydro-4H-pyrrolo [1,2-b] pyrazolyl, pyrrolyl, thiazolyl, imidazolyl, thiadiazolyl, cyclobutyl, cyclopropyl, or. Azetidinil.

In certain embodiments, A is phenyl.

In certain embodiments, L is absent, -S (O).₂-Or -C (R)⁸)₂-.

In one particular embodiment, two Rs⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring.

In certain embodiments, R⁹Is phenyl or 2,3-dihydro-1H-indenyl. In certain embodiments, R⁹Is phenyl. In certain embodiments, R⁹Is 2-F-Phenyl. In certain embodiments, R⁹Is pyridil. In certain embodiments, R⁹Is optionally substituted pyridyl, phenyl or 2,3-dihydro-1H-indenyl.

In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, R¹⁰Is methyl.

In one embodiment, the formula Ia:<chemistry num="31"><img file="JP6974331B2_D0033.tif" /></chemistry>During the ceremony Y¹Is O or NR²Is; X¹And X²Are independently nitrogen or carbon, and X¹And X²Together, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. Forming and also R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl or Y¹Is NR²When is R²And R¹Together with the nitrogen atoms to which they are attached form an arbitrarily substituted heterocyclyl or an optionally substituted heteroaryl ring, or X.¹And R¹Together with the atoms to which they are attached form a heterocyclyl that is optionally substituted or a heteroaryl ring that is optionally substituted, and also X.²Is -CH₂-Is either; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Is a compound of optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; Provided are pharmaceutically acceptable salts, prodrugs, metamutants, stereoisomers or mixtures of stereoisomers.

In certain embodiments, sites<chemistry num="32"><img file="JP6974331B2_D0034.tif" /></chemistry>teeth<chemistry num="33"><img file="JP6974331B2_D0035.tif" /></chemistry>Is. In certain embodiments, sites<chemistry num="34"><img file="JP6974331B2_D0036.tif" /></chemistry>But<chemistry num="35"><img file="JP6974331B2_D0037.tif" /></chemistry>When, q is 0, or R¹⁰Is halo or alkyl, L is absent, and ring A is a 3-, 4- or 5-membered monocyclic ring. In certain embodiments, sites<chemistry num="36"><img file="JP6974331B2_D0038.tif" /></chemistry>But<chemistry num="37"><img file="JP6974331B2_D0039.tif" /></chemistry>When and also the site<chemistry num="38"><img file="JP6974331B2_D0040.tif" /></chemistry>But<chemistry num="39"><img file="JP6974331B2_D0041.tif" /></chemistry>When, q is 0, or R¹⁰Is halo or alkyl, L is absent, and ring A is a 3-, 4- or 5-membered monocyclic ring.

In certain embodiments, in any of the equations disclosed herein, R⁹Is replaced by at least one cyano.

In certain embodiments, the compound is formulated II :.<chemistry num="40"><img file="JP6974331B2_D0042.tif" /></chemistry>In the formula q is 0, 1, or 2; X⁶, X⁷, X⁸And X⁹Are N or CH, respectively; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Is an independently substituted cyano, halo or optionally substituted alkyl; provided that at least one of the following occurs: (1) R³And R⁴At least one of the halos, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And each R⁸Is optionally replaced by C₁-C₆Alkyl or halo, or two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (3) Y²Is -C (R⁶)₂-And; one R⁶Is replaced with hydrogen, halo, or optionally C₁-C₆Alkyl and the other R⁶Is halo or optionally replaced with C₁-C₆Alkyl; or two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (4) Y²Is -O-; A is substituted with halo or cyano; or A is thiazolyl or 3- or 4-membered ring; (5) Y²Is -S-, -S (O)-or-S (O)₂-And; A is other than isoxazole, or Y²Is -S (O) N (H)-; (6) Y²Is -NR⁵-And; X⁶, X⁷, X⁸And X⁹Together form a optionally substituted phenyl, where A is other than isoxazole, pyrazole and triazole; X⁶, X⁷, X⁸And X⁹Together form a pyridyl that is optionally substituted; A is other than triazole; or X⁶, X⁷, X⁸And X⁹Is an optionally substituted pyrimidyl, where A is other than pyrazole and triazole; or (7) Y²Is -O-; X¹And X²Together form a pyridyl that is optionally substituted; A is other than isoxazole; (8) R¹Is optionally substituted with halo, hydroxy or cyano C₂-C₆Alkyl; or (9) X¹And X²But the part<chemistry num="41"><img file="JP6974331B2_D0043.tif" /></chemistry>When forming a phenyl ring that is optionally substituted as in, at least one substituent is at the 1- or 4-position, and (a) at the 1-position is other than fluoro, chloro or methyl. And / or (b) at position 4 other than fluoro or methyl; In addition, the compound is: 5- (difluoro (phenyl) methyl) -N- (4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) isooxazole. -3-Carboxamide; 5- (difluoro (phenyl) methyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) Isoxazole-3-carboxamide; 2- (4-bromobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl ) Thiazole-4-carboxamide; 2-benzyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) thiazole-4- Carboxamide; 4- (1,4-dihydro-2-oxo-3 (2H) -quinazolinyl) -N- [2,3,4,5-tetrahydro-1- (1-methylethyl) -2-oxo-1H -1-benzazepine-3-yl] -1-piperidincarboxamide; 4- (2-amino-7-chloro-4-quinolinyl) -N-[(3S) -2,3,4,5-tetrahydro-2- Oxo-1H-1-benzazepine-3-yl] -1-piperazincarboxamide; or 4- (2-amino-7-chloro-4-quinolinyl) -N-[(3S) -2,3,4,5- Tetrahydro-1-methyl-2-oxo-1H-1-benzazepine-3-yl] -1-piperazine Carboxamide, provided that it is not; or a pharmaceutically acceptable salt thereof, prodrug. , Alternates, steric isomers or mixtures of steric isomers.

In certain embodiments, the compound is Formula II: where q is 0, 1, or 2; X.⁶, X⁷, X⁸And X⁹Are N or CH, respectively; R¹Is H or C which is optionally replaced₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Are independently replaced by H, halo, and optionally C₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; L is absent, -O-, -S-, -S (O). )-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently halos or optionally substituted alkyls; provided that at least one of the following occurs: (1) R³And R⁴At least one of the halos, or optionally C₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And each R⁸Is optionally replaced by C₁-C₆Alkyl or halo, provided that the compound is 5- (difluoro (phenyl) methyl) -N- (4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl ) Not isoxazole-3-carboxamide, or 5- (difluoro (phenyl) methyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4) ] Oxazepine-3-yl) Isoxazole-3-carboxamide, provided that it is not, or two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (3) Y²Is -C (R⁶)₂-And; one R⁶Is replaced with hydrogen, halo, or optionally C₁-C₆Alkyl and the other R⁶Is halo or optionally replaced with C₁-C₆Alkyl; or two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (4) Y²Is -O-; A is substituted with halo or cyano; or A is thiazolyl or 3- or 4-membered ring; where the compound is 2- (4-bromobenzyl)-. N- (5-Methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) thiazole-4-carboxamide or 2-benzyl-N- (5-) Methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) thiazole-4-carboxamide; (5) Y²Is -S-, -S (O)-or-S (O)₂-And; A is other than 1,3-isoxazole, or Y²Is -S (O) N (H)-; (6) Y²Is -NR⁵-And; X⁶, X⁷, X⁸And X⁹Together form a optionally substituted phenyl, where A is other than isoxazole, pyrazole and triazole; X⁶, X⁷, X⁸And X⁹Together form a pyridyl that is optionally substituted; A is other than triazole; or X⁶, X⁷, X⁸And X⁹Is an optionally substituted pyrimidyl and A is other than pyrazole and triazole; or is a pharmaceutically acceptable salt thereof, prodrug, tautomer, stereoisomer. It is a mixture of isomers or stereoisomers.

In certain embodiments, the compound is of formula II, where L is absent or -C (R).⁸)₂-And two Rs⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring.

In any of the embodiments of Equation II (or its sub-formulas), R¹Is H or C which is optionally replaced₁-C₆It is alkyl. In any of the embodiments of Equation II (or its sub-formulas), R¹Is H or C₁-C₆It is alkyl.

In any of the embodiments of Equation II (or its sub-expressions), q is 0, 1 or 2, and when present, each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl or -S (O)₂-C₁-C₆It is alkyl. In any of the embodiments of Equation II (or its sub-expressions), q is 0, 1 or 2, and when present, each R¹⁰Is an independently substituted cyano, halo or optionally substituted alkyl. In any of the embodiments of Equation II (or its sub-formulas), each R¹⁰Is independently a halo. In certain embodiments, each R¹⁰Is independently fluoro. In any of the embodiments of Equation II (or its sub-expressions), q is 0. In any of the embodiments of Equation II (or its sub-formulas), q is 1. In any of the embodiments of Equation II (or its sub-formulas), q is 2.

In certain embodiments, the compound is formulated in Formula IIa :.<chemistry num="42"><img file="JP6974331B2_D0044.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached to form an optionally substituted cycloalkyl or heterocyclyl ring, or R³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Is an independently substituted cyano, halo or optionally substituted alkyl; provided that at least one of the following occurs: (1) R³And R⁴At least one of the halos, or optionally C₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (3) Y²Is -C (R⁶)₂-And; two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (4) R¹Is optionally substituted with halo, hydroxy or cyano C₂-C₆Alkyl; or (5) X¹And X²But the part<chemistry num="43"><img file="JP6974331B2_D0045.tif" /></chemistry>When forming a phenyl ring that is optionally substituted as in, at least one substituent is at the 1- or 4-position, and (a) at the 1-position is other than fluoro, chloro or methyl. And / or (b) at position 4 other than fluoro or methyl; In addition, the compound is: 5- (difluoro (phenyl) methyl) -N- (4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) isooxazole. -3-Carboxamide; 5- (difluoro (phenyl) methyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) Isoxazole-3-carboxamide; 2- (4-bromobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl ) Thiazole-4-carboxamide; 2-benzyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) thiazole-4- Carboxamide; 4- (1,4-dihydro-2-oxo-3 (2H) -quinazolinyl) -N- [2,3,4,5-tetrahydro-1- (1-methylethyl) -2-oxo-1H -1-benzazepine-3-yl] -1-piperidincarboxamide; 4- (2-amino-7-chloro-4-quinolinyl) -N-[(3S) -2,3,4,5-tetrahydro-2- Oxo-1H-1-benzazepine-3-yl] -1-piperazincarboxamide; or 4- (2-amino-7-chloro-4-quinolinyl) -N-[(3S) -2,3,4,5- Tetrahydro-1-methyl-2-oxo-1H-1-benzazepine-3-yl] -1-piperazine Carboxamide, provided that it is not; or a pharmaceutically acceptable salt thereof, prodrug. , Alternates, steric isomers or mixtures of steric isomers.

In certain embodiments, Equation IIa: In Equation R¹Is H or C which is optionally replaced₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Are independently replaced by H, halo, and optionally C₁-C₆Alkyl and R³And R⁴, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or heterocyclyl ring, or R.³And R⁶Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; L is absent, -O-, -S-, -S (O). )-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; where: Provided that at least one of them occurs: (1) R³And R⁴At least one of the halos, or optionally C₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y.²Is -C (R⁶)₂-And; two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl, forming an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt thereof, pro. It is a drug, a homozygous, a steric isomer or a mixture of steric isomers.

In certain embodiments, the compound is of formula IIa-1 ::<chemistry num="44"><img file="JP6974331B2_D0046.tif" /></chemistry>In the formula, R¹¹Or R¹²One is halo and the other is C_1-6Alkyl or C_1-6It is cycloalkyl and the remaining variables are as defined throughout;

In certain embodiments, the compound is of formula IIa-2 :.<chemistry num="45"><img file="JP6974331B2_D0047.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; R⁴Is H, halo, or optionally replaced C₁-C₆Alkyl; A is a cycloalkyl optionally substituted, a heterocyclyl optionally substituted, an aryl optionally substituted or a heteroaryl ring optionally substituted. Yes; L is non-existent, -O-, -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently cyano, halo or optionally substituted alkyl; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or It is a mixture of stereoisomers.

In certain embodiments, the compound is of formula IIa-2a. In certain embodiments, the compound is of formula IIa-2b. In certain embodiments, the compound is of formula IIa-3. In certain embodiments, the compound is of formula IIa-4. In certain embodiments, the compound is of formula IIa-5.<chemistry num="46"><img file="JP6974331B2_D0048.tif" /></chemistry>

In certain embodiments, the compound is of formula IIb:<chemistry num="47"><img file="JP6974331B2_D0049.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Is an independently substituted cyano, halo or optionally substituted alkyl; provided that at least one of the following occurs: (1) R³And R⁴At least one of the halos, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (3) Y²Is -C (R⁶)₂-And; two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yls, forming optionally substituted cycloalkyl or optionally substituted heterocyclyl rings; or (4) The compound is 5- (phenylmethyl) -N-[(3S) -1,2,3,4-tetrahydro-7-methyl-2-oxopyrido [2,3-b] [1,4] oxazepine. -3-yl] -3-isooxazolecarboxamide; N-[(3S) -8-fluoro-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-pyrido [2,3-b] ] [1,4] diazepine-3-yl] -3- (phenylmethyl) -1H-1,2,4-triazole-5-carboxamide; 5- (phenylmethyl) -N-[(3S) -1, 2,3,4-Tetrahydro-7-methyl-2-oxopyrido [2,3-b] [1,4] oxazepine-3-yl] -3-isooxazolecarboxamide; or N-[(3S) -8- Fluoro-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-pyrido [2,3-b] [1,4] diazepine-3-yl] -3- (phenylmethyl) -1H Not -1,2,4-triazole-5-carboxamide; or a pharmaceutically acceptable salt thereof, prodrug, homozygous, steric isomer or mixture of steric isomers thereof. ..

In certain embodiments, the compound is formulated in Formula IIb: Formulation R.¹Is H or C which is optionally replaced₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; L is absent, -O-, -S-, -S (O). )-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; however, Provided that at least one of them occurs: (1) R³And R⁴At least one of the halos, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y.²Is -C (R⁶)₂-And; two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl, forming an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt thereof, pro. It is a drug, a homozygous, a steric isomer or a mixture of steric isomers.

In certain embodiments, the compound is of formula IIb-1 :.<chemistry num="48"><img file="JP6974331B2_D0050.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; R⁴Is H, halo, or optionally replaced C₁-C₆Alkyl; A is a cycloalkyl optionally substituted, a heterocyclyl optionally substituted, an aryl optionally substituted or a heteroaryl ring optionally substituted. Yes; L is non-existent, -O-, -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently cyano, halo or optionally substituted alkyl; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or It is a mixture of stereoisomers.

In certain embodiments, the compound is of formula IIb-2. In certain embodiments, the compound is of formula IIb-3. In certain embodiments, the compound is of formula IIb-4. In certain embodiments, the compound is of formula IIb-5. In certain embodiments, the compound is of formula IIb-6.<chemistry num="49"><img file="JP6974331B2_D0051.tif" /></chemistry>

In certain embodiments, the compound is of formula IIc:<chemistry num="50"><img file="JP6974331B2_D0052.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl ring, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O -, -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently cyano, halo or optionally substituted alkyl; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or It is a mixture of stereoisomers.

In certain embodiments, the compound is formulated in Formula IIc: Formulation R.¹Is H or C which is optionally replaced₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Are independently replaced by H, halo, and optionally C₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; L is absent, -O-, -S-, -S (O). )-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; however, Provided that at least one of them occurs: (1) R³And R⁴At least one of the Cs is halo or optionally substituted₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y.²Is -C (R⁶)₂-And; two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl, forming an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt thereof, pro. It is a drug, a homozygous, a steric isomer or a mixture of steric isomers.

In certain embodiments, a compound of formula IIc or a pharmaceutically acceptable salt thereof, a prodrug, a tautomer, a stereoisomer or a mixture of stereoisomers is provided; in the formula q is 0, 1 Or 2; R¹Is H or C₁-C₆Alkyl; Y²Is -O- or -C (R)⁶)₂-And each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- Or -C (R)⁸)₂-And each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl or -S (O)₂-C₁-C₆It is alkyl.

In certain embodiments, the compound is of formula IIc-1 :.<chemistry num="51"><img file="JP6974331B2_D0053.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; R⁴Is H, halo, or optionally replaced C₁-C₆Alkyl; A is a cycloalkyl optionally substituted, a heterocyclyl optionally substituted, an aryl optionally substituted or a heteroaryl ring optionally substituted. Yes; L is non-existent, -O-, -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently cyano, halo or optionally substituted alkyl; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or It is a mixture of stereoisomers.

In certain embodiments, the compound is of formula IIc-2. In certain embodiments, the compound is of formula IIc-3. In certain embodiments, the compound is of formula IIc-4. In certain embodiments, the compound is of formula IIc-5. In certain embodiments, the compound is of formula IIc-6.<chemistry num="52"><img file="JP6974331B2_D0054.tif" /></chemistry>

In certain embodiments, Equation IIc-4:<chemistry num="53"><img file="JP6974331B2_D0055.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H or C₁-C₆Alkyl; Y²Is -O- or -C (R)⁶)₂-And each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- Or -C (R)⁸)₂-And each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl or -S (O)₂-C₁-C₆Provided are compounds of alkyl; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or mixtures of stereoisomers thereof.

In certain embodiments, the compound is expressed in formula IId:<chemistry num="54"><img file="JP6974331B2_D0056.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Is an independently substituted cyano, halo or optionally substituted alkyl; provided that at least one of the following occurs: (1) R³And R⁴At least one of the halos, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (3) Y²Is -C (R⁶)₂-And; two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or (4) the compound is 5- (phenylmethyl) -N- [ (3S) -2,3,4,5-Tetrahydro-4-oxopyrido [4,3-b] [1,4] Oxazepine-3-yl] -3-isooxazolecarboxamide; or 5- (phenylmethyl)- N-[(3S) -2,3,4,5-tetrahydro-4-oxopyrido [4,3-b] [1,4] oxazepine-3-yl] -3-isooxazolecarboxamide; not; Or a pharmaceutically acceptable salt thereof, a prodrug, a metavariant, a steric isomer or a mixture of steric isomers thereof.

In certain embodiments, the compound is expressed in Formula IId: R in Formula.¹Is H or C which is optionally replaced₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; L is absent, -O-, -S-, -S (O). )-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; however, Provided that at least one of them occurs: (1) R³And R⁴At least one of the halos, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y.²Is -C (R⁶)₂-And; two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl, forming an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt thereof, pro. It is a drug, a homozygous, a steric isomer or a mixture of steric isomers.

In certain embodiments, the compound is expressed in formula IId-1 :.<chemistry num="55"><img file="JP6974331B2_D0057.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; R⁴Is H, halo, or optionally replaced C₁-C₆Alkyl; A is a cycloalkyl optionally substituted, a heterocyclyl optionally substituted, an aryl optionally substituted or a heteroaryl ring optionally substituted. Yes; L is non-existent, -O-, -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently cyano, halo or optionally substituted alkyl; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or It is a mixture of stereoisomers.

In certain embodiments, the compound is of formula IId-2. In certain embodiments, the compound is of formula IId-3. In certain embodiments, the compound is of formula IId-4. In certain embodiments, the compound is of formula IId-5. In certain embodiments, the compound is of formula IId-6.<chemistry num="56"><img file="JP6974331B2_D0058.tif" /></chemistry><chemistry num="57"><img file="JP6974331B2_D0059.tif" /></chemistry>

In certain embodiments, Equation IIe:<chemistry num="58"><img file="JP6974331B2_D0060.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl or -S (O)₂-C₁-C₆Provided are compounds of alkyl; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or mixtures of stereoisomers thereof.

In certain embodiments, the compound is of formula IIe or is a pharmaceutically acceptable salt thereof, a prodrug, a tautomer, a steric isomer or a mixture of steric isomers thereof: in the formula. q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Is an independently substituted cyano, halo or optionally substituted alkyl.

In certain embodiments, the compound is formulated in Formula IIe: Formulation R.¹Is H or C which is optionally replaced₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Are independently replaced by H, halo, and optionally C₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; L is absent, -O-, -S-, -S (O). )-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; where: Provided that at least one of them occurs: (1) R³And R⁴At least one of the Cs is halo or optionally substituted₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y.²Is -C (R⁶)₂-And; two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl, forming an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt thereof, pro. It is a drug, a homozygous, a steric isomer or a mixture of steric isomers.

In certain embodiments, a compound of formula IIe or a pharmaceutically acceptable salt thereof, a prodrug, a tautomer, a stereoisomer or a mixture of stereoisomers is provided; in the formula q is 0, 1 Or 2; R¹Is H or C₁-C₆Alkyl; Y²Is -O- or -C (R)⁶)₂-And each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- Or -C (R)⁸)₂-And each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl or -S (O)₂-C₁-C₆It is alkyl.

In certain embodiments, the compound is of formula IIe-1 ::<chemistry num="59"><img file="JP6974331B2_D0061.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; R⁴Is H, halo, or optionally replaced C₁-C₆Alkyl; A is a cycloalkyl optionally substituted, a heterocyclyl optionally substituted, an aryl optionally substituted or a heteroaryl ring optionally substituted. Yes; L is non-existent, -O-, -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently cyano, halo or optionally substituted alkyl; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or It is a mixture of stereoisomers.

In certain embodiments, the compound is of formula IIe-2. In certain embodiments, the compound is of formula IIe-3. In certain embodiments, the compound is of formula IIe-4. In certain embodiments, the compound is of formula IIe-5. In certain embodiments, the compound is of formula IIe-6.<chemistry num="60"><img file="JP6974331B2_D0062.tif" /></chemistry>

In certain embodiments, a compound of formula IIe-4 or a pharmaceutically acceptable salt thereof, a prodrug, a tautomer, a stereoisomer or a mixture of stereoisomers is provided; in the formula q is 0. , 1 or 2; R¹Is H or C₁-C₆Alkyl; Y²Is -O- or -C (R)⁶)₂-And each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- Or -C (R)⁸)₂-And each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl or -S (O)₂-C₁-C₆It is alkyl.

In certain embodiments, Equation IIf:<chemistry num="61"><img file="JP6974331B2_D0063.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl or -S (O)₂-C₁-C₆Provided are compounds of alkyl; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or mixtures of stereoisomers thereof.

In certain embodiments, the compound is of formula IIf or is a pharmaceutically acceptable salt thereof, prodrug, tautomer, stereoisomer or mixture of stereoisomers; in the formula. q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Is an independently substituted cyano, halo or optionally substituted alkyl.

In certain embodiments, the compound is formulated in Formula IIf: Formulation R.¹Is H or C which is optionally replaced₁-C₆Alkyl; Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Are independently replaced by H, halo, and optionally C₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; L is absent, -O-, -S-, -S (O). )-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; where: Provided that at least one of them occurs: (1) R³And R⁴At least one of the Cs is halo or optionally substituted₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y.²Is -C (R⁶)₂-And; two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl, forming an optionally substituted cycloalkyl or optionally substituted heterocyclyl ring; or a pharmaceutically acceptable salt thereof, pro. It is a drug, a homozygous, a steric isomer or a mixture of steric isomers.

In certain embodiments, a compound of formula IIf or a pharmaceutically acceptable salt thereof, a prodrug, a tautomer, a stereoisomer or a mixture of stereoisomers is provided; in the formula q is 0, 1 Or 2; R¹Is H or C₁-C₆Alkyl; Y²Is -O- or -C (R)⁶)₂-And each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- Or -C (R)⁸)₂-And each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl or -S (O)₂-C₁-C₆It is alkyl.

In certain embodiments, the compound is of formula IIf-1 :.<chemistry num="62"><img file="JP6974331B2_D0064.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; R⁴Is H, halo, or optionally replaced C₁-C₆Alkyl; A is a cycloalkyl optionally substituted, a heterocyclyl optionally substituted, an aryl optionally substituted or a heteroaryl ring optionally substituted. Yes; L is non-existent, -O-, -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently cyano, halo or optionally substituted alkyl; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or It is a mixture of stereoisomers.

In certain embodiments, the compound is of formula IIf-2. In certain embodiments, the compound is of formula IIf-3. In certain embodiments, the compound is of formula IIf-4. In certain embodiments, the compound is of formula IIf-5. In certain embodiments, the compound is of formula IIf-6.<chemistry num="63"><img file="JP6974331B2_D0065.tif" /></chemistry><chemistry num="64"><img file="JP6974331B2_D0066.tif" /></chemistry>

In certain embodiments, a compound of formula IIf-4 or a pharmaceutically acceptable salt thereof, a prodrug, a tautomer, a stereoisomer or a mixture of stereoisomers is provided; in the formula q is 0. , 1 or 2; R¹Is H or C₁-C₆Alkyl; Y²Is -O- or -C (R)⁶)₂-And each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- Or -C (R)⁸)₂-And each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl or -S (O)₂-C₁-C₆It is alkyl.

In certain embodiments of compounds of formula I (or subforms thereof), R³Is H. In certain embodiments of compounds of formula I (or subforms thereof), R⁴Is optionally replaced by C₁-C₆It is alkyl. In certain embodiments of compounds of formula I (or subforms thereof), R³Is H and R⁴Is optionally replaced by C₁-C₆It is alkyl. In certain embodiments of compounds of formula I (or subforms thereof), R³Is H and R⁴Is methyl.

In certain embodiments of compounds of formula I (or subforms thereof), R³Is H and R⁴Is H.

In certain embodiments of compounds of formula II (or subforms thereof), R³Is H. In certain embodiments of compounds of formula II (or subforms thereof), R⁴Is optionally replaced by C₁-C₆It is alkyl. In certain embodiments of compounds of formula II (or subforms thereof), R³Is H and R⁴Is optionally replaced by C₁-C₆It is alkyl. In certain embodiments of compounds of formula II (or subforms thereof), R³Is H and R⁴Is C₁-C₆It is alkyl. In certain embodiments of compounds of formula II (or subforms thereof), R³Is H and R⁴Is methyl.

In certain embodiments of compounds of formula IIa, IIb, IIc, IId, IIe and IIf (or their subforms), R.³Is H and R⁴Is H. In certain embodiments of the compounds of formulas IIe-4 and IIe-5, R³Is H and R⁴Is H.

In certain embodiments of compounds of formula I (or subforms thereof), ring A is a heteroaryl ring that is optionally substituted. In certain embodiments of compounds of formula I (or subforms thereof), ring A is an unsubstituted heteroaryl ring. In certain embodiments of compounds of formula I (or subforms thereof), the A ring is pyrazolyl, isooxazolyl, oxadiazolyl or triazolyl. In certain embodiments of compounds of formula I (or subforms thereof), ring A is oxadiazolyl. In certain embodiments of compounds of formula I (or subforms thereof), ring A is triazolyl.

In certain embodiments of compounds of formula II (or subforms thereof), ring A is a heteroaryl ring that is optionally substituted. In certain embodiments of compounds of formula II (or subforms thereof), ring A is an unsubstituted heteroaryl ring. In certain embodiments of compounds of formula II (or subforms thereof), the A ring is a 5-membered heteroaryl ring that is optionally substituted. In certain embodiments of compounds of formula II (or subforms thereof), ring A is an unsubstituted 5-membered heteroaryl ring. In certain embodiments of compounds of formula II (or subforms thereof), ring A is a 6-membered heteroaryl ring that is optionally substituted. In certain embodiments of compounds of formula II (or subforms thereof), ring A is a heteroaryl ring substituted with at least one halo. In certain embodiments of compounds of formula II (or subforms thereof), ring A is a 5-membered heteroaryl ring substituted with at least one halo. In certain embodiments of compounds of formula II (or subforms thereof), the A ring is pyrazolyl, isooxazolyl, oxadiazolyl or triazolyl. In certain embodiments of compounds of formula II (or subforms thereof), ring A is oxadiazolyl. In certain embodiments of compounds of formula II (or subforms thereof), ring A is triazolyl.

In certain embodiments of compounds of formula II (or subforms thereof), the A ring is of formula :.<chemistry num="65"><img file="JP6974331B2_D0067.tif" /></chemistry>In the formula X¹⁰, X¹¹And X¹²Are S, O, N, CR, respectively¹³Or NR¹³And X¹³Is C or N; each R¹³Is independently substituted with H, halo, cyano or optionally C₁-C₆It is alkyl;

In certain embodiments, X¹⁰, X¹¹And X¹²At least one of the CR¹³Or NR¹³And at least one R¹³Is replaced with halo, cyano or optionally C₁-C₆It is alkyl. In certain embodiments, X¹⁰, X¹¹And X¹²At least one of the CR¹³Or NR¹³And at least one R¹³Is halo. In certain embodiments, each R¹³Are independently H, fluoro, chloro, cyano or methyl.

In certain embodiments of compounds of formula II (or subforms thereof), ring A is one of the following:<chemistry num="66"><img file="JP6974331B2_D0068.tif" /></chemistry>In the formula, each ring is one or more halos, cyanos or Cs.₁-C₆It may be optionally substituted with alkyl.

In certain embodiments of compounds of formula II (or subforms thereof), ring A is one of the following:<chemistry num="67"><img file="JP6974331B2_D0069.tif" /></chemistry> 。

In certain embodiments of compounds of formula I (or subforms thereof), L is absent, -O- or -C (R).⁸)₂-And each R⁸Is independently H or C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form a cycloalkyl that is optionally substituted. In certain embodiments of compounds of formula I (or subforms thereof), L is -C (R).⁸)₂-And each R⁸Together with the carbon atoms to which they are bonded form cyclopropyl.

In certain embodiments of compounds of formula II (or subforms thereof), L is absent, -O- or -C (R).⁸)₂-And each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring. In certain embodiments of compounds of formula II (or subforms thereof), L is absent, -O- or -C (R).⁸)₂-And each R⁸Is H independently, or two Rs⁸Together with the carbon atoms to which they are attached, they form a cycloalkyl that is optionally substituted.

In certain embodiments of compounds of formula II (or subforms thereof), L is absent. In certain embodiments of compounds of formula II (or subforms thereof), L is -O-. In certain embodiments of compounds of formula II (or subforms thereof), L is -C (R).⁸)₂-And each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring. In certain embodiments of compounds of formula II (or subforms thereof), L is -C (R).⁸)₂-And each R⁸Is independently H, or two Rs⁸Together with the carbon atoms to which they are attached, they form a cycloalkyl that is optionally substituted. In certain embodiments of compounds of formula II (or subforms thereof), L is -C (R).⁸)₂-And each R⁸Together with the carbon atoms to which they are bonded form cyclopropyl.

In certain embodiments of compounds of formula I (or subforms thereof), R⁹Is an optionally substituted aryl. In certain embodiments of compounds of formula I (or subforms thereof), R⁹Is optionally replaced by one or more halos, cyanos, or halos.₁-C₆Phenyl optionally substituted with alkyl. In certain embodiments of compounds of formula I (or subforms thereof), R⁹Is phenyl.

In certain embodiments of compounds of formula II (or subforms thereof), R⁹Is an optional substituted cycloalkyl, an optional substituted aryl or an optional substituted heteroaryl. In certain embodiments of compounds of formula II (or subforms thereof), R⁹Phenyl, dihydroindenyl, pyridyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 3-cyano -4-Fluorophenyl, or 5-fluoropyridin-3-yl.

In certain embodiments of compounds of formula II (or subforms thereof), q is 0. In certain embodiments of compounds of formula II (or subforms thereof), q is 1 or 2; each R.¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl, or -S (O)₂-C₁-C₆It is alkyl. In certain embodiments of compounds of formula II (or subforms thereof), q is 1 or 2; each R.¹⁰Independently, cyano, halo, methyl, or -S (O)₂-Methyl.

In certain embodiments, the compound is of formula III :.<chemistry num="68"><img file="JP6974331B2_D0070.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; X¹And X²Are N or CH, respectively; X³, X⁴And X⁵Are S, O, N, NH, or CH, respectively, and Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently cyano, halo or optionally substituted alkyl; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or It is a mixture of stereoisomers.

In certain embodiments, at least one of the following occurs: (1) R³And R⁴At least one of the halos, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; (2) L is non- Existence or -C (R)⁸)₂-And each R⁸Is optionally replaced by C₁-C₆Alkyl or halo, or two Rs⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; or (3) Y.²Is -C (R⁶)₂-And; one R⁶Is replaced with hydrogen, halo, or optionally C₁-C₆Alkyl and the other R⁶Is halo or optionally replaced with C₁-C₆Alkyl; or two Rs⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yls form optionally substituted cycloalkyl or optionally substituted heterocyclyl rings.

In certain embodiments, the compound is Formula III: X in Formula.¹And X²Are N or CH, respectively; X³, X⁴And X⁵Are S, O, N, NH, or CH, respectively, and Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Are independently replaced by H, halo, and optionally C₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; L is absent, -O-, -S-, -S (O). )-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; Or a pharmaceutically acceptable salt thereof, a prodrug, a metamutant, a steric isomer or a mixture of steric isomers thereof.

In certain embodiments, the compound is of formula IIIa, IIIb, or IIIc :.<chemistry num="69"><img file="JP6974331B2_D0071.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; X³, X⁴And X⁵Are S, O, N, NH, or CH, respectively, and Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R¹Is H or C₁-C₆Alkyl; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Are combined with the carbon atoms to which they are attached to form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl ring; L is absent, -O- , -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently cyano, halo or optionally substituted alkyl; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or It is a mixture of stereoisomers.

In certain embodiments, the compound is of formula IIIa-1, IIIb-1, or IIIc-1 :.<chemistry num="70"><img file="JP6974331B2_D0072.tif" /></chemistry><chemistry num="71"><img file="JP6974331B2_D0073.tif" /></chemistry>In the formula q is 0, 1 or 2; R¹Is H, or C optionally substituted with halo, hydroxy or cyano₁-C₆Alkyl; X³, X⁴And X⁵Are S, O, N, NH, or CH, respectively; R¹Is H or C₁-C₆Alkyl; R⁴Is H, halo, or optionally replaced C₁-C₆Alkyl; A is a cycloalkyl optionally substituted, a heterocyclyl optionally substituted, an aryl optionally substituted or a heteroaryl ring optionally substituted. Yes; L is non-existent, -O-, -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently cyano, halo or optionally substituted alkyl; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or It is a mixture of stereoisomers.

In certain embodiments, the compound is of formula IIIa, IIIb, or IIIc :.<chemistry num="72"><img file="JP6974331B2_D0074.tif" /></chemistry><chemistry num="73"><img file="JP6974331B2_D0075.tif" /></chemistry>In the formula X³, X⁴And X⁵Are S, O, N, NH, or CH, respectively, and Y²Is -O-, -S-, -S (O)-, -S (O)₂-, -S (O) (NH)-, -NR⁵-Or -C (R)⁶)₂-And; R⁵Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁶Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁶But together with the carbon atoms to which they are bonded, C₁-C₆Alken-1-yl forms an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R³And R⁴Are independently replaced by H, halo, and optionally C₁-C₆Alkyl and R³And R⁴Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, or R.³And R⁶Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; A is optionally substituted. Substituted cycloalkyl, optionally substituted heterocyclyl ring or optionally substituted heteroaryl ring; L is absent, -O-, -S-, -S (O). )-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; Or a pharmaceutically acceptable salt thereof, a prodrug, a metamutant, a steric isomer or a mixture of steric isomers thereof.

In certain embodiments, the compound is of formula IIIa-1, IIIa-2, IIIa-3, IIIa-4, IIIa-5, IIIa-6, IIIa-7, IIIa-8 or IIIa-9:<chemistry num="74"><img file="JP6974331B2_D0076.tif" /></chemistry><chemistry num="75"><img file="JP6974331B2_D0077.tif" /></chemistry>The variable parts of equations IIIa-1 to IIIa-9 are defined throughout;

In certain embodiments, the compound is of formula IVa, IVb, IVc, IVd, IVe, IVf or IVg:<chemistry num="76"><img file="JP6974331B2_D0078.tif" /></chemistry><chemistry num="77"><img file="JP6974331B2_D0079.tif" /></chemistry>In the formula q is 0, 1 or 2; R⁴Is H, halo, or optionally replaced C₁-C₆Alkyl; A is a cycloalkyl optionally substituted, a heterocyclyl optionally substituted, an aryl optionally substituted or a heteroaryl ring optionally substituted. Yes; L is non-existent, -O-, -S-, -S (O)-, -S (O)₂-, -NR⁷-Or -C (R)⁸)₂-And; R⁷Is H, or C which is optionally replaced₁-C₆Alkyl; each R⁸Is independently replaced by H, halo, or optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached, they form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R.⁹Are optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl; each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl, or -S (O)₂-C₁-C₆It is an alkyl; or a pharmaceutically acceptable salt thereof, a prodrug, a tautomer, a stereoisomer or a mixture of stereoisomers thereof.

In certain embodiments, Equation V:<chemistry num="78"><img file="JP6974331B2_D0080.tif" /></chemistry>In the formula q is 0, 1, or 2; X⁶And X⁹Independently, N or CR¹⁴Is; R¹Is H or C which is optionally replaced₁-C₆Alkyl; Y²Is -O- or -C (R)⁶)₂-And each R⁶Are independently replaced by H, halo, and optionally C₁-C₆Alkyl; R³Is H, halo, C optionally replaced₁-C₆Alkyl or R³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; L is -C (R).⁸)₂-And each R⁸Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R⁹Is an optionally substituted aryl or an optional substituted heteroaryl; each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted C₁-C₆Alkoxy, or -S (O)₂-C₁-C₆Alkyl; each R¹⁴Is independently and optionally substituted with hydrogen, cyano, halo, halo.₁-C₃C optionally substituted with alkyl or halo₁-C₃Alkoxy; however, X⁶And X⁹Both are CR¹⁴When, one or more of (i), (ii), (iii), (iv) and (v) applies: (i) R³And R⁶Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring, (ii) L is-. C (R⁸)₂-And each R⁸Form cyclopropyl together with the carbon atoms to which they are attached, (iii) R⁹Is replaced by at least one cyano, (iv) X⁹Is CH, CF, C-Cl or C-CH₃Other than, and / or (v) X⁶Is CH, CF or C-CH₃Provided are compounds other than; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or mixtures of stereoisomers thereof.

In certain embodiments of compounds of formula V (or subforms thereof), X⁹Is N. In certain embodiments, X⁹Is N and X⁶Is CR¹⁴Is. In certain embodiments, X⁹And X⁶Is N.

In certain embodiments of compounds of formula V (or subforms thereof), Y²Is O. In certain embodiments, R³Is H. In certain embodiments, R³Is methyl. In certain embodiments, R³And R⁶Together with the carbon atoms to which they are attached form cycloalkyls that are optionally substituted. In certain embodiments, R³And R⁶Together with the carbon atoms to which they are attached form a cyclopropyl ring that is optionally substituted.

In certain embodiments of compounds of formula V (or subforms thereof), X⁶And X⁹Is CR¹⁴And R³And R⁶Together with the carbon atoms to which they are attached form cycloalkyls that are optionally substituted. In certain embodiments, R³And R⁶Together with the carbon atoms to which they are attached form a cyclopropyl ring that is optionally substituted. In certain embodiments, X⁹Is CH. In certain embodiments, X⁹Is CF.

In certain embodiments of compounds of formula V (or subforms thereof), X⁶And X⁹Is CR¹⁴And L is -C (R)⁸)₂-And each R⁸Together with the carbon atoms to which they are bonded form cyclopropyl.

In certain embodiments of compounds of formula V (or subforms thereof), X⁶And X⁹Is CR¹⁴And L is -C (R)⁸)₂-And each R⁸Together with the carbon atoms to which they are bonded form cyclopropyl, R³And R⁶Together with the carbon atoms to which they are attached form a cyclopropyl ring that is optionally substituted.

In certain embodiments of compounds of formula V (or subforms thereof), each R¹⁰Independently, cyano, halo, or -S (O)₂-C₁-C₆It is alkyl. In certain embodiments, q is 1 or 2 and each R¹⁰Independently, cyano, halo, or -S (O)₂-C₁-C₆It is alkyl. In certain embodiments, q is 2 and both Rs.¹⁰However, it is halo. In certain embodiments, q is 2 and both Rs.¹⁰However, it is fluoro. In certain embodiments, q is 2 and at least one R.¹⁰However, it is fluoro.

In certain embodiments of compounds of formula V (or subforms thereof), R¹Is H or methyl. In certain embodiments of compounds of formula V (or subforms thereof), R¹Is H.

In certain embodiments of compounds of formula V (or subforms thereof), R¹Is methyl.

In certain embodiments of compounds of formula V (or subforms thereof), L is CH.₂Or two Rs⁸Together with the carbon atoms to which they are bonded form a cycloalkyl ring. In certain embodiments, L is CH.₂Is. In certain embodiments, R⁹Is an optionally substituted phenyl. In certain embodiments, R⁹Is phenyl. In certain embodiments, R⁹Is a phenyl substituted with one or two substituents independently selected from the group consisting of cyano and halo. In certain embodiments, R⁹Is a phenyl substituted with cyano.

In certain embodiments of compounds of formula V (or subforms thereof), R¹⁴Is a methyl optionally substituted with hydrogen, halo, or 1-3 fluoros. In certain embodiments, R¹⁴Is hydrogen or halo. In certain embodiments, R¹⁴Is hydrogen. In certain embodiments, R¹⁴Is halo. In certain embodiments, R¹⁴Is fluoro.

In certain embodiments, the equation Va:<chemistry num="79"><img file="JP6974331B2_D0081.tif" /></chemistry>In the formula q is 0, 1, or 2; X⁶Is N or CR¹⁴Is; R¹Is H or C which is optionally replaced₁-C₆Alkyl; Y²Is -O- or -C (R)⁶)₂-And each R⁶Are independently replaced by H, halo, and optionally C₁-C₆Alkyl; R³Is H, halo, C optionally replaced₁-C₆Alkyl or R³And R⁶Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; L is -C (R).⁸)₂-And each R⁸Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R⁹Is an optionally substituted aryl or an optional substituted heteroaryl; each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted C₁-C₆Alkoxy, or -S (O)₂-C₁-C₆Alkyl; R¹⁴Is optionally substituted with hydrogen, cyano, halo, halo or oxo C₁-C₃C optionally substituted with alkyl, or halo or oxo₁-C₃Provided are compounds of alkoxy; or pharmaceutically acceptable salts thereof, prodrugs, tautomers, stereoisomers or mixtures of stereoisomers thereof.

In certain embodiments of the compound of formula Va, X⁶Is CR¹⁴Is. In certain embodiments, X⁶Is N.

In certain embodiments of the compounds of formula Va, each R¹⁰Independently, cyano, halo, or -S (O)₂-C₁-C₆It is alkyl. In certain embodiments, q is at least 1 and at least 1 R.¹⁰Is halo. In certain embodiments, q is at least 1 and at least 1 R.¹⁰Is fluoro. In certain embodiments, q is at least 1 and at least 1 R.¹⁰Is cyano.

In certain embodiments of the compounds of formula Va, q is 0.

In certain embodiments of the compound of formula Va, Y²Is O. In certain embodiments, R³Is H. In certain embodiments, R³Is methyl. In certain embodiments, R³And R⁶Together with the carbon atoms to which they are attached form cycloalkyls that are optionally substituted. In certain embodiments, R³And R⁶Together with the carbon atoms to which they are attached form a cyclopropyl ring that is optionally substituted.

In certain embodiments of the compound of formula Va, R¹Is H or methyl.

In certain embodiments of the compound of formula Va, R¹Is methyl.

In certain embodiments of the compounds of formula Va, L is CH.₂Or two Rs⁸Together with the carbon atoms to which they are bonded form a cycloalkyl ring. In certain embodiments, L is CH.₂Is.

In certain embodiments of the compound of formula Va, R⁹Is an optionally substituted phenyl. In certain embodiments, R⁹Is phenyl. In certain embodiments, R⁹Is a phenyl substituted with one or two substituents independently selected from the group consisting of cyano and halo. In certain embodiments, R⁹Is a phenyl substituted with cyano.

In certain embodiments of compounds of formula Va (or subforms thereof), R¹⁴Is a methyl optionally substituted with hydrogen, cyano, halo, or 1-3 fluoros or oxos. In certain embodiments, R¹⁴Is hydrogen or halo. In certain embodiments, R¹⁴Is hydrogen. In certain embodiments, R¹⁴Is cyano.

In certain embodiments, the compounds of formulas V and Va do not easily cross the blood-brain barrier. In certain embodiments, the compounds of formulas V and Va have an efflux ratio of MDCKII-MDR1 greater than 2.5. In certain embodiments, X⁶And X⁹Compounds of formula II, Va and V, wherein at least one of them is N, are less than 5, 4, 3, 2, or 1 mL / min / kg when tested according to the human liver stability assay described below. Has liver clearance.

In certain embodiments, the compound is of formula VI :.<chemistry num="80"><img file="JP6974331B2_D0082.tif" /></chemistry>In the formula q is 0, 1, or 2; X⁶Is N or CR¹⁴Is; R¹Is H or C which is optionally replaced₁-C₆Alkyl; Y²Is -O- or -C (R)⁶)₂-And each R⁶Are independently replaced by H, halo, and optionally C₁-C₆Alkyl; R³Is H, halo, C optionally replaced₁-C₆Alkyl or R³And R⁶, Together with the carbon atoms to which they are attached, form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; L is -C (R).⁸)₂-And each R⁸Are independently replaced by H, halo, and optionally C₁-C₆Alkyl or two R⁸Together with the carbon atoms to which they are attached form an arbitrarily substituted cycloalkyl or optionally substituted heterocyclyl ring; R⁹Are optionally substituted aryls; each R¹⁰Is independently replaced by halo, optionally C₁-C₆Alkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, or optionally substituted C that has been₁-C₆Alkoxy; R¹⁴Is optionally substituted with hydrogen, cyano, halo, halo or oxo C₁-C₃C optionally substituted with alkyl, or halo or oxo₁-C₃It is alkoxy; or a pharmaceutically acceptable salt thereof, prodrug, tautomer, stereoisomer or mixture of stereoisomers thereof.

In certain embodiments of the compounds of formula VI, X⁶Is CR¹⁴Is. In certain embodiments, X⁶Is N.

In certain embodiments of the compounds of formula VI, each R¹⁰Is independently a halo. In certain embodiments, q is 1 and R¹⁰Is fluoro.

In certain embodiments of the compounds of formula VI, Y²Is O. In certain embodiments, R³Is H. In certain embodiments, R³Is methyl. In certain embodiments, R³And R⁶Together with the carbon atoms to which they are attached form cycloalkyls that are optionally substituted. In certain embodiments, R³And R⁶Together with the carbon atoms to which they are attached form a cyclopropyl ring that is optionally substituted.

In certain embodiments of the compounds of formula VI, R¹Is H or methyl. In certain embodiments of the compounds of formula VI, R¹Is methyl.

In certain embodiments of the compounds of formula VI, L is CH.₂Or two Rs⁸Together with the carbon atoms to which they are bonded form a cycloalkyl ring. In certain embodiments, L is CH.₂Is.

In certain embodiments of the compounds of formula VI, R⁹Is phenyl. In certain embodiments, R⁹Is an optionally substituted phenyl. In certain embodiments, R⁹Is a phenyl substituted with one or two halos.

In certain embodiments of the compounds of formula VI, R¹⁴Is a methyl optionally substituted with hydrogen, halo, or 1-3 fluoros or oxos. In certain embodiments, R¹⁴Is hydrogen or halo. In certain embodiments, R¹⁴Is hydrogen.

In certain embodiments, the compound of formula VI easily crosses the blood-brain barrier. In certain embodiments, the compounds of formula VI have an MDCKII-MDR1 runoff ratio of 2.5 or less. In certain embodiments, the compounds of formula VI are 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 μL when tested according to the human liver stability assay described below. Has liver clearance of less than / min / kg.

In any of the embodiments described throughout, q is 0, 1 or 2; each R.¹⁰Is an independently substituted cyano, halo or optionally substituted alkyl. In any of the embodiments described throughout, q is 0, 1 or 2; each R.¹⁰Is an independently substituted alkyl optionally by cyano, halo, or 1-3 halos or oxos.

In any of the embodiments described throughout, q is 0, 1 or 2; each R.¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl, or -S (O)₂-C₁-C₆It is alkyl. In any of the embodiments described throughout, q is 1 or 2; each R¹⁰Are independently substituted with cyano, halo, and optionally C₁-C₆Alkyl, or -S (O)₂-C₁-C₆It is alkyl. In any of the embodiments described throughout, q is 0, 1 or 2; each R.¹⁰Independently, cyano, fluoro, chloro, bromo, methyl, trifluoromethyl, or -S (O)₂-Methyl. In any of the embodiments described throughout, q is 1 or 2; each R¹⁰Independently, cyano, fluoro, chloro, bromo, methyl, trifluoromethyl, or -S (O)₂-Methyl.

In any of the embodiments described throughout, the A ring is an optionally substituted heteroaryl ring. In any of the embodiments described throughout, the A ring is an unsubstituted heteroaryl ring. In any of the embodiments described throughout, the A ring is a 5-membered heteroaryl ring that is optionally substituted. In any of the embodiments described throughout, the A ring is an unsubstituted 5-membered heteroaryl ring. In any of the embodiments described throughout, the A ring is a 6-membered heteroaryl ring that is optionally substituted. In any of the embodiments described throughout, the A ring is a heteroaryl ring substituted with at least one halo. In any of the embodiments described throughout, the A ring is a 5-membered heteroaryl ring substituted with at least one halo.

In any of the embodiments described throughout, the A ring is optionally substituted with isooxazolyl, pyrazolyl, oxadiazolyl or triazolyl; L is -C (R).⁸)₂-And each R⁸Together with the carbon atoms to which they are bonded form cyclopropyl.

In any of the embodiments described throughout, the A ring is optionally substituted with isooxazolyl, pyrazolyl, oxadiazolyl or triazolyl; R.³And R⁶Together with the carbon atoms to which they are attached form a cyclopropyl ring that is optionally substituted.

In any of the embodiments described throughout, the A ring is the formula:<chemistry num="81"><img file="JP6974331B2_D0083.tif" /></chemistry>In the formula X¹⁰, X¹¹And X¹²Are S, O, N, CR, respectively¹³Or NR¹³And X¹³Is C or N; each R¹³Is independently substituted with H, halo, cyano or optionally C₁-C₆It is alkyl;

In certain embodiments, X¹⁰, X¹¹And X¹²At least one of the CR¹³Or NR¹³And at least one R¹³Is replaced with halo, cyano or optionally C₁-C₆It is alkyl. In certain embodiments, X¹⁰, X¹¹And X¹²At least one of the CR¹³Or NR¹³And at least one R¹³Is halo.

In any of the embodiments described throughout, the A ring is one of the following:<chemistry num="82"><img file="JP6974331B2_D0084.tif" /></chemistry>In the equation, each ring may be optionally substituted.

In any of the embodiments described throughout, the A ring is one of the following:<chemistry num="83"><img file="JP6974331B2_D0085.tif" /></chemistry><chemistry num="84"><img file="JP6974331B2_D0086.tif" /></chemistry> 。

In any of the embodiments described throughout, the A ring is one of the following:<chemistry num="85"><img file="JP6974331B2_D0087.tif" /></chemistry> 。

In any of the embodiments described throughout, the A ring is one of the following:<chemistry num="86"><img file="JP6974331B2_D0088.tif" /></chemistry> 。

It is recognized that certain features described herein, described in the context of separate embodiments for clarity, may also be provided in combination in a single embodiment. In contrast, the various features described herein, described in the context of a single embodiment for clarity, are also provided separately or in any suitable subcombination. May be good. All combinations of embodiments relating to the chemical groups represented by the variables contained within Formula I (and all other formulas described herein) are individually and clearly defined as if any combination were individual. As described herein, to the extent that such combinations include compounds that result in stable compounds (ie, compounds that can be isolated, characterized and tested for biological activity). Included in. Also, all subcombinations of the chemical groups listed in the embodiments describing such variables, as well as the uses and medical indications described herein, eg, receptor-interacting protein kinase 1 All sub-combinations of these conditions or disorders mediated by are also as if all sub-combinations of chemical groups and all sub-combinations of use and medical indication are described individually and explicitly herein. , Specifically included herein. Also, some embodiments include any combination of one or more additional agents disclosed herein, as if every combination were described individually and explicitly.

In certain embodiments, the compound may be selected from these compounds in Tables 1, 2, 3 or 4. Stereoisomers and mixtures of these stereoisomers are also included in the present disclosure. The compounds selected from Tables 1, 2, 3 or 4, or pharmaceutically acceptable salts thereof, are also included in the present disclosure.<tables num="1-1"><img file="JP6974331B2_D0089.tif" /></tables><tables num="1-2"><img file="JP6974331B2_D0090.tif" /></tables><tables num="1-3"><img file="JP6974331B2_D0091.tif" /></tables><tables num="1-4"><img file="JP6974331B2_D0092.tif" /></tables><tables num="1-5"><img file="JP6974331B2_D0093.tif" /></tables><tables num="1-6"><img file="JP6974331B2_D0094.tif" /></tables><tables num="1-7"><img file="JP6974331B2_D0095.tif" /></tables><tables num="1-8"><img file="JP6974331B2_D0096.tif" /></tables><tables num="1-9"><img file="JP6974331B2_D0097.tif" /></tables><tables num="1-10"><img file="JP6974331B2_D0098.tif" /></tables><tables num="1-11"><img file="JP6974331B2_D0099.tif" /></tables><tables num="1-12"><img file="JP6974331B2_D0100.tif" /></tables><tables num="1-13"><img file="JP6974331B2_D0101.tif" /></tables><tables num="1-14"><img file="JP6974331B2_D0102.tif" /></tables><tables num="1-15"><img file="JP6974331B2_D0103.tif" /></tables><tables num="1-16"><img file="JP6974331B2_D0104.tif" /></tables><tables num="1-17"><img file="JP6974331B2_D0105.tif" /></tables><tables num="2"><img file="JP6974331B2_D0106.tif" /></tables><tables num="3"><img file="JP6974331B2_D0107.tif" /></tables><tables num="4-1"><img file="JP6974331B2_D0108.tif" /></tables><tables num="4-2"><img file="JP6974331B2_D0109.tif" /></tables><tables num="4-3"><img file="JP6974331B2_D0110.tif" /></tables><tables num="4-4"><img file="JP6974331B2_D0111.tif" /></tables><tables num="4-5"><img file="JP6974331B2_D0112.tif" /></tables><tables num="4-6"><img file="JP6974331B2_D0113.tif" /></tables><tables num="4-7"><img file="JP6974331B2_D0114.tif" /></tables><tables num="4-8"><img file="JP6974331B2_D0115.tif" /></tables><tables num="4-9"><img file="JP6974331B2_D0116.tif" /></tables><tables num="4-10"><img file="JP6974331B2_D0117.tif" /></tables><tables num="4-11"><img file="JP6974331B2_D0118.tif" /></tables><tables num="4-12"><img file="JP6974331B2_D0119.tif" /></tables><tables num="4-13"><img file="JP6974331B2_D0120.tif" /></tables>

4. Treatment method and use "Treatment" or "treatment" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical outcomes may include one or more of the following: a) Inhibiting a disease or condition (eg, reducing one or more symptoms resulting from the disease or condition, and / or Reducing the degree of disease or condition); b) Delaying or stopping the onset of one or more clinical symptoms associated with the disease or condition (eg, stabilizing the disease or condition, exacerbating or worsening the disease or condition) Preventing or delaying progression and / or preventing or delaying the spread of the disease or condition (eg, metastasis); and / or c) alleviating the disease, i.e. causing regression of clinical symptoms ( For example, ameliorating a disease state, granting partial or complete remission of a disease or condition, improving the effectiveness of another drug, delaying the progression of the disease, improving the quality of life, and so on. / Or to prolong survival.

"Prevention" or "prevention" means any treatment of a disease or condition that eliminates the occurrence of clinical manifestations of the disease or condition. In some embodiments, the compound may be administered to a subject (including humans) who is at risk of disease or condition or has a family history.

"Subject" refers to an animal that is or becomes the object of treatment, observation or experiment, such as a mammal (including humans). The methods described herein may be useful in human treatment and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

A "therapeutically effective amount" or of a compound described herein, or a pharmaceutically acceptable salt thereof, a metavariant, a stereoisomer, a mixture of stereoisomers, a prodrug, or a dehydrogenated analog. The term "effective amount" means an amount sufficient to be administered to a subject to provide therapeutic utility, eg, treatment when conferring remission of symptoms or delay in disease progression. For example, the therapeutically effective amount may be sufficient to reduce the symptoms of the disease or condition as described herein. The therapeutically effective amount may vary depending on the subject and the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the method of administration and can be readily determined by one of ordinary skill in the art.

The term "trauma" as used herein refers to any physical damage to the body caused by violence, accidents, fractures, etc. The term "ischemia" usually refers to cardiovascular disorders characterized by hypoxia resulting from obstruction of the arterial blood supply or poor blood flow resulting in oxygen deficiency in tissues. The term "stroke" refers to a cardiovascular disorder caused by a blood clot or bleeding in the brain, most commonly caused by a disruption of blood flow in the brain by a clogged mass, and certain embodiments of the present disclosure. In, the term stroke refers to ischemic stroke or hemorrhagic stroke. The term "myocardial infarction" refers to a cardiovascular disorder characterized by local necrosis resulting from an obstruction of the blood supply.

The methods described herein may be applied to cell populations in vivo or ex vivo. By "in vivo" is meant within a living individual, such as within an animal or human. In this regard, the methods described herein may be used therapeutically in an individual. "Ex vivo" means the outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary body fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this regard, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein determine the optimal schedule and / or dose of administration of the compounds of the present disclosure for a given sign, cell type, individual, and other parameters. May be used ex vivo to. The information collected from such use may be for experimental purposes or in It may be used in the clinic to set up a protocol for vivo treatment. Other ex vivo applications to which the compounds and compositions described herein may be compatible are described below and will be apparent to those of skill in the art. Selected compounds may be further characterized for testing safety or tolerated doses in human or non-human subjects. Such properties may be inspected using methods commonly known to those of skill in the art.

Experiments with knockout animal models and necrostatin 1, receptor-interacting protein kinase 1 inhibitors have shown inflammatory bowel disease (eg, ulcerative colonitis and Crohn's disease), psoriasis, optic nerve necrosis due to retinal detachment, retinal pigment degeneration. , Cerrain-induced acute pancreatitis, and when protecting tissues from septicemia / systemic inflammatory response syndrome (SIRS), as well as ischemic brain injury, retinal ischemia / reperfusion injury, Huntington's disease, renal ischemia-reperfusion injury, cisplatin induction Effectiveness of Receptor Interaction Protein Kinase 1 Inhibition in Relieving Renal Injury, Traumatic Brain Injury, Hematological and Solid Organ Malignant Tumors, Bacterial and Viral Infectious Diseases (eg, Tuberculosis and Inflammation) and Lysosome Accumulation Diseases Demonstrate sex.

The receptor-interacting protein kinase 1 inhibitors of the present disclosure are therefore, but not limited to, inflammatory or disorders, necrotic cell diseases, neurodegenerative diseases, central nervous system (CNS) diseases, eye diseases, infectious diseases, and malignant. It is useful for treating diseases and conditions mediated by receptor-interacting protein kinase 1, including tumors. In certain embodiments, the receptor-interacting protein kinase 1 inhibitors described herein inhibit inflammation and tissue or cells in a patient suffering from any of the given diseases or conditions. Can protect against damage or unwanted cell death (eg, necrosis or apoptosis), ameliorate symptoms, and improve immune response or neurological function. The compounds may also be suitable for treating immune-mediated diseases such as, but not limited to, allergic diseases, autoimmune diseases, and preventing graft rejection.

Compounds and compositions for use in pharmaceuticals are provided herein. In certain embodiments, the compounds and compositions are for use in the treatment of receptor-interacting protein kinase 1-mediated diseases or disorders. Also, a method of treating a receptor-interacting protein kinase 1-mediated disease or disorder in which a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein is administered to a subject in need thereof. The above methods are also provided, including. In certain embodiments, the disease or disorder is an inflammatory disease associated with A20SNP.

Various specific diseases and disorders are described below. In certain embodiments, the disease or disorder is necrotizing enteritis, nodular sclerosis, Tanzier's disease, Wolman's syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colonitis, psoriasis, retinal detachment, retinal pigment degeneration, Yellow spot degeneration, pancreatitis (eg, acute pancreatitis), atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, SoJIA, systemic erythematosus, Schegren syndrome, systemic dermatosis, antiphospholipid syndrome, vasculitis, degenerative joints Disease, non-alcoholic fatty hepatitis, alcoholic fatty hepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, solid Ischemic reperfusion injury of organs, septicemia, systemic inflammatory reaction syndrome, cerebrovascular disorder, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic disease, asthma, atopic dermatitis, polysclerosis, type 1. Diabetes, Wegner's granulomatosis, pulmonary sarcoidosis, Bechet's disease, interleukin-1 converting enzyme-related fever syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-related periodic syndrome, periodontitis, bacterial infection, staphylococcal infection Disease, mycobacterial infection, retinal pigment degeneration, influenza, transplant rejection, burns or hypoxia. In certain embodiments, the disease or disorder is trauma, ischemia, stroke, myocardial infarction, infection, lysosome accumulation disease, Niemannpic disease, Gauche disease, Clave disease, septicemia, Parkinson's disease, Alzheimer's disease, muscle atrophy. Side cord sclerosis (ALS / Lou Gehrig's disease), Huntington's disease, HIV-related dementia, encephalopathy, retinal degenerative disease, glaucoma, age-related luteal degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease. In certain embodiments, the disease or disorder is Alzheimer's disease, ALS, Friedrich's ataxia, Huntington's disease, Levy's body disease, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neuropathy, polyglutamine ( polyQ) Disease, Stroke, Farr's Disease, Menquez's Disease, Wilson's Disease , Brain ischemia, lysosomal accumulation disease or prion disease. In certain embodiments, the disease is ALS. In certain embodiments, the disease is Alzheimer's disease. In certain embodiments, the disease is a lysosomal accumulation disease. In certain embodiments, the disease is Parkinson's disease. In certain embodiments, the disorder is an ischemic disease of an organ, including, but not limited to, the brain, heart, kidneys and liver. In several different embodiments, the disorder is an eye disorder, such as retinal degenerative disease, glaucoma or age-related macular degeneration. In several different embodiments, the disorder is a central nervous system (CNS) disorder.

In certain embodiments, the compounds and compositions are useful in treating psoriasis.

In certain embodiments, the disorder is an inflammatory bowel disease, such as Crohn's disease or ulcerative colitis, both commonly known as inflammatory bowel disease. In certain embodiments, the mammal is a primate, dog or cat subject. In certain embodiments, the mammal is a human subject. Without wishing to be constrained by theory, inhibition of the receptor-interacting protein kinase 1 by the compounds of the present disclosure has been attributed to, at least in part, anti-inflammatory activity. Accordingly, embodiments of the present disclosure are also methods for inhibiting receptor-interacting protein kinase 1 either in vitro or in a subject in need thereof, the receptor-interacting protein kinase 1. Also includes the above methods comprising contacting with the compounds disclosed herein. In some of these embodiments, inhibition of the receptor-interacting protein kinase 1 is effective in blocking (partially or completely) the release of inflammatory mediators such as TNF and / or IL6. ..

In certain embodiments, it is selected from the group consisting of rheumatoid arthritis, systemic juvenile idiopathic arthritis (SoJIA), spondyloarthritis, osteoarthritis, psoriasis, Crohn's disease, ulcerative colitis, and polysclerosis. A method of treating a disease or disorder, comprising administering a therapeutically effective amount of a compound provided herein to a subject in need thereof. In certain embodiments, a disease or disorder selected from the group consisting of autoimmune hepatitis, atherosclerosis, neutrophil dermatosis, or a bizarre disease caused by A20, NEMO, and / or LUBAC mutations. Provided above are methods of treatment comprising administering a therapeutically effective amount of a compound provided herein to a subject in need thereof. In certain embodiments, the compounds are of formula I (or any of the formulas described herein or tautomers thereof), where A is triazole. In certain embodiments, the compound is of formula V or Va. In certain embodiments, the method comprises administering compound 42 or a tautomer thereof.

Inflammatory Diseases or Disorders The receptor-interacting protein kinase 1 inhibitors described herein can be used to treat inflammatory diseases and disorders. Inflammatory diseases and disorders typically indicate high levels of inflammation in connective tissue, or degeneration of these tissues.

Non-limiting examples of inflammatory diseases and disorders include Alzheimer's disease, tonic spondylitis, osteoarthritis, arthritis including rheumatoid arthritis (RA), psoriasis, asthma, atherosclerosis, Crohn's disease, colitis, These include dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), systemic erythematosus (SLE), nephritis, Parkinson's disease, and ulcerative colitis.

In certain embodiments, the compounds and compositions of the present disclosure are useful for treating rheumatoid arthritis (RA). In certain embodiments, the compounds and compositions of the present disclosure are useful in treating ulcerative colitis. In certain embodiments, the compounds and compositions of the present disclosure are useful in treating psoriasis. In certain embodiments, the compounds and compositions of the present disclosure are useful in treating psoriasis or psoriatic arthritis. In certain embodiments, the disease is spondyloarthritis.

Necrotic Cell Disease The compounds described herein can be used in the treatment of diseases / disorders caused by or otherwise associated with necrosis. The term "necrotizing cell disease" refers to cell necrosis, such as trauma, ischemia, stroke, myocardial infarction, infectious disease, Gauche disease, Clave's disease, septicemia, Parkinson's disease, Alzheimer's disease, muscular atrophic lateral sclerosis, Huntington's disease, Refers to diseases associated with or caused by HIV-related dementia, retinal degenerative disease, glaucoma, age-related luteal degeneration, rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease.

Necrotic cell disease can be acute disease such as trauma, ischemia, stroke, myocardial infarction, septic shock due to charcoal lethal toxin, septicemia, LPS-induced cell death, and HIV-induced T cell death resulting in immunodeficiency. .. Necrotizing cell disease also includes chronic neurodegenerative diseases such as Parkinson's disease, Huntington's disease, muscular atrophic lateral sclerosis, Alzheimer's disease, infectious encephalopathy, and dementia such as HIV-related dementia.

Neurodegenerative and CNS Diseases The receptor-interacting protein kinase 1 inhibitors described herein can also be used to treat neurodegenerative diseases. Neurodegenerative diseases can affect much of physical activity, such as balance, exercise, conversation, breathing, and cardiac function. Neurodegenerative diseases can be hereditary or caused by medical conditions such as alcoholism, tumors, stroke, toxins, drugs, and viruses.

Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Levy's body disease, Parkinson's disease, and spinal muscular atrophy. In certain embodiments, the neurodegenerative and CNS disorders include Niemannpic disease type C1 (NPC1), Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Levy's body. Includes disease, Parkinson's disease, and spinal muscle atrophy.

In certain embodiments, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat NPC1 through inhibiting the necroptosis that causes neuronal deficiency. In certain embodiments, the compounds and compositions of the present disclosure are useful in treating Alzheimer's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful in treating Parkinson's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful in treating amyotrophic lateral sclerosis (ALS).

More generally, the receptor-interacting protein kinase 1 inhibitors described herein maintain neuronal viability and axonal growth and neural function within the central nervous system (CNS). Can be used to promote. Thus, the compound reduces or further reduces cognitive, motor, and sensory loss associated with CNS disease or disorder by preserving neuronal viability and / or promoting axonal regeneration and / or neural function. Can be used to disable.

The receptor-interacting protein kinase 1 inhibitors described herein promote axonal regeneration in CNS neurons, such as CNS sensory neurons, motor neurons, cortical neurons, brain neurons, hippocampal neurons, and midbrain neurons. Can be used in the method for Receptor-interacting protein kinase 1 inhibitors described herein can be used in methods for promoting neural function or maintaining viability after injury to CNS neurons. In another embodiment, these compounds can be used to promote axonal regeneration in CNS neurons that are degenerated in CNS disease or disorder. The RIP receptor interaction protein kinase 1 inhibitor may be administered ex vivo by any conventional means, eg, topically to neurons or prior to replantation.

Thus, in one aspect, the present disclosure is a method of treating a CNS disorder in a subject in need thereof, wherein the symptom of the CNS disorder is axonal degeneration or injury within the CNS neuron. offer. The method comprises promoting axonal regeneration in CNS neurons affected by CNS disorders by administering to the subject an effective amount of a compound or composition disclosed herein. After administration, neural function may be measured, for example, as a sign of axonal regeneration. It is also contemplated that after administration of the compound or composition, the neuronal function of CNS neurons will be preserved or improved as compared to pre-administration neuronal function.

Non-limiting examples of CNS disease or disorder include brain injury, spinal cord injury, dementia, stroke, Alzheimer's disease, muscular atrophic lateral sclerosis (ALS / Lou Gehrig's disease), Parkinson's disease, Huntington's disease, multiple sclerosis. , Diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Farr's disease, Menquez's disease, Wilson's disease, cerebral ischemia, and prion's disease.

In an exemplary embodiment, the CNS disorder is brain injury or spinal cord injury.

Also provided herein are methods for promoting neuronal survival and axonal regeneration in the CNS. CNS disorders characterized by loss or failure of axillary growth or axonal degeneration are CNS neurological disorders (eg, trauma, surgery, nerve compression, nerve contusion, nerve transection, neurotoxicity, or other body to the brain or spinal cord. It may result from traumatic injury) or neurodegenerative CNS disease, and the symptoms of the disorder are axonal degeneration (eg, Alzheimer's disease, muscular atrophic lateral sclerosis (ALS / Lou Gehrig's disease), Parkinson's disease, multiple sclerosis). Disease, diabetic neuropathy, polyglutamine (polyQ) disease, stroke, Farr's disease, Menquez's disease, Wilson's disease, cerebral ischemia, prion's disease (eg, Kreuzfeld-Jakob's disease). CNS disorders are brain injuries (eg, traumatic brain injuries) or spinal cord injuries (eg, chronic, acute or traumatic spinal cord injuries). In certain embodiments, CNS disorders, such as brain stem injuries or brain stems. Aneurysms in the subject affect basic vital functions such as breathing, heartbeat and blood pressure.

In certain embodiments, the CNS disease or disorder affects the cognitive ability of the subject. In certain embodiments, the CNS disease or disorder affects the subject's exercise and / or intensity. In certain embodiments, the CNS disease or disorder affects subject coordination.

In certain embodiments, CNS disorders, such as brain damage to the cerebral cortex, or neurodegenerative CNS disorders, such as Alzheimer's disease, frontotemporal dementia, Lewy body dementia, corticobasal degeneration, Advanced nuclear paralysis and prion disease affect the subject's cognitive ability.

In certain embodiments, CNS disorders, such as brain or spinal cord injury, or neurodegenerative CNS disorders, such as Parkinson's disease, frontotemporal dementia, Lewy body dementia, corticobasal degeneration, Progressive nuclear paralysis, Huntington's disease, multiple system atrophy, amyotrophic lateral sclerosis and hereditary spastic paralysis affect the subject's exercise and / or intensity.

In certain embodiments, CNS disorders, such as brain damage to the cerebellum, or neurodegenerative CNS disorders, such as spinocerebellar atrophy, Friedreich's ataxia, and prion disease, affect subject coordination.

In each of the above methods, CNS disorders include, but are not limited to, brain injury, spinal cord injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS / Lou Gehrig's disease), Parkinson's disease, multiple sclerosis, diabetic nerve. Disorders, polyglutamine (polyQ) disease, stroke, Farr's disease, Menquez's disease, Wilson's disease, cerebral ischemia, prion's disease (eg, Kreuzfeld-Jakob's disease), dementia (eg, frontotemporal dementia, Levy small) Body type dementia), cerebral cortical basal nuclear degeneration, progressive supranuclear paralysis, multiple system atrophy, hereditary spastic vs. paralysis and spinal cord cerebral atrophy.

Non-limiting examples of neurodegenerative diseases include Alzheimer's disease, lithosome accumulation disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, Huntington's disease, Levy's body disease, Parkinson's disease, and spinal muscle atrophy. Can be mentioned.

In certain embodiments, the compounds and compositions of the present disclosure are useful in treating Alzheimer's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful in treating Parkinson's disease. In certain embodiments, the compounds and compositions of the present disclosure are useful in treating amyotrophic lateral sclerosis (ALS). In certain embodiments, the compounds and compositions of the present disclosure are useful in treating lysosomal storage disorders.

In certain embodiments, the disorder is a brain disorder such as, but not limited to, Alzheimer's disease, ALS, frontotemporal dementia, defective dementia, Huntington's disease, Parkinson's disease, Levy body dementia, progressive. Nuclear paralysis, polysclerosis, optic neuromyelitis, ischemic brain injury (stroke), hypoxic brain injury, traumatic brain injury, spinal cord injury, septicemia-induced brain injury, CNS infection, CNS abscess, polymorphism Glioblastoma, epilepsy, neuropathic pain, major depression, bipolar depression, schizophrenia, autism, Niemannpic disease, Neuro-Bechett disease.

In certain embodiments, the method of treating a CNS disease or disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein. offer. In certain embodiments, the disease or disorder is Alzheimer's disease or amyotrophic lateral sclerosis (ALS). In certain embodiments, the compound is of formula I (or any of the formulas described herein), where A is other than triazole. In certain embodiments, the compound is of formula VI.

Ocular Conditions The receptor-interacting protein kinase 1 inhibitors described herein reduce or prevent the loss of viability of photoreceptor cells and / or retinal pigment epithelial cells that treat the ocular condition. Can also be used.

In certain embodiments, the present disclosure is a method of maintaining the visual function of an eye of a subject having an ocular condition, wherein the symptoms of the ocular condition are the viability of photoreceptor cells in the retina of the eye having the condition. The above method, which is a loss, is provided. The above method maintains the viability of photoreceptor cells located within the retina of the eye by administering to the subject eye an effective amount of a compound or composition described herein. include. After administration, the visual function of the eye (eg, visual acuity) can be maintained or improved compared to the visual function of the eye before administration.

Eye conditions include age-related macular degeneration (AMD), retinitis pigmentosa (RP), macular edema, diabetic retinopathy, central ring-shaped choroidal dystrophy, vest disease, adult oval-like disease, pattern dystrophy, and myopic degeneration. , Central serous retinopathy, Stargard's disease, pyramidal rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, retinal inflammation, toxic retinitis and photoinduced toxicity. It's okay. AMD may be angiogenic AMD or arid form of AMD. Retinal detachment may be ruptured, serous, and tractional retinal detachment. In certain embodiments, the ocular condition may be a condition selected from the group consisting of geographic atrophy, glaucoma, and other ischemic eye diseases.

In certain embodiments, the present disclosure provides a method of maintaining the viability of retinal pigment epithelial (RPE) cells in the retina of a subject having an ocular condition by administration of the compounds of the present disclosure. Subjects to be treated may have loss of retinal pigment epithelial cells in the retina of the eye with the above symptoms, and ocular conditions include age-related macular degeneration (AMD), Best disease, myopic degeneration, Stargard's disease, uveitis. , Adult central macular dystrophy, macular fundus, multiple disappearing white spot syndrome, parenchymal choroidosis, acute posterior multiple evanescent pigment epitheliosis (AMPPE), and other uveitis disorders selected from the group good. In certain embodiments, the method comprises maintaining the viability of retinal pigment epithelial cells by administering to the subject's eye an effective amount of a compound or composition described herein. ..

In another embodiment, age-related retinitis pigmentosa (AMD), retinitis pigmentosa (RP), retinal edema, diabetic retinopathy, central ring-shaped choroidal dystrophy, vest disease, adult oval-like disease, pattern dystrophy, myopia. Eyes selected from the group consisting of sexual degeneration, central serous retinopathy, Stargard's disease, pyramidal rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, retinal inflammation, toxic retinitis and photoinduced toxicity Provided is a method for maintaining the viability of photoreceptive cells located in the retina of a subject having a condition. Thus, in certain embodiments, the method is such that by administering to the eye an effective amount of a compound or composition described herein, light is placed within the retina of the subject having the condition. Includes maintaining the viability of the receiving cells.

In another embodiment, there is provided a method of maintaining the viability of photoreceptor cells located within the retina of a mammalian eye after retinal detachment. The retinal detachment may be a ruptured retinal detachment, a tractional retinal detachment, or a serous retinal detachment. In other embodiments, retinal detachment is of retinal tear, retinoblastoma, melanoma or other cancer, diabetic retinopathy, vasculitis, choroidal neovascularization, retinal ischemia, pathological myopia, or trauma. It can happen as a result. In certain embodiments, the above method is sufficient to maintain the viability of photoreceptor cells located within the detached retinal region, in an amount of the eye with the detached retinal region. Includes administration of the compounds or compositions described herein.

In another embodiment, age-related retinitis pigmentosa (AMD), retinitis pigmentosa (RP), retinal edema, central ring-shaped choroidal dystrophy, retinal detachment, diabetic retinopathy, vest disease, adult oval-like disease, pattern. Select from the group consisting of dystrophy, myopic degeneration, central serous retinitis, Stargard's disease, pyramidal rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, retinal inflammation, toxic retinitis and photoinduced toxicity. A method of maintaining the visual function of an eye of a subject having an ocular condition that is described herein as a symptom of the ocular condition is a loss of viability of photoreceptive cells in the retina of the eye. Provided are the above methods comprising treating a subject with a compound or composition of the retina.

In another embodiment, the present disclosure is a method of maintaining the visual function of an eye of a subject having an ocular condition, wherein the symptoms of the ocular condition are the viability of photoreceptor cells and / or the viability of RPE in the retina of the eye. Provided above is a loss and comprises treating the subject with a compound or composition described herein to the subject.

In certain embodiments, it is a method of maintaining the visual function of an eye of a subject having an ocular condition, wherein the symptom of the ocular condition is a loss of viability of retinal ganglion cells in the retina of the eye having the condition. , The above method is provided. The method comprises maintaining the viability of retinal ganglion cells located within the retina of the eye by administering to the subject eye an effective amount of the compound or composition. After administration of the compound or composition, the visual function of the eye can be maintained or improved compared to the visual function of the eye before administration. In addition, the retinal ganglion cells maintained after the administration can support axonal regeneration.

Non-limiting examples of ocular condition-related symptoms include loss of viability of retinal ganglion cells in the retina of the eye, glaucoma, optic nerve damage, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal vein occlusion, and retina. Central retinal occlusion may be mentioned.

The compounds described herein are optic neuropathy, eg, ischemic optic neuropathy (eg, arteritis or non-arteritis anterior ischemic optic neuropathy and posterior ischemic optic neuropathy), compression optic neuropathy,. Infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (eg, Labor optic neuropathy), dystrophic optic neuropathy, toxic optic neuropathy, and hereditary optic neuropathy (eg, Labor optic neuropathy, dominant optic neuropathy, veil) May be used to treat optic neuropathy).

Also disclosed are methods of maintaining visual function of the eye of a subject having an ocular condition selected from the group consisting of glaucoma, optic nerve injury, optic neuropathy, diabetic retinopathy, central retinal artery occlusion and central retinal vein occlusion. The method described above is the viability of retinal ganglion cells located within the retina of the eye and the viability of the eye by administering to the subject eye an effective amount of a compound or composition described herein. Includes maintaining visual function.

In another embodiment, it is placed within the retina of the eye of a mammal suffering from, for example, glaucoma, optic nerve injury, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion and central retinal vein occlusion. Disclosed herein are methods of maintaining the viability of retinal ganglion cells. The above method is described herein in an eye affected by an area of the retina in an amount sufficient to maintain the viability of the retinal ganglion cells located within the area of the affected retina. Includes administration of a compound or composition that is present. Retained retinal ganglion cells are capable of supporting axonal regeneration.

A method for promoting axonal regeneration in the eye of a subject having an ocular condition, wherein the symptom of the ocular condition is a loss of viability of retinal ganglion cells in the retina of the eye having the symptom. Disclose. The method comprises promoting axonal regeneration of retinal ganglion cells within the retina of the eye by administering to the subject eye an effective amount of a compound or composition described herein.

In each of the above embodiments, the methods and compositions described herein are, but are not limited to, glaucoma, optic nerve injury, optic neuritis, optic neuropathy, diabetic retinopathy, central retinal artery occlusion and central retinal vein. It is understood that it can be used to maintain the viability of retinal ganglion cells and / or promote axonal regeneration of retinal ganglion cells during treatment of underlying diseases, including obstruction.

Tissue Injury or Injury The ability of a compound described herein to inhibit inflammation and cell death is to make the compound suitable for ameliorating tissue injury or injury. Tissue injury or injury can be the result of any of the above diseases or conditions. For example, the above compounds may be associated with brain tissue injury or injury remission after ischemic or traumatic brain injury, cardiac tissue injury or injury remission after myocardial infarction, Huntington's disease, Alzheimer's disease or Parkinson's disease. Relief of injury or injury, remission of liver tissue injury or injury associated with non-alcoholic fatty hepatitis, alcoholic fatty hepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease or primary sclerosing cholangitis, acet It can be used for remission of liver tissue injury or injury associated with overdose of aminophen, or for remission of kidney tissue injury or injury after kidney transplantation or administration of nephrotoxic agents or substances. In certain embodiments, for example, the compounds may be used for lung tissue injury or remission of brain tissue injury or injury after injury.

Non-limiting examples of brain injury or injury include stroke (eg, hemorrhagic and non-hemorrhagic), traumatic brain injury (TBI), brain hemorrhage, submucosal hemorrhage, intracranial hemorrhage secondary to cerebral arterial malformation, cerebral infarction, perinatal Early brain injury, non-traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, muscular atrophic lateral sclerosis, intracerebral hemorrhage, brain infection, brain tumor, subclinical brain injury, spinal cord injury, Anoxic-ischemic brain injury, local cerebral ischemia, whole cerebral ischemia, and hypoxic hypoxia.

In embodiments, the compounds and compositions of the present disclosure can be used to treat peritoneal tissue injury. Non-limiting examples of peritoneal tissue injury include peritoneal deterioration, peritoneal sclerosis, and peritoneal cancer. For example, the receptor-interacting protein kinase 1 inhibitors described herein can be used to treat peritoneal dialysis (PDF) and peritoneal damage caused by PD-related side effects.

Liver Injury and Disease In embodiments, the compounds and compositions of the present disclosure can be used to treat liver injury and disease. As a non-limiting example of liver injury or injury, not only degeneration or necrosis of liver parenchymal cells resulting from injury caused by a particular factor, but also unwanted phenomena caused by a biological response to the injury, eg, response alone or in combination. It also includes mobilization, infiltration, activation of Kupffer cells, leukocytes, and fibrosis of liver tissue. In certain embodiments, the receptor-interacting protein kinase 1 inhibitors described herein are mediated by hepatocellular receptor-interacting protein kinase 1 activity-dependent apoptosis and inhibition of the development of hepatocellular carcinoma. Can be used to treat fatty hepatitis and hepatocellular carcinoma. In embodiments, the receptor-interacting protein kinase 1 inhibitors described herein are used to treat alcoholic hepatitis, autoimmune hepatitis, fulminant liver failure, acute cholestasis and liver injury. obtain.

Renal Injury and Disease In embodiments, the compounds and compositions of the present disclosure can be used to treat renal injury and disease. Non-limiting examples of renal disease include chronic kidney disease (CKD) (eg, glomerular disease, tubulointerstitial disease, obstruction, multiple cystic kidney disease), acute renal injury (AKI), diabetic nephropathy, fibrosis, Examples include glomerular nephritis, focal glomerular sclerosis, immune complex nephropathy, crystalline nephropathy, or lupus nephritis. Renal disease can be caused by drug-induced renal injury or kidney transplant rejection. Renal disease can be characterized as nephrotic syndrome or renal dysfunction. In embodiments, the receptor-interacting protein kinase 1 inhibitors described herein are used to treat renal disease (eg, AKI) through inhibition of the cell death pathway in renal disease. obtain. In embodiments, the receptor-interacting protein kinase 1 inhibitors described herein treat patients with kidney stones and inhibit receptor-interacting protein kinase 3-MLKL-mediated necroptosis. It can be used to prevent crystal-induced cytotoxicity and acute renal injury through.

Skin Diseases In embodiments, the compounds and compositions of the present disclosure can be used to treat skin-related (or skin) diseases, including, but not limited to, inflammatory skin diseases or neutrophil dermatosis.

Malignant Tumors In embodiments, the compounds and compositions of the present disclosure are useful for treating malignant tumors / cancers such as cancers, sarcomas, melanomas, lymphomas or leukemias. Non-limiting examples of malignant tumors suitably treated with the receptor-interacting protein kinase 1 inhibitors described herein include lung cancer (eg, non-small cell lung cancer, small cell lung cancer), lung cell cancer, black. Tumor, pancreatic cancer, urinary tract cancer, bladder cancer, colon cancer, colon cancer, breast cancer, prostate cancer, kidney cancer, thyroid cancer, bile sac cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer , Head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumor (eg, glioma, degenerative oligodendroglioma, adult polymorphic glioblastoma, and adult undifferentiated stellate cell tumor), osteosarcoma, soft tissue Sacoma, retinal blastoma, neuroblastoma, ascites, malignant pleural effusion, mesopharyngeal tumor, Wilms tumor, vegetative membrane neoplasm, perivascular cell tumor, Kaposi sarcoma, mucilage-like cancer, round cell cancer, squamous cell carcinoma, esophagus Examples include squamous cell carcinoma, oral cancer, genital cancer, cancer of the adrenal cortex, ACTH-producing tumors, lymphomas, and leukemia.

Infectious Diseases In embodiments, the compounds and compositions of the present disclosure are pathogenic factors, including pathogenic viruses, pathogenic bacteria, fungi, protozoa, multicellular parasites, and aberrant proteins known as prions. It is useful for treating infectious diseases that result from its presence. Non-limiting examples of infectious diseases suitably treated by the receptor-interacting protein kinase 1 inhibitors described herein include viral and bacterial infectious diseases. The virus-infectious disease is not particularly limited, and is, for example, an infectious disease caused by a respiratory infectious virus (for example, a respiratory infectious virus such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, RS virus, adenovirus). Infectious diseases caused by viruses, leoviruses, etc.), Staphylococcus aureus (MRSA) pneumonia, Serratia marcescens hemorrhagic pneumonia, herpesvirus-induced herpes zoster, rotavirus-induced diarrhea, viral hepatitis, AIDS, etc. Bacterial infectious diseases are not particularly limited, for example, Bacillus cereus, Vibrio. Infectious diseases caused by parahaemolyticus, enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRSA, salmonella, botulinum, candida and the like can be mentioned.

Bone disease In embodiments, the compounds and compositions of the present disclosure are useful in treating bone disorders that may result from impaired bone remodeling, thereby shifting the balance between bone formation and bone resorption. Non-limiting examples of bone remodeling disorders include osteoporosis, Paget's disease, osteoarthritis, rheumatoid arthritis, chondrosis dysplasia, transected osteochondritis, parathyroidism, bone dysplasia, and congenital hypoplasia. Phosphataseemia, fibromas lesions, fibrous bone dysplasia, multiple myeloma, abnormal bone turnover, osteolytic bone disease and periodontal disease. Further examples of bone disorders suitably treated by the receptor-interacting protein kinase 1 inhibitors described herein are post-traumatic bone surgery, post-prosthesis joint surgery, post-orthopedic bone surgery, and dentistry. Postoperatively, fractures, bone trauma, or bone loss conditions associated with bone chemotherapeutic treatment or bone radiotherapy treatment may be mentioned. Further examples of diseases involving bone or osteoarthritis that are suitably treated with the receptor-interacting protein kinase 1 inhibitors described herein are metastatic osteosarcoma, rheumatoid arthritis, eg, rheumatoid arthritis, deformity. Includes osteoarthritis and other inflammatory arthropathy. In embodiments, the receptor interacting protein kinase 1 inhibitors described herein are used to treat postmenopausal osteoporosis through inhibition of osteocytic necrotosis and trabecular deterioration. Can be used.

Cardiovascular Disease In embodiments, the compounds and compositions of the present disclosure are useful in treating cardiovascular disease that may be associated with fragile plaque disorders, obstructive disorders and stenotic cardiovascular disorders. Non-limiting cardiovascular diseases include coronary and peripheral arterial disorders, especially atherosclerosis, arterial closure, aneurysm formation, thrombosis, post-traumatic aneurysm formation, restenosis, and postoperative grafting. Examples include obstruction. Atherosclerosis has been implicated as a result of maladaptive inflammation primarily caused by macrophages. Therefore, the compounds and compositions of the present disclosure can be used to treat atherosclerosis through inhibition of macrophage necroptosis.

Transplant Surgery In embodiments, the compounds and compositions of the present disclosure are useful for treating transplant patients. Non-limiting examples of transplant patients suitably treated with the receptor-interacting protein kinase 1 inhibitors described herein include patients who have undergone transplant surgery and transplantation of solid and non-solid organs and tissues, eg, These include patients who have undergone liver, heart, kidney, and heterogeneous and autologous bone marrow transplant surgery / transplantation. Immunosuppressive therapy is typically used to avoid graft rejection in recipients of solid organ transplants. Recipients of bone marrow transplants are usually subjected to extensive radiation and chemotherapy prior to transplant surgery. Receptor interaction protein kinase 1 and NF-κB signaling in stained cells are CD8⁺It is said to determine T cell cross-priming. Therefore, the receptor-interacting protein kinase 1 inhibitors described herein are CD8.⁺By regulating cross-priming of T cells, it can be used to treat transplant patients and avoid graft rejection.

Other diseases and conditions Pancreatitis, atopic dermatitis, spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis are further examples of diseases and disorders suitably treated by the receptor-interacting protein kinase 1 inhibitors described herein. (SoJIA), Systemic Elythematosus (SLE), Sjogren's Syndrome, Systemic Skin Sclerosis, Antiphospholipid Syndrome (APS), Vascularitis, Primary Sclerosing Biliary Tubeitis (PSC), Acetaminophen Intoxication, Kidney Injury / Injury (Nephritis, kidney transplantation, surgery, nephrotoxic drug administration, eg syndrome, acute renal injury (AKI)), Celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), cerebrovascular disorder (CVA, stroke) ), Myocardial infarction (MI), allergic disease (including asthma), diabetes, Wegner's granulomatosis, pulmonary sarcoidosis, Bechet's disease, interleukin-1 converting enzyme (ICE / caspase-1) related fever syndrome, chronic obstructive Pulmonary disease (COPD), tumor necrosis factor receptor-related periodic syndrome (TRAPS), periodontitis, NEMO-deficiency syndrome (F-kappa-B essential modulator gene (also known as IKK gamma or IKKG) deficiency syndrome) ), HOIL-1 deficiency (also known as RBCK1) hem-oxidized IRP2 ubiquitin ligase-1 deficiency, linear ubiquitin chain-forming complex (LUBAC) deficiency syndrome, hematological and solid organ malignant tumors, bacteria Infectious and viral infections (eg, tuberculosis and influenza), as well as lysosome accumulation disorders. Further examples of diseases and disorders suitably treated by the receptor-interacting protein kinase 1 inhibitors described herein include Gaucher's disease or organ failure.

Non-limiting examples of lithosome accumulation diseases include Gauche disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosamine urine disease, cholesteryl ester accumulation disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease. , Faber's disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infant free sialic acid storage disease, juvenile hexosaminidase A deficiency, Clave's disease, lysosomal acid lipase deficiency, metachromatic white dystrophy, mucopolysaccharide Disease disorders, various sulfatase deficiencies, Niemannpic's disease, neuroceroid lipofustinosis, Pompe's disease, concentrated dysostosis, Sandhoff's disease, Sindler's disease, sialic acid accumulation, Tay Sax and Wolman's disease.

5. Kit A kit containing the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs, and suitable packaging. Also provided herein. In certain embodiments, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, a mixture of stereoisomers, a prodrug, or a dehydrogenated analog, as well as herein. Includes labels and / or instructions for use of the above compounds in the treatment of signs including the diseases or conditions described in.

Products containing the compounds described herein, or pharmaceutically acceptable salts thereof, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or dehydrogenated analogs in suitable containers. Also provided herein. Containers may be vials, bottles, amplifiers, pre-built syringes, and drip bags.

6. Pharmaceutical Compositions and Dosages The compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, with one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, homovariants, stereoisomers, mixtures of stereoisomers, prodrugs, or dehydrogenated analogs. Also provided herein are pharmaceutical compositions containing one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared by methods well known in the pharmaceutical field. For example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker &amp; See CTRhodes, Eds.).

The pharmaceutical composition may be administered in single or multiple doses. The pharmaceutical composition may be administered by a variety of methods, including, for example, transrectal, buccal, nasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or inhalation.

One embodiment for administration is parenteral, eg, by injection. As forms in which the pharmaceutical compositions described herein can be incorporated for administration by injection, for example, sesame oil, corn oil, cottonseed oil, or peanut oil, and elixirs, mannitol, dextrose, or sterile aqueous solutions, and Aqueous or oily suspensions, or emulsions, with similar pharmaceutical vehicles.

Oral administration may be another route of administration of the compounds described herein. Administration may be via, for example, capsules or enteric-coated tablets. A pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, a metavariant, a steric isomer, a mixture of steric isomers, a prodrug, or a dehydrogenated analog. In the preparation of the product, the active ingredient is usually diluted with excipients and / or encapsulated in a carrier that may be in the form of capsules, sachets, paper or other containers. Excipients can be in the form of solid, semi-solid, or liquid materials that act as vehicles, carriers or vehicles for the active ingredient when acting as a diluent. Therefore, the above compositions can be tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, liquids, syrups, aerosols (as solids or in liquid media), eg, max. It can be in the form of ointments, soft and hard gelatin capsules, sterile injectables, and sterile packaging powders containing 10% by weight of active compound.

Some examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile. Examples include water, syrup, and methylcellulose. The formulation further comprises a lubricant including, for example, talc, magnesium stearate, and mineral oil; a wetting agent; an emulsifying and suspending agent; a preservative, for example, methyl hydroxybenzoate and a propyl; a sweetener; and a flavoring agent. be able to.

Compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or dehydrogenated analog. Can be formulated to result in rapid, sustained or delayed release after administration to a subject by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and lysis systems containing polymer coated reservoirs or drug-polymer matrix formulations. Another formulation for use in the methods disclosed herein uses a transdermal delivery device ("patch"). Such transdermal patches can be used to provide controlled continuous or discontinuous infusions of the compounds described herein and can be constructed for continuous, pulsatile or on-demand delivery of pharmaceutical products. ..

In order to prepare a solid composition, for example, a tablet, the main active ingredient is mixed with a pharmaceutical excipient to form a compound described herein, or a pharmaceutically acceptable salt thereof, which is mutated. It is possible to form a solid preform composition containing a sex compound, a steric isomer, a mixture of steric isomers, a prodrug, or a homogeneous mixture of dehydrogenated analogs. When these preform compositions are referred to as uniform, the active ingredient is such that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules. Can be evenly distributed throughout.

Tablets or pills of the compounds described herein are coated or otherwise formulated to give a dosage form that imparts the benefit of long-lasting action, or to protect against acidic conditions in the stomach. Can be done. For example, a tablet or pill can contain an inner and outer dosage component, the latter in the form of an envelope covering the former. These two components can be separated by an enteric layer that resists degradation in the stomach and serves to allow the inner component to pass intact into the duodenum or to delay its release. Various materials can be used for such enteric layers or coatings, which include many polymeric acids or mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

Compositions for inhalation or inhalation may include liquids and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid composition may contain suitable pharmaceutically acceptable excipients as described herein. In certain embodiments, the composition is administered by the oral or nasal respiratory route for topical or systemic effects. In other embodiments, the composition in a pharmaceutically acceptable solvent may be sprayed by the use of an inert gas. The sprayed solution may be inhaled directly from the spray device, or the spray device may be attached to a face mask tent or an intermittent positive pressure ventilator. The solution, suspension, or powder composition may be administered orally or nasally, preferably from a device that delivers the formulation in an appropriate manner.

7. Combination therapy In certain embodiments, the compounds described herein may be administered in combination with at least one other therapeutically active agent. Two or more agents may be co-administered, co-formulated, or administered separately. In certain embodiments, other therapeutically active agents include thrombolytic agents, tissue plasminogen activators, anticoagulants, platelet aggregation inhibitors, antibacterial agents (antibiotics, broad-spectrum antibiotics, lactams, etc.). Anti-acid bacillus agent, bactericidal antibiotic, anti-MRSA treatment), long-acting β-agonist, combination of inhaled corticosteroid and long-acting β-agonist, short-acting β-agonist, leukotrien modification Substances, anti-IgE, methylxanthine bronchial dilators, obesity cell inhibitors, protein tyrosine kinase inhibitors, CRTH2 / D prostanoid receptor antagonists, epinephrine inhaled aerosols, phosphodiesterase inhibitors, phosphodiesterase-3 inhibitors and phosphodiesterase-4 inhibitors In combination with agents, long-acting inhaled anticholinergic agents, muscarin antagonists, long-acting muscarinic antagonists, low-dose steroids, inhaled corticosteroids, oral corticosteroids, topical corticosteroids, antithoracic cytoglobulans, Salidamide, chlorambusyl, calcium channel blockers, topical palliatives, ACE inhibitors, serotonin reuptake inhibitors, endoserin-1 receptor inhibitors, antifibrotic agents, proton pump inhibitors, cystic fibrosis membrane conductance regulator enhancement Agents, mucolytic agents, pancreatic enzymes, bronchial dilators, intraocular injection, antivascular endothelial growth factor inhibitors, hairy neuronutrient growth factor agents, trivalent (IIV3) inactivated influenza vaccine, tetravalent (IIV4) Inactivated influenza vaccine, trivalent recombinant influenza vaccine, tetravalent attenuated live influenza vaccine, antiviral drug, inactivated influenza vaccine, hairy neuronutrient growth factor, gene transfer agent, local immunomodulator, carcinulin inhibitor, Interferon gamma, anti-histamine, monoclonal antibody, polyclonal anti-T cell antibody, horse anti-chest cell gamma globulin anti

Other exemplary therapeutically active agents include heparin, kumadin, formoterol, dipyridamole, tyclopidin HCL, eptifibatide, aspirin, bancomycin, cepeprim, piperacilin with tazobactam, imipenem, melopenem, dripenem, cyprofloxacin, Levofloxacin, offloxacin, moxyfloxacin, hydrocortisone, vedrizumab, aricaforsen, remethemcel-L, ixekizumab, tildrakizumab, sekkinumab, chlorhexidine, doxicycline, minocycline, fluticasone, fluticasone, fluticasone, fluticasone, fluticasone, fluticasone. Budesonide, Trimcinolone Acetonide, Fluticasone, Mometazone Folate, Cycresonide, Alformoterol Tartrate, Formoterol Fumarate, Salmetherol Xinafoate, Albuterol (Albuterol Sulfate), Levalvterol Tartrate, Ipratropium Bromide, Montercast Zafillucast, dileutone, omalizumab, theophylline, sodium chromoglycate, nedocromyl sodium, macitinib, AMG853, indacaterol, E004, leslizumab, salbutamol, thiotropium bromide, VR506, rebriquizumab, RPL554, fluticasone Hydroate, acridinium bromide, loflumirast, SCH527123, glycopyrronium bromide, orodaterol, fluticasone flocate and fluticasone viranterol, fluticasone propionate and salmeterol, fluticasone flocate and fluticasone propionate, propion Fluticasone acid in combination with formoterol dihydrate fumarate, formoterol in combination with budesonide, vechrometazone dipropionate in combination with formoterol, mometazone floate in combination with formoterol dihydrate, umecridiniumAnd viranterol, ipratropium bromide and albuterol sulfate, glycopyrronium bromide and indacatorol maleate, glycopyrrolate and formoterol fumarate, acridinium and formoterol, isoniazide , Etambutol, rifampin, pyrazinamide, rifabtin, rifapentin, capreomycin, levofloxacin, moxifloxacin, offroxacin, etionamide, cyclosporine, canamycin, streptomycin, biomycin, vedakirin fumarate, PNU-100480, delamanid, imatinib, ARG201 Tosirizumab, muromonab-CD3, baciliximab, dacrizumab, rituximab, prednisolone, anti-thoracic cytoglobulin, FK506 (tacrolimus), methotrexate, cyclosporine, silolimus, eberolimus, sodium mycophenolate, mycophenolic acid mofetyl, cyclophosphatide , Chlorambusil, Nifedipine, Nicaldipine, Nitroglycerin, Rifampicin, Zyrthiazem, Fluoxetin, Bosentan, Epoprostenol, Corhitin, Para-aminobenzoic acid, dimethylsporoxide, D-peniciramine, Interferonalpha, Interferon gamma (INF-g), Omeprazole , Metoclopramide, Lansoprazole, Esomeprazole, Pantoprazole, Labeprazole, Imatinib, Berimumab, ARG201, Tosirizumab, Ibacaftor, Dornasealpha, Panclelipase, Tobramycin, Aztreonum, Sodium choristinmethanthinate, Cefadroxyl monohydrate , Cefazoline, moxifloxacin, levofloxacin, gemifloxacin, azithromycin, gentamicin, ceftazim, combination of trimetprim and sulfametoxazole, combination of chloramphenicol, ivacaftol and lumacaftolCombined, atallen, NT-501-CNTF, gene-introducing agent encoding myosin VIA (MY07A), ranibizumab, pegaptanib sodium, NT501, humanized sphingomab, betamethasone, oseltamibir, zanamibir, limantazine, amantazine, naphthylin, sulfa Metoxazole, Trimethotoprim, Sulfamethoxazole, Acetylsulfisoxazole, Bancomycin, Muromonab-CD3, ASKP-1240, ASP015K, TOL101, Pimechlorimus, Hydrocortisone, Betamethasone, Flucloxacillin, Triamcinolone, Fluosinolide, Clobetazol, Hydrocortisone , Prednisolone, recombinant synthetic type I interferon, interferon alpha-2a, interferon alpha-2b, hydroxydine, diphenhydramine, flucloxacillin, dichromoxacillin, and erythromycin.

The compounds described herein are oral or topical corticosteroids, anti-TNF agents, 5-aminosalicylic acid and melanasamine preparations, hydroxychlorokin, thiopurine, methotrexate, cyclophosphamide, cyclosporin, calcineurin inhibitors, myco. Phenolic acid, mTOR inhibitor, JAK inhibitor, Syk inhibitor, anti-inflammatory biofactor (anti-IL6 biologic, anti-ILl drug, anti-ILl7 biologic, anti-CD22, anti-integrin drug, anti-IFNa, anti-CD20 or CD4 organism Formulations include), and other cytokine inhibitors or biologics for T cells or B cell receptors or interleukins, administered in combination with other anti-inflammatory agents for any of the above signs. good.

In the treatment of ALS, the compounds described herein may be administered in combination with riluzole.

In the treatment of Parkinson's disease, the compounds described herein are with levodopa, carbidopa or combinations thereof, pramipexol, ropinirole, rotigotine, selegiline, rasagiline, entacapone, tolcapone, benztropin, trihexyphenidyl, or amantadin. It may be administered in combination.

In the treatment of Alzheimer's disease, the compounds described herein include donepezil, galantamine, memantin, rivastigmin, anti-Aβ (amyloid beta) therapy (including aducanumab, crenezumab, solanezumab and gantenerumab), velvecestat. Also, a small molecule inhibitor of BACE1, AZD3293 (LY3314814), Ellenbecestat (E2609), LY2886721, PF-05297909, JNJ-54861911, TAK-070, VTP-37948, HPP854, CTS-21166, or anti-tau therapy. , For example, may be administered in combination with LMTM (leuco-methylthioninium-bis (hydromethanesulfonate)).

In the treatment of rheumatoid arthritis, the compounds described herein are ibuprofen, naproxene, prednison, methotrexate, reflunomid, hydroxychloroquin, sulfasalazine, abatacept, adalimumab, anakinra, sertrizumab, etanercept, golimumab, infliximab, lyximab, lyximab. It may be administered in combination with tocilizumab.

In the treatment of CVA, the compounds described herein are thrombolytic agents (eg, tissue plasminogen activator (TPA®), Activase®, Lanoteplase®, Reteplase. (Registered Trademarks), Staphylokinase®, Streptokinase®, Tenecteplase®, Urokinase®), anticoagulants (eg, heparin, kumadin, clopidogrel (Plavix®)), It may also be administered in combination with a thromboagulant inhibitor (eg, dipyridamole (Persantine®), ticlopidine HCL (Ticlid®), eptifibatide (Integrillin®), and / or aspirin).

In the treatment of SIRS, the compounds described herein are broad-spectrum antibiotics (eg, vancomycin) or other anti-MRSA treatments (cefeprime (Maxipime®), piperacillin / tazobactam (Zosyn®)). , Carbapenem (imipenem, meropenem, doripenem), quinolone (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, etc.), and low-dose steroids, such as hydrocortisone.

In the treatment of inflammatory bowel disease (particularly Crohn's disease and / or ulcerative colitis), the compounds of any of the formulas described herein are vedolizumab (Entyvio®), Aricaforsen,. Alternatively, it may be administered in combination with Remethemcell-L (Prochymal®). Specifically, in the treatment of inflammatory bowel disease (particularly Crohn's disease and / or ulcerative colitis), the compounds described herein are Alica forsen, or Remethemcell-L (Prochymal). It may be administered in combination with trademark)). In the treatment of psoriasis, the compounds described herein may be administered in combination with ixekizumab, tildrakizumab (MK-3222), or secukinumab (AIN457).

Specifically, in the treatment of psoriasis, the compounds described herein may be administered in combination with ixekizumab or tildrakizumab (MK-3222). In the treatment of periodontitis, the compounds of any of the formulas described herein are antibacterial agents such as chlorhexidine (eg, Peridex®, PerioChip®, PerioGard®, etc.). Or antibiotics (eg, Doxycycline (Vibrox®, Periodat®, Monodox®, Oracea®, Doryx®, etc.) or Minocycline (Dynacin®, Minocin (Registered Trademark), etc.) It may be administered in combination with (registered trademark), Arestin (registered trademark), Dynacin (registered trademark), etc.).

In the treatment of asthma, the compounds of any of the formulas described herein are inhaled corticosteroids ((ICS), such as fluticazone propionate (Flovent®), budesonide dipropionate (QVAR (QVAR)). (Registered Trademarks)), Budesonide (Pulmicort), Triamcinolone Acetonide (Azmacort®), Flunisolide (Aerobid®), Mometazonefolate (Asmanex® Twisthaler®), or Ciclesonide ( Alvesco®)), long-acting β-agonists ((LABA), eg, foradil fumarate (Foradil®), salmeterol xinafoate (Serevent®)), with ICS and LABA. Combination (eg, fluticazone flocate and virantelol (Breo) Ellipta®), formoterol / budesonide inhalation (Symbicort®), bechrometazone dipropionate / formoterol (Inuvair®), and fluticazone propionate / salmeterol (Advair®), short-acting action Type β agonist ((SABA), eg salmeterol sulfate (ProAir®, Proventil HFA®, Ventolin) HFA®, AccuNeb® Inhalation Solution), Revaverterol Tartrate (Xopenex® HFA), Ipratropium Bromide / Arbuterol (Combivent® Respimat®), Ipratropium Bromide (Atrovent® HFA), leukotriene modifiers (eg, Singulair®), Zafirlukast (Accolate®) or Zyflo (Zyflo®), and anti-IgE (eg, omalizumab). (Xolair®)), Methylxanthin bronchial dilators (eg, Theophylline (Accurbron®, Aerolate®, Aquaphyllin®), Asbron®, Bronkodyl®, Duraphyl (Registered Trademarks), Elixicon (Registered Trademarks), Elixomin (Registered Trademarks), Elixophyllin (Registered Trademarks), Labid (Registered Trademarks), Lanophyllin (Registered Trademarks), Quibron-T (Registered Trademarks), Slo-Bid (Registered Trademarks) , Slo-Phyllin®, Somophyllin®, Sustaire®, Synophylate®, T-Phyll®, Theo-24®, Theo-Dur® , Theobid®, Theochron®, Theoclear®, Theolair®, Theolixir®, Theophyl®, Theovent®, Uni-dur® , Uniphyl®), obese cell inhibitors (eg, sodium cromoglycate (Nasalcrom®) and Nedocromyl sodium (Tilade®)), long-acting muscarinic antagonists ((LAMA)). , For example, mometazone floate / formotero fumarateIt may be administered in combination with Ludihydrate (Dulera®).

Other agents that may be suitable for use in combination therapy in the treatment of asthma include protein tiotropium kinase inhibitors (machitinib), CRTH2 / D-prostanoid receptor antagonists (AMG853), and indacaterol (Arcapta®). ) Neohaler®), epinephrine inhalation aerosol (E004), fluticasone flocate / fluticasone propionate, fluticasone viranterol inhalation / fluticasone flocate powder (Relovair ), fluticasone propionate / formoterol fumarate dihydrate ( Flutiform®), resurizumab, salbutamoll dry powder inhalation, tiotropium bromide (Spiriva® HandiHaler®), formotelol / budesonide (Symbicort® SMART®), fluticasone flocate (registered trademark) Veramyst®), Vectura VR506, fluticasone (RG3637), a combination of phosphodiesterase (PDE) -3 and (PDE) -4 inhibitor (RPL554).

In the treatment of COPD, the compounds of any of the formulas described herein are LABA (eg, formoterol xinafoate (Serevent), umeclidinium / viranterol (Anuro Ellipta®), umeclidinium (Incruse Ellipta®). Trademarks)), Alformoterol Tartrate (Brovana®), Formoterol Inhalation Powder Fumarate (Foradil®), Indacaterol Maleate (Arcapta® Neohaler®), Or fluticasone propionate / formoterol inhalate dehydrated (Flutiform®)), long-acting inhaled anticholinergic agents (or muscarinic antagonists such as thiotropium bromide (Spiriva®), and acridinium bromide (Tudorza). (Registered Trademarks) Pressair®), Phosphodiesterase (PDE-r) Inhibitors (eg, Loflumirast, Daliresp®), Combinations ICS / LABA (eg, Fluticasone Floate and Viranterol (Breo)) Ellipta®), fluticazone propionate / salbutamol (Advair®), budesonide / formoterol (Symbicort®), mometazone / formoterol (Dulera®), ipratropium bromide / albuterol sulfate (Duoneb) (Registered Trademarks), Atrovent®), albuterol / ipratropium (Combivent Respimat®)), SABA (eg, Ipratropium bromide (Atrovent®), and albuterol sulfate (ProAir®), Proventil®)), as well as ICS (eg, budesonide (Pulmicort®) and fluticazone propionate (Flovent®), vecrometazone dipropionate (QVAR®). good.

Other agents that may be suitable for use in combination therapy in the treatment of COPD include SCH527123 (CXCR2 antagonist), glycopyrronium bromide ((NVA237) Seebri® Breezhaler®), glycopyrronium bromide. And indacaterol maleate ((QVA149) Ultibro® Breezhaler®), glycopyrronium and formoterol fumarate (PT003), indacaterol maleate (QVA149), orodaterol (Striverdi®). ) Respimat®), Tiotropium (Spiriva®) / Orodaterol (Striverdi® Respimat®), and acridinium / formotelol inhalation.

In the treatment of mycobacterial infections (tuberculosis), the compounds of any of the formulas described herein are anti-antioxidant agents (eg, isoniazid (INH), ethambutol (registered trademark)). Rifadin (Rifadin®), and pyrazineamide (PZA)), bactericidal antibiotics (eg, Mycobutin® or Priftin®), aminoglycoside (capreomycin), fluoroquinolone (Levofloxacin, Moxyfloxacin, Ofluxin), Thioamide (Ethionamide), Cyclosporin (Sandimmune®), Para-aminosalicylic acid (Paser®), Cycloserin (Seromycin®), Kantrex (Registered Trademarks)), Streptomycin, Biomycin, Capreomycin (Capastat®)), Bedakirin fumarate (Sirturo®), Isoniazid (Sutezolid®), or Delamandide (OPC-67683) May be administered in combination with.

Specifically, in the treatment of mycobacterial infection (tuberculosis), the compounds described herein are anti-acidic agents (eg, isoniazid (INH), etambutol (registered trademark)). Rifapentine (Rifadin®), and pyrazinamide (PZA)), bactericidal antibiotics (eg, Mycobutin® or Priftin®), aminoglycoside (capreomycin®) ), Fluoroquinolone (revofloxacin, moxyfloxacin, ofloxacin), thioamide (ethionamide), cycloserine (Seromycin®), kantrex (Kantrex®), streptomycin, biomycin, capreomycin (Capastat®) ))), Bedakirin fumarate (Sirturo®), oxazolidinone (Sutezolid®), or delamandide (OPC-67683).

In the treatment of systemic sclerosis, the compounds of any of the formulas described herein are oral corticosteroids such as prednisolone (Delatsone®, Orapred, Millipred, Omnipred, Econopred, Flo- Pred), immunosuppressants (eg, methotrexate (Rhuematrex®, Trexall®), cyclosporin (Sandimmune®), anti-thoracic cytoglobulin (Atgam®), mofetil mycophenolate ( CellCept®), Cyclophosphamide (Cytoxan®), FK506 (Tachlorimus), Salidamide (Thalomid®), Leukeran®, Azatiopurine (Imuran®), Azasan®)), calcium channel blockers (eg, nifedipine (Procardia®, Adalat®) or nifedipine (Cardene®), topical palliatives (nitroglycerin ointment), ACE inhibition Agents (eg, Zestril®, Prinivil®), Diltiazem (Cardizem®, Cardizem SR®, CardizemCD®, Cardia®, Dilacor®, Tiazac®)), serotonin reuptake inhibitor (eg, fluoxetin (Prozac®)), endoserin-1 receptor inhibition Agents (eg, Tracler® or epoprostenol (Flolan®, Veletri®, Prostacyclin®)), antifibrotic agents (eg, Colcrys®) )), Para-aminobenzoic acid (PABA), dimethylsulfoxide (KMSO), and D-penicillamine (Cuprimine®, Depen®), Interferon Alpha and Interferon Gamma (INF-g)), Proton Pump Inhibitors (eg, Omeprazole (Prilosec®), Metoclopramide (Reglan®), Lansoprazole (Prevacid®), Esomeprazole (Nexium®), Pantoprazole (Protonix®) )), Labeprazole (Aciphex®)) or Imatinib (Gleevec®) ARG201 (arGentis Pharmaceutical), Berimumab (Benlysta®), Tosirizumab (Actema®). good.May be administered in combination with Pharmaceutical), belimumab (Benlysta®), tocilizumab (Actema®).May be administered in combination with Pharmaceutical), belimumab (Benlysta®), tocilizumab (Actema®).

Specifically, in the treatment of systemic skin sclerosis, the compounds of any of the formulas described herein are oral corticosteroids such as prednisolone (Delatsone®, Orapred, Millipred, Omnipred). , Econopred, Flo-Pred, Anti-chest gland cytoglobulin (Atgam®), FK506 (Tachlorimus), Salidamide (Thalomid®), Chlorambusil (Leukeran®), Calcium channel blocker (eg, Econopred, Flo-Pred) Nifedipine (Procardia®, Adalat®) or Nifedipine (Cardene®), topical palliatives (nitroglycerin ointment), ACE inhibitors (eg, Zestril®, Prinivil® Trademark)), Diltiazem (Cardizem®, Cardizem SR®, Cardizem CD®, Cardia®, Dilacor®, Tiazac®)), serotonin reuptake inhibitor (eg, fluoxetin (Prozac®)), endoserin-1 receptor inhibition Agents (eg, Tracler® or epoprostenol (Flolan®, Veletri®, Prostacyclin®)), antifibrotic agents (eg, Colcrys®) )), Para-aminobenzoic acid (PABA), dimethylsulfoxide (KMSO), and D-penicillamine (Cuprimine®, Depen®), Interferon Alpha and Interferon Gamma (INF-g)), Proton Pump Inhibitors (eg, Omeprazole (Prilosec®), Metoclopramide (Reglan®), Lansoprazole (Prevacid®), Esomeprazole (Nexium®), Pantoprazole (Protonix®) )), Labeprazole (Aciphex®)) or Imatinib (Gleevec®) ARG201 (arGentis Pharmaceutical), or tosirizumab (Actema®).

In the treatment of cystic fibrosis, the compounds described herein are cystic fibrosis membrane conductance regulator (CFTR) enhancers (Ibakaftor (Kalydeco®)), mucolytic agents (eg, dollars). Nase alfa (Pulmozyme®)), pancrelipase (eg, Pancrelipase (Creon®, Pancreaze®, Ultresa®, Zenpep®)), bronchodilators ( For example, albuterol (AccuNeb®, ProAir®, Proventil HFA®, VoSpire ER®, Ventolin HFA®), antibiotics (inhalation, oral or parenteral) Includes, for example, tobramycin solution for inhalation (TOBI®, Bethkis®, TOBI Podhaler®), Azactam Inhalation (Azactam®, Cayston®), Sodium Collistine Methanate (Coly-Mycin®), Cefazolin (Cefazolin Monohydrate) (Duricef®) Trademarks)), Cefazolin (Kefzol®), Cephalexin (Keflex®), Cefazolin (Ancef®, etc.), Fluoroquinolone (moxyfloxacin, levofloxacin, gemifloxacin, etc.), Zithromax (Zithromax) Registered Trademarks)), Gentamycin (Garamycin®), Piperacilin / Tazobactam (Zosyn®), Ceflex, Ceftazidime (Fortaz, Tazicef), Cipro Floxin (Cipro XR, Proquin XR), Trimethoprim / Sul Famethoxazole (Bactrim DS, Septra) DS), chloramphenicol)), or Ivacaftor (Kalydeco®) / Luma Kaftor (VX-809), Atallen (Translarna®), or tiotropium bromide as an addition to standard treatment ( It may be administered in combination with Spiriva® Handihaler®).

In the treatment of retinitis pigmentosa, the compounds described herein may be administered in combination with ciliary neurotrophic growth factor (NT-501-CNTF) or a gene transfer agent, UshStat®. ..

In the treatment of yellow spot degeneration, compounds of any of the formulas described herein can be used in combination with intravitreal injection (aflibercept (Eylea®)) or anti-vascular endothelial growth factor ( VEGF) inhibitors (eg, ranibizumab (Lucentis®) or pegaptanib sodium (Macugen®)), intravitreal neurotrophic growth factor drug (NT501), iSONEP®, or bevacizumab ( May be administered in combination with Avastin®).

In the treatment of influenza, the compounds described herein are trivalent (IIV3) inactivated influenza vaccines (eg, Afluria®, Fluarix®, Flucelvax®, FluLaval®. ), Fluvirin®, Fluzone®), Four-valent (IIV4) inactivated influenza vaccine (eg Fluarix® Quadrivalent, Flulaval® Quadrivalent, Fluzone® Quadrivalent), three Hydrate-recombinant influenza vaccine (eg, FluBlok®), tetravalent attenuated live influenza vaccine (eg, FluMist® Quadrivalent), antiviral drugs (eg, oseltamivir (Tamiflu®)), Zanamivir (eg, FluMist®) Relenza®), Limantagen (Flumadine®), or Amantazine (Symmetrel®), or Fluad®, Fludase, FluNhance®, Preflucel, or VaxiGrip® May be administered in combination with.

In the treatment of vancomycin infections, the compounds of any of the formulas described herein are antibiotics such as a-lactam cephalosporins (Duricef®, Kefzol®, Ancef (eg. (Registered Trademarks), Biocef®, etc.), Nafcillin (Unipen®), Sulfamethoxazole and Trimethoprim (Bacrim®, Septra®), Sulfamethoxazole (Registered Trademarks) It may be administered in combination with (trademark)), acetylsulfisoxazole (such as Gantrisin®), or vancomycin (Vancocin®)).

In the treatment of transplant rejection, compounds of any of the formulas described herein are high-dose corticosteroids (eg, Deltasone®, SoluMedrol®). , Etc.), Calcinurin inhibitors (eg, cyclosporine (Sandimmune®, Neoral®, Gengraf®), tacrolimus (Prograf®, Astragraf XL®)), mTor inhibitors (For example, Cyclolimus (Rapamune®) or Everolimus (Afinitor®)), antiproliferative agents (eg, Imuran®, Azasan®), mycophenolate mofetil (CellCept (eg) Registered trademark)), or sodium mycophenolate (Myfortic®)), monoclonal antibody (eg, muromonab-CD3 (Orthoclone)) OKT3 (R))), interleukin-2 receptor antagonist ((Basiliximab (registered trademark), Simulect (registered trademark)), daclizumab (Zenapax (R)) or Rituximab (Rituxan (R)) ), polyclonal anti-T cell antibody (eg, horse anti-thymocyte gamma globulin (Atgam®), or rabbit anti-thymocyte globulin (Thymoglobulin®)) anti-CD40 antagonist (ASKP-1240), JAK inhibition It may be administered in combination with the agent (ASP015K) or mouse anti-TCR mAb (TOL101).

Specifically, in the treatment of graft rejection, the compounds of any of the formulas described herein are monoclonal antibodies (eg, mulomonab-CD3 (Orthoclone OKT3®)), polyclonal anti-T. Cellular antibodies (eg, horse anti-thymocyte gamma globulin (Atgam®), or rabbit anti-thymocyte globulin (Thymoglobulin®)) anti-CD40 antagonist (ASKP-1240), JAK inhibitor (ASP015K), Alternatively, it may be administered in combination with mouse anti-TCR mAb (TOL101).

In the treatment of atopic dermatitis, the compounds of any of the formulas described herein are topical immunomodulators or carcinulinin inhibitors (eg, Pimechlorimus (Elidel®) or Tachlorimus ointment (Protopic®). Trademarks))), topical corticosteroids (eg, hydrocortisone (Synacort®, Westcort®), betamethazone (Diprolene®), prednisolone (Cordan®), fluticazone ( Cutivate®), triamcinolone (Kenalog®), fluorinide (Lidex®), and clobetazol (Temovate®)), oral corticosteroids (eg, hydrocortisone (registered trademark)). ), Methylprednisolone (Medrol®), or prednisolone (Pediapred®, Prelone®), immunosuppressants (eg, cyclosporin (Neoral®) or interferon gamma (Alferon). N®, Infergen®, Intron A, Roferon-A®)), antihistamines (for pruritus, eg Atarax®, Vistaril®, Benadryl®) , Antibiotics (eg, penicillin derivative Fluxacillin (Floxapen®) or Dikroxacillin (Dynapen®), Erythromycin (Eryc®, T-Stat®, Erythra-Derm® Trademarks, etc.)), non-steroidal immunosuppressants (eg, azathioprine (Imuran®, Azasan®), methotrexate (Rhuematrex®, Trexall®), cyclosporin (Sandimmune®). It may be administered in combination with (trademark))) or mofetyl mycophenolate (CellCept®)).

Specifically, in the treatment of atopic dermatitis, the compounds of any of the formulas described herein are local immunomodulators or carcinulinin inhibitors (eg, Pimechlorimus (Elidel®) or Tachlorimus. Ointment (Protopic®)), topical corticosteroids (eg, hydrocortisone (Synacort®, Westcort®), betamethazone (Diprolene®), fullland lenolide (Cordan®). )), Fruticazone (Cutivate®), Triamcinolone (Kenalog®), Fluoronide (Lidex®), and Clobetazol (Temovate®)), Oral corticosteroids (eg, hydrocortisone (eg, hydrocortisone) Cortef®), Methylprednisolone (Medrol®), or Prednisolone (Pediapred®, Prelone®), Interferon Gamma (Alferon) N®, Infergen®, Intron A, Roferon-A®)), antihistamines (for pruritus, eg Atarax®, Vistaril®, Benadryl®) , Or antibiotics (eg, penicillin derivative flucloxacillin (Floxapen®) or dicloxacillin (Dynapen®), erythromycin (Eryc®, T-Stat®, Erythra-Derm (eg) It may be administered in combination with registered trademark) etc.)).

In the treatment of burns, for example burns or burn shock, the compounds of any of the formulas described herein may be administered alone or with antibacterial agents, typically topical antibiotics (acetic acid). It may be administered in combination with maphenide cream, silver sulfadiazine cream) and / or analgesics (opioid analgesics such as morphine, oxycodone). Other therapeutic agents that may be useful in the treatment of burns include retinoids and pirfenidone.

In certain embodiments, the at least one other therapeutically active agent is selected from thrombolytic agents, tissue plasminogen activators, anticoagulants, and platelet aggregation inhibitors. In certain embodiments, the at least one other therapeutically active agent is selected from heparin, kumadin, clopidrogel, dipyridamole, ticlopidine HCL, eptifibatide, and aspirin. In certain embodiments, the kinase-mediated disease or disorder treated by these agents is cerebrovascular accident.

In certain embodiments, at least one other therapeutically active agent is selected from broad-spectrum antibiotics, anti-MRSA treatments and low-dose steroids. In certain embodiments, at least one other therapeutically active agent is vancomycin, cefeprim, piperacillin in combination with tazobactam, imipenem, meropenem, doripenem, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin. , And hydrocortisone. In certain embodiments, the disease or disorder treated with these agents is systemic inflammatory response syndrome.

In certain embodiments, at least one other therapeutically active agent is Arica forsen or Remestem Cell-L. In certain embodiments, the disease or disorder treated by these agents is Crohn's disease or ulcerative colitis.

In certain embodiments, at least one other therapeutically active agent is ixekizumab, or tildrakizumab. In certain embodiments, the kinase-mediated disease or disorder treated by these agents is psoriasis.

In certain embodiments, at least one other therapeutically active agent is an antibacterial agent or antibiotic. In certain embodiments, the at least one other therapeutically active agent is selected from chlorhexidine, doxycycline and minocycline. In certain embodiments, the disease or disorder treated by these agents is periodontitis.

In certain embodiments, at least one other therapeutically active agent is an inhaled corticosteroid, a long-acting β-agonist, a combination of an inhaled corticosteroid with a long-acting β-agonist, short It is selected from time-acting β agonists, leukotriene modifiers, anti-IgE, methylxanthine bronchodilators, mast cell inhibitors, and long-acting muscarinic antagonists. In certain embodiments, at least one other therapeutically active agent is fluticasone propionate, vechrometazone dipropionate, budesonide, trimsinolone acetonide, flunisolide, mometazonefolate, or cyclesonide, formoterol fumarate. , Salmeterol xinafoate, fluticasone flocate with viranterol, formoterol with budesonide inhalation, vecrometazone dipropionate with formoterol, fluticasone propionate with salmeterol, albuterol sulfate, levalvterol tartrate, Choose from combinations of ipratropium bromide and albuterol, ipratropium bromide, sodium montelcasto, zafilurcast, dileuton, omalizumab, theophylline, sodium chromoglycate, sodium nedochromyl, and combinations of fluticasone and formoterol fumarate. Will be done. In certain embodiments, at least one other therapeutically active agent is a protein tyrosine kinase inhibitor, a CRTH2 / D-prostanoid receptor antagonist, an epinephrine inhalation aerosol, and a phosphodiesterase-3 inhibitor and a phosphodiesterase-. 4 Selected from combinations with inhibitors. In certain embodiments, at least one other therapeutically active agent is macitinib, AMG853, indacaterol, E004, a combination of fluticasone flocate and fluticasone propionate, a combination of bianterol and fluticasone flocate. , Combination of fluticasone propionate and formoterol dihydrate fumarate, It is selected from reslizumab, salbutamol, tiotropium bromide, formoterol in combination with budesonide, fluticasone flocate, VR506, lebrikizumab, and RPL554. In certain embodiments, the kinase-mediated disease or disorder treated by these agents is asthma.

In certain embodiments, at least one other therapeutically active agent is a long-acting β-agonist, a long-acting inhaled anticholinergic or muscariner antagonist, a phosphodiesterase inhibitor, an inhaled corticosteroid and the like. It is selected from long-acting β-agonists, short-acting β-agonists, and inhaled corticosteroids. In certain embodiments, at least one other therapeutically active agent is salmerol xinafoate, a combination of umecridinium and viranterol, umecridinium, formoterol tartrate, formoterol fumarate, indacaterol maleate, Fluticasone propionate with formoterol dihydrate, thiotropium bromide, acridinium bromide, loflumirast, fluticasone flocate with viranterol, fluticasone propionate with formoterol, budesonide with formoterol, mometazone It is selected from the combination with formoterol, the combination of ipratropium bromide and albuterol sulfate, the combination of albuterol and ipratropium, the combination of ipratropium bromide, albuterol sulfate, budesonide, fluticasone propionate, and bechrometazone dipropionate. In certain embodiments, at least one other therapeutically active agent is SCH527123, glycopyrronium bromide, a combination of glycopyrronium bromide and indacaterol maleate, glycopyrrolate and formoterol fumarate. , Indacaterol maleate, olodaterol, tiotropium, olodaterol, and combinations of acridinium and formoterol. In certain embodiments, the disease or disorder treated by these agents is COPD.

In certain embodiments, at least one other therapeutically active agent is an acid-fast bacillus or a bactericidal antibiotic. In certain embodiments, at least one other therapeutically active agent is isoniazid, etamanid, rifampin, pyrazinamide, rifabutin, rifapentine, capreomycin, levofloxacin, moxyfloxacin, offloxacin, etionamide, cycloserine, kanamycin. , Streptomycin, Biomycin, Bedakirin fumarate, PNU-100480, and Delamanid. In certain embodiments, the kinase-mediated disease or disorder treated by these agents is a mycobacterium infection.

In certain embodiments, at least one other therapeutically active agent is an oral corticosteroid, anti-thoracic cytoglobulin, salidamide, chlorambusyl, calcium channel blocker, topical palliative, ACE inhibitor, serotonin reuptake. It is selected from inhibitors, endoserin-1 receptor inhibitors, antifibrotic agents, proton pump inhibitors or imatinib, ARG201, and tosirizumab. In certain embodiments, the at least one activator is prednisolone, anti-thoracic cytoglobulin, FK506 (tachlorimus), salidamide, chlorambusyl, nifedipine, nicardipine, nitroglycerin ointment, lysinopril, diltiazem, fluoxetine, bocentan, epoprostenol, Choose from corhitin, para-aminobenzoic acid, dimethylsulfoxide, D-peniciramine, interferon alpha, interferon gamma (INF-g)), omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole, imatinib, ARG201, and tosirizumab. Will be done. In certain embodiments, the disease or disorder treated with these agents is systemic lupus erythematosus.

In certain embodiments, at least one other therapeutically active agent is a cystic fibrosis membrane conductance regulator enhancer, a mucolytic agent, a pancreatic enzyme, a bronchodilator, an antibiotic, or ivacaftor / lumacaftor. It is selected from atallen and tiotropium bromide. In certain embodiments, at least one other therapeutically active agent is ibacaftor, dronase alpha, pancrelipase, albuterol, tobramycin, aztreonam, sodium choristinmethanate, cefadroxil monohydrate, cefazolin, cephalexin. , Cefazolin, Moxifloxacin, Levofloxacin, Gemifloxacin, Azthromycin, Gentamicin, Piperacilin / Tazobactam, Cefazolin, Ciprofloxacin, Trimethoprim / Sulfametoxazole, Chloramphenicol, or Ibacaftor / Lumacaftol, Atallen, and Thiotropium. Will be done. In certain embodiments, the disease or disorder treated with these agents is cystic fibrosis.

In certain embodiments, at least one other therapeutically active agent is ciliary neurotrophic growth factor or gene transfer agent. In certain embodiments, at least one other therapeutically active agent is NT-501-CNTF, or a gene transfer agent encoding myosin VIA (MY07A). In certain embodiments, the disease or disorder treated with these agents is retinitis pigmentosa.

In certain embodiments, the at least one other therapeutically active agent is selected from intravitreal injections, anti-vascular endothelial growth factor inhibitors, and ciliary neurotrophic growth factor agents. In certain embodiments, the at least one other therapeutically active agent is selected from aflibercept, ranibizumab, sodium pegaptanib, NT501, humanized sphingomab, and bevacizumab. In certain embodiments, the disease or disorder treated with these agents is macular degeneration.

In certain embodiments, at least one other therapeutically active agent is a trivalent (IIV3) inactivated influenza vaccine, a tetravalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a tetravalent attenuated vaccine. Choose from a bio-influenza vaccine, an antiviral drug, or an inactivated influenza vaccine. In certain embodiments, the at least one other therapeutically active agent is selected from oseltamivir, zanamivir, rimantadine, or amantadine. In certain embodiments, the kinase-mediated disease or disorder treated by these agents is influenza.

In certain embodiments, the at least one other therapeutically active agent is selected from beta-lactams, nafcillin, sulfamethoxazole, trimethoprim, sulfasalazine, acetylsulfisoxazole, and vancomycin. In certain embodiments, the disease or disorder treated with these agents is a staphylococcal infection.

In certain embodiments, at least one other therapeutically active agent is a monoclonal antibody, polyclonal anti-T cell antibody, horse anti-thymocyte gamma globulin antibody, rabbit anti-thymocyte globulin antibody, anti-CD40 antagonist, JAK. Selected from inhibitors and mouse anti-TCR mAbs.

In certain embodiments, at least one other therapeutically active agent is selected from muromonab-CD3, ASKP-1240, ASP015K, and TOL101. In certain embodiments, the disease or disorder treated by these agents is graft rejection.

In certain embodiments, the at least one other therapeutically active agent is selected from local immunomodulators or calcineurin inhibitors, topical corticosteroids, oral corticosteroids, interferon gamma, antihistamines, or antibiotics. Will be done. In certain embodiments, at least one other therapeutically active agent is pimechlorimus, tachlorimus, hydrocortisone, betamethasone, flulandrenoride, fluticasone, triamcinolone, fluosinonide, clobetasol, hydrocortisone, methylprednisolone, prednisolone, interferon alpha. It is selected from proteins, recombinant synthetic type I interferon, interferon alpha-2a, interferon alpha-2b, hydroxydine, diphenhydramine, fluticasylin, dichromaxylin, and erythromycin. In certain embodiments, the disease or disorder treated by these agents is atopic dermatitis.

8. Dosing The specific dose levels of the compounds of this application for any particular subject are the activity, age, body weight, general condition, gender, diet, time of administration, route of administration, etc. of the specific compounds used. And excretion rate, as well as various factors including the combination of drugs in the subject being treated and the severity of the particular disease. For example, the dosage can be expressed as the number of milligrams (mg / kg) of the compounds described herein per kilogram of body weight of the subject. Dosings between about 0.1-150 mg / kg may be appropriate. In certain embodiments, about 0.1-100 mg / kg may be appropriate. In other embodiments, dosages between 0.5 and 60 mg / kg may be appropriate. Normalization according to the subject's weight is particularly useful when adjusting dosages between subjects of a wide range of different sizes, eg, when using the drug in both children and adults, or in non-human subjects, eg, eg. It is performed when converting a dosage effective in dogs to a dosage suitable for a human subject.

The daily dosage may be described as the total amount of the compounds disclosed herein given per dose or per day. The daily dosage of the compounds disclosed herein is between about 1 mg and 4,000 mg, between about 2,000 and 4,000 mg / day, between about 1 and 2,000 mg / day, and about 1 to 1,000 mg. Between about 10-500 mg / day, between about 20-500 mg / day, between about 50-300 mg / day, between about 75-200 mg / day, or between about 15-150 mg / day May be.

When orally administered, the total daily dosage for human subjects is between 1 mg and 1,000 mg, between about 1,000 and 2,000 mg / day, between about 10 and 500 mg / day, and about 50 to 300 mg / day. It may be between about 75-200 mg / day, or between about 100-150 mg / day.

The compounds of this application or compositions thereof may be administered once, twice, three or four times daily using any of the above preferred forms. Also, administration or treatment with the compound may be continued for several days; for example, in general, treatment is continued for at least 7, 14 or 28 days per cycle of treatment. Treatment cycles are well known in cancer chemotherapy and are often alternated between cycles with a rest period of about 1-28 days, typically about 7 or about 14 days. The treatment cycle may be continuous in other embodiments.

In certain embodiments, the method comprises administering to the subject the compounds described herein at an initial daily dose of approximately 1-800 mg, and in constant doses until clinical efficacy is achieved. Including increasing the dose. Dose can be increased using increments of approximately 5, 10, 25, 50, or 100 mg. Dosing can be increased daily, every other day, twice a week, or once a week.

9. Synthesis of Compounds The compounds may be prepared using the methods disclosed herein and conventional modifications thereof, which are apparent on the premise of the disclosure herein and methods well known in the art. .. In addition to the teachings herein, conventional and well-known synthetic methods may be used. The synthesis of typical compounds described herein may be accomplished as described in the examples below. Reagents may be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers, if available.

The compounds of the present disclosure may be prepared using the methods disclosed herein and conventional modifications thereof, which are apparent on the premise of the disclosure herein and the methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods may be used. The synthesis of typical compounds described herein, eg, compounds having a structure described by one or more formulas or compounds disclosed herein, is described in the examples below. May be achieved as it is. Reagents may be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers, if available.

The compounds of this disclosure can be prepared from readily available starting materials, for example using the following general methods and means: If typical or preferred process conditions (ie, reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may be used unless otherwise stated. Is recognized. Optimal reaction conditions may vary depending on the particular reactant or solvent used, but such conditions may be determined by one of ordinary skill in the art by routine optimization procedures.

In addition, as will be apparent to those of skill in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, a number of protecting groups are described in Wuts, PGM, Greene, TW, &amp; Greene, TW (2006). Greene's protective group in organic synthesis. Hoboken, NJ, Wiley-Interscience, and the references listed therein. Has been done.

Further, the compounds of this disclosure may contain one or more chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e. as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such character isomers (and enriched mixtures) are included within the scope of this disclosure unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, the racemic mixture of such compounds can be separated using, for example, chiral column chromatography, chiral dividers and the like.

The starting material for the following reactions may be generally known compounds or may be prepared by known procedures or obvious variants thereof. For example, many of the starting materials are commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). It is available from. Others are found in the text of standard references, for example, Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compound, Volumes 1-5, and Supplementals. (Elsevier Science Publishers, 1989) Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5)^th It may be prepared by the procedure described in Edition, 2001) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) or an obvious variant thereof.

The terms "solvent", "inert organic solvent" or "inert solvent" refer to a solvent that is inert under the conditions of the reactions described together (eg, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"). ), Dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, etc.). Unless the opposite is specified, the solvent used in the reactions of the present disclosure is an inert organic solvent and the reaction is carried out under an inert gas, preferably nitrogen.

The term "appropriate amount (qs)" means adding an amount sufficient to achieve the described function, eg, to bring the solution to the desired volume (ie, 100%).

Scheme 1 shows the synthesis of the compound of formula I, in which LG is the leaving group and X¹, X², Y¹, Y², A, L, R², R³, R⁴, And R⁹As defined herein. Scheme 1<chemistry num="87"><img file="JP6974331B2_D0121.tif" /></chemistry>As shown in Scheme 1, compounds of formula I can be prepared by contacting compound 1-b with a preferably substituted 1-a under standard amide bond forming reaction conditions. Activators may be used to facilitate the reaction, as is typical in peptide coupling reactions. Suitable coupling agents (or activators) are known to those of skill in the art and include, for example, carbodiimides (eg, N, N'-dicyclohexylcarbodiimide (DCC), N, N'-dicyclopentylcarbodiimide, N, N'-. Diisopropylcarbodiimide (DIC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), Nt-butyl-N-methylcarbodiimide (BMC), Nt-butyl-N-ethylcarbodiimide (BEC), 1, 3-Bis (2,2-dimethyl-1,3-dioxolan-4-ylmethyl) carbodiimide (BDDC), etc.), anhydrides (eg, symmetric, mixed, or cyclic anhydrides), activated esters (eg, phenyl) Activated ester derivatives, p-hydroxamic acid activated esters, hexafluoroacetone (HFA), etc.), acylazoles (acylimidazoles using CDI, acylbenzotriazoles, etc.), acyl azides, acidifieds, phosphonium salts (HOBt, PyBOP) , HOAt, etc.), Aminium / uronium salt (eg, tetramethylaminium salt, bispyrrolidinoaminium salt, bispiperidinoaminium salt, imidazolium uronium salt, pyridinium uronium salt, N, N, N'- Uronium salts derived from trimethyl-N'-phenylurea, morpholino-based aminium / uronium coupling reagents, uronium antimonate salts, etc., organic phosphorus reagents (eg, phosphinic acid and phosphate derivatives), organic sulfur reagents (eg, phosphinic acid and phosphate derivatives). , Sulphonic acid derivative), Triazine coupling reagent (eg 2-chloro-4,6-dimethoxy-1,3,5-triazine, 4- (4,6-dimethoxy-1,3, 5-Triazine-2-yl) -4methylmorpholinium chloride, 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4methylmorpholinium tetrafluoroborate, etc.), Pyridinium coupling reagents (eg, Mukaiyama reagent, pyridinium tetrafluoroborate coupling reagent, etc.), polymer supporting reagents (eg, polymer-bound carbodiimide, polymer-bound TBTU, polymer-bound 2,4,6-trichloro) Examples include -1,3,5-triazine, polymer-bound HOBt, polymer-bound HOSu, polymer-bound IIDQ, polymer-bound EEDQ, etc. (eg, El-Faham, et al. Chem. Rev., 2011,111 (11): 6557-6602; see Han, et al. Tetrahedron, 2004, 60: 2447-2467). The compounds of formulas 1-a and 1-b for use in Scheme 1 are as described in the schemes and examples provided herein, or using suitable starting materials in the art. It may be obtained from the conventional synthetic method known in the above. See 2447-2467). The compounds of formulas 1-a and 1-b for use in Scheme 1 are as described in the schemes and examples provided herein, or using suitable starting materials in the art. It may be obtained from the conventional synthetic method known in the above. See 2447-2467). The compounds of formulas 1-a and 1-b for use in Scheme 1 are as described in the schemes and examples provided herein, or using suitable starting materials in the art. It may be obtained from the conventional synthetic method known in the above.

Scheme 2 contains a 6,7-condensed ring and Y¹Shown is an exemplary synthesis of a compound where is O. In Scheme 2, PG is a protecting group (eg, BOC) and X⁶, X⁷, X⁸, X⁹, Y², Q, R¹, R³, R⁴, And R¹⁰As defined herein. Scheme 2<chemistry num="88"><img file="JP6974331B2_D0122.tif" /></chemistry>

In Scheme 2, the appropriately substituted 2-a can be cyclized under standard amide bond forming reaction conditions (eg, described above). The compounds of formula 2-a may be obtained from commercial sources, or as described in the examples provided herein, or using suitable starting materials in the art. It may be prepared from a known conventional synthetic method. In addition, Y², R¹, R³, R⁴And R¹⁰The desired functional group in the above may be provided before or after cyclization by using conventional synthetic methods known in the art (eg, halogenation, reduction, oxidation, olefination, alkylation, etc.).

Scheme 3 contains a 5,7-condensed ring and Y¹Shown is an exemplary synthesis of a compound where is O. In Scheme 3, Z is halo and X¹, X², X³, X⁴, X⁵, Y², Q, R¹, R³, R⁴, And R¹⁰As defined herein. Scheme 3<chemistry num="89"><img file="JP6974331B2_D0123.tif" /></chemistry>

In Scheme 3, the appropriately substituted 3-a can be contacted with hydroxylamine hydrochloride under reaction conditions sufficient to give 3-b. Ring expansion of 3-b giving lactam 3-c can be done by contacting oxime 3-b with phosphorus pentoxide. Alternatively, lactam 3-c can be given by contacting 3-a with sodium azide in the presence of sulfuric acid. Α-Halogenation of 3-c with suitable reagents (eg NBS, imidazole trimethylsilane, etc.), and formula R¹-LG: In the formula, LG is a suitable leaving group (eg, halo); 3-d is given by the optional N-alkylation of nitrogen of azapanone with the compound. Contacting 3-d with sodium azide yields 3-e. Reduction of the azide in 3-e (eg, hydrogenation, triphenylphosphine, etc.) gives 3-f. The compounds of formula 3-a may be obtained from commercial sources, or as described in the examples provided herein, or using suitable starting materials in the art. It may be prepared from a known conventional synthetic method. In addition, alternative functional groups can be used before, during or after the steps shown in Scheme 3 by using conventional synthetic methods known in the art (eg, halogenation, reduction, oxidation, olefination, alkylation, etc.). , May be provided at any point.

Also, Equation II:<chemistry num="90"><img file="JP6974331B2_D0124.tif" /></chemistry>A process for preparing a compound or a salt thereof, a tautomer, a stereoisomer or a mixture of stereoisomers of the formula XVI :.<chemistry num="91"><img file="JP6974331B2_D0125.tif" /></chemistry>The compound of the formula or a salt thereof, a homovariant, a stereoisomer or a mixture of stereoisomers is brought into contact with the compound of the formula XVI or a salt thereof, a homovariant, a stereoisomer or a mixture of stereoisomers thereof. Equation XVII:<chemistry num="92"><img file="JP6974331B2_D0126.tif" /></chemistry>It comprises contacting the compound of formula II with a compound of formula II or a salt thereof, a tautomer, a stereoisomer or a mixture of stereoisomers under reaction conditions sufficient to give the compound in the formula Y.²Is -O-, -S-, or -NR⁵-And; R⁵Is replaced with H, or optionally C₁-C₆Alkyl; L, ring A, q, R¹, R³, R⁴, R⁹, R¹⁰, X⁶, X⁷, X⁸And X⁹As defined herein; the above process is also provided herein.

In certain embodiments, Equation II:<chemistry num="93"><img file="JP6974331B2_D0127.tif" /></chemistry>A process for preparing a compound of the above or a salt thereof, a tautomer, a stereoisomer or a mixture of stereoisomers: (a) Formula X:<chemistry num="94"><img file="JP6974331B2_D0128.tif" /></chemistry>Compounds or salts thereof, tautomers, steric isomers or mixtures of steric isomers of the formula XI :.<chemistry num="95"><img file="JP6974331B2_D0129.tif" /></chemistry>Compound and formula XII:<chemistry num="96"><img file="JP6974331B2_D0130.tif" /></chemistry>Contacting under reaction conditions sufficient to give the compound of the compound or a salt thereof, a homovariant, a stereoisomer or a mixture of the stereoisomers; A steric isomer or a mixture of steric isomers, formula (XIII) :.<chemistry num="97"><img file="JP6974331B2_D0131.tif" /></chemistry>Contacting under reaction conditions sufficient to give the compound of the compound or a salt thereof, a homovariant, a stereoisomer or a mixture of stereoisomers; (c) a compound of formula XIII or a salt thereof, a homovariant, A steric isomer or a mixture of steric isomers, given the formula XIV:<chemistry num="98"><img file="JP6974331B2_D0132.tif" /></chemistry>Contacting under reaction conditions sufficient to give the compound of or a salt thereof, a homozygous, a stereoisomer or a mixture of stereoisomers; (d) optionally the compound of formula XIV or a salt thereof, A mixture of metavariants, steric isomers or steric isomers can be combined with an alkylating agent and formula XV :.<chemistry num="99"><img file="JP6974331B2_D0133.tif" /></chemistry>Contacting under reaction conditions sufficient to give the compound or a salt thereof, a homozygous, a stereoisomer or a mixture of stereoisomers; and (e) a compound of formula XV or a salt thereof, a homovariant. , A steric isomer or a mixture of steric isomers, formula XVI:<chemistry num="100"><img file="JP6974331B2_D0134.tif" /></chemistry>Deprotection under reaction conditions sufficient to give the compound or salt thereof, homovariant, sterically isomer or mixture of steric isomers of the compound of formula XVI or its salt, homoisomer, steric isomer. Alternatively, a mixture of stereoisomers can be expressed in Formula XVII :.<chemistry num="101"><img file="JP6974331B2_D0135.tif" /></chemistry>The compound of the formula II or a salt thereof, a tautomer, a stereoisomer or a mixture of the stereoisomers is contacted under sufficient reaction conditions; P is a protecting group in the formula. Yes; Y²Is -O-, -S-, or -NR⁵-And; R⁵Is replaced with H, or optionally C₁-C₆Alkyl; L, ring A, q, R¹, R³, R⁴, R⁹, R¹⁰, X⁶, X⁷, X⁸And X⁹Is as defined herein; the above process is provided.

In certain embodiments of the process described above, X⁷Or X⁹At least one of is N. In certain embodiments of the process described above, X⁷Is N and X⁶, X⁸And X⁹Is CH. In certain embodiments of the process described above, X⁹Is N and X⁶, X⁷And X⁸Is CH. In certain embodiments of the process described above, R¹Is methyl. In certain embodiments of the process described above, Y²Is -O-.

In certain embodiments of the process described above, P is tert-butoxycarbonyl. In certain embodiments of the process described above, the reaction conditions in step (b) include hydrogen gas. In certain embodiments of the process described above, the reaction conditions in step (c) include a peptide coupling agent. In certain embodiments of the process described above, the alkylating agent in step (d) is methyl iodide.

In each of the above schemes, the addition of any substituent can result in the formation of a large number of isomer products, including but not limited to enantiomers or one or more diastereomers, any of these. Or it will also be appreciated that all can be isolated and purified using conventional techniques. When an enantiomerically pure or enriched compound is desired, chiral chromatography and / or an enantiomerically pure or enriched starting material is as conventionally used or practiced in the art. It can be used as described in the example.

<p> The following examples are included to demonstrate the specific embodiments of the present disclosure. Those skilled in the art will appreciate that the techniques disclosed in the embodiments that follow represent techniques that work well in the practice of the present disclosure and that they may constitute a specific embodiment for that practice. Should be recognized by. However, one of ordinary skill in the art may make many changes in the specific embodiments disclosed in the light of the present disclosure, as well as similar or similar results without such changes departing from the spirit and scope of the present disclosure. It should be recognized that can still be obtained.</p><p> General Procedure Liquid Chromatography-Mass Spectrometry Method A: Total ion current (TIC) and DAD UV chromatograph traces, along with MS and UV spectra with peaks, equipped with a PDA detector and alternating positive and negative. Taken in a UPLC / MS Acquity system connected to a Waters single quadrupole mass spectrometer operating in an electrospray ionization mode. [LC / MS-ES (+/-): Acquity UPLC CSH, C18 column (50 × 2.1 mm, 1.7 μm particle size), column temperature 40 ° C, mobile phase: A-water + 0.1% HCOOH / B-CH₃CN + 0.1% HCOOH, flow velocity: 1.0 mL / min, execution time = 2.0 min, gradient: t = 0 min 3% B, t = 1.5 min 99.9% B, t = 1.9 min 99.9% B, t = 2.0 Analysis was performed using B at 3% min and downtime: 2.0 min. Positive ES: 100-1000, Negative ES: 100-1000, UV detection DAD: 210 ~ 350nm.</p><p> Liquid Chromatography-Mass Spectrometry Method B: Total ion current (TIC) and DAD UV chromatograph traces, along with peaked MS and UV spectra, equipped with a PDA detector and alternating positive and negative electrospray. Collected in a UPLC / MS Acquity system connected to a Waters single quadrupole mass spectrometer operating in ionization mode. [LC / MS-ES (+/-): Acquity UPLC BEH, C18 column (50 × 2.1 mm, 1.7 μm particle size), column temperature 40 ° C, mobile phase: A-0.1% v / v ammonia Aqueous solution (pH 10) / B-CH₃CN, flow rate: 1.0 mL / min, execution time = 2.0 min, gradient: t = 0 min 3% B, t = 1.5 min 99.9% B, t = 1.9 min 99.9% B, t = 2.0 min 3% B, downtime: 2.0 minutes was used for the analysis. Positive ES: 100-1000, Negative ES: 100-1000, UV detection DAD: 210 ~ 350nm.</p><p> Liquid chromatography-mass spectrometry C: LCMS analysis was performed on SHIMADZU LCMS consisting of UFLC20-AD and LCMS2020MS detectors. The diode array detector was scanned from 190 nm to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90-900 with a scanning time of 0.5-1.0 seconds. The column used was Shim-pack XR-ODS, 2.2 μm, 3.0 × 50 mm. Apply a linear gradient, starting with 95% A (A: 0.05% TFA in water) and 100% B (B: 0.05% TFA in MeCN) over 2.2 minutes with a total run time of 2.6 minutes. It ended with. The column temperature was 40 ° C at a flow rate of 1.0 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry D: LCMS analysis was performed on SHIMADZU LCMS consisting of UFLC20-AD and LCMS2020MS detectors. The diode array detector was scanned from 190 nm to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90-900 with a scanning time of 0.5-1.0 seconds. The column used was Shim-pack XR-ODS, 2.2 μm, 3.0 × 50 mm. Apply a linear gradient, starting with 95% A (A: 0.05% TFA in water) and 100% B (B: 0.05% TFA in MeCN) over 3.2 minutes with a total run time of 3.6 minutes. It ended with. The column temperature was 40 ° C at a flow rate of 1.0 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry Method E: LCMS analysis was performed on SHIMADZU LCMS consisting of UFLC20-AD and LCMS2020MS detectors. The diode array detector was scanned from 190 nm to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90-900 with a scanning time of 0.5-1.0 seconds. The column used was Ascentis Express C18, 2.7 μm, 3.0 × 50 mm. Apply a linear gradient, starting with 95% A (A: 0.05% TFA in water) and 100% B (B: 0.05% TFA in MeCN) over 1.8 minutes with a total run time of 2.0 minutes. It ended with. The column temperature was 45 ° C at a flow rate of 1.5 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry F: LCMS analysis was performed on SHIMADZU LCMS consisting of UFLC20-AD and LCMS2020MS detectors. The diode array detector was scanned from 190 nm to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90-900 with a scanning time of 0.5-1.0 seconds. The column used was Ascentis Express C18, 2.7 μm, 3.0 × 50 mm. Apply a linear gradient, starting with 95% A (A: 0.05% TFA in water) and 100% B (B: 0.05% TFA in MeCN) over 2.8 minutes with a total run time of 3.0 minutes. It ended with. The column temperature was 45 ° C at a flow rate of 1.5 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry G: LCMS analysis was performed on SHIMADZU LCMS consisting of UFLC20-AD and LCMS2020MS detectors. The diode array detector was scanned from 190 nm to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90-900 with a scanning time of 0.5-1.0 seconds. The column used was Kinetex EVO, 2.6 μm, 3.0 × 50 mm. Apply a linear gradient, with a total run time of 2.0 minutes, over 1.7 minutes, 90% A (A: 0.05% NH in water)₄HCO₃) And ended with 95% B (B: MeCN). The column temperature was 40 ° C at a flow rate of 1.3 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry H: LCMS analysis was performed on SHIMADZU LCMS consisting of UFLC20-AD and LCMS2020MS detectors. The diode array detector was scanned from 190 nm to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90-900 with a scanning time of 0.5-1.0 seconds. The column used was Kinetex EVO, 2.6 μm, 3.0 × 50 mm. Apply a linear gradient, with a total run time of 3.0 minutes, over 2.7 minutes, 90% A (A: 0.05% NH in water)₄HCO₃) And ended with 95% B (B: MeCN). The column temperature was 40 ° C at a flow rate of 1.3 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry Method I: LCMS analysis was performed on SHIMADZU LCMS consisting of UFLC20-AD and LCMS2020MS detectors. The diode array detector was scanned from 190 nm to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90-900 with a scanning time of 0.5-1.0 seconds. The column used was Ascentis Express C18, 2.7 μm, 2.1 × 50 mm. Apply a linear gradient, starting with 90% A (A: 0.10% formic acid in water) and 100% B (B: 0.10% formic acid in MeCN) over 1.70 minutes with a total run time of 2.0 minutes. It ended with. The column temperature was 45 ° C at a flow rate of 1.0 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry J: LCMS analysis was performed on SHIMADZU LCMS consisting of UFLC20-AD and LCMS2020MS detectors. The diode array detector was scanned from 190 nm to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90-900 with a scanning time of 0.5-1.0 seconds. The column used was Ascentis Express C18, 2.7 μm, 2.1 × 50 mm. Apply a linear gradient, starting with 90% A (A: 0.10% formic acid in water) and 95% B (B: 0.10% formic acid in MeCN) over 2.70 minutes with a total run time of 3.0 minutes. finished. The column temperature was 45 ° C at a flow rate of 1.0 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry K: LCMS analysis was performed on SHIMADZU LCMS consisting of UFLC20-AD and LCMS2020MS detectors. The diode array detector was scanned from 190 nm to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90-900 with a scanning time of 0.5-1.0 seconds. The column used was Ascentis Express C18, 2.7 μm, 3.0 × 50 mm. Apply a linear gradient, starting with 95% A (A: 0.05% TFA in water) and 100% B (B: 0.05% TFA in MeCN) over 1.6 minutes with a total run time of 2.0 minutes. It ended with. The column temperature was 40 ° C at a flow rate of 1.5 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry L: LCMS analysis was performed on SHIMADZU LCMS consisting of UFLC20-AD and LCMS2020MS detectors. The diode array detector was scanned from 190 nm to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90-900 with a scanning time of 0.5-1.0 seconds. The column used was Ascentis Express C18, 2.7 μm, 3.0 × 50 mm. Apply a linear gradient, starting with 95% A (A: 0.05% TFA in water) and 100% B (B: 0.05% TFA in MeCN) over 2.6 minutes with a total run time of 3.0 minutes. It ended with. The column temperature was 40 ° C at a flow rate of 1.5 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry M: LCMS analysis was performed on SHIMADZU LCMS consisting of UFLC20-AD and LCMS2020MS detectors. The diode array detector was scanned from 190 nm to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90-900 with a scanning time of 0.5-1.0 seconds. The column used was Kinetex XB-C18, 2.6 μm, 3.0 × 50 mm. Apply a linear gradient, starting with 95% A (A: 0.05% TFA in water) and 100% B (B: 0.05% TFA in MeCN) over 2.8 minutes with a total run time of 3.0 minutes. It ended with. The column temperature was 40 ° C at a flow rate of 1.5 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry Method N: LCMS analysis was performed on SHIMADZU LCMS consisting of UFLC20-AD and LCMS2020MS detectors. The diode array detector was scanned from 190 nm to 400 nm. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive or negative mode. The mass spectrometer was scanned between m / z 90-900 with a scanning time of 0.5-1.0 seconds. The column used was Ascentis Express C18, 2.7 μm, 3.0 × 50 mm. Apply a linear gradient, starting with 95% A (A: 0.05% TFA in water) and 100% B (B: 0.05% TFA in MeCN) over 1.7 minutes with a total run time of 2.0 minutes. It ended with. The column temperature was 40 ° C at a flow rate of 1.5 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry Method O: The column used was Agilent Poroshell HPH-C18, 2.7 μm, 3.0 × 50 mm. Apply a linear gradient, with a total run time of 3 minutes, over 2.7 minutes, 95% A (A: 0.05% NH in water)₄HCO₃) And 95% B (B: 0.05% NH in MeCN)₄HCO₃) Ended. The column temperature was 45 ° C at a flow rate of 1.5 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry Method P: The column used was Ascentis Express C18, 3.5 μm, 4.6 × 50 mm. Apply a linear gradient, with a total run time of 5.6 minutes, over 5.2 minutes, 90% A (A: 0.05% NH in water)₄HCO₃) And 95% B (B: 0.05% NH in MeCN)₄HCO₃) Ended. The column temperature was 40 ° C at a flow rate of 1.5 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry Q: The column used was Agilent Poroshell HPH-C18, 2.7 μm, 3.0 × 50 mm. Apply a linear gradient, with a total run time of 5.0 minutes, over 4.7 minutes, 95% A (A: 0.05% NH in water)₄HCO₃) And 95% B (B: 0.05% NH in MeCN)₄HCO₃) Ended. The column temperature was 40 ° C at a flow rate of 1.5 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry Method R: The column used was Agilent Poroshell HPH-C18, 2.7 μm, 3.0 × 50 mm. Apply a linear gradient, with a total run time of 2.0 minutes, over 1.8 minutes, 95% A (A: 0.05% NH in water)₄HCO₃) And 95% B (B: 0.05% NH in MeCN)₄HCO₃) Ended. The column temperature was 40 ° C at a flow rate of 1.5 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry Method S: The column used was Ascentis Express C18, 2.7 μm, 3.0 × 50 mm. Apply a linear gradient, starting with 95% A (A: 0.05% TFA in water) and 100% B (B: 0.05% TFA in MeCN) over 1.8 minutes with a total run time of 2.0 minutes. It ended with. The column temperature was 40 ° C at a flow rate of 1.5 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry Method T: The column used was Ascentis Express C18, 2.7 μm, 3.0 × 50 mm. Apply a linear gradient, starting with 95% A (A: 0.05% TFA in water) and 100% B (B: 0.05% TFA in MeCN) over 2.7 minutes with a total run time of 3.0 minutes. It ended with. The column temperature was 40 ° C at a flow rate of 1.5 mL / min.</p><p> Liquid Chromatography-Mass Analysis Method U: The column used was Acquity UPLCTM BEH, C18 column (50 × 2.1 mm, 1.7 μm particle size), column temperature 40 ° C, mobile phase: adjusted to pH 10 with A-ammonia aqueous solution. 10 mM ammonium bicarbonate aqueous solution / B-CH3CN, flow rate: 1.0 mL / min, execution time = 2.0 minutes, gradient: t = 0 min 3% B, t = 1.5 min 99.9% B, t = 1.9 min 99.9% B, t = 2.0 minutes 3% B, downtime: 2.0 minutes. Positive ES: 100-1000, Negative ES: 100-1000, UV detection DAD: 210-350nm.</p><p> Liquid Chromatography-Mass Spectrometry Method V: The column used was Shim-pack XR-ODS, 2.2 μm, 3.0 × 50 mm. Apply a linear gradient, starting with 95% A (A: 0.05% TFA in water) and 100% B (B: 0.05% TFA in MeCN) over 4.2 minutes with a total run time of 5.3 minutes. It ended with. The column temperature was 40 ° C at a flow rate of 1.0 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry W: The column used was Shim-pack XR-ODS, 2.2 μm, 3.0 × 50 mm. Apply a linear gradient, starting with 95% A (A: 0.05% TFA in water) and 100% B (B: 0.05% TFA in MeCN) over 4.2 minutes with a total run time of 5.3 minutes. It ended with. The column temperature was 40 ° C at a flow rate of 1.0 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry Method X: The column used was Ascentis Express C18, 2.7 μm, 3.0 × 50 mm. Apply a linear gradient, starting with 95% A (A: 0.05% TFA in water) and 95% B (B: 0.05% TFA in MeCN) over 4.1 minutes with a total run time of 5.3 minutes. finished. The column temperature was 40 ° C at a flow rate of 1.5 mL / min.</p><p> Liquid Chromatography-Mass Spectrometry Y: The column used was Poroshell HPH-C18, 2.7 μm, 3.0 × 50 mm. Apply a linear gradient, with a total run time of 2 minutes, over 1.8 minutes, 95% A (A: 0.05% NH in water)₄HCO₃) And 95% B (B: 0.05% NH in MeCN)₄HCO₃) Ended. The column temperature was 45 ° C at a flow rate of 1.5 mL / min.</p><p> HPLC analysis was performed on a SHIMADZU UFLC equipped with two LC20 AD pumps and an SPD-M20A optical diode array detector. The columns used were XBridge C18, 3.5 μm, 4.6 × 100 mm. Apply a linear gradient, starting with 90% A (A: 0.05% TFA in water) and 95% B (B: 0.05% TFA in MeCN) over 10 minutes with a total run time of 15 minutes. finished. The column temperature was 40 ° C at a flow rate of 1.5 mL / min. The diode array detector was scanned from 200 to 400 nm.</p><p> Thin layer chromatography (TLC) was performed on Alugram® (silica gel 60F254) from Mancherey-Nagel and spots were typically visualized using UV. In some cases, additional visualization methods were also used. In these cases, the TLC plate is replaced with iodine (approximately 1 g of I).₂Add ~ 10g of silica gel and mix thoroughly to produce), Ninhydrin (commercially available from Aldrich), or Magic Stain (25g (NH)₄)₆Mo₇O₂₄. 4H₂O, 5g (NH₄)₂Ce (IV) (NO)₃)₆450 mL of water and 50 mL of concentrated H₂SO₄The compound was visualized by developing by (produced by mixing thoroughly in). Flash chromatography is performed on a 40-63 μm (230-400 mesh) made by Silicycle according to a technique similar to that disclosed in Still, WC; Kahn, M .; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923. ) Performed using silica gel. Typical solvents used for flash chromatography or thin layer chromatography were mixtures of chloroform / methanol, dichloromethane / methanol, ethyl acetate / methanol and hexane / ethyl acetate.</p><p> Analytical method¹Bruker Avance III with BBFO 300MHz probe operating at 300MHz for H nuclear magnetic resonance (NMR) spectroscopy, or Bruker Avance 400 instrument with probe DUAL 400MHz S1, all operating at 400MHz, probe 6S1 (400MHz, 5mm) ,¹H-¹³Performed using one of the Bruker Avance400 instrument with C ID), the Bruker AvanceIII400 instrument with nanobay with the wideband probe BBFO (5 mm, direct), and the Bruker Mercury Plus400 NMR spectrometer with the Bruker400BBO probe; .. Spectrum spectra were obtained near room temperature in the described solvents unless otherwise stated. In all cases, the NMR data were consistent with the proposed structure. Flash chromatography is performed on a 40-63 μm (230-400 mesh) made by Silicycle according to a technique similar to that disclosed in Still, WC; Kahn, M .; and Mitra, M. Journal of Organic Chemistry, 1978, 43, 2923. ) Performed using silica gel.</p><p> Compound Preparation If the preparation of starting materials is not described, these starting materials are commercially available, are known in the literature, or can be readily obtained by one of ordinary skill in the art using standard procedures. .. If the compound is described as being prepared similar to the previous example or intermediate, the reaction time, reagent equivalents, and temperature can be varied for each specific reaction, as well as different workups. Or it will be recognized by those skilled in the art that it may be necessary or desirable to use purification techniques. If the reaction is carried out using microwave irradiation, the microwave used is the Biotage Initiator. The actual power supplied fluctuates during the course of the reaction in order to maintain a constant temperature.</p><p> Example 1: 5-Benzyl-N- (2-chloro-4-methyl-5-oxo-4H, 5H, 6H, 7H, 8H-thieno [3,2-b] azepine-6-yl) -1, 2-Oxazole-3-Carboxamide<chemistry num="102"><img file="JP6974331B2_D0136.tif" /></chemistry> Step 1: Preparation of N- [4,5,6,7-Tetrahydro-1-benzothiophen-4-iriden] hydroxylamine of hydroxylamine hydrochloride (4.56 g, 65.7 mmol) in 5N sodium acetate solution (120 mL) The solution was added to a solution of 6,7-dihydro-1-benzothiophene-4 (5H) -one (2.00 g, 13.1 mmol) in EtOH (200 mL). The reaction mixture was heated to 100 ° C and stirred for 2 hours. Volatiles were removed under reduced pressure and the crude product was dissolved in water and extracted with EtOAc. Wash the organic part with salt water and Na₂SO₄It was dried on top, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane- EtOAc, 100: 0-50: 50) to give the title compound (1.10 g, 51%).¹1 H NMR (400 MHz, CDCl₃) δ 7.76-7.42 (m, 1H), 7.30 (d, J = 5.3 Hz, 1H), 7.09 (d, J = 5.3 Hz, 1H), 2.89 (t, J = 6.1 Hz, 2H), 2.82-2.77 (m, 2H), 2.02 (singlet, J = 6.3 Hz, 2H). LC-MS (method A): m / z = 168.0 [M + H]⁺, 0.83 minutes.</p><p> Step 2: Preparation of 4H, 5H, 6H, 7H, 8H-thieno [3,2-b] azepine-5-one Phosphorus pentoxide (11.3 g, 79.5 mmol) to methanesulfonic acid (10.9 g, 113.6 mmol) The mixture was added and the mixture was stirred for 2 hours. N- [4,5,6,7-Tetrahydro-1-benzothiophen-4-iriden] hydroxylamine (1.10 g, 6.58 mmol) was then added to the above stirring solution previously heated to 100 ° C. .. After stirring at 110 ° C for 4 hours, cool the reaction and saturate NaHCO.₃Carefully quenched by the addition of the solution. The mixture was extracted with chloroform. Saturate the combined organic part ₃Wash with solution and water, Na₂SO₄It was dried on top, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane- EtOAc, 80: 20-0: 100) to give the desired compound (450 mg, 41%).¹1 H NMR (400 MHz, CDCl₃) δ 7.90-7.69 (m, 1H), 7.08 (d, J = 5.3 Hz, 1H), 6.64 (d, J = 5.3 Hz, 1H), 3.00 (t, J = 6.9 Hz, 2H), 2.67-2.60 (m, 2H), 2.26-2.14 (m, 2H).</p><p> Step 3: Preparation of 2-chloro-4H, 5H, 6H, 7H, 8H-thieno [3,2-b] azepine-5-one N-chlorosuccinimide (356 mg, 2.68 mmol), 4H, 5H, 6H, 7H,8H-thieno [3,2-b] azepine-5-one (450 mg, 2.69 mmol) was added to a solution of DMF (10 mL). The reaction was heated to 50 ° C and stirred at that temperature for 16 hours. Dilute the reaction with EtOAc and saturate NH₄Wash twice with Cl solution and Na₂SO₄It was dried on top, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane / EtOAc, 100: 0-0: 100) to give the title compound (190 mg, 35%).¹1 H NMR (400 MHz, CDCl₃) δ 7.73 (brs, 1H), 6.50 (s, 1H), 2.89 (t, J = 6.9 Hz, 2H), 2.66-2.59 (m, 2H), 2.23-2.13 (m, 2H). LC-MS ( Method A): m / z = 202.1 [M + H]⁺, 0.84 minutes.</p><p> Step 4: Preparation of 2-chloro-6-iodo-4H, 5H, 6H, 7H, 8H-thieno [3,2-b] azepine-5-one Iodtrimethylsilane (264 μL, 0.189 mmol), -10 ° CH of 2-chloro-4H, 5H, 6H, 7H, 8H-thieno [3,2-b] azepine-5-one (190 mg, 0.945 mmol) and TMEDA (430 μL, 22.8 mmol) pre-cooled to C₂Cl₂(3 mL) was added to the solution. The reaction was stirred at -10 ° C for 30 minutes. Powdered iodine (360 mg, 1.42 mmol) was added. The mixture is stirred at -10 ° C for 1 hour, allowed to reach room temperature over 1.5 hours, then stirred for an additional 30 minutes, 1 M Na.₂S₂O₃Quenched with solution. Separate the layers and CH the aqueous part₂Cl₂Extracted twice. The combined organic part is Na₂SO₄It was dried on top, filtered and concentrated under reduced pressure. CH crude product₂Cl₂Tritulated with to give the title compound (135 mg, 44%).¹1 H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 6.69 (s, 1H), 4.99-4.91 (m, 1H), 3.15-3.06 (m, 1H), 2.95 (ddd, J = 17.4, 11.9, 5.5 Hz, 1H), 2.19-208 (m, 1H), 1.88 (dddd, J = 14.9, 11.9, 5.1, 2.0 Hz, 1H).</p><p> Step 5: Preparation of 2-chloro-6-iodo-4-methyl-4H, 5H, 6H, 7H, 8H-thieno [3,2-b] azepine-5-one Iodomethane (29 μL, 0.460 mmol), 2 -Chloro-6-iodine-4H, 5H, 6H, 7H, 8H-thieno [3,2-b] azepine-5-one (135 mg, 0.418 mmol) and Cs₂CO₃(205 mg, 0.627 mmol) was added to the mixture in DMF (6 mL). The reaction was stirred at room temperature for 4 hours, cooled to 4 ° C and stirred at that temperature for 36 hours. Further iodomethane (29 μL, 0.460 mmol) was added and the mixture was stirred at room temperature for 5 hours. Add EtOAc and wash the organic moieties twice with 0.5M HCl solution, Na₂SO₄It was dried on top, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane / EtOAc, 100: 0-50: 50) to give the title compound (72 mg, 51%).¹1 H NMR (400 MHz, DMSO-d₆) δ 7.28 (s, 1H), 4.82 (dd, J = 9.2, 6.7 Hz, 1H), 3.17 (s, 3H), 2.90-2.56 (m, 4H) .LC-MS (Method A): m / z = 342.0 [M + H]⁺, 1.10 minutes.</p><p> Step 6: Preparation of 6-azido-2-chloro-4-methyl-4H, 5H, 6H, 7H, 8H-thieno [3,2-b] azepine-5-one 2-chloro-6-iodo-4- Methyl-4H, 5H, 6H, 7H, 8H-thieno [3,2-b] azepine-5-one (70 mg, 0.205 mmol) and NaN₃The mixture in (20 mg, 0.307 mmol) DMF (2 mL) was stirred at 33 ° C for 2 hours. Add EtOAc and wash the organic moieties twice with 0.5M HCl solution, Na₂SO₄It was dried on top, filtered and concentrated under reduced pressure to give the title compound (52 mg), which was taken directly to the next step.¹1 H NMR (400 MHz, DMSO-d₆) δ 7.28 (s, 1H), 4.11 (dd, J = 11.7, 7.4 Hz, 1H), 3.20 (s, 3H), 2.88-2.77 (m, 2H), 2.53-2.40 (m, 1H), 2.28- 2.13 (m, 1H) .LC-MS (Method A): m / z = 257.1 [M + H]⁺, 1.04 minutes.</p><p> Step 7: Preparation of 6-amino-2-chloro-4-methyl-4H, 5H, 6H, 7H, 8H-thieno [3,2-b] azepine-5-one 6-azido-2-chloro-4- Methyl-4H, 5H, 6H, 7H, 8H-thieno [3,2-b] azepine-5-one (52mg) and triphenylphosphine (60mg, 0.229mg) 3: 1THF-H₂The mixture in O (2 mL) was stirred at room temperature for 18 hours. The reaction was diluted with EtOAc and washed twice with water. The organic part is Na₂SO₄It was dried on top, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane / EtOAc, 60:40) to give the title compound (37 mg, 85% purity).¹1 H NMR (400 MHz, DMSO-d₆) δ 7.25 (s, 1H), 3.37-3.28 (m, 1H), 3.16 (s, 3H), 2.71-2.64 (m, 2H), 2.37-2.26 (m, 1H), 1.90-1.77 (m, 1H) ), 1.66 (br. S, 2H) .LC-MS (Method A): m / z = 231.1 [M + H]⁺, 0.41 minutes.</p><p> Amide Coupling Procedure A Step 8: 5-Benzyl-N- (2-chloro-4-methyl-5-oxo-4H, 5H, 6H, 7H, 8H-thieno [3,2-b] azepine-6-yl )-1,2-Oxazole-3-Carboxamide Preparation and Separation 6-Amino-2-Chloro-4-methyl-4H, 5H, 6H, 7H, 8H-Tieno [3,2-b] Azepine-5-one (27 mg, about 85% purity), HBTU (39.6 mg, 0.104 mmol), 1-hydroxybenzotriazole (14 mg, 0.104 mmol), DIPEA (45 μL, 0.261 mmol) and 5-benzyl-1,2-oxazol-3- A solution of carboxylic acid (19 mg, 0.092 mmol) in DMF (3.5 mL) was stirred at room temperature for 4 hours. Add EtOAc and saturate the organic part NH₄Wash twice with Cl solution and Na₂SO₄It was dried on top, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane / EtOAc, 100: 0-50: 50) to give the title compound as a mixture of enantiomers. This mixture is mixed with 20/80% v / v n-hexane / (45/45/10 EtOH / MeOH / CH).₂Cl₂Using a mobile phase of + 0.1% isopropylamine), Whelk O-1 (R, R) (25 × 2.0 cm) was split by chiral HPLC on a 10 μm column to give the two title compounds as separated enantiomers. rice field.</p><p> 1st Elution Enantiomer, Enantiomer 1:¹1 H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 7.5 Hz, 1H), 7.42-7.20 (m, 5H), 6.80 (s, 1H), 6.34 (s, 1H), 4.81 (dt, J = 11.2, 7.2 Hz, 1H) , 4.13 (s, 2H), 3.31 (s, 3H), 3.02-2.78 (m, 2H), 2.77-2.66 (m, 1H), 2.23-2.09 (m, 1H) .LC-MS (Method A): m / z = 416.2 [M + H]⁺, 1.16 minutes. 20/80% v / v n-hexane / (45/45/10 EtOH / MeOH / CH₂Cl₂Using a mobile phase of + 0.1% isopropylamine), Whelk O-1 (R, R) (25 × 2.0 cm), ee&gt; 99.5% determined on a 10 μm column.</p><p> Second Elution Enantiomer, Enantiomer 2:¹1 H NMR (400 MHz, CDCl₃) δ 7.82-7.71 (m, 1H), 7.39-7.23 (m, 5H), 6.80 (s, 1H), 6.34 (s, 1H), 4.81 (dt, J = 11.2, 7.1 Hz, 1H), 4.13 ( s, 2H), 3.31 (s, 3H), 3.00-2.78 (m, 2H), 2.76-2.66 (m, 1H), 2.21-2.10 (m, 1H). LC-MS (Method A): m / z = 416.2 [M + H]⁺, 1.16 minutes. 20/80% v / v n-hexane / (45/45/10 EtOH / MeOH / CH₂Cl₂Using a mobile phase of + 0.1% isopropylamine), Whelk O-1 (R, R) (25 × 2.0 cm), ee = 98.4% determined on a 10 μm column.</p><p> Example 2: 5-Benzyl-N- (5-Fluoro-1-methyl-2-oxo-2,3,4,5-Tetrahydro-1H-benzo [b] azepine-3-yl) Isoxazole-3- Carboxamide<chemistry num="103"><img file="JP6974331B2_D0137.tif" /></chemistry><chemistry num="104"><img file="JP6974331B2_D0138.tif" /></chemistry> Step 1: Preparation of (2R) -4- (2-aminophenyl) -2-[[(tert-butoxy) carbonyl] amino] -4-oxobutanoic acid di-tert-butyl dicarbonate (7.19 g, 32.9 mmol) In a dioxane (50 mL) solution of (2R) -2-amino-4- (2-aminophenyl) -4-oxobutanoic acid sulfate (9.18 g, 29.9 mmol) and triethylamine (12.1 g, 119.6 mmol). It was added with stirring under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum to give the title compound (9.18 g, crude). LC-MS (Method C): m / z = 309.1 [M + H]⁺, 1.307 minutes.</p><p> Step 2: Preparation of (2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) carbamic acid (R) -tert-butyl 2- (7-aza- 1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (13.6 g, 35.9 mmol) and ethyldiisopropylamine (11.6 g, 89.7 mmol), (2R) -4 -(2-Aminophenyl) -2-[[(tert-butoxy) carbonyl] amino] -4-oxobutanoic acid (9.21 g, 29.8 mmol) was added to a stirred solution of N, N-dimethylformamide (50 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/6) to give the title compound (2.2 g, 25%). LC-MS (Method C): m / z = 291.1 [M + H]⁺, 1.298 minutes.</p><p> Step 3: Preparation of tert-butyl carbamic acid (1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) iodomethane (1.08 g, 7.60 mmol) ), (2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) carbamic acid (R) -tert-butyl (2.01 g, 6.89 mmol) and carbonate. Cesium (2.47 g, 7.58 mmol) was added dropwise to a stirred solution of N, N-dimethylformamide (20 mL) with stirring. The resulting solution was stirred at room temperature for 3 hours. Water (10 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/10) to give the title compound (1.20 g, 57%). LC-MS (Method G): m / z = 305.0 [M + H]⁺, 1.004 minutes.</p><p> Step 4: Preparation of tert-butyl carbamate (5-hydroxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) in methanol (20 mL) (1-Methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) tert-butyl carbamate (506.0 mg, 1.66 mmol), 10% Hydrogenated in the presence of palladium-bearing carbon (50.0 mg) under a hydrogen atmosphere (2-3 atm). The resulting solution was stirred at room temperature overnight. The solid was removed by filtration and the filtrate was evaporated under vacuum to give the title compound (0.5 g, crude). LC-MS (Method C): m / z = 307.2 [M + H]⁺, 1.273 minutes.</p><p> Step 5: Preparation of tert-butyl N- [5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3-yl] carbamic acid diethylaminosulfur trifluoride (40.3 mg, 0.25 mmol), (5-hydroxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) tert-butyl carbamic acid ( It was added to a solution of 30.6 mg (0.10 mmol) in dichloromethane (2 mL) at 0 ° C under a nitrogen atmosphere. The resulting solution was stirred at 0 ° C for 3 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (2 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (25 mg, 81%). LC-MS (Method K): m / z = 208.9 [M-Boc + H]⁺, 0.946 minutes.</p><p> Step 6: Preparation of 3-amino-5-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one hydrochloride 4N in dioxane (2mL) N in hydrogen chloride -[5-Fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3-yl] tert-butyl carbamic acid (25.0 mg, 0.08 mmol) at room temperature Was stirred for 0.5 hours. The resulting mixture was concentrated under vacuum to give the title compound (20 mg, crude). LC-MS (Method K): m / z = 208.9 [M + H]⁺, 0.555 minutes</p><p> Step 7: 5-benzyl-N- (5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) isooxazole-3-carboxamide Preparation of 5-benzyl-1,2-oxazol-3-carboxylic acid (16.0 mg, 0.08 mmol) in N, N-dimethylformamide (2 mL) in 2- (7-aza-1H-benzotriazole-1-). Il) -1,1,3,3-tetramethyluronium hexafluorophosphate (45.6 mg, 0.12 mmol), ethyldiisopropylamine (38.7 mg, 0.30 mmol), 3-amino-5-fluoro-1-methyl-2 , 3,4,5-Tetrahydro-1H-1-benzazepine-2-one hydrochloride (20.0 mg, 0.08 mmol) was added to a stirred solution of N, N-dimethylformamide (10 mL). The resulting solution was stirred at room temperature for 2 hours and then diluted with water (10 mL). The reaction mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Crude product, Xbridge Phenyl OBD 5 μm, 19 × 150 mm column; mobile phase, water (10 mmol / L NH)₄HCO₃) And ACN (50.0% ACN ~ 70.0% in 7 minutes) were purified by reverse phase chromatography to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.85 (d, J = 7.6 Hz, 1H), 7.59 --7.52 (m, 2H), 7.44 --7.26 (m, 7H), 6.54 (s, 1H), 5.76 (dd, J = 4.4, 48.8 Hz, 1H), 4.52 --4.45 (m, 1H), 4.22 (s, 2H), 3.25 (s, 3H), 2.74 --2.71 (m, 1H), 2.66 --2.61 (m, 1H) .LC-MS (Method L) ): m / z = 394.1 [M + H]⁺, 1.482 minutes.</p><p> Amide Coupling Procedure B Step 8: 5-benzyl-N- (5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) iso Oxazole-3-carboxamide (first elution isomer, Example 2A) and 5-benzyl-N- (5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [ b] Preparation of azepine-3-yl) isooxazole-3-carboxamide (second elution isomer, Example 2B)<chemistry num="105"><img file="JP6974331B2_D0139.tif" /></chemistry> 3-Amino-5-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (30 mg, 0.140 mmol), 5-benzyl-1,2-oxazole-3 -Carboxylic acid (32.3 mg, 0.159 mmol), N, N, N', N'-tetramethyl-O- (7-azabenzotriazole-1-yl) uronium hexafluorophosphate (65.7 mg, 0.173 mmol) and N, N-diisopropylethylamine (55.7 mg, 0.432 mmol) was added to a stirred solution of N, N-dimethylformamide (5 mL). After stirring at room temperature for 3 hours, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Crude products under the following conditions: column, Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN (45.0% ACN ~ 70.0% over 7 minutes); detector, UV254 Purification by preparative HPLC using / 220 nm; gave the title compound:</p><p> Example 2A, 1st elution isomer:¹1 H NMR (300 MHz, CD₃OD) δ 8.53 (d, J = 6.9 Hz, 1H), 7.55-7.50 (m, 1H), 7.50-7.42 (m, 1H), 7.40-7.14 (m, 7H), 6.36 (s, 1H), 5.79 -5.28 (m, 1H), 4.73-4.48 (m, 1H), 4.13 (s, 2H), 3.32 (s, 3H), 2.91-2.72 (m, 1H), 2.64-2.40 (m, 1H) .LC -MS (Method D): m / z = 394.1 [M + H]⁺, 2.075 minutes.</p><p> Example 2B, second elution isomer:¹H NMR (300 MHz, DMSO-d6) δ 8.84 (d, J = 7.5 Hz, 1H), 7.51-7.39 (m, 4H), 7.38-7.25 (m, 5H), 6.52 (s, 1H), 5.98- 5.28 (m, 1H), 4.34-4.25 (m, 1H), 4.21 (s, 2H), 3.29 (s, 3H), 2.91-2.83 (m, 1H), 2.42-2.32 (m, 1H) .LC- MS (Method D): m / z = 394.1 [M + H]⁺, 2.164 minutes.</p><p> Example 3: (S) -5-benzyl-N- (1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) iso Oxazole-3-carboxamide<chemistry num="106"><img file="JP6974331B2_D0140.tif" /></chemistry> Step 1: Preparation of (2S) -4- (2-aminophenyl) -2-[[(tert-butoxy) carbonyl] amino] -4-oxobutanoic acid di-tert-butyl dicarbonate (0.96 g, 4.39 mmol) In a dioxane (10 mL) solution of (2S) -2-amino-4- (2-aminophenyl) -4-oxobutanoic acid sulfate (1.22 g, 4.00 mmol) and triethylamine (1.21 g, 11.98 mmol). It was added with stirring under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum to give the title compound (1.22 g, crude). LC-MS (Method K): m / z = 309.1 [M + H]⁺, 1.549 minutes.</p><p> Step 2: Preparation of N-[(3S) -2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3-yl] tert-butyl carbamic acid 2- (7-aza- 1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (1.82 g, 4.80 mmol) and ethyldiisopropylamine (1.55 g, 11.99 mmol), (2S) -4. -(2-Aminophenyl) -2-[[(tert-butoxy) carbonyl] amino] -4-oxobutanoic acid (1.23 g, 4.00 mmol) was added to a stirred solution of N, N-dimethylformamide (10 mL). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic moieties were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (850 mg). LC-MS (Method K): m / z = 291.1 [M + H]⁺, 0.850 minutes.</p><p> Step 3: Preparation of tert-butyl carbamic acid N-[(3S) -1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3-yl] iodomethane (118 mg) , 0.83 mmol), N-[(3S) -2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3-yl] tert-butylcarbamate (220.0 mg, 0.76 mmol) ) And cesium carbonate (272 mg, 0.83 mmol) in N, N-dimethylformamide (20 mL). The resulting mixture was stirred at room temperature for 6 hours, then water (10 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (130 mg, 56%). LC-MS (Method K): m / z = 305.0 [M + H]⁺, 0.907 minutes.</p><p> Step 4: Preparation of N-[(3S) -1-methyl-5-methylidene-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3-yl] tert-butyl carbamic acid A suspension of methyltriphenylphosphonium bromide (382 mg, 1.07 mmol) and sodium hydride (20.0 mg, 0.83 mmol) in tetrahydrofuran (2 mL) was stirred at 50 ° C. for 1 hour under a nitrogen atmosphere. Then N-[(3S) -1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3-yl] tert-butylcarbamate (101.0 mg, 0.33 mmol) ) Was added dropwise to the reaction mixture with stirring. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of saturated aqueous ammonium chloride (5 mL). The resulting solution was extracted with ethyl acetate (3 x 10 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/10) to give the title compound (75 mg, 75%). LC-MS (Method C): m / z = 303.2 [M + H]⁺, 1.531 minutes.</p><p> Step 5: Preparation of (S) -3-amino-1-methyl-5-methylene-4,5-dihydro-1H-benzo [b] azepine-2 (3H) -one hydrochloride Hydrogen chloride (4N) in dioxane , 6 mL) in N-[(3S) -1-methyl-5-methylidene-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3-yl] carbamate tert-butyl ( The solution (40.0 mg, 0.13 mmol) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to give the title compound (25.2 mg, crude). LC-MS (Method C): m / z = 203.2 [M + H]⁺, 0.635 minutes.</p><p> Amide Coupling Procedure C Step 6: (S) -5-benzyl-N- (1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3 -Il) Preparation of isooxazole-3-carboxamide (S) -3-amino-1-methyl-5-methylene-4,5-dihydro-1H-benzo [b] azepine-2 (3H) -one hydrochloride ( 25.4 mg, 0.10 mmol) N, N-dimethylformamide (2 mL) solution, 5-benzyl-1,2-oxazol-3-carboxylic acid (20 mg, 0.10 mmol), 1-hydroxybenzotriazole (16 mg, 0.12 mmol). ), 1- (3-Dimethylaminopropyl) -3-ethylcarboxamide (23 mg, 0.12 mmol), ethyldiisopropylamine (39 mg, 0.30 mmol) in N, N-dimethylformamide (8 mL) stirred solution. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Crude product, Xbridge Phenyl OBD 5 μm, 19 × 150 mm column; mobile phase, water (10 mmol / L NH)₄HCO₃) And ACN (50.0% ACN ~ 70.0% in 7 minutes) were purified by reverse phase chromatography to give the title compound (17.8 mg, 44%) as a white solid. Chilarpak AS-H (25 x 2.0 cm) using a mobile phase of 60/40% v / v n-hexane / (1/1 2-propanol / MeOH + 0.1% isopropylamine) for this compound. , Further purified by chiral HPLC on a 5 μm column to give the title compound.¹H NMR (400MHz, CDCl₃) δ 7.87 (d, J = 6.8 Hz, 1H), 7.44-7.22 (m, 8H), 7.18 (d, J = 7.8 Hz, 1H), 6.33 (s, 1H), 5.25-5.20 (m, 1H) , 5.14-5.08 (m, 1H), 4.91 (td, J = 6.9, 12.1 Hz, 1H), 4.13 (s, 2H), 3.55 (tdd, J = 2.9, 6.5, 15.7 Hz, 1H), 3.39 (s) , 3H), 2.84 (dd, J = 12.0, 15.6 Hz, 1H) .LC-MS (Method A): m / z = 388.1 [M + H]⁺, 1.21 minutes. Using a mobile phase of 60/40% v / v n-hexane / (1/1 2-propanol / MeOH + 0.1% isopropylamine) in Chilarpak AS-H (25 × 0.46 cm), in a 5 μm column. Obtained ee&gt; 99.5%.</p><p> Example 4: (S) -1-benzyl-4-chloro-5-methyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine -3-yl) -1H-pyrazole-3-carboxamide<chemistry num="107"><img file="JP6974331B2_D0141.tif" /></chemistry> Step 1: Preparation of ethyl 4-chloro-5-methyl-1H-pyrazole-3-carboxylate N-chlorosuccinimide (0.81 g, 5.99 mmol) to ethyl 5-methyl-1H-pyrazole-3-carboxylate (1.01 g) , 6.49 mmol) added to a solution of N, N-dimethylformamide (5 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/5) to give the title compound (0.81 g, 65%). LC-MS (Method C): m / z = 230.1 [M + CH₃CN + H]⁺, 1.240 minutes.</p><p> Step 2: Preparation of 1-benzyl-4-chloro-5-methyl-1H-pyrazole-3-ethyl carboxylate Sodium hydride (108 mg, 4.50 mmol) 4-chloro-5-methyl-1H-pyrazole-3- It was added to a solution of ethyl carboxylate (600 mg, 3.18 mmol) in tetrahydrofuran (3 mL). After stirring at 0 ° C. for 1 hour, benzyl bromide (550 mg, 3.22 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. After quenching with water (3 mL), the reaction mixture was extracted with ethyl acetate (2 x 3 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/1) to give the title compound (500 mg, 56%). LC-MS (Method E): m / z = 278.9 [M + H]⁺, 0.986 minutes.</p><p> Step 3: Preparation of 1-benzyl-4-chloro-5-methyl-1H-pyrazole-3-carboxylic acid Potassium hydroxide (80 mg, 1.43 mmol), 1-benzyl-4-chloro-5-methyl-1H- It was added to a solution of ethyl pyrazole-3-carboxylate (120 mg, 0.43 mmol) in methanol (1.5 mL) and water (0.5 mL). The resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and diluted with water (5 mL). The pH was adjusted to 3 by adding 3N hydrochloric acid. The resulting solid was collected by filtration to give the title compound (110 mg). LC-MS (Method F): m / z = 251.0 [M + H]⁺, 1.323 minutes.</p><p> Step 4: (S) -1-benzyl-4-chloro-5-methyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine- 3-Il) -1 Preparation of H-pyrazole-3-carboxamide The crude material obtained using the amide coupling procedure B is Xbridge Prep C18 5 μm, 19 × 150 mm column; mobile phase: phase A: aqueous ammonium bicarbonate. Purification by reverse phase chromatography using (0.05%); Phase B: acetonitrile; (20% -80% in 12 minutes) gave the title compound.¹H-NMR (400 MHz, DMSO-d₆) δ 8.18 (d, J = 7.9 Hz, 1H), 7.50 (dd, J = 7.6, 1.9 Hz, 1H), 7.43 --7.14 (m, 8H), 5.46 (s, 2H), 4.83 (dt, J = 11.5, 7.8 Hz, 1H), 4.56 (dd, J = 11.5, 9.8 Hz, 1H), 4.42 (dd, J = 9.8, 7.7 Hz, 1H), 3.32 (s, 3H), 2.20 (s, 3H). LC-MS (Method E): m / z = 425.0 [M + H]⁺, 1.488 minutes.</p><p> Example 5: (S) -5-benzyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) thiazole-2 -Carboxamide<chemistry num="108"><img file="JP6974331B2_D0142.tif" /></chemistry> Step 1: Preparation of ethyl 5-methylthiazole-2-carboxylate Add oxalyl chloride (5 mL, 50.0 mmol) to a stirring solution of 5-methylthiazole-2-carboxylic acid (1.43 g, 10.0 mmol) in dichloromethane (10 mL). bottom. The resulting solution was stirred at room temperature for 2 hours and concentrated under vacuum. The residue was quenched by the addition of ethanol (50 mL) and concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (1.6 g, 90%) as a white solid. LC-MS (Method E): m / z = 172 [M + H]⁺, 0.607 minutes.</p><p> Step 2: Preparation of ethyl 5- (bromomethyl) thiazole-2-carboxylate N-bromosuccinimide (900 mg, 5.0 mmol) and carbon tetrachloride (20 mL) of ethyl 5-methylthiazole-2-carboxylate (850 mg, 5.0 mmol) ) Added to the solution. The reaction was initiated with benzoyl peroxide (1 mg), then heated at 75 ° C and stirred for 16 hours. The reaction mixture was cooled to 0 ° C. and the solid was removed by filtration. The filtrate was diluted with water (20 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / hexane, 1/20) to give the title compound (1.0 g, 80%). LC-MS (Method F): m / z = 250, 252 [M + H]⁺, 1.490 minutes.</p><p> Step 3: Preparation of ethyl 5-benzylthiazole-2-carboxylate In a 50 mL round bottom flask, ethyl 5- (bromomethyl) thiazole-2-carboxylate (300 mg, 1.38 mmol), toluene (10 mL), ethanol (5 mL), Phenylboronic acid (100 mg, 2.00 mmol) and sodium carbonate (372 mg, 5.52 mmol) were added. The reaction mixture was placed in a nitrogen atmosphere and tetrakis (triphenylphosphine) palladium (147 mg, 0.13 mmol) was added. The resulting solution was stirred at 85 ° C overnight under a nitrogen atmosphere and then quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / hexane, 1/15) to give the title compound (250 mg, 56%). LC-MS (Method C): m / z = 248 [M + H]⁺, 1.971 minutes.</p><p> Step 4: Preparation of 5-benzylthiazole-2-carboxylic acid A solution of lithium hydroxide (5.4 mg, 2.02 mmol) in water (3 mL) and ethyl 5-benzylthiazole-2-carboxylate (100 mg, 0.405 mmol) in tetrahydrofuran. (9 mL) was added to the solution. The resulting solution was stirred at room temperature for 2 hours and diluted with water (10 mL). The pH value of the solution was adjusted to 3-4 with 1N aqueous hydrogen chloride. The resulting solution was extracted with ethyl acetate (3 x 20 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (80 mg, 76%). LC-MS (Method F): m / z = 220 [M + H]⁺, 0.790 minutes.</p><p> Step 5: (S) -5-benzyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) thiazole-2- Preparation of Carboxamide The crude material obtained using the amide coupling procedure C is Xbridge Prep C18 5 μm, 19 × 150 mm column; mobile phase: phase A: aqueous ammonium bicarbonate (0.05%); phase B: acetonitrile; Purification by reverse phase chromatography using 20% -80%) in 12 minutes gave the title compound.¹H NMR (300 MHz, chloroform-d) δ 8.12 (d, J = 7.3 Hz, 1H), 7.62 (s, 1H), 7.41-7.16 (m, 9H), 5.12-4.95 (m, 1H), 4.81- 4.69 (m, 1H), 4.37-4.21 (m, 1H), 4.19 (s, 2H), 3.46 (s, 3H) .LC-MS (Method D): m / z = 394 [M + H]⁺, 2.232 minutes.</p><p> Example 6: (S) -1-benzyl-4-fluoro-5-methyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine -3-yl) -1H-pyrazole-3-carboxamide<chemistry num="109"><img file="JP6974331B2_D0143.tif" /></chemistry> Step 1: Preparation of ethyl 4-fluoro-5-methyl-1H-pyrazole-3-carboxylate Select Fluol (3.5 g, 9.9 mmol) to ethyl 5-methyl-1H-pyrazole-3-carboxylate (1.01 g, 6.49 mmol) was added to an acetonitrile (10 mL) solution. The resulting solution was stirred in an oil bath at 65 ° C. overnight. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/1) to give the title compound (660 mg, 59%). LC-MS (Method E): m / z = 172.9 [M + H]⁺, 0.607 minutes.</p><p> Step 2: Preparation of 1-benzyl-4-fluoro-5-methyl-1H-pyrazole-3-ethyl carboxylate Sodium hydride (118 mg, 4.92 mmol), 4-fluoro-5-methyl-1H-pyrazole-3 -It was added to a solution of ethyl carboxylate (600 mg, 3.49 mmol) in tetrahydrofuran (3 mL). After stirring at 0 ° C. for 1 hour, benzyl bromide (595 mg, 3.48 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/1) to give the title compound (240 mg, 26%). LC-MS (Method C): m / z = 263.1 [M + H]⁺, 1.490 minutes.</p><p> Step 3: Preparation of 1-Benzyl-4-fluoro-5-methyl-1H-pyrazole-3-carboxylic acid Potassium hydroxide (80 mg, 1.43 mmol), 1-benzyl-4-fluoro-5-methyl-1H- It was added to a solution of ethyl pyrazole-3-carboxylate (113 mg, 0.43 mmol) in methanol (1.5 mL) and water (0.5 mL). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum and the residue was diluted with water (1.5 mL). Hydrochloric acid (3N) was added to adjust the pH to 3. The resulting solid was collected by filtration to give the title compound (110 mg). LC-MS (Method E): m / z = 235.1 [M + H]⁺, 1.257 minutes.</p><p> Step 4: (S) -1-benzyl-4-fluoro-5-methyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine- 3-Il) -1 Preparation of H-pyrazole-3-carboxamide The crude material obtained using the amide coupling procedure B, Xbridge Prep C18 5 μm 19 × 150 mm column; Mobile phase: Phase A: Aqueous ammonium bicarbonate (Aqueous ammonium bicarbonate) Purification by reverse phase chromatography using 0.05%); Phase B: acetonitrile; (20% -80% in 12 minutes) gave the title compound.¹H-NMR (400 MHz, DMSO-d₆) δ 8.10 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 7.6, 2.0 Hz, 1H), 7.43 --7.20 (m, 6H), 7.20 --7.13 (m, 2H), 5.39 (s, 2H), 4.83 (dt, J = 11.4, 7.8 Hz, 1H), 4.56 (dd, J = 11.5, 9.8 Hz, 1H), 4.42 (dd, J = 9.8, 7.7 Hz, 1H), 3.32 (s, 3H) ), 2.16 (d, J = 1.4 Hz, 3H). LC-MS (Method F): m / z = 409.1 [M + H]⁺, 1.412 minutes.</p><p> Example 7: 5-Benzyl-N-((2S) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl ) Isoxazole-3-carboxamide<chemistry num="110"><img file="JP6974331B2_D0144.tif" /></chemistry> Step 1: Preparation of (1-methyl-2-oxo-2,3-dihydro-1H-benzo [b] azepine-3-yl) carbamic acid (Z) -tert-butyl (5-Hydroxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) tert-butyl carbamate (918.0 mg, 3.00 mmol) and triethylamine (5-hydroxy-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) A solution of methanesulfonyl chloride (687 mg, 6.00 mmol) in dichloromethane (2 mL) was added dropwise to a solution of 909.0 mg, 9.00 mmol) in dichloromethane (20 mL) at 0 ° C. After stirring overnight at room temperature, the reaction mixture was quenched by the addition of water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. 1,8-Diazabicyclo [5.4.0] undec-7-ene was added to the crude solid with stirring. The resulting solution was stirred at 90 ° C for 1 hour. Water (20 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (0.3 g, crude). LC-MS (Method C): m / z = 289.0 [M + H]⁺, 1.494 minutes.</p><p> Step 2: N- [7-Methyl-6-oxo-7-azatricyclo [6.4.0.0-[2,4]] dodeca-1 (8), 9,11-triene-5-yl] tert-butyl carbamic acid Preparation Add a solution of 1-methyl-1-nitrosourea (1.073 g, 10.41 mmol) in ether (10 mL) to a solution of potassium hydroxide (1.166 g, 20.78 mmol) in water (1.75 mL) at 0 ° C with stirring. bottom. After stirring at 0 ° C. for 1 hour, the organic phase was separated to obtain a solution of diazomethane (10 mL). A solution of diazomethane (10 mL), (1-methyl-2-oxo-2,3-dihydro-1H-benzo [b] azepine-3-yl) carbamic acid (Z) -tert-butyl (300.0 mg, 1.04 mmol) ) Was added to a solution of tetrahydrofuran (4 mL) at 0 ° C with stirring. A solution of palladium diacetate (23.3 mg, 0.10 mmol) in tetrahydrofuran (1 mL) was added dropwise to the mixture at 0 ° C. with stirring. The resulting mixture was stirred at room temperature overnight. The solid was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/5) to give the title compound (50 mg, 16%). LC-MS (Method N): m / z = 303.1 [M + H]⁺, 1.043 minutes.</p><p> Step 3: Preparation of 5-amino-7-methyl-7-azatricyclo [6.4.0.0- [2,4]] dodeca-1 (8), 9,11-triene-6-one hydrochloride N- [7- Methyl-6-oxo-7-azatricyclo [6.4.0.0-[2,4]] dodeca-1 (8), 9,11-triene-5-yl] tert-butyl carbamic acid (151.0 mg, 0.50 mmol) The solution was treated with 4N hydrogen chloride in dioxane (10 mL) at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to give the title compound (50 mg, crude). LC-MS (Method C): m / z = 203.1 [M + H]⁺, 1.043 minutes.</p><p> Step 4: 5-Benzyl-N-((2S) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) Preparation of Isoxazole-3-Carboxamide The crude product obtained using the amide coupling procedure C is Xbridge Phenyl OBD 5 μm, 19 × 150 mm column; mobile phase, water (10 mmol / L NH).₄HCO₃) And ACN (50.0% ACN ~ 70.0% in 7 minutes) were purified by reverse phase chromatography to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.82 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.39-7.20 (m, 8H), 6.60 (s, 1H), 4.45 (d, J = 7.5 Hz) , 1H), 4.22 (s, 2H), 3.22 (s, 3H), 2.30-2.21 (m, 1H), 1.92-1.84 (m, 1H), 1.08-1.01 (m, 2H) .LC-MS (Method H): m / z = 388.1 [M + H]⁺, 1.700 minutes.</p><p> Chiralpak IB was used with this mixture using a mobile phase of 60/40% v / v n-hexane / (45/45/10 ethanol / methanol / dichloromethane + 0.1% isopropylamine) at a flow rate of 18 mL / min. (25 × 2.0 cm), split by chiral HPLC on a 5 μm column to give two separated enantiomers.</p><p> 1st Elution Enantiomer (6.3 minutes), Enantiomer 1:¹1 H NMR (400 MHz, CDCl₃) δ 8.13 (d, J = 7.0 Hz, 1H), 7.40-7.16 (m, 8H), 7.10 (dd, J = 7.8, 1,4 Hz, 1H), 6.35 (s, 1H), 4.76 (d, J = 7.2 Hz, 1H), 4.12 (s, 2H), 3.35 (s, 3H), 2.17-2.08 (m, 1H), 2.02 (td, J = 8.7, 4.9 Hz, 1H), 1.22 (q, J) = 5.3 Hz, 1H), 1.05 (td, J = 8.5, 6.5 Hz, 1H) .LC-MS (Method A): m / z = 388.3 [M + H]⁺, 1.17 minutes. Chilarpak IB (25 x 0.46 cm) using a mobile phase of 60/40% v / v n-hexane / (45/45/10 ethanol / methanol / dichloromethane + 0.1% isopropylamine) at a flow rate of 1 mL / min ), Ee&gt; 99.9% obtained in a 5 μm column.</p><p> Second Elution Enantiomer (7.9 minutes), Enantiomer 2:¹1 H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 7.3 Hz, 1H), 7.41-7.17 (m, 8H), 7.12 (dd, J = 7.7, 1.6 Hz, 1H), 6.37 (s, 1H), 4.78 (d, J = 7.0 Hz, 1H), 4.14 (s, 2H), 3.36 (s, 3H), 2.14 (td, J = 9.2, 5.4 Hz, 1H), 2.03 (td, J = 8.7, 5.0 Hz, 1H), 1.23 ( q, J = 5.3 Hz, 1H), 1.07 (td, J = 8.5, 6.3 Hz, 1H). LC-MS (Method A): m / z = 388.3 [M + H]⁺, 1.17 minutes. Chilarpak IB (25 x 0.46 cm) using a mobile phase of 60/40% v / v n-hexane / (45/45/10 ethanol / methanol / dichloromethane + 0.1% isopropylamine) at a flow rate of 1 mL / min ), Ee&gt; 99.9% obtained in a 5 μm column.</p><p> Example 8: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (1-Phenyl) Cyclopropyl) Isoxazole-3-Carboxamide<chemistry num="111"><img file="JP6974331B2_D0145.tif" /></chemistry> Step 1: Preparation of Methyl 5- (1-phenylcyclopropyl) -1,2-oxazol-3-carboxylate 1-Methyl-1-nitrosourea (449.8 mg, 4.36 mmol) in ether (10 mL) solution in water. It was added dropwise to a solution of potassium oxide (359.1 mg, 6.40 mmol) in water (0.54 mL) at 0 ° C with stirring. After stirring at 0 ° C. for 0.5 hours, the organic phase was separated to obtain a solution of diazomethane (10 mL). A solution of diazomethane (10 mL) in a solution of ethyl 5- (1-phenylethenyl) -1,2-oxazol-3-carboxylate (50.0 mg, 0.21 mmol) in tetrahydrofuran (3 mL) at 0 ° C. Addition was subsequently made, followed by a solution of palladium diacetate (4.7 mg, 0.02 mmol) in tetrahydrofuran (1 mL) at 0 ° C. with stirring. The resulting solution was stirred at room temperature overnight. The solid was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/5) to give the title compound (30 mg, 57%) as a yellow solid. LC-MS (Method C): m / z = 244.0 [M + H]⁺, 1.519 minutes.</p><p> Step 2: Preparation of 5- (1-phenylcyclopropyl) -1,2-oxazol-3-carboxylic acid Methyl 5- (1-phenylcyclopropyl) -1,2-oxazol-3-carboxylate (25.0 mg,) A solution of 0.10 mmol) and lithium hydroxide (4.8 mg, 0.20 mmol) in methanol / water = 3/1 (2 mL) was stirred at room temperature for 2 hours. The pH value of the solution was adjusted to 6-7 with 1N hydrochloric acid. The resulting solution was extracted with ethyl acetate (3 x 10 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (20 mg, crude). LC-MS (Method G): m / z = 230 [M + H]⁺, 0.700 minutes.</p><p> Step 3: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (1-Phenylcyclo) Preparation of propyl) isooxazole-3-carboxamide The crude product obtained using the amide coupling procedure B is Xbridge Phenyl OBD 5 μm, 19 × 150 mm column; mobile phase, water (10 mmol / L NH).₄HCO₃) And ACN (50.0% ACN ~ 70.0% in 7 minutes) were purified by reverse phase chromatography to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.82 (d, J = 8.1 Hz, 1H), 7.52 --7.84 (m, 1H), 7.38 --7.25 (m, 7H), 7.24 --7.20 (m, 1H), 6.36 (s, 1H), 4.87- 4.77 (m, 1H), 4.55 (dd, J = 9.9, 11.7 Hz, 1H), 4.38 (dd, J = 8.1, 9.9 Hz, 1H), 3.30 (s, 3H), 1.57 --1.52 (m, 2H) , 1.45 --1.41 (m, 2H) .LC-MS (Method H): m / z = 404.2 [M + H]⁺, 1.766 minutes.</p><p> Example 9: (S) -5-benzyl-N- (1-methyl-2-oxo-1,2,3,4-tetrahydrospiro [benzo [b] azepine-5,1'-cyclopropane] -3 -Il) Isoxazole-3-carboxamide<chemistry num="112"><img file="JP6974331B2_D0146.tif" /></chemistry> Step 1: N-[(3S) -1-methyl-2-oxo-1,2,3,4-tetrahydrospiro [1-benzazepine-5,1-cyclopropane] -3-yl] tert-butyl carbamic acid Preparation A solution of 1-methyl-1-nitrosourea (255.8 mg, 2.48 mmol) in ether (10 mL) was added dropwise to a solution of potassium hydroxide (278 mg, 4.96 mmol) in water (0.4 mL) at 0 ° C with stirring. .. After stirring at 0 ° C. for 0.5 hours, the organic phase was separated to obtain a solution of diazomethane (10 mL). N-[(3R) -1-methyl-2-oxo-2,3-dihydro-1H-1-benzazepine-3-yl] tert-butyl carbamate (75.0 mg, 0.25 mmol) in tetrahydrofuran (1.5 mL) A solution of diazomethane (10 mL) was added dropwise to the mixture, followed by a solution of palladium diacetate (5.5 mg, 0.02 mmol) in tetrahydrofuran (0.5 mL) at 0 ° C. with stirring. The resulting solution was stirred at room temperature overnight. The solid was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/5) to give the title compound (55 mg, 70%). LC-MS (Method C): m / z = 317.2 [M + H]⁺, 1.531 minutes.</p><p> Step 2: Preparation of (3S) -3-amino-1-methyl-1,2,3,4-tetrahydrospiro [1-benzazepine-5,1-cyclopropane] -2-one hydrochloride N-[(3S) ) -1-Methyl-2-oxo-1,2,3,4-tetrahydrospiro [1-benzazepine-5,1-cyclopropane] -3-yl] tert-butyl carbamic acid (40.0 mg, 0.13 mmol) , Treated with 4N hydrogen chloride in dioxane (6 mL) at room temperature for 1 hour. The resulting mixture was concentrated under vacuum to give the title compound (25.2 mg) as a yellow solid. LC-MS (Method K): m / z = 217.2 [M + H]⁺, 0.635 minutes.</p><p> Step 3: (S) -5-benzyl-N- (1-methyl-2-oxo-1,2,3,4-tetrahydrospiro [benzo [b] azepine-5,1'-cyclopropane] -3- Il) Preparation of isooxazole-3-carboxamide The crude product obtained using the amide coupling procedure C is Xbridge Phenyl OBD 5 μm, 19 × 150 mm column; mobile phase, water (10 mmol / L NH).₄HCO₃) And ACN (50% to 70% in 7 minutes) were purified by reverse phase chromatography to give the title compound (17.8 mg, 44%) as a white solid. Chilarpak AS-H (25 x 2.0 cm) using a mobile phase of 60/40% v / v n-hexane / (1/1 2-propanol / MeOH + 0.1% isopropylamine) for this compound. , Further purified by chiral HPLC on a 5 μm column to give the title compound.¹1 H NMR (400 MHz, CDCl₃) δ 7.78 (d, J = 7.0 Hz, 1H), 7.39-7.19 (m, 9H), 6.31 (s, 1H), 4.69 (td, J = 7.6, 10.9 Hz, 1H), 4.11 (s, 2H) , 3.43 (s, 3H), 3.13 (dd, J = 12.3, 8.3 Hz, 1H), 1.33 (dd, J = 12.5, 11.0 Hz, 1H), 1.16-1.08 (m, 1H), 0.88 (ddd, J) = 9.3, 5.5, 4.3 Hz, 1H), 0.71 (td, J = 5.5, 9.3 Hz, 1H), 0.51-0.42 (m, 1H). LC-MS (Method A): m / z = 402.2 [M + H]⁺, 1.21 minutes. Using a mobile phase of 60/40% v / v n-hexane / (1/1 2-propanol / MeOH + 0.1% isopropylamine) in Chilarpak AS-H (25 × 0.46 cm), in a 5 μm column. Obtained ee&gt; 99.5%.</p><p> Example 10: 5-Benzyl-N- (5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) -4H- 1,2,4-Triazole-3-carboxamide<chemistry num="113"><img file="JP6974331B2_D0147.tif" /></chemistry> Step 1: Preparation of (5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3-yl) tert-butyl carbamic acid (1-methyl- 2,5-Dioxo-2,3,4,5-Tetrahydro-1H-benzo [b] azepine-3-yl) tert-butyl carbamic acid (200 mg, 0.658 mmol) bis (2-methoxyethyl) aminosulfatrifluo The lid (6 mL) solution was heated to 65 ° C and stirred overnight. The reaction mixture was cooled to ambient temperature, quenched with water (30 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with saturated aqueous sodium carbonate and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / hexane, 1/20) to give the title compound (60 mg, 30%). LC-MS (Method E): m / z = 327 [M + H]⁺, 1.035 minutes.</p><p> Step 2: Preparation of 3-amino-5,5-difluoro-1-methyl-4,5-dihydro-1H-benzo [b] azepine-2 (3H) -one (5,5-difluoro-1-methyl-) 2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) tert-butyl carbamic acid (40 mg, 0.184 mmol) (4N) 1,4-dioxane of hydrogen chloride (4N) 30 mL) Added to the solution. The resulting solution was stirred at ambient temperature for 2 hours and concentrated under vacuum to give the title compound (50 mg, crude) as a yellow solid. LC-MS (Method N): m / z = 227 [M + H]⁺, 0.995 minutes.</p><p> Step 3: 5-benzyl-N- (5,5-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) -4H-1 Preparation of 2,4-triazole-3-carboxamide The crude product obtained using the amide coupling procedure C is Xbridge Prep C18 5 μm, 19 × 150 mm column; mobile phase: phase A: aqueous ammonium bicarbonate ( Purification by reverse phase chromatography using 0.05%); Phase B: acetonitrile; (20% -80% in 12 minutes); gave the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 14.25 (s, 1H), 8.59 (s, 1H), 7.63 (m 3H), 7.44 (t, J = 7.5 Hz, 1H), 7.35 --7.18 (m, 5H), 4.52 (dt, J = 11.8) , 7.8 Hz, 1H), 4.10 (s, 2H), 3.26 (s, 3H), 3.15 --2.81 (m, 2H) .LC-MS (Method L): m / z = 412.1 [M + H]⁺, 1.309 minutes.</p><p> Examples 11 and 12: 5-benzyl-N-((3S, 5R) -5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3 -Il) -4H-1,2,4-triazole-3-carboxamide and 5-benzyl-N-((3R, 5S) -5-fluoro-1-methyl-2-oxo-2,3,4,5 -Tetrahydro-1H-benzo [b] azepine-3-yl) -4H-1,2,4-triazole-3-carboxamide (Example 11) and 5-benzyl-N-((3S, 5S) -5- Fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) -4H-1,2,4-triazole-3-carboxamide and 5-benzyl -N-((3R, 5R) -5-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) -4H-1,2 , 4-Triazole-3-Carboxamide (Example 12)<chemistry num="114"><img file="JP6974331B2_D0148.tif" /></chemistry> The crude product obtained using amide coupling procedure A, Xbridge Phenyl OBD 5 μm, 19 × 150 mm column; mobile phase, water (10 mmol / L NH).₄HCO₃) And ACN (25.0% -55.0% in 7 minutes) were purified by reverse phase chromatography to give the title compound:</p><p> Example 11, first elution isomer:¹1 H NMR (400 MHz, DMSO-d₆) δ 14.41 (s, 1H), 8.41 (s, 1H), 7.65-7.49 (m, 2H), 7.45 (dt, J = 7.7, 1.7 Hz, 1H), 7.40 --7.20 (m, 6H), 5.76 ( dd, J = 47.0, 4.8 Hz, 1H), 4.47 (dt, J = 11.4, 7.5 Hz, 1H), 4.12 (s, 2H), 3.27 (s, 3H), 2.94 --2.56 (m, 2H) .LC -MS (Method F): m / z = 394.1 [M + H]⁺, 1.085 minutes.</p><p> Example 12, second elution isomer:¹1 H NMR (400 MHz, DMSO-d₆) δ 14.37 (s, 1H), 8.41 (s, 1H), 7.58 --7.38 (m, 4H), 7.38 --7.20 (m, 5H), 5.92 (ddd, J = 46.6, 10.5, 8.1 Hz, 1H), 4.30 (dt, J = 11.4, 7.9 Hz, 1H), 4.12 (s, 2H), 3.31 (s, 3H), 2.96-2.78 (m, 1H), 2.41 --2.30 (m, 1H) .LC-MS ( Method F): m / z = 394.1 [M + H]⁺, 1.156 minutes.</p><p> Example 11: Chiral Separation This mixture was subjected to Whelk O-1 (R) using a mobile phase of 30 / 70% v / v n-hexane / (ethanol + 0.1% isopropylamine) at a flow rate of 18 mL / min. , R) (25 × 2.0 cm), divided by chiral HPLC on a 10 μm column to give two separated enantiomers.</p><p> 1st Elution Enantiomer (6.8 minutes), Enantiomer 1:¹1 H NMR (400 MHz, CDCl₃) δ 8.27 (d, J = 6.8 Hz, 1H), 7.35 (m, 9H), 5.51 (m, 1H), 4.74 (dt, J = 11.0, 7.1 Hz, 1H), 4.15 (s, 2H), 3.41 (s, 3H), 3.07 (m, 1H), 2.44 (m, 1H) .LC-MS (Method A): m / z = 394.3 [M + H]⁺, 0.87 minutes. Whelk O-1 (R, R) (25 × 0.46 cm), using a mobile phase of 30/70% v / v n-hexane / (ethanol + 0.1% isopropylamine) at a flow rate of 1 mL / min, Ee&gt; 99.9% obtained in a 5 μm column.</p><p> Second Elution Enantiomer (8.9 minutes), Enantiomer 2:¹1 H NMR (400 MHz, CDCl₃) δ 8.27 (d, J = 6.8 Hz, 1H), 7.35 (m, 9H), 5.51 (m, 1H), 4.74 (dt, J = 11.0, 7.1 Hz, 1H), 4.15 (s, 2H), 3.41 (s, 3H), 3.07 (m, 1H), 2.44 (m, 1H) .LC-MS (Method A): m / z = 394.3 [M + H]⁺, 0.86 minutes. Whelk O-1 (R, R) (25 × 0.46 cm), using a mobile phase of 30/70% v / v n-hexane / (ethanol + 0.1% isopropylamine) at a flow rate of 1 mL / min, Ee&gt; 99.9% obtained in a 5 μm column.</p><p> Example 12: Chiral Separation This mixture was subjected to a mobile phase of 30/70% v / v n-hexane / (1/1 ethanol / methanol + 0.1% isopropylamine) at a flow rate of 18 mL / min. Chiralcel OJ-H (25 × 2.0 cm) was split by chiral HPLC on a 5 μm column to give two separated enantiomers.</p><p> 1st Elution Enantiomer (4.8 minutes), Enantiomer 1:¹1 H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 6.1 Hz, 1H), 7.62-7.14 (m, 9H), 5.87-5.64 (m, 1H), 4.67-4.54 (m, 1H), 4.17 (s, 2H), 3.44 ( s, 3H), 3.03-2.85 (m, 1H), 2.66-2.53 (m, 1H) .LC-MS (Method U): m / z = 394.2 [M + H]⁺, 0.75 minutes. Chiralcel OJ-H (25 x 0.46 cm) using a mobile phase of 50/50% v / v n-hexane / (1/1 ethanol / methanol + 0.1% isopropylamine) at a flow rate of 1 mL / min. , Ee&gt; 99.9% determined on a 5 μm column.</p><p> 2nd Elution Enantiomer (7.0 minutes), Enantiomer 2:¹1 H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 6.3 Hz, 1H), 7.62-7.15 (m, 10H), 5.86-5.63 (m, 1H), 4.66-4.53 (m, 1H), 4.12 (s, 2H), 3.42 ( s, 3H), 3.00-2.82 (m, 1H), 2.64-2.52 (m, 1H) .LC-MS (Method U): m / z = 394.2 [M + H]⁺, 0.74 minutes. Chiralcel OJ-H (25 x 0.46 cm) using a mobile phase of 50/50% v / v n-hexane / (1/1 ethanol / methanol + 0.1% isopropylamine) at a flow rate of 1 mL / min. , Ee&gt; 99.9% determined on a 5 μm column.</p><p> Example 13: (R) -N-((S) -5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) -4-yl) Phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazole-2-carboxamide<chemistry num="115"><img file="JP6974331B2_D0149.tif" /></chemistry> Step 1: Preparation of (2S, 3R) -1-nitroso-3-phenylpyrrolidin-2-carboxylic acid (2S, 3R) -3-phenylpyrrolidin-2-carboxylic acid (1.01 g, 5.23 mmol) in sodium nitrite It was added to a solution of (800 mg, 11.59 mmol) in water (5 mL). Concentrated hydrochloric acid (5 mL) was added at 0 ° C. The reaction mixture was stirred at room temperature overnight, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (700 mg, crude). LC-MS (Method I): m / z = 220.95 [M + H]⁺, 0.741 minutes.</p><p> Step 2: Preparation of (R) -3-oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo [1,2c] [1,2,3] oxadiazole-7-ium-3a-id Trifluoroacetate anhydride (1.01 g, 4.76 mmol) in an ether (7 mL) solution of (2S, 3R) -1-nitroso-3-phenylpyrrolidine-2-carboxylic acid (700 mg, 3.18 mmol) at 0 ° C. Dropped. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and diluted with water (50 mL). The pH value of the solution was adjusted to 8 with potassium carbonate (0.5 M). The resulting solution was extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1: 1) to give the title compound (380 mg, 59%). LC-MS (Method I): m / z = 202.9 [M + H]⁺, 0.725 minutes.</p><p> Step 3: Preparation of (4R) -4-phenyl-4H, 5H, 6H-pyrrolo [1,2-b] pyrazole-3-ethyl carboxylate, purged and maintained in an inert atmosphere of nitrogen, (R)- 3-Oxo-4-phenyl-3,4,5,6-tetrahydropyrrolo [1,2-c] [1,2,3] oxadiazole-7-ium-3a-id (380 mg, 1.88 mmol) Ethyl 2-propate (240 mg, 2.45 mmol) was added dropwise to the solution of o-xylene (6 mL). The resulting solution was stirred in an oil bath at 125 ° C. overnight. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1: 1) to give the title compound (100 mg, 21%). LC-MS (Method J): m / z = 257.1 [M + H]⁺, 1.376 minutes.</p><p> Step 4: Preparation of (4R) -4-phenyl-4H, 5H, 6H-pyrrolo [1,2-b] pyrazole-2-carboxylic acid (4R) -4-phenyl-4H, 5H, 6H-pyrrolo [1 , 2-b] Potassium hydroxide (67 mg, 1.19 mmol) was added to a solution of ethyl pyrazole-2-carboxylate (100 mg, 0.39 mmol) in methanol (2.1 mL) and water (0.7 mL). The resulting solution was stirred at room temperature overnight, concentrated under vacuum and the resulting residue was diluted with water. The pH value of the solution was adjusted to 3 with 3N hydrochloric acid. The resulting solid was collected by filtration to give the title compound (80 mg, 90%). LC-MS (Method I): m / z = 228.9 [M + H]⁺, 0.804 minutes.</p><p> Step 5: (R) -N-((S) -5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -4-Phenyl Preparation of -5,6-dihydro-4H-pyrrolo [1,2-b] pyrazole-2-carboxamide The crude product obtained using amide coupling procedure B was subjected to Xbridge Phenyl OBD 5 μm, 19 × 150 mm column; Mobile phase, water (10 mmol / L NH)₄HCO₃) And ACN (25.0% to 55.0% in 7 minutes) were purified by reverse phase chromatography to give the title compound.¹H-NMR (400 MHz, DMSO-d₆) δ 8.12 (d, J = 8.1 Hz, 1H), 7.51 (dd, J = 7.5, 1.9 Hz, 1H), 7.39 --7.20 (m, 8H), 6.32 (d, J = 0.9 Hz, 1H), 4.84 (dt, J = 11.5, 7.9 Hz, 1H), 4.61 --4.48 (m, 2H), 4.45 --4.31 (m, 2H), 4.22 (dt, J = 11.0, 7.7 Hz, 1H), 3.32 (s, 3H) ), 3.09 (dtd, J = 12.7, 8.3, 4.2 Hz, 1H), 2.51 --2.41 (m, 1H) .LC-MS (Method J): m / z = 403.2 [M + H]⁺, 1.499 minutes.</p><p> Example 14: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (2,2) , 2-Trifluoroethyl) Isoxazole-3-Carboxamide<chemistry num="116"><img file="JP6974331B2_D0150.tif" /></chemistry> Step 1: Preparation of Methyl 5- (bromomethyl) isooxazole-3-carboxylate Over solution of methyl 5-methylisoxazole-3-carboxylate (4.65 g, 30 mmol) and N-bromosuccinimide in carbon tetrachloride (250 mL). Benzoyl oxide (2 mg, 0.1 mol%) was added. The resulting mixture was refluxed at 80 ° C for 24 hours. The solid was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / hexane, 1/5) to give the title compound (1.6 g, 23%) as a white solid. LC-MS (Method C): m / z = 221.7 [M + H]⁺, 0.746 minutes.</p><p> Step 2: Preparation of 5- (2,2,2-trifluoroethyl) isooxazole-3-carboxylate methyl 5- (bromomethyl) isooxazole-3-carboxylate methyl (350 mg, 1.59 mmol) and iodide first Methyl 2,2-difluoro-2- (fluorosulfonyl) acetate (1.44 g, 7.50 mmol) was added to the mixture of copper (570 mg, 3.00 mmol) in N, N-dimethylformamide (10 mL). The resulting mixture was heated at 100 ° C. for 20 hours. After cooling to room temperature, the reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / hexane, 1/5) to give the title compound (125 mg, 37%) as a yellow solid. LC-MS (Method C): m / z = 209.9 [M + H]⁺, 0.788 minutes.</p><p> Step 3: Preparation of 5- (2,2,2-trifluoroethyl) isoxazole-3-carboxylic acid Methyl 5- (2,2,2-trifluoroethyl) isoxazole-3-carboxylate (90 mg, 0.43) mmol) 4: 1 THF: H₂Lithium hydroxide (72 mg, 3 mmol) was added to the O (2.5 mL) solution. The resulting solution was stirred at room temperature for 40 minutes. After completion of the reaction, the solvent was evaporated under reduced pressure and water (25 mL) was added to the resulting residue. The solution was washed with ethyl acetate (3 x 50 mL). The aqueous layer was acidified to pH 3-4 with 1N hydrochloric acid and extracted with ethyl acetate (3 × 20 mL). The combined organic phase from this extraction is dried over sodium sulphate, filtered and concentrated under reduced pressure to give the title compound (43 mg, crude), which can be used directly in the next step without further purification. bottom. LC-MS (Method D): m / z = 196.9 [M + H]⁺, 0.290 minutes.</p><p> Step 4: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (2,2, Preparation of 2-Trifluoroethyl) Isoxazole-3-Carboxamide The crude product obtained using amide coupling procedure C was purified by crystallization (ethanol / n-hexane) to give the title compound.¹1 H NMR (300 MHz, chloroform-d) δ 7.80 (d, J = 7.0 Hz, 1H), 7.26 --7.19 (m, 4H), 6.71 (s, 1H), 5.04 (dt, J = 11.1, 7.1 Hz, 1H), 4.76 (dd, J = 9.8, 7.4 Hz, 1H), 4.28 (dd, J = 11.1, 9.7 Hz, 1H), 3.69 (q, J = 9.7 Hz, 2H), 3.46 (s, 3H). LC-MS (Method E): m / z = 370.2 [M + H]⁺, 2.462 minutes.</p><p> Example 15: 5-Benzyl-N- (6,7,8,9-tetrahydro-5H-benzo [7] annulene-7-yl) isoxazole-3-carboxamide<chemistry num="117"><img file="JP6974331B2_D0151.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: column, Xbridge Phenyl OBD column, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol / L NH).₄HCO₃) And ACN (50.0% ACN ~ 70.0% over 7 minutes); purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.63 (d, J = 8.4 Hz, 1H), 7.25-7.14 (m, 5H), 7.15-7.07 (m, 4H), 6.52 (s, 1H), 4.19 (s, 2H), 4.17-4.04 ( m, 1H), 2.89-2.69 (m, 4H), 2.02-1.97 (m, 2H), 1.43-1.23 (m, 2H) .LC-MS (Method F): m / z = 347.1 [M + H]⁺, 1.652 minutes.</p><p> Example 16: (S) -1-benzyl-3-methyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl ) -1H-Pyrazole-5-Carboxamide<chemistry num="118"><img file="JP6974331B2_D0152.tif" /></chemistry> Step 1: Preparation of 1-benzyl-3-methyl-1H-pyrazole-5-ethyl carboxylate Ethyl 2,4-dioxopentate (0.5 g, 3.20 mmol) and benzylhydrazine hydrochloride (0.75 g, 3.84 mmol) N, N-diisopropylethylamine (1.2 g, 9.60 mmol) was added to the ethanol (10 mL) solution of. After stirring overnight at room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/1) to give the title compound (0.5 g, 65%) as a yellow oil. LC-MS (Method S): m / z = 245.2 [M + H]⁺, 1.070 minutes.</p><p> Step 2: Preparation of 1-benzyl-3-methyl-1H-pyrazole-5-carboxylic acid A solution of sodium hydroxide (0.25 g, 6.02 mmol) in water (1 mL), 1-benzyl-3-methyl-1H-pyrazole -Ethyl carboxylate (0.5 g, 2.01 mmol) was added to an ethanol (2 mL) stirring solution. The resulting mixture was stirred at 80 ° C overnight. After cooling to room temperature, the reaction mixture was adjusted to pH = 3-4 with aqueous hydrochloric acid (1N, 20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.4 g, 90%) as a white solid, which is further purified. Not used directly in the next step. LC-MS (Method C): m / z = 217.2 [M + H]⁺, 1.219 minutes.</p><p> Step 3: (S) -1-benzyl-3-methyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) Preparation of -1H-pyrazole-5-carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: column, Xbridge Phenyl OBD column, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol). / L NH₄HCO₃) And ACN (50.0% ACN ~ 70.0% over 7 minutes); purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.68 (d, J = 8.4 Hz, 1H), 7.53-7.47 (m, 1H), 7.35-7.19 (m, 6H), 7.11-7.07 (m, 2H), 6.82 (s, 1H), 5.64- 5.51 (m, 2H), 4.88-4.81 (m, 1H), 4.55-4.49 (m, 1H), 4.40-4.35 (m, 1H), 3.30 (s, 3H), 2.20 (s, 3H) .LC- MS (method L): m / z = 391.1 [M + H]⁺, 1.437 minutes.</p><p> Example 17: (R) -N-((S) -5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) -4-yl Phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazole-3-carboxamide<chemistry num="119"><img file="JP6974331B2_D0153.tif" /></chemistry> Step 1: Preparation of (4R) -4-phenyl-4H, 5H, 6H-pyrrolo [1,2-b] ethyl pyrazole-3-carboxylate under a nitrogen atmosphere, (R) -3-oxo-4-phenyl- 3,4,5,6-Tetrahydropyrolo [1,2-c] [1,2,3] Oxadiazole-7-ium-3a-id (380 mg, 1.88 mmol) in o-xylene (6 mL) stirring solution 2-Ethyl 2-propate (240 mg, 2.45 mmol) was added. The resulting mixture was heated to 125 ° C. and stirred in an oil bath overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the obtained residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/1), and the title compound (120 mg, 25%) was used as a pale yellow oil. Obtained. LC-MS (Method J): m / z = 257.0 [M + H]⁺, 1.323 minutes.</p><p> Step 2: Preparation of (4R) -4-phenyl-4H, 5H, 6H-pyrrolo [1,2-b] pyrazole-3-carboxylic acid with a solution of potassium hydroxide (67 mg, 1.19 mmol) in water (7 mL), It was added to a solution of (4R) -4-phenyl-4H, 5H, 6H-pyrrolo [1,2-b] ethyl pyrazole-3-carboxylate (100 mg, 0.39 mmol) in methanol (2.1 mL). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure and diluted with water. The pH value of the solution was adjusted to 3 with hydrochloric acid (3N, 20 mL). The precipitate was collected by filtration to give the title compound (50 mg, 47%) as a yellow solid. LC-MS (Method I): m / z = 228.9 [M + H]⁺, 0.738 minutes.</p><p> Step 3: (R) -N-((S) -5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -4-Phenyl Preparation of -5,6-dihydro-4H-pyrrolo [1,2-b] pyrazole-3-carboxamide The crude product obtained using amide coupling procedure B was subjected to the following conditions: column, Xbridge Phenyl OBD. Column, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol / L NH)₄HCO₃) And ACN (25.0% ACN ~ 55.0% over 7 minutes); purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ8.02 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 7.6, 2.0 Hz, 1H), 7.34-7.14 (m, 6H), 7.10-7.02 (m) , 2H), 4.77-4.58 (m, 2H), 4.35-4.23 (m, 1H), 4.22-4.03 (m, 3H), 3.26 (s, 3H), 3.19-3.05 (m, 1H), 2.39 (dq) , J = 8.8, 4.3 Hz, 1H) .LC-MS (Method O): m / z = 403.0 [M + H]⁺, 1.334 minutes.</p><p> Example 18: (S) -N-benzyl-2-((5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) amino) Acetamide<chemistry num="120"><img file="JP6974331B2_D0154.tif" /></chemistry> (3S) -3-amino-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one hydrochloride (40 mg, 0.175 mmol, ee = 90%), N- Benzyl-2-chloroacetamide (18 mg, 0.097 mmol), K₂CO₃The mixture in DMF (3 mL) of (27 mg, 0.195 mmol) and KI (32 mg, 0.195 mmol) was stirred at 30 ° C. for 16 hours. Dilute the mixture with EtOAc and saturate NH₄Washed twice with Cl solution. The aqueous moiety was extracted with EtOAc. The combined organic part is Na₂SO₄It was dried on top, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane- EtOAc, 80: 20-0: 100) to give the title compound.¹1 H NMR (400 MHz, CDCl₃) δ 7.46-7.08 (m, 10H), 4.51-4.37 (m, 2H), 4.33 (dd, J = 10.2, 7.4 Hz, 1H), 4.12 (t, J = 10.8 Hz, 1H), 3.61-3.43 ( m, 3H), 3.41 (s, 3H), 3.06-2.97 (m, 1H) .LC-MS (Method A): m / z = 340.0 [M + H]⁺, 0.70 minutes. Chiralcel OD-H (25 × 0.46 cm), ee = 88% determined on a 5 μm column using a mobile phase of 35/65% v / v n-hexane / (ethanol + 0.1% isopropylamine).</p><p> Example 19: (S) -5-Benzyl-N- (5-Ethyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) Isoxazole- 3-Carboxamide<chemistry num="121"><img file="JP6974331B2_D0155.tif" /></chemistry> Step 1: Preparation of N-((3S) -5-ethyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-3-yl) tert-butyl carbamic acid hydrogenation Sodium (8.64 mg, 0.22 mmol), N-((3S) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-3-yl) carbamic acid tert-butyl ((3S) -4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-3-yl) 50 mg (0.18 mmol) was added to a stirred solution of N, N-dimethylformamide (5 mL). The resulting mixture was stirred at room temperature for 1 hour. Ethyl iodide (33.7 mg, 0.21 mmol) was added dropwise. After stirring at room temperature for 3 hours, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (40 mg, 73%) as a yellow solid. LC-MS (Method S): m / z = 307.2 [M + H]⁺, 1.021 minutes.</p><p> Step 2: Preparation of (3S) -3-amino-5-ethyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one hydrochloride N-((3S) -5- Ethyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzooxazepine-3-yl) tert-butylcarbamate (40 mg, 0.13 mmol) in a dioxane solution of hydrogen chloride (4M, 10 mL) was added. The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure to give the title compound (30 mg) as a white solid, which was used directly in the next step without further purification. LC-MS (Method D): m / z = 207.1 [M + H]⁺, 0.930 minutes.</p><p> Step 3: (S) -5-Benzyl-N- (5-Ethyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) Isoxazole-3 -Preparation of carboxamide The crude product obtained using amide coupling procedure B was subjected to the following conditions: column, Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN ( Purification by preparative HPLC using 45.0% ACN ~ 70.0%); detector, UV254 &amp; 220 nm; over 7 minutes gave the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.82 (d, J = 7.8 Hz, 1H), 7.54-7.51 (m, 1H), 7.38-7.21 (m, 8H), 6.54 (s, 1H), 4.84-4.75 (m, 1H), 4.56 ( t, J = 11.4 Hz, 1H), 4.39-4.33 (m, 1H), 4.21 (s, 2H), 4.10-4.03 (m, 1H), 3.67-3.60 (m, 1H), 1.02 (t, J = 7.2 Hz, 3H) .LC-MS (Method D): m / z = 392.2 [M + H]⁺, 2.181 minutes.</p><p> Example 20: 5-Benzyl-N- (1-methyl-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) -4H-1,2,4-triazole-3-yl Carboxamide<chemistry num="122"><img file="JP6974331B2_D0156.tif" /></chemistry> Boranetetrahydrofuran complex (1M solution in THF, 570 μL, 0.570 mmol) was precooled to 0 ° C to 3-amino-1-methyl-2,3,4,5-tetrahydro-1H-1-benzazepine-2-. It was added dropwise to a solution of on (50 mg, 0.26 mmol) in THF (1 mL). The reaction was gradually warmed to room temperature, stirred for 18 hours and then quenched with 1M HCl solution. The resulting mixture was stirred at room temperature for 3 hours. Volatiles were removed under reduced pressure. Crude product in SCX cartridge (MeOH, then in MeOH 7M NH₃) Was purified by ion exchange chromatography to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 7.14-7.02 (m, 2H), 6.93-6.85 (m, 1H), 6.84-6.74 (m, 1H), 3.10-2.85 (m, 2H), 2.84-2.68 (m, 4H), 2.66-2.54 (m, 1H), 2.48-2.36 (m, 1H), 1.89-1.77 (m, 1H), 1.75-1.55 (m, 2H), 1.33-1.06 (m, 1H) .LC-MS (Method A): m / z = 177.2 [M + H]⁺, 0.40 minutes.</p><p> The crude product obtained using amide coupling procedure C is subjected to column chromatography (CH).₂Cl₂-MeOH, 95: 5-80: 20), then reverse phase chromatography (water-CH)₃Purification by CN, 100: 0 ~ 50: 50) gave the title compound as a mixture of enantiomers.¹1 H NMR (400 MHz, DMSO-d₆) δ 14.61-14.37 (m, 1H), 8.37-8.25 (m, 1H), 7.35-7.10 (m, 7H), 6.99-6.93 (m, 1H), 6.85 (td, J = 7.3, 1.1 Hz, 1H) ), 4.19-4.11 (m, 1H), 4.08 (s, 2H), 3.05-2.98 (m, 1H), 2.84 (s, 3H), 2.81-2.73 (m, 2H), 2.65-2.58 (m, 1H) ), 1.89-1.78 (m, 1H), 1.68-1.55 (m, 1H) .LC-MS (Method A): m / z = 362.4 [M + H]⁺, 1.02 minutes.</p><p> Example 21: 5-Benzyl-N-((4S, 9aR) -5-oxohexahydro-1H, 3H-pyrrolo [2,1-c] [1,4] oxazepine-4-yl) isoxazole-3 -Carboxamide<chemistry num="123"><img file="JP6974331B2_D0157.tif" /></chemistry> Example 22: 5-Benzyl-N-((4S, 9aS) -5-oxohexahydro-1H, 3H-pyrrolo [2,1-c] [1,4] oxazepine-4-yl) isoxazole-3 -Carboxamide<chemistry num="124"><img file="JP6974331B2_D0158.tif" /></chemistry> Example 23: (S) -5-benzyl-N- (1-methyl-2-oxoazepan-3-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="125"><img file="JP6974331B2_D0159.tif" /></chemistry> The crude product obtained using amide coupling procedure C was subjected to column chromatography (CH).₂Cl₂/ MeOH = 9: 1), then by column chromatography on KP-NH modified silica gel (EtOAc / MeOH = 9: 1), then by reverse phase chromatography (water-CH)₃CN, 70:30) Purification to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 14.44 (s, 1H), 8.34 (d, J = 6.2 Hz, 1H), 7.37-7.20 (m, 5H), 4.75-4.65 (m, 1H), 4.11 (s, 2H), 3.68 (dd, J = 15.4, 11.4 Hz, 1H), 3.23 (dd, J = 15.3, 5.2 Hz, 1H), 2.94 (s, 3H), 2.01-1.93 (m, 1H), 1.92-1.82 (m, 1H), 1.81 -1.67 (m, 2H), 1.45-1.28 (m, 2H) .LC-MS (Method A): m / z = 328.3 [M + H]⁺, 0.74 minutes.</p><p> Example 24: (S) -5-cyano-1-methyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl ) -1H-Pyrrole-2-carboxamide<chemistry num="126"><img file="JP6974331B2_D0160.tif" /></chemistry> The crude product obtained using amide coupling procedure C was purified by column chromatography (cyclohexane- EtOAc, 100: 0-70: 30) to give the title compound.¹1 H NMR (400 MHz, CDCl₃) δ 7.32-7.19 (m, 4H), 7.11 (d, J = 6.6 Hz, 1H), 6.77 (d, J = 4.3 Hz, 1H), 6.69 (d, J = 4.3 Hz, 1H), 5.00 (dt , J = 11.2, 6.9 Hz, 1H), 4.77 (dd, J = 9.7, 7.4 Hz, 1H), 4.25 (dd, J = 11.1, 9.7 Hz, 1H), 4.00 (s, 3H), 3.47 (s, 3H) .LC-MS (Method A): m / z = 325.0 [M + H]⁺, 0.93 minutes.</p><p> Example 25: (S) -5-Methyl-N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -4H- 1,2,4-Triazole-3-carboxamide<chemistry num="127"><img file="JP6974331B2_D0161.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: column, Xbridge Phenyl OBD column, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol / L NH).₄HCO₃) And ACN (50.0% ACN ~ 70.0% over 7 minutes); purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 14.2 (br. S, 1H), 8.43 (d, J = 6.8 Hz, 1H), 7.54-7.45 (m, 1H), 7.22-7.18 (m, 3H), 4.90-4.75 (m, 1H), 4.58 (t, J = 10.0 Hz, 1H), 4.47-4.35 (m, 1H), 4.39 (s, 3H), 2.39 (s, 3H). LC-MS (Method L): m / z = 302.0 [M + H]⁺, 0.885 minutes.</p><p> Example 26: (S) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) acetamide<chemistry num="128"><img file="JP6974331B2_D0162.tif" /></chemistry> Acetic anhydride (20.5 mg, 0.20 mmol) with (3S) -3-amino-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one hydrochloride (45.6 mg,) 0.20 mmol) and triethylamine (40 mg, 0.40 mmol) were added to a solution of dichloromethane (5 mL). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Residues under the following conditions: column, Xbridge Phenyl OBD column, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol / L NH)₄HCO₃) And ACN (50.0% ACN ~ 70.0% over 7 minutes); purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, J = 8.4 Hz, 1H), 7.50-7.45 (m, 1H), 7.36-7.15 (m, 3H), 4.76-4.65 (m, 1H), 4.38-4.15 (m, 2H), 3.29 (s, 3H), 1.84 (s, 3H) .LC-MS (Method D): m / z = 235.1 [M + H]⁺, 1.340 minutes.</p><p> Example 27: 5-Benzyl-N-((4S, 9aS) -5-oxohexahydro-1H, 3H-pyrrolo [2,1-c] [1,4] oxazepine-4-yl) -4H-1 , 2,4-Triazole-3-carboxamide<chemistry num="129"><img file="JP6974331B2_D0163.tif" /></chemistry> Step 1: Preparation of (2S) -2-{[(2S) -2-{[(benzyloxy) carbonyl] amino} -3-methoxy-3-oxopropoxy] methyl} pyrrolidine-1-carboxylate tert-butyl Borone trifluoride diethyl etherate (0.52 mL, 4.25 mmol), 2-methyl (2S) -aziridine-1,2-dicarboxylic acid 1-benzyl (2.00 g, 8.50 mmol) and N-Boc-L-prolinol (6.85 g, 34.03 mmol) dry CHCl₃It was added to the (20 mL) solution at -30 ° C under a nitrogen atmosphere. Leave the solution at room temperature overnight, then CH₂Cl₂It was diluted with (20 mL) and washed with water (3 x 10 mL) by back extraction. Combined organic extracts with Na₂SO₄It was dried on top, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (cyclohexane-diethyl ether, 50:50) to give the title product (3.30 g, 89%) as a colorless oil.¹H NMR (400MHz, CDCl₃) δ 7.47-7.30 (m, 5H), 5.97-5.50 (m, 1H), 5.23-5.08 (m, 2H), 4.49 (br. S, 1H), 4.07-3.21 (m, 10H), 1.97-1.73 (m, 4H), 1.49-1.38 (m, 9H) .LC-MS (Method A): m / z = 437.5 [M + H]⁺, 1.18 minutes.</p><p> Step 2: Preparation of (2S) -2-{[(benzyloxy) carbonyl] amino} -3-[(2S) -pyrrolidin-2-ylmethoxy] methyl propanoate (2S) -2-{[(2S)- CH of 2-{[(benzyloxy) carbonyl] (methyl) amino} -3-methoxy-3-oxopropoxy] methyl} pyrrolidine-1-carboxylate tert-butyl (450 mg, 1.03 mmol)₂Cl₂The (5 mL) and TFA (5 mL) solutions were stirred at 0 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by column chromatography on KP-NH modified silica (cyclohexane- EtOAc, 80: 20-60: 40, then pure MeOH), title compound (313 mg, 90). %) Was obtained as a colorless oil.¹H NMR (400MHz, CDCl₃) δ 7.48-7.29 (m, 5H), 6.23 (br. S, 1H), 5.22-5.10 (m, 2H), 4.50 (br. S, 1H), 3.96 (dd, J = 9.9, 3.1 Hz, 1H) ), 3.78 (s, 3H), 3.72 (dd, J = 9.8, 3.3 Hz, 1H), 3.51-3.44 (m, 1H), 3.39-3.32 (m, 1H), 3.25 (dq, J = 4.5, 7.0) Hz, 1H), 3.02-2.93 (m, 1H), 2.91-2.81 (m, 1H), 1.87-1.63 (m, 3H), 1.44-1.32 (m, 1H) .LC-MS (Method A): m /z=337.3 [M + H]⁺, 0.49 minutes.</p><p> Step 3: Preparation of N-[(4S, 9aS) -5-oxo-octahydropyrrolo [2,1-c] [1,4] oxazepine-4-yl] benzyl carbamate trimethylaluminum solution (2M in heptane, 0.56 mL, 1.12 mmol), CH of (2S) -2-{[(benzyloxy) carbonyl] amino} -3-[(2S) -pyrrolidin-2-ylmethoxy] methyl propanoate (313 mg, 0.93 mmol)₂Cl₂To the (5 mL) stirred solution was added dropwise at -30 ° C. The solution was left as it was, heated to room temperature, and left at room temperature for 1 hour. The reaction was cooled to 0 ° C. and 1N aqueous HCl solution (4.63 mL, 4.63 mmol) and water (5 mL) were added. Separate the phases and CH the aqueous fraction₂Cl₂Extracted twice with, filtered through a hydrophobic frit (phase divider) and concentrated under reduced pressure. The crude product is purified by column chromatography (CH)₂Cl₂-MeOH, 95: 5), title compound (217 mg, 77%) was obtained as a colorless oil.¹H NMR (400MHz, CDCl₃) δ 7.45-7.29 (m, 5H), 5.73 (br. S, 1H), 5.14 (br. S, 2H), 4.41 (br. S, 1H), 4.18-3.89 (m, 3H), 3.82-3.58 (m, 2H), 3.54-3.19 (m, 2H), 2.18-2.04 (m, 1H), 1.97-1.83 (m, 1H), 1.81-1.64 (m, 1H), 1.56 --1.39 (m, 1H) .LC-MS (Method A): m / z = 305.3 [M + H]⁺, 0.74 minutes.</p><p> Step 4: Preparation of (4S, 9aS) -4-amino-octahydropyrrolo [2,1-c] [1,4] oxazepine-5-one Palladium-supported carbon (10%, 75 mg), N-[( 4S, 9aS) -5-oxo-octahydropyrrolo [2,1-c] [1,4] oxazepine-4-yl] benzyl carbamate (215 mg, 0.71 mmol) in MeOH (5 mL) solution under nitrogen atmosphere Added. The nitrogen atmosphere was replaced with a hydrogen atmosphere and the reaction was stirred for 15 hours. The reaction was quenched by filtration through a Cerite plug and washed with sufficient MeOH. The filtrate was concentrated under reduced pressure to give the title compound (116 mg, 96%), which was used directly in the next step.¹H NMR (400MHz, CDCl₃) δ 4.23-4.11 (m, 1H), 4.02 (dd, J = 12.5, 1.3 Hz, 1H), 3.93 (dd, J = 12.8, 4.5 Hz, 1H), 3.80-3.68 (m, 2H), 3.64 ( dd, J = 4.4, 0.9 Hz, 1H), 3.41 (ddd, J = 11.9, 10.4, 6.8 Hz, 1H), 3.23 (dd, J = 12.7, 9.4 Hz, 1H), 2.18-2.08 (m, 1H) , 2.00-1.87 (m, 1H), 1.86-1.68 (m, 1H), 1.57-1.44 (m, 1H) .LC-MS (Method B): m / z = 171.1 [M + H]⁺, 0.35 minutes.</p><p> Step 5: 5-benzyl-N-((4S, 9aS) -5-oxohexahydro-1H, 3H-pyrrolo [2,1-c] [1,4] oxazepine-4-yl) -4H-1, Preparation of 2,4-triazole-3-carboxamide 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (50 mg, 0.246 mmol) and (4S, 9aS) -4-amino-octahydropyrrolo [ 2,1-c] [1,4] Oxazepine-5-one (42 mg, 0.246 mmol) CH₂Cl₂N, N-diisopropylethylamine (0.107 mL, 0.49 mmol) was added to the (2 mL) suspension. The reaction mixture was stirred for 10 minutes and then a T3P solution (50 wt% in EtOAc, 0.22 mL, 0.37 mmol) was added. After 40 minutes, the reaction mixture was quenched by the addition of water and the two phases were separated. Organic phase 0.5N HCl solution, saturated NaHCO₃The cells were washed with solution and brine and concentrated under reduced pressure. The crude product is purified by column chromatography (CH)₂Cl₂-MeOH, 90: 10 ~ 70: 30), the title compound was obtained.¹H NMR (400MHz, CDCl₃) δ 8.05 (d, J = 6.3 Hz, 1H), 7.40-7.17 (m, 5H), 4.72 (dd, J = 6.9, 4.9 Hz, 1H), 4.33-4.03 (m, 5H), 3.84 (d, J = 12.8 Hz, 1H), 3.75-3.62 (m, 1H), 3.43 (dt, J = 6.8, 11.2 Hz, 1H), 3.31 (dd, J = 12.8, 9.5 Hz, 1H), 2.21-2.08 (m) , 1H), 1.95-1.83 (m, 1H), 1.81-1.64 (m, 1H), 1.58-1.43 (m, 1H) .LC-MS (Method A): m / z = 356.3 [M + H]⁺, 0.67 minutes.</p><p> Examples 28 and 29: 5-Benzyl-N-((3R, 4S) -4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3 -Ixazole-3-carboxamide and 5-benzyl-N-((3S, 4R) -4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] ] Azepine-3-yl) isoxazole-3-carboxamide (28); and 5-benzyl-N-((3R, 4R) -4-fluoro-1-methyl-2-oxo-2,3,4,5 -Tetrahydro-1H-benzo [b] azepine-3-yl) isoxazole-3-carboxamide and 5-benzyl-N-((3S, 4S) -4-fluoro-1-methyl-2-oxo-2,3 , 4,5-Tetrahydro-1H-benzo [b] azepine-3-yl) isoxazole-3-carboxamide (29)<chemistry num="130"><img file="JP6974331B2_D0164.tif" /></chemistry><chemistry num="131"><img file="JP6974331B2_D0165.tif" /></chemistry> Example 30: (S) -5-benzyl-N- (5,6-dihydro-4H-benzo [f] imidazole [1,2-a] azepine-4-yl) isoxazole-3-carboxamide<chemistry num="132"><img file="JP6974331B2_D0166.tif" /></chemistry> Step 1: Preparation of 3-amino-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one 3-iodo-2,3,4,5-tetrahydro-1H-1-benzazepine-2- Sodium azide (1.23 g, 18.8 mmol) was added to a solution of on (4.50 g, 15.7 mmol) N, N-dimethylformamide (20 mL) and the reaction mixture was stirred at room temperature. Precipitates were formed after 30 minutes. The reaction mixture was diluted with water (300 mL). Further solids were precipitated and the mixture was stirred for an additional 10 minutes. The solid was collected by filtration, washed with water (20 mL) and dried in vacuo. The crude product was dissolved in tetrahydrofuran (30 mL) and water (0.5 mL). Triphenylphosphine (4.50 g, 17.2 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The solid was removed by filtration. The filtrate was dried over anhydrous sodium sulfate and concentrated to give the title compound (2.00 g, 72%) as a white solid. LC-MS (Method E): m / z = 177.0 [M + H]⁺, 0.413 minutes.</p><p> Step 2: Preparation of (3S) -3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one 3-amino-2,3,4,5-tetrahydro at 70 ° C- A solution of 1H-1-benzazepin-2-one (1.85 g, 11.0 mmol) in isopropanol (200 mL) was followed by L-pyroglutamic acid (1.42 g, 11.0 mmol) followed by 2-hydroxy-5-nitrobenzaldehyde (0.06 g). , 0.33 mmol) was added. The reaction mixture was stirred at 70 ° C for 4 days. After cooling to room temperature, the solid was collected by filtration, rinsed with isopropanol and the filtrate was basified with ammonium hydroxide (28%, 10 mL). The resulting solution was extracted with dichloromethane (4 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (0.91 g, 49%) as a white solid. LC-MS (Method E): m / z = 177.0 [M + H]⁺, 0.421 minutes.</p><p> Step 3: Preparation of N-((3S) -2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3-yl) benzyl carbamate Potassium carbonate (2.00 g, 15 mmol) in water ( 4 mL) solution is added to a solution of (3S) -3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (0.5 g, 3 mmol) in dichloromethane (30 mL), followed by Benzyl chloroformate (0.77 g, 4.5 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (0.87 g, 99%) as a white solid. LC-MS (Method E): m / z = 311.0 [M + H]⁺, 0.838 minutes.</p><p> Step 4: Preparation of N-((3S) -2-sulfanilidene-2,3,4,5-tetrahydro-1H-1-benzazepine-3-yl) benzyl carbamate Lawesson's reagent (1.05 g, 2.6 mmol), N-((3S) -2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-3-yl) benzyl carbamate (0.80 g, 2.6 mmol) was added to a solution in tetrahydrofuran (40 mL). , The reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound (0.82 g, 98%) as a white solid. LC-MS (Method E): m / z = 349.1 [M + Na]⁺, 0.946 minutes.</p><p> Step 5: Preparation of benzyl N-((3S) -2-((2,2-dimethoxyethyl) amino) -4,5-dihydro-3H-1-benzazepine-3-yl) carbamate 2,2-dimethoxy Etanamine (1.06 g, 10.1 mmol), N-((3S) -2-sulfanilidene-2,3,4,5-tetrahydro-1H-1-benzazepine-3-yl) benzyl carbamate (0.81 g, 2.5) It was added to a mixture of mmol) and dimercuric chloride (0.89 g, 3.3 mmol) in tetrahydrofuran (25 mL). The resulting mixture was heated at 55 ° C for 20 minutes. After cooling to room temperature, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (20 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.89 g, 90%) as a pale yellow solid. LC-MS (Method C): m / z = 398.2 [M + H]⁺, 1.182 minutes.</p><p> Step 6: Preparation of (5,6-dihydro-4H-benzo [f] imidazole [1,2-a] azepine-4-yl) carbamic acid (S) -benzyl N-((3S) -2-(( 2,2-Dimethoxyethyl) amino) -4,5-dihydro-3H-1-benzazepine-3-yl) benzyl carbamate (0.85 g, 3 mmol) in formic acid (8 mL, 96%) at 100 ° C 2 Heated for hours. The black precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (50 mL), basified with aqueous sodium hydroxide (1N, 30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (0.68 g, 95%) as a white solid. LC-MS (Method E): m / z = 334.0 [M + H]⁺, 0.671 minutes.</p><p> Step 7: Preparation of (S) -5,6-dihydro-4H-benzo [f] azepine-4-amine (5,6-dihydro-4H-benzo [f] imidazole [1] , 2-a] Azepine-4-yl) Carbamic acid (S) -benzyl (0.68 g, 2 mmol) in ethanol (20 mL) under a hydrogen atmosphere (2-3 atm), palladium-bearing carbon (10%, 0.5) Aged overnight in the presence of g). The reaction mixture was filtered through Cerite and the filtrate was concentrated under reduced pressure to give the title compound (0.40 g, 99%) as a yellow oil. LC-MS (Method C): m / z = 200.1 [M + H]⁺, 0.915 minutes.</p><p> Step 8: Preparation of (S) -5-benzyl-N- (5,6-dihydro-4H-benzo [f] imidazole [1,2-a] azepine-4-yl) isooxazole-3-carboxamide amide cup The crude product obtained using ring procedure C was subjected to the following conditions: column, Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.1% formic acid) and ACN (45.0% over 7 minutes). ACN ~ 70.0%); Purified by preparative HPLC using a detector, UV254 / 220 nm; to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 9.00 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 1.5 Hz, 1H), 7.46-7.41 (m, 3H), 7.40-7.21 (m, 6H), 6.96 (d, J = 1.5 Hz, 1H), 6.53 (s, 1H), 4.80 (dd, J = 10.2, 7.5 Hz, 1H), 4.18 (s, 2H), 2.72 (dd, J = 11.7, 6.0 Hz, 1H), 2.45- 2.27 (m, 3H) .LC-MS (Method O): m / z = 385.0 [M + H]⁺, 1.587 minutes.</p><p> Examples 31 and 34: 5-Benzyl-N-((3R, 4R) -4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3 -Il) -4H-1,2,4-triazole-3-carboxamide and 5-benzyl-N-((3S, 4S) -4-fluoro-1-methyl-2-oxo-2,3,4,5 -Tetrahydro-1H-benzo [b] azepine-3-yl) -4H-1,2,4-triazole-3-carboxamide (31); and 5-benzyl-N-((3R, 4S) -4-fluoro) -1-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) -4H-1,2,4-triazole-3-carboxamide and 5-benzyl- N-((3S, 4R) -4-fluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) -4H-1,2, 4-Triazole-3-Carboxamide (34)<chemistry num="133"><img file="JP6974331B2_D0167.tif" /></chemistry> Example 32: (S) -5-benzyl-N- (9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl ) -4H-1,2,4-triazole-3-carboxamide<chemistry num="134"><img file="JP6974331B2_D0168.tif" /></chemistry> Step 1: Preparation of (2S) -2-(((tert-butoxy) carbonyl) amino) -3- (2-chloro-6-nitrophenoxy) propanoic acid Sodium hydride (60%, 0.39 g, 97.6 mmol) Was added to a solution of (S) -2- (tert-butoxycarbonylamino) -3-hydroxypropanoic acid (10.0 g, 48.8 mmol) in N, N-dimethylformamide (50 mL) under a nitrogen atmosphere. After stirring at 0 ° C for 2 hours, 1-chloro-2-fluoro-3-nitrobenzene (8.6 g, 48.8 mmol) was added. The reaction mixture was stirred at room temperature overnight, quenched with hydrochloric acid (0.5 M, 50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography using an RP-C18 column (acetonitrile / water, 7/3) to give the title compound (5.5 g, 31%) as a yellow solid. LC-MS (Method G): m / z = 361.0 [M + H]⁺, 0.665 minutes.</p><p> Step 2: Preparation of (2S) -3- (2-amino-6-chlorophenoxy) -2-(((tert-butoxy) carbonyl) amino) propanoic acid Zinc (8.13 g, 125 mmol) and ammonium chloride (6.70 g) , 125 mmol), (2S) -2-(((tert-butoxy) carbonyl) amino) -3- (2-chloro-6-nitrophenoxy) propanoic acid (4.5 g, 12.5 mmol) in methanol / tetrahydrofuran (100 mL) , 1/1) Added to the stirred solution. The resulting mixture was stirred at 25 ° C for 2 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to give the title compound (4 g, crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method G): m / z = 331.0 [M + H]⁺, 0.704 minutes.</p><p> Step 3: Preparation of N-((3S) -9-chloro-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-3-yl) tert-butylcarbamate 2- (7-aza-1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (1.1 g, 2.91 mmol) and ethyldiisopropylamine (0.94 g, 7.26 mmol), Stirring (2S) -3- (2-amino-6-chlorophenoxy) -2-(((tert-butoxy) carbonyl) amino) propanoic acid (0.80 g, 2.42 mmol) with N, N-dimethylformamide (10 mL) Added to the solution. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/6) to give the title compound (0.18 g, 24%) as a yellow solid. LC-MS (Method G): m / z = 313.0 [M + H]⁺, 1.006 minutes.</p><p> Step 4: N-((3S) -9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-3-yl) tert-butyl carbamic acid Preparation of iodomethane (82 mg, 0.58 mmol), N-((3S) -9-chloro-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-3-yl) carbamine It was added dropwise to a stirred mixture of tert-butyl acid (180 mg, 0.58 mmol) and cesium carbonate (188 mg, 0.58 mmol) in N, N-dimethylformamide (10 mL). After stirring at room temperature for 2 hours, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/6) to give the title compound (120 mg, 64%) as a white solid. LC-MS (Method G): m / z = 327.0 [M + H]⁺, 1.045 minutes.</p><p> Step 5: Preparation of (3S) -3-amino-9-chloro-5-methyl-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one hydrochloride N-((3S) )-9-Chloro-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzooxazepine-3-yl) tert-butyl carbamic acid (120 mg, 0.37 mmol) chloride It was added to a dioxane solution of hydrogen (4M, 10 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give the title compound (83 mg, crude) as a white solid. LC-MS (Method G): m / z = 227.0 [M + H]⁺, 0.772 minutes.</p><p> Step 6: (S) -5-benzyl-N- (9-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) Preparation of -4H-1,2,4-triazole-3-carboxamide The crude product obtained using amide coupling procedure C is subjected to the following conditions: column, Xbridge Phenyl OBD column, 5 μm, 19 × 150 mm; Mobile phase, water (10 mmol / L NH)₄HCO₃) And ACN (50.0% ACN ~ 70.0% over 7 minutes); purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (400 MHz, CD₃OD) δ 7.44-7.20 (m, 8H), 4.98 (dd, J = 15.2, 10.0 Hz, 1H), 4.68 (dd, J = 13.2, 10.0 Hz, 1H), 4.46 (dd, J = 15.2, 13.2 Hz) , 1H), 4.17 (s, 2H), 3.42 (s, 3H) .LC-MS (Method Q): m / z = 412.2 [M + H]⁺, 1.336 minutes.</p><p> Example 33: (S) -1-benzyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) azetidine-3 -Carboxamide<chemistry num="135"><img file="JP6974331B2_D0169.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: column, Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol / L NH).₄HCO₃) And ACN (30.0% ACN ~ 60.0% over 7 minutes); purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (300 MHz, CDCl₃) δ 7.29 (s, 4H), 7.19 (m, 4H), 7.06 (d, J = 6.9 Hz, 1H), 4.95-4.80 (m, 1H), 4.67 (dd, J = 9.6, 7.5 Hz, 1H) , 4.14 (dd, J = 11.1, 9.6 Hz, 1H), 3.65 (s, 2H), 3.57 (s, 2H), 3.51 (s, 3H), 3.34 (m, 2H), 3.22-3.02 (m, 1H) ). LC-MS (Method O): m / z = 365.9 [M + H]⁺, 1.215 minutes.</p><p> Example 35: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (1-Phenyl) Cyclopropyl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="136"><img file="JP6974331B2_D0170.tif" /></chemistry> Step 1: Preparation of 1-Phenylcyclopropane-1-Carbohydrazide A solution of hydrazine in tetrahydrofuran (1M, 30 mL), 1-Phenylcyclopropane-1-carboxylic acid (0.48 g, 3.00 mmol), 2- (7-aza N, N-dimethyl of -1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (1.37 g, 3.60 mmol) and ethyldiisopropylamine (1.16 g, 8.98 mmol) It was added to a solution of formamide (10 mL). After stirring at room temperature for 1 hour, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/2) to give the title compound (0.53 g, 98%) as a yellow oil. LC-MS (Method R: m / z = 177.2 [M + H]⁺, 0.670 minutes.</p><p> Step 2: Preparation of 2-amino-2-(((1-phenylcyclopropyl) formamide) imino) ethyl acetate 2-ethoxy-2-imino ethyl acetate (452 mg, 3.11 mmol), 1-phenylcyclopropane-1 -Carbohydrazide (528 mg, 3.00 mmol) was added to an ethanol / ether (12 mL, 1/3) stirred solution. The reaction mixture was stirred at room temperature for 2 hours. The yellow solid was collected by filtration to give the title compound (300 mg, 36%). LC-MS (Method S: m / z = 276.2 [M + H]⁺, 0.663 minutes.</p><p> Step 3: Preparation of ethyl 5- (1-phenylcyclopropyl) -4H-1,2,4-triazole-3-carboxylate 2-amino-2-(((1-phenylcyclopropyl) formamide) imino) acetate A solution of ethyl (275 mg, 1.00 mmol) in xylene (10 mL) was irradiated with microwave radiation at 170 ° C. for 10 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (100 mg, 39%) as a yellow solid. LC-MS (Method C): m / z = 258.1 [M + H]⁺, 1.641 minutes.</p><p> Step 4: Preparation of 5- (1-phenylcyclopropyl) -4H-1,2,4-triazole-3-carboxylic acid Add a solution of lithium hydroxide (28 mg, 1.17 mmol) in water (1 mL) to 5- (1). -Phenylcyclopropyl) -4H-1,2,4-triazole-3-ethyl carboxylate (100 mg, 0.39 mmol) was added to a solution in tetrahydrofuran (3 mL) and the resulting mixture was stirred overnight at room temperature. After adjusting the pH to 6-7 with aqueous hydrochloric acid (1N, 20 mL), the reaction mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (90 mg, crude) as a yellow solid, which was not further purified. Used directly in the next step. LC-MS (Method R): m / z = 230.2 [M + H]⁺, 0.530 minutes.</p><p> Step 5: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (1-Phenylcyclo) Preparation of propyl) -4H-1,2,4-triazole-3-carboxamide The crude product obtained using amide coupling procedure C was subjected to the following conditions: column, Xbridge Phenyl OBD column, 5 μm, 19 × 150mm; mobile phase, water (10 mmol / L NH)₄HCO₃) And ACN (50.0% ACN ~ 70.0% over 7 minutes); purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (400 MHz, CD₃OD) δ 7.44-7.20 (m, 9H), 4.99 (dd, J = 11.6, 7.6 Hz, 1H), 4.58 (dd, J = 9.6, 7.6 Hz, 1H), 4.39 (dd, J = 11.6, 10.0 Hz , 1H), 3.57 (s, 3H), 1.67-1.56 (m, 2H), 1.46-1.29 (m, 2H) .LC-MS (Method D): m / z = 404.1 [M + H]⁺, 1.966 minutes.</p><p> Example 36: 5-Benzyl-N- (1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [4,5] imidazo [1,2-a] [1,3] Diazepine-3-yl) Isoxazole-3-carboxamide<chemistry num="137"><img file="JP6974331B2_D0171.tif" /></chemistry> Example 37: (R) -5-benzyl-N- (4,4-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl ) -4H-1,2,4-triazole-3-carboxamide<chemistry num="138"><img file="JP6974331B2_D0172.tif" /></chemistry> Examples 38A and 38B: (S) -5-benzyl-N- (2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo [4,5-b] azepine-6 -Il) -4H-1,2,4-triazole-3-carboxamide and (R) -5-benzyl-N- (2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H) -Thiazolo [4,5-b] azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="139"><img file="JP6974331B2_D0173.tif" /></chemistry>Step 1: Preparation of azepan-2,7-dione Azepan-2-one (11.3 g, 100 mmol), 2-hydroxyisoindoline-1,3-dione (1.63 g, 10 mmol), and cobalt acetate (88.5 mg, 0.5) Oxygen (balloon) was flowed through a stirred solution of mmol) in acetonitrile (100 mL). The reaction mixture was heated overnight at 85 ° C in an oxygen atmosphere. The solid was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (3.70 g, 29.1%) as a white solid. LC-MS (Method C): m / z = 128.2 [M + H]⁺, 0.683 minutes.</p><p> Step 2: Preparation of 1-Methylazepan-2,7-dione Iodomethane (1.68 g, 11.8 mmol), Azepan-2,7-dione (1.50 g, 11.8 mmol) and cesium carbonate (3.85 g, 5.0 mmol) N , N-Dimethylformamide (25 mL) was added dropwise at 0 ° C to the stirred mixture. The reaction mixture was stirred at room temperature overnight, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (1.1 g, 66.1%) as a yellow oil. LC-MS (Method C): m / z = 142.1 [M + H]⁺, 0.863 minutes.</p><p> Step 3: Preparation of 3-bromo-1-methylazepan-2,7-dione Add bromine (632 mg, 4.00 mmol) to a stirred solution of 1-methylazepan-2,7-dione (564 mg, 4.0 mmol) in chloroform (10 mL). Added. The reaction mixture was stirred in a closed tube at 110 ° C. for 1.5 hours. The reaction mixture was concentrated under high vacuum to give the title compound (600 mg, crude) as a brown oil. LC-MS (Method C): m / z = 220.1 [M + H]⁺, 0.940 minutes.</p><p> Step 4: Preparation of 2,4-dimethyl-7,8-dihydro-4H-thiazolo [4,5-b] azepine-5 (6H) -one Ethanethioamide (300 mg, 4.0 mmol) 3-bromo-1- Methylazepine-2,7-dione (600 mg, 4.0 mmol) was added to a solution of pyridine (10 mL). The reaction mixture was stirred at 50 ° C. for 16 hours, quenched by the addition of water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (70 mg, 9%) as a yellow solid. LC-MS (Method C): m / z = 197.1 [M + H]⁺, 0.981 minutes.</p><p> Step 5: 6-Iodine-2,4-Dimethyl-7,8-Dihydro-4H-Thiazolo [4,5-b] Azepine-5 (6H) -On Preparation N¹, N¹, N², N²-Tetramethylethane-1,2-diamine (124 mg, 1.07 mmol), 2,4-dimethyl-7,8-dihydro-4H-thiazolo [4,5-b] azepine-5 (6H) -one (70 mg) , 0.36 mmol) in dichloromethane (5 mL) with stirring solution at 0 ° C., followed by iodotrimethylsilane (214 mg, 1.07 mmol). The reaction mixture was stirred at 0 ° C for 1 hour. After adding iodine (137.2 mg, 0.54 mmol), the reaction mixture was stirred at 0 ° C for an additional 2 hours and quenched with aqueous sodium thiosulfate (5%, 15 mL). The resulting solution was stirred for an additional 15 minutes and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (61 mg, crude) as a yellow solid, which was then without further purification. Used directly in the step. LC-MS (Method R): m / z = 323.2 [M + H]⁺, 0.820 minutes.</p><p> Step 6: Preparation of 6-amino-2,4-dimethyl-7,8-dihydro-4H-thiazolo [4,5-b] azepine-5 (6H) -one 6-iodo-2,4-dimethyl-7 , 8-Dihydro-4H-thiazolo [4,5-b] Azepine-5 (6H) -one (61 mg, 0.19 mmol) in N, N-dimethylformamide (2 mL) solution with sodium azide (37.1 mg, 0.57) mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (3 mL) and water (1 mL), and triphenylphosphine (149.3 mg, 0.57 mmol) was added in portions. The reaction mixture was stirred at 50 ° C. overnight, diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (33 mg, 83%) as a yellow solid. LC-MS (Method C): m / z = 212.1 [M + H]⁺, 0.735 minutes.</p><p> Step 7: 5-Benzyl-N- (2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo [4,5-b] azepine-6-yl) -4H-1 Preparation of 2,4-triazole-3-carboxamide The crude product obtained using the amide coupling procedure C is as follows: Column: Xbridge Prep C18, 19 × 150 mm, 5 μm; Mobile phase: Phase A : Water (10 mmol / L NH₄HCO₃); Phase B: ACN (20% -80% in 12 minutes); Purified by preparative HPLC using a detector, UV220 &amp; 254nm; to give the title compound. LC-MS (Method R): m / z = 397.1 [M + H]⁺, 1.095 minutes.</p><p> Step 8: (R) -5-benzyl-N- (2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo [4,5-b] azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide (first elution isomer) and (S) -5-benzyl-N- (2,4-dimethyl-5-oxo-5,6,7,8) -Tetrahydro-4H-thiazolo [4,5-b] azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide (second elution isomer) preparation 5-benzyl-N- (2) , 4-Dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo [4,5-b] azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide ( 24 mg, 0.06 mmol) isomers under the following conditions: Column: Chiralpak IA, 2 × 25 cm, 5 μm; Mobile phase A: hexane, Mobile phase B: EtOH; Flow rate: 15 mL / min; Gradient: 50% over 17.5 minutes B ~ 50% of B; UV220 &amp; 254nm; RT1: 10.18 min; RT2: 15.13 min; separated by preparative chiral HPLC to give the title compound:</p><p> Example 38B (first elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 7.36-7.25 (m, 5H), 4.73-4.69 (m, 1H), 4.18 (s, 2H), 3.39 (s, 3H), 3.05-2.88 (m, 2H), 2.73-2.64 (m, 4H) ), 2.36-2.27 (m, 1H) .LC-MS (Method D): m / z = 397.1 [M + H]⁺, 1.623 minutes.</p><p> Example 38A (second elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 7.36-7.24 (m, 5H), 4.73-4.68 (m, 1H), 4.18 (s, 2H), 3.39 (s, 3H), 3.06-2.87 (m, 2H), 2.73-2.63 (m, 4H) ), 2.36-2.27 (m, 1H) .LC-MS (Method D): m / z = 397.1 [M + H]⁺, 1.623 minutes.</p><p> Example 39: (S) -5-benzyl-N- (1-methyl-2-oxo-8- (trifluoromethyl) -2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] ] [1,3] diazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="140"><img file="JP6974331B2_D0174.tif" /></chemistry> Example 40: (S) -5-benzyl-N- (5-methyl-4-oxo-6- (trifluoromethyl) -2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine -3-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="141"><img file="JP6974331B2_D0175.tif" /></chemistry> Example 41: (S) -5-benzyl-N- (1-methyl-2-oxo-1,2,3,4-tetrahydropyrido [3,4-b] [1,4] oxazepine-3- Il) -4H-1,2,4-triazole-3-carboxamide<chemistry num="142"><img file="JP6974331B2_D0176.tif" /></chemistry>Step 1: Preparation of (2S) -2-(((tert-butoxy) carbonyl) amino) -3-((4-nitropyridin-3-yl) oxy) propanoic acid Sodium hydride (60%, 1.92 g, 80.1 mmol) was added to a stirred solution of (2S) -2- (tert-butoxycarbonylamino) -3-hydroxypropanoic acid (8.21 g, 40.0 mmol) in dimethylformamide (30 mL) at 0 ° C under a nitrogen atmosphere. bottom. After stirring at 0 ° C. for 2 hours, a solution of 3-fluoro-4-nitropyridine (5.52 g, 40.0 mmol) in dimethylformamide (10 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight, quenched by the addition of water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase CombiFlash using an RP-C18 column (acetonitrile / water, 1/4) to give the title compound (2.41 g, 18%) as a yellow solid. LC-MS (Method S): m / z = 328.1 [M + H]⁺, 0.829 minutes.</p><p> Step 2: Preparation of (2S) -3-((4-aminopyridin-3-yl) oxy) -2-(((tert-butoxy) carbonyl) amino) propanoic acid in methanol (20 mL), (2S)- 2-(((tert-Butyloxy) carbonyl) amino) -3-((4-nitropyridin-3-yl) oxy) propanoic acid (2.41 g, 7.34 mmol) under a hydrogen atmosphere (2 to 3 atmospheres), Aged overnight at room temperature in the presence of palladium-bearing carbon (10%, 345 mg). The reaction mixture was filtered through Cerite and the filtrate was concentrated under reduced pressure to give the title compound (1.8 g, 83%) as a yellow solid, which was used directly in the next step without further purification. LC-MS (Method S): m / z = 298.1 [M + H]⁺, 0.601 minutes.</p><p> Step 3: Preparation of N-((3S) -2-oxo-1H, 2H, 3H, 4H-pyrido [3,4-b] [1,4] oxazepine-3-yl) tert-butyl carbamic acid 2- (7-aza-1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (1.5 g, 4.04 mmol) and ethyldiisopropylamine (1.30 g, 10.1 mmol), N, N-dimethylformamide of (2S) -3-((4-aminopyridine-3-yl) oxy) -2-(((tert-butoxy) carbonyl) amino) propanoic acid (1.01 g, 3.37 mmol) 13 mL) Added to the stirred solution. After stirring at room temperature for 3 hours, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (0.4 g, 83%) as a yellow solid. LC-MS (Method S): m / z = 280.1 [M + H]⁺, 0.604 minutes.</p><p> Step 4: N-((3S) -1-methyl-2-oxo-1H, 2H, 3H, 4H-pyrido [3,4-b] [1,4] oxazepine-3-yl) tert-butylcarbamate Preparation of iodomethane (203 mg, 1.43 mmol), N-((3S) -2-oxo-1H, 2H, 3H, 4H-pyrido [3,4-b] [1,4] oxazepine-3-yl) carbamine A mixture of tert-butyl acid (400 mg, 1.43 mmol) and cesium carbonate (467 mg, 1.43 mmol) in N, N-dimethylformamide (7 mL) was added dropwise. After stirring at 0 ° C for 10 minutes, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (300 mg, 72%) as a yellow solid. LC-MS (Method S): m / z = 294.1 [M + H]⁺, 0.650 minutes.</p><p> Step 5: Preparation of (3S) -3-amino-1-methyl-1H, 2H, 3H, 4H-pyrido [3,4-b] [1,4] oxazepine-2-one hydrochloride 1, of hydrogen chloride 4-Dioxane solution (4M, 5 mL, 20 mmol), N-((3S) -1-methyl-2-oxo-1H, 2H, 3H, 4H-pyrido [3,4-b] [1,4] oxazepine -3-yl) It was added to a solution of tert-butyl carbamate (300 mg, 1.02 mmol) in 1,4-dioxane (7 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated to give the title compound (215 mg, 92%) as a white solid. LC-MS (Method S): m / z = 194.1 [M + H]⁺, 0.184 minutes.</p><p> Step 6: (S) -5-benzyl-N- (1-methyl-2-oxo-1,2,3,4-tetrahydropyrido [3,4-b] [1,4] oxazepine-3-yl )-Preparation of -4H-1,2,4-triazole-3-carboxamide (3S) -3-amino-1-methyl-1H, 2H, 3H, 4H-pyrido [3,4-b] [1,4] A solution of oxazepine-2-one hydrochloride (115 mg, 0.50 mmol) in N, N-dimethylformamide (1 mL) to 5-benzyl-2H-1,2,4-triazole-3-carboxylic acid (102 mg, 0.50 mmol). , Ethyldiisopropylamine (129 mg, 1.00 mmol), N¹-((Ethylimino) methylene)-N³, N³-Dimethylpropane-1,3-diamine hydrochloride (115 mg, 0.60 mmol) and 1-hydroxybenzotriazole (92 mg, 0.60 mmol) were added to a stirred solution of N, N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. Residues under the following conditions: Column: XBridge Prep C18OBD Column 19 × 150mm 5μm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 30 mL / min; Gradient: Purified by preparative HPLC using 15% B ~ 45% B; 254 nm; over 10 minutes. The collected fractions were combined and concentrated under reduced pressure to give the title compound.¹1 H NMR (400 MHz, CDCl₃) δ 12.34 (s, 1H), 8.54-8.46 (m, 2H), 8.06 (d, J = 7.3 Hz, 1H), 7.36-7.29 (m, 5H), 7.16 (d, J = 5.2 Hz, 1H) , 5.09 (m, 1H), 4.77 (dd, J = 10.0, 3.2 Hz, 1H), 4.41 (dd, J = 11.6, 10.0 Hz, 1H), 4.20 (s, 2H), 3.46 (s, 3H). LC-MS (Method T): m / z = 379.2 [M + H]⁺, 0.888 minutes.</p><p> Example 42: (S) -5-benzyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3- Il) -4H-1,2,4-triazole-3-carboxamide<chemistry num="143"><img file="JP6974331B2_D0177.tif" /></chemistry> Step 1: Preparation of (2S) -2-(((tert-butoxy) carbonyl) amino) -3-((2-nitropyridin-3-yl) oxy) propanoic acid Sodium hydride (60%, 2g, 50 mmol) ) Was added to a stirred solution of (2S) -2- (tert-butoxycarbonylamino) -3-hydroxypropanoic acid (5 g, 25.0 mmol) in N, N-dimethylformamide (100 mL). The resulting mixture was stirred at 0 ° C for 2 hours. 3-Fluoro-2-nitropyridine (3.6 g, 25.3 mmol) was added and the reaction mixture was stirred at room temperature for an additional 8 hours and then quenched with hydrochloric acid (3N, 5 mL). After adjusting the pH to 3-4 with hydrochloric acid (3N, 20 mL), the resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on an RP-C18 column (acetonitrile / water, 1/2) to give the title compound (3.2 g, 39%) as a pale yellow oil. LC-MS (Method C): m / z = 272.1 [M + H- (t-BuO)]⁺, 1.269 minutes.</p><p> Step 2: Preparation of (2S) -3-((2-aminopyridine-3-yl) oxy) -2-(((tert-butoxy) carbonyl) amino) propanoic acid in methanol (20 mL), (2S)- 2-(((tert-Butyloxy) carbonyl) amino) -3-((2-nitropyridine-3-yl) oxy) propanoic acid (0.45 g, 1.4 mmol) under a hydrogen atmosphere (2 to 3 atmospheres), Aged overnight at room temperature in the presence of palladium-bearing carbon (10%, 0.5 g). The reaction mixture was filtered through Cerite and the filtrate was concentrated under reduced pressure to give the title compound (0.32 g, 78%) as a yellow oil. LC-MS (Method C): m / z = 298.1 [M + H]⁺, 0.982 minutes.</p><p> Step 3: Preparation of N-((3S) -4-oxo-2H, 3H, 4H, 5H-pyrido [3,2-b] [1,4] oxazepine-3-yl) tert-butyl carbamic acid N, N, N', N'-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (0.73 g, 1.92 mmol) and N, N-diisopropylethylamine (0.25 g, 1.93 mmol) , N, N-dimethyl of (2S) -3-((2-aminopyridine-3-yl) oxy) -2-(((tert-butoxy) carbonyl) amino) propanoic acid (0.45 g, 1.51 mmol). Formamide (5 mL) was added to the stirred solution. After stirring at room temperature for 6 hours, the reaction mixture was quenched by the addition of water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (0.11 g, 26%) as a white solid. LC-MS (Method C): m / z = 280.1 [M + H]⁺, 1.248 minutes.</p><p> Step 4: N-((3S) -5-methyl-4-oxo-2H, 3H, 4H, 5H-pyrido [3,2-b] [1,4] oxazepine-3-yl) tert-butylcarbamate Preparation of iodomethane (50 mg, 0.35 mmol), N-((3S) -4-oxo-2H, 3H, 4H, 5H-pyrido [3,2-b] [1,4] oxazepine-3-yl) carbamine It was added dropwise to a stirred solution of tert-butyl acid (100 mg, 0.36 mmol) and cesium carbonate (120 mg, 0.36 mmol) in N, N-dimethylformamide (5 mL). After stirring at room temperature for 3 hours, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (90 mg, 86%) as a white solid. LC-MS (Method C): m / z = 294.1 [M + H]⁺, 1.333 minutes.</p><p> Step 5: Preparation of (3S) -3-amino-5-methyl-2H, 3H, 4H, 5H-pyrido- [3,2-b] [1,4] oxazepine-4-one hydrochloride N-((( 3S) -5-Methyl-4-oxo-2H, 3H, 4H, 5H-pyrido [3,2-b] [1,4] Oxazepine-3-yl) tert-butyl carbamate (90 mg, 0.31 mmol) , Added to a dioxane solution of hydrogen chloride (4M, 10 mL). The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure to give the title compound (65 mg, 93%) as a white solid, which was used directly in the next step without further purification. LC-MS (Method C): m / z = 194.1 [M + H]⁺, 0.847 minutes.</p><p> Step 6: (S) -5-benzyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl )-Preparation of -4H-1,2,4-triazole-3-carboxamide (3S) -3-amino-5-methyl-2H, 3H, 4H, 5H-pyrido- [3,2-b] [1,4] Oxazepine-4-one hydrochloride (55 mg, 0.24 mmol) N, N-dimethylformamide (1 mL) solution, 5-benzyl-2H-1,2,4-triazole-3-carboxylic acid (80 mg, 0.40 mmol), 1-hydroxy-benzotrizole (70 mg, 0.53 mmol), N -(3-Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) and N, N-diisopropylethylamine (160 mg, 1.21 mmol) were added to a stirred solution of N, N-dimethylformamide (2 mL). .. After stirring at room temperature for 8 hours, the reaction mixture was quenched by the addition of water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue can be used under the following conditions: Column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.1% formic acid) and ACN (30.0% ACN ~ 60.0% over 7 minutes); detector, purified by preparative HPLC using UV254 &amp; 220 nm; title compound Got¹1 H NMR (300 MHz, DMSO-d₆) δ 14.45 (s, 1H), 8.67 (d, J = 7.2 Hz, 1H), 8.37 (dd, J = 4.8, 1.8 Hz, 1H), 7.71 (dd, J = 7.8, 1.5 Hz, 1H), 7.37 -7.21 (m, 6H), 4.92-4.82 (m, 1H), 4.73 (dd, J = 11.4, 9.6 Hz, 1H), 4.53 (dd, J = 9.6, 7.5 Hz, 1H), 4.14 (s, 2H) ), 3.37 (s, 3H) .LC-MS (Method D): m / z = 379.1 [M + H]⁺, 1.611 minutes.</p><p> Example 43: 3-Benzyl-N-((S) -5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) Cyclobutane-1 -Carboxamide<chemistry num="144"><img file="JP6974331B2_D0178.tif" /></chemistry> Step 1: Preparation of 3- (Phenylmethylidene) Cyclobutane-1-carboxylate Ethyl hexane (2.5M, 3.4mL, 8.5 mmol) solution of n-butyllithium, benzyltriphenylphosphonium chloride (3.3g, 8.5 mmol) To a suspension of anhydrous tetrahydrofuran (50 mL) at -60 ° C. The resulting mixture was stirred at -60 ° C for 0.5 hours and then warmed to room temperature. Ethyl 3-oxocyclobutane carboxylate (1.2 g, 8.5 mmol) was added, the reaction mixture was heated to reflux and stirred overnight. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/20) to give the title compound (0.14 g, 8%) as a pale yellow oil. LC-MS (Method S): m / z = 217.2 [M + H]⁺, 1.144 minutes.</p><p> Step 2: Preparation of ethyl 3-benzylcyclobutane-1-carboxylate: Ethyl 3- (phenylmethylidene) cyclobutane-1-carboxylate (130 mg, 0.6 mmol) in ethanol (5 mL), carrying palladium in a hydrogen atmosphere. carbon (10%, 15mg) water in the presence of the hydrogenation. After stirring at room temperature for 2 hours, the reaction mixture is filtered through Cerite and the filtrate is concentrated under reduced pressure to give the title compound (100 mg, crude) as a yellow oil, which is the next step without further purification. Used directly in. LC-MS (Method S): m / z = 219.3 [M + H]⁺, 1.160 minutes.</p><p> Step 3: Preparation of 3-benzylcyclobutane-1-carboxylic acid: A solution of sodium hydroxide (60 mg, 1.5 mmol) in water (1 mL) to ethyl 3-benzylcyclobutane-1-carboxylate (100 mg, 0.5 mmol) in tetrahydrofuran ( 3 mL) Added in solution. After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (10 mL), adjusted to pH = 3 with aqueous hydrochloric acid (3N, 10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (85 mg, 97%) as a yellow oil. LC-MS (Method I): m / z = 190.9 [M + H]⁺, 0.954 minutes.</p><p> Step 4: 3-Benzyl-N-((S) -5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) Cyclobutane-1- Preparation of Carboxamide The crude product obtained using the amide coupling procedure C was subjected to the following conditions: column, Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% NH).₃H₂Purification by preparative HPLC using O), ACN (25% ACN ~ 55% B over 7 minutes); detector, UV254 &amp; 220 nm; gave the title compound.¹1 H NMR (400 MHz, CDCl₃) δ 7.29-7.13 (m, 9H), 6.41 (d, J = 6.0 Hz, 1H), 4.93-4.86 (m, 1H), 4.69 (t, J = 7.6 Hz, 1H), 4.12 (t, J = 10.0 Hz, 1H), 3.44 (s, 3H), 2.88-2.69 (m, 3H), 2.48 (q, J = 7.6 Hz, 1H), 2.35-2.24 (m, 2H), 2.09-1.91 (m, 2H) ). LC-MS (Method O): m / z = 365.0 [M + H]⁺, 1.585 minutes.</p><p> Example 44: (S) -5-benzyl-N- (1-methyl-2-oxo-1,2,3,4-tetrahydrospiro [benzo [b] azepine-5,1'-cyclopropane] -3 -Il) -4H-1,2,4-triazole-3-carboxamide<chemistry num="145"><img file="JP6974331B2_D0179.tif" /></chemistry> Step 1: Preparation of tert-butyl 1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-ylcarboxylate Sodium hydride (60%, 0.30 g, 12.3 mmol) was added to the mixture of methyltriphenylphosphonium bromide (4.4 g, 12.3 mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at 50 ° C. for 1 hour under a nitrogen atmosphere. Tetrahydrofuran (1.50 g, 4.93 mmol) of 1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-ylcarbamic acid tert-butyl (1.50 g, 4.93 mmol) was added to this mixture. 20 mL) The solution was added dropwise at 50 ° C. After stirring overnight at 50 ° C., the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/10) to give the title compound (600 mg, 40%) as a yellow solid. LC-MS (Method C): m / z = 303.2 [M + H]⁺, 1.531 minutes.</p><p> Step 2: N- [7-Methyl-6-oxo-7-azatricyclo [6.4.0.0-[2,4]] dodeca-1 (8), 9,11-triene-5-yl] tert-butyl carbamic acid Preparation A solution of 1-methyl-1-nitrosourea (2.05 g, 19.7 mmol) in ether (100 mL) was added dropwise to a solution of potassium hydroxide (2.23 g, 39.7 mmol) in water (3.3 mL) at 0 ° C. The resulting mixture was stirred at 0 ° C. for 1 hour, then the organic phase was separated to give a diazomethane solution (100 mL). Tetrahydrofuran (5 mL) solution of 1-methyl-5-methylene-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-ylcarboxylate tert-butyl (0.6 g, 1.99 mmol) Diazomethane solution (100 mL) was added dropwise to the mixture, followed by a mixture of palladium diacetate (45 mg, 0.20 mmol) in tetrahydrofuran (1 mL) at 0 ° C. The reaction mixture was stirred at room temperature overnight. The solid was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/10) to give the title compound (0.15 g, 24%) as a yellow solid. LC-MS (Method C): m / z = 317.2 [M + H]⁺, 1.531 minutes.</p><p> Step 3: Preparation of 3-amino-1-methyl-1,2,3,4-tetrahydrospiro [1-benzazepine-5,1-cyclopropane] -2-one hydrochloride Solution of 1,4-dioxane of hydrogen chloride (4N, 10 mL), N- [7-methyl-6-oxo-7-azatricyclo [6.4.0.0-[2,4]] dodeca-1 (8), 9,11-triene-5-yl] carbamine It was added to a solution of tert-butyl acid (150 mg, 0.60 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated under vacuum to give the title compound (95 mg, crude) as a yellow solid. LC-MS (Method K): m / z = 217.2 [M + H]⁺, 0.635 minutes.</p><p> Step 4: (3S) -3-amino-1-methyl-1,2,3,4-tetrahydrospiro [1-benzazepine-5,1-cyclopropane] -2-one (first elution isomer) and ( 3R) -3-Amino-1-methyl-1,2,3,4-Tetrahydrospiro [1-benzazepine-5,1-cyclopropane] -2-one (second elution isomer) preparation 3-amino- 1-Methyl-1,2,3,4-tetrahydrospiro [1-benzazepine-5,1-cyclopropane] -2-one hydrochloride (90 mg, crude), with the following conditions: Column: Phenomenex Lux cellulose-4 , AXIA Packed, 2.12 × 25 cm, 5 μm; Mobile Phase A: Hexane (0.1% DEA), Mobile Phase B: EtOH; Flow: 20 mL / min; Gradient: 35% B ~ 35% B over 17.5 minutes; 220 Separation by preparative chiral HPLC using / 254 nm; RT1: 11.24 min; RT2: 13.82 min; to give the title compound.</p><p> The first eluted isomer: (36 mg, 38%) was obtained as a white solid. LC-MS (Method D): m / z = 217.2 [M + H]⁺, 1.096 minutes.</p><p> Second elution isomer: (46 mg, 48%) was obtained as a white solid. LC-MS (Method D): m / z = 217.2 [M + H]⁺, 1.089 minutes.</p><p> Step 5: (S) -5-benzyl-N- (1-methyl-2-oxo-1,2,3,4-tetrahydrospiro [benzo [b] azepine-5,1'-cyclopropane] -3- Il) -4H-1,2,4-Triazole-3-Carboxamide preparation The crude product obtained using amide coupling procedure C is subjected to the following conditions: column, Xbridge Phenyl OBD column, 5 μm, 19 × 150mm; mobile phase, water (10 mmol / L NH)₄HCO₃) And ACN (50.0% ACN ~ 70.0% in 7 minutes); purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.20 (d, J = 7.5 Hz, 1H), 7.45-7.32 (m, 2H), 7.35-7.20 (m, 7H), 4.46-4.36 (m, 1H), 4.07 (s, 2H), 3.30 ( s, 3H), 2.71-2.65 (m, 1H), 1.57 (t, J = 12.6 Hz, 1H), 1.10-1.07 (m, 1H), 0.75-0.63 (m, 2H), 0.42-0.37 (m, 1H) .LC-MS (Method D): m / z = 402.2 [M + H]⁺, 1.871 minutes.</p><p> Example 45: (S) -1-benzyl-4-fluoro-5-methyl-N- (4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl ) -1H-Pyrazole-3-carboxamide<chemistry num="146"><img file="JP6974331B2_D0180.tif" /></chemistry> Step 1: Preparation of (3S) -3-amino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one hydrochloride N-((3S) -4-oxo-2, Add tert-butyl carbamic acid (100 mg, 0.36 mmol) 3,4,5-tetrahydro-1,5-benzooxazepine-3-yl) to a 1,4-dioxane solution (4M, 5 mL) of hydrogen chloride. bottom. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give the title compound (100 mg, crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method E): m / z = 178.9 [M + H]⁺, 0.397 minutes.</p><p> Step 2: (S) -1-benzyl-4-fluoro-5-methyl-N- (4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) Preparation of -1H-pyrazole-3-carboxamide The crude product obtained using the amide coupling procedure B is subjected to the following conditions: Column: Xbridge Prep C18OBD Column 19 × 150 mm 5 μm; Mobile phase A: Water (10 mmol /) L NH₄HCO₃), Mobile phase B: ACN; flow rate: 30 mL / min; gradient: 15% B ~ 45% B; 254 nm; at 10 min; purified by preparative HPLC. The collected fractions were combined and concentrated under reduced pressure to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 10.15 (s, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.43-7.28 (m, 3H), 7.20-7.09 (m, 6H), 5.39 (s, 2H), 4.80 (dt, J = 10.0, 7.3 Hz, 1H), 4.53-4.39 (m, 2H), 2.17 (d, J = 1.4 Hz, 3H) .LC-MS (Method F): m / z = 395.0 [M + H]⁺, 2.860 minutes.</p><p> Example 46: 5-Benzyl-N-((2S) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl ) -4H-1,2,4-triazole-3-carboxamide<chemistry num="147"><img file="JP6974331B2_D0181.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: Xbridge Prep C18OBD Column, 5 μm, 19 × 150 mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN Flow: 20 mL / min; Gradient: Purification by preparative HPLC using 35% B ~ 65% B; 254/220 nm; over 7 minutes to give the title compound. LC-MS (Method J): m / z = 388.2 [M + H]⁺, 1.305 minutes.</p><p> 5-benzyl-N- {7-methyl-6-oxo-7-azatricyclo [6.4.0.0 ^ {2,4}] dodeca-1 (8), 9,11-triene-5-yl} -4H-1 , 2,4-Triazole-3-carboxamide enantiomer, under the following conditions: Column: CHIRALPAK IC, 2.0 cm × 25 cm (5 μm); Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient Separation by preparative chiral HPLC using: 50% B to 50% B; 254/220 nm; RT1: 10.478 minutes; RT2: 13.826 minutes; over 30 minutes to give the title compound:</p><p> Example 46A (first elution isomer):¹H NMR (400 MHz, chloroform-d) δ 8.54 (d, J = 7.1 Hz, 1H), 7.39-7.17 (m, 8H), 7.11 (d, J = 7.5 Hz, 1H), 4.80 (d, J = 7.0 Hz, 1H), 4.22 (s, 2H), 3.35 (s, 3H), 2.28-1.80 (m, 2H), 1.21 (m, 1H), 1.04 (m, 1H) .LC-MS (Method J) : m / z = 388.2 [M + H] +, 1.302 minutes.</p><p> Example 46B (second elution isomer):¹H NMR (400 MHz, chloroform-d) δ 8.53 (d, J = 7.1 Hz, 1H), 7.39-7.18 (m, 8H), 7.12 (d, J = 7.7 Hz, 1H), 4.80 (d, J = 7.0 Hz, 1H), 4.23 (s, 2H), 3.35 (s, 3H), 2.09 (m, 1H), 2.02 (m, 1H), 1.21 (m, 1H), 1.05 (m, 1H) .LC- MS (Method J): m / z = 388.2 [M + H]⁺, 1.306 minutes.</p><p> Example 47: (S) -4-Fluoro-5-Methyl-N- (4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -1- (1-Phenylcyclopropyl) -1H-Pyrazole-3-Carboxamide<chemistry num="148"><img file="JP6974331B2_D0182.tif" /></chemistry> Example 48: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (3-Phenyl) Oxetane-3-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="149"><img file="JP6974331B2_D0183.tif" /></chemistry> Example 49: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (Phenylsulfonyl) Thiazole-2-carboxamide<chemistry num="150"><img file="JP6974331B2_D0184.tif" /></chemistry> Step 1: Preparation of ethyl 5- (phenylthio) thiazole-2-carboxylate 1 of 5-iodo-1,3-thiazole-2-ethyl carboxylate (300 mg, 1.06 mmol), sodium benzenethiolate (220 mg, 1.66 mmol) -Carboxylic iodide (40 mg, 0.21 mmol) was added to the stirred mixture in methyl-2-pyrrolidinone (10 mL) under an argon atmosphere. The resulting solution was stirred at 70 ° C. for 4 hours, quenched with water (20 mL) and extracted with ethyl acetate (4 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative TLC (ethyl acetate / petroleum ether, 5/1) to give the title compound (120 mg, 43%) as a yellow oil. LC-MS (Method S): m / z = 266.0 [M + H]⁺, 1.040 minutes.</p><p> Step 2: Preparation of ethyl 5- (phenylsulfonyl) thiazole-2-carboxylate In a stirred mixture of ethyl 5- (phenylthio) thiazole-2-carboxylate (100 mg, 0.38 mmol) in dichloromethane (4 mL), 3-chloro. Peroxybenzoic acid (167 mg, 0.97 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/5) to give the title compound (100 mg, 88%) as a yellow oil. LC-MS (Method S): m / z = 298.0 [M + H]⁺, 0.931 minutes.</p><p> Step 3: Preparation of 5- (phenylsulfonyl) thiazole-2-carboxylic acid Stirring mixture of ethyl 5- (phenylsulfonyl) thiazole-2-carboxylate (100 mg, 0.34 mmol) in tetrahydrofuran (3 mL) and water (1 mL). Lithium hydroxide (12 mg, 0.50 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The residue was diluted with water (10 mL) and adjusted to pH = 6 with aqueous hydrochloric acid (1N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (90 mg, crude) as a white oil, which was used directly in the next step without further purification. LC-MS (Method E): m / z = 270.0 [M + H]⁺, 0.635 minutes.</p><p> Step 4: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (Phenylsulfonyl) Thiazole -2- Preparation of carboxamide The crude product obtained using the amide coupling procedure B is subjected to the following conditions: Column: Xbridge Prep C18, 19 × 150 mm, 5 μm; Mobile phase: Phase A: Water (10 mmol / L) NH₄HCO₃); Phase B: ACN (20% -80% over 12 minutes); Purified by preparative HPLC using a detector, UV220 &amp; 254nm; to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 9.24 (br. S, 1H), 8.76 (s, 1H), 8.10-8.01 (m, 2H), 7.82-7.63 (m, 3H), 7.52-7.44 (m, 1H), 7.38-7.17 (m) , 3H), 4.83-4.70 (m, 1H), 4.71-4.59 (m, 1H), 4.45-4.32 (m, 1H), 3.30 (s, 3H). LC-MS (Method O): m / z = 443.9 [M + H]⁺, 1.594 minutes.</p><p> Example 50: (1R, 2S) -2-benzyl-N-((S) -5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3 -Il) Cyclopropane-1-Carboxamide<chemistry num="151"><img file="JP6974331B2_D0185.tif" /></chemistry> Step 1: Preparation of (±) -trans-2-benzylcyclopropanecarboxylic acid Sodium hydroxide (60%, 74 mg, 1.84 mmol), 2-benzylcyclopropanecarboxylic acid (±) -trans-ethyl (200 mg, 0.74) mmol) was added to a solution of methanol (12 mL) and water (6 mL). The reaction mixture was stirred at room temperature overnight. After removing methanol under reduced pressure, the pH value of the solution was adjusted to 6 with aqueous hydrochloric acid (1N, 10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (95 mg, 73%) as a yellow oil. LC-MS (Method I): m / z = 177.0 [M + H]⁺, 0.877 minutes.</p><p> Step 2: Trans-2-benzyl-N-((S) -5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) cyclopropane Preparation of Carboxamide The crude product obtained using the amide coupling procedure C was subjected to the following conditions: column, Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol / L NH).₄HCO₃) And ACN (40.0% ACN ~ 65.0% over 8 minutes); detector, UV254nm; purified by preparative HPLC to give the title compound. LC-MS (Method J): m / z = 351.1 [M + H]⁺, 2.116 minutes.</p><p> Step 3: (1R, 2S) -2-benzyl-N-((S) -5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3- Il) Cyclopropane Carboxamide and (1S, 2R) -2-benzyl-N-((S) -5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine -3-yl) Preparation of cyclopropanecarboxamide Trans2-benzyl-N-((S) -5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine- 3-Il) Cyclopropane carboxamide diastereomers under the following conditions: Column: Phenomenex Lux Cellulose-4, AXIA Packed, 2.12 × 25 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 20 mL / Minutes; Gradient: 30% B to 30% B over 12 minutes; 254/220 nm; RT1: 7.474 minutes; RT2: 8.916 minutes; separated by preparative chiral HPLC using to give the title compound:</p><p> Example 50A (first elution isomer):¹H NMR (400 MHz, chloroform-d) δ 7.31-7.23 (m, 2H), 7.24-7.11 (m, 7H), 6.65 (d, J = 6.4 Hz, 1H), 4.94-4.85 (m, 1H), 4.69-4.61 (m, 1H), 4.18-4.09 (m, 1H), 3.44 (s, 3H), 2.79-2.71 (m, 1H), 2.58-2.50 (m, 1H), 1.57 (s, 1H), 1.37-1.33 (m, 1H), 1.20-1.16 (m, 1H), 0.80-0.75 (m, 1H) .LC-MS (Method J): m / z = 351.1 [M + H]⁺, 2.116 minutes.</p><p> Example 50B (second elution isomer):¹H NMR (400 MHz, chloroform-d) δ 7.31-7.26 (m, 2H), 7.21-7.13 (m, 7H), 6.59 (d, J = 6.4 Hz, 1H), 4.95-4.84 (m, 1H), 4.69-4.58 (m, 1H), 4.16-4.09 (m, 1H), 3.43 (s, 3H), 2.79-2.70 (m, 1H), 2.63-2.54 (m, 1H), 1.67-1.57 (m, 1H) ), 1.37-1.32 (m, 1H), 1.17-1.13 (m, 1H), 0.78-0.73 (m, 1H) .LC-MS (Method J): m / z = 351.1 [M + H]⁺, 1.451 minutes.</p><p> Example 51: 5- (2,3-dihydro-1H-inden-1-yl) -N-((S) -5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="152"><img file="JP6974331B2_D0186.tif" /></chemistry> Step 1: Preparation of 2,3-dihydro-1H-inden-1-carbohydrazide Hydrazine in tetrahydrofuran (1M, 31 mL, 31 mmol), 2,3-dihydro-1H-inden-1-carboxylic acid (1.0 g,) 6.2 mmol), 2- (7-aza-1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (2.8 g, 7.4 mmol) and ethyldiisopropylamine (2.4 g) , 18.6 mmol) added to a solution of N, N-dimethylformamide (20 mL). After stirring at room temperature for 1 hour, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (0.87 g, 80%) as a white solid. LC-MS (Method E): m / z = 177.0 [M + H]⁺, 0.506 minutes.</p><p> Step 2: Preparation of 2-amino-2- (2- (2,3-dihydro-1H-inden-1-carbonyl) hydrazono) ethyl acetate 2-ethoxy-2-iminoethyl acetate (412 mg, 2.8 mmol), 2,3-Dihydro-1H-inden-1-carbohydrazide (500 mg, 2.8 mmol) was added to ethanol (5 mL) and diethyl ether (5 mL) solutions. The resulting suspension was stirred at room temperature for 2 hours. The solid was removed by filtration and the filtrate was concentrated under vacuum to give the title compound (600 mg, 78%) as a yellow solid. LC-MS (Method S): m / z = 276.2 [M + H]⁺, 0.709 minutes.</p><p> Step 3: Preparation of 5- (2,3-dihydro-1H-inden-1-yl) -4H-1,2,4-triazole-3-ethyl carboxylate 2-amino-2- (2- (2,,) 3-Dihydro-1H-inden-1-carbonyl) hydrazono) ethyl acetate (600 mg, 2.2 mmol) was added to xylene (10 mL) in a closed tube. The reaction mixture was heated at 170 ° C. for 5 hours by microwave irradiation. After concentration under high vacuum, the residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (340 mg, 60%) as a yellow oil. LC-MS (Method I): m / z = 258.1 [M + H]⁺, 0.848 minutes.</p><p> Step 4: Preparation of 5- (2,3-dihydro-1H-inden-1-yl) -4H-1,2,4-triazole-3-carboxylic acid Lithium hydroxide (95.3 mg, 4.0 mmol) 5- Addition of (2,3-dihydro-1H-inden-1-yl) -4H-1,2,4-triazole-3-ethyl carboxylate (340 mg, 1.3 mmol) to a solution of tetrahydrofuran (6 mL) and water (3 mL). bottom. After stirring at room temperature for 4 hours and removing tetrahydrofuran under reduced pressure, the reaction mixture is diluted with water (20 mL), the pH is adjusted to 2 with aqueous hydrochloric acid (1N, 20 mL) and with ethyl acetate (3 x 50 mL). Extracted. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (140 mg, 47%) as a yellow solid. LC-MS (Method E): m / z = 229.9 [M + H]⁺, 0.642 minutes.</p><p> Step 5: 5- (2,3-dihydro-1H-inden-1-yl) -N-((S) -5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [ 1,4] Oxazepine-3-yl) -4H-1,2,4-Triazole-3-Carboxamide preparation The crude product obtained using the amide coupling procedure B is subjected to the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: Purification by preparative HPLC using 25% B ~ 50% B; 254 nm; over 10 minutes to give the title compound.¹H NMR (400 MHz, chloroform-d) δ 8.12 (d, J = 7.2 Hz, 1H), 7.33 (d, J = 7.2, 1H), 7.29-7.19 (m, 6H), 5.17-5.06 (m, 1H) ), 4.77-4.67 (m, 2H), 4.34-4.27 (m, 1H), 3.45 (s, 3H), 3.16-3.01 (m, 2H), 2.68-2.63 (m, 1H), 2.46-2.39 (m) , 1H) .LC-MS (Method J): m / z = 404.3 [M + H]⁺, 1.332 minutes.</p><p> Example 52: (S) -5-benzyl-N- (5,6-dihydro-4H-benzo [f] imidazole [1,2-a] azepine-4-yl) -4H-1,2,4- Triazole-3-carboxamide<chemistry num="153"><img file="JP6974331B2_D0187.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: column, XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase, water (0.05% TFA) and ACN (7 minutes). 10.0% ACN ~ 40.0%); purified by preparative HPLC using a detector, UV220 &amp; 254nm; to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 14.43 (s, 1H), 8.67 (s, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.53-7.47 (m, 3H), 7.46-7.22 (m, 6H), 7.04 (d, J = 1.5 Hz, 1H), 4.87-4.77 (m, 1H), 4.14 (s, 2H), 2.80-2.73 (m, 1H), 2.67-2.56 (m, 1H), 2.46-2.32 (m, 2H) .LC-MS (Method O): m / z = 385.0 [M + H]⁺, 1.229 minutes.</p><p> Example 53: 3-Benzyl-N- (8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrrolo [1,2-a] [1,3] diazepine- 3-Il) -1H-1,2,4-triazole-5-carboxamide<chemistry num="154"><img file="JP6974331B2_D0188.tif" /></chemistry> Examples 54A and 54B: 5-((R) -2,3-dihydro-1H-inden-1-yl) -N-((S) -5-methyl-4-oxo-2,3,4,5 -Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide and 5-((S) -2,3-dihydro- 1H-inden-1-yl) -N-((S) -5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3 -Il) -4H-1,2,4-triazole-3-carboxamide<chemistry num="155"><img file="JP6974331B2_D0189.tif" /></chemistry><chemistry num="156"><img file="JP6974331B2_D0190.tif" /></chemistry> Step 1: 5- (2,3-dihydro-1H-inden-1-yl) -N-((S) -5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3, 2-b] [1,4] Oxazepine-3-yl) -4H-1,2,4-Triazole-3-Carboxamide Preparation A toluene (2M, 0.6 mL, 1.2 mmol) solution of trimethylaluminum (S) -3-Amino-5-Methyl-2,3-dihydropyrido [3,2-b] [1,4] Oxazepine-4 (5H) -one hydrochloride (60 mg, 0.26 mmol) in toluene (2 mL) Was added dropwise at 0 ° C. The resulting solution was warmed to room temperature and stirred for 30 minutes. A solution of ethyl 5- (2,3-dihydro-1H-inden-1-yl) -4H-1,2,4-triazole-3-carboxylate (108 mg, 0.42 mmol) in toluene (2 mL) was obtained. Dropped into. The resulting solution was stirred at room temperature overnight. The solution was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined and concentrated under vacuum. Residues under the following conditions: Column: XBridge Prep Phenyl OBD column 19 × 150mm, 5mm; mobile phase A: water (0.05% NH)₃H₂O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 25% B to 50% B over 7 minutes; 254 nm; Rt: 6 min; purified by preparative HPLC using the title compound. (25 mg, 23.8%) was obtained as a white solid. LC-MS (Method D): m / z = 405.1 [M + H]⁺, 1.759 minutes.</p><p> Step 2: 5-((R) -2,3-dihydro-1H-inden-1-yl) -N-((S) -5-methyl-4-oxo-2,3,4,5-tetrahydropyri Do [3,2-b] [1,4] Oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide and 5-((S) -2,3-dihydro-1H-inden -1-yl) -N-((S) -5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl) Preparation of -4H-1,2,4-triazole-3-carboxamide 5- (2,3-dihydro-1H-inden-1-yl) -N-((S) -5-methyl-4-oxo-2 , 3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide (25 mg) under the following conditions : Column: Chilarpak IA, 2 × 25 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 16 mL / min; gradient: 50% B to 50% B over 40 minutes; 220/254 nm; RT 1: 9.716 min Separation by preparative chiral HPLC using RT2: 29.084 min; to give the title compound:</p><p> 54A (first elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 8.36-8.35 (m, 1H), 7.70-7.68 (m, 1H), 7.34-7.31 (m, 2H), 7.25-7.24 (m, 1H), 7.22-7.19 (m, 1H), 7.16-7.07 (m, 1H), 5.07-5.02 (m, 1H), 4.72-4.65 (m, 2H), 4.55-4.50 (m, 1H), 3.49 (s, 3H), 3.18-3.15 (m, 1H), 3.07 -3.05 (m, 1H), 2.65-2.62 (m, 1H), 2.43-2.38 (m, 1H) .LC-MS (Method T): m / z = 405.3 [M + H]⁺, 1.296 minutes.</p><p> 54B (second elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 8.36-8.35 (m, 1H), 7.70-7.68 (m, 1H), 7.34-7.31 (m, 2H), 7.25-7.24 (m, 1H), 7.22-7.19 (m, 1H), 7.16-7.07 (m, 1H), 5.07-5.02 (m, 1H), 4.72-4.65 (m, 2H), 4.55-4.50 (m, 1H), 3.49 (s, 3H), 3.18-3.15 (m, 1H), 3.07 -3.05 (m, 1H), 2.65-2.62 (m, 1H), 2.43-2.38 (m, 1H) .LC-MS (Method T): m / z = 405.3 [M + H]⁺, 1.301 minutes.</p><p> Example 55: (S) -4-Fluoro-N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -1- (Pyridine-2-ylmethyl) -1H-pyrazole-3-carboxamide<chemistry num="157"><img file="JP6974331B2_D0191.tif" /></chemistry> Step 1: Preparation of 4-fluoro-1H-pyrazole-3-carboxylate ethyl 1- (chloromethyl) -4-fluoro-1,4-diazonia-bicyclo [2.2.2] octanetetrafluoroborate (14 g, 39.5 mmol) ) Was added to a mixture of ethyl 1H-pyrazole-3-carboxylate (5 g, 35.7 mmol) in acetonitrile (50 mL). The resulting mixture was stirred at 100 ° C. for 48 hours. After cooling to room temperature, the solid was removed by filtration and the filtrate was concentrated under vacuum to give the title compound (2.4 g) as a yellow solid. LC-MS (Method S): m / z = 159.2 [M + H]⁺, 0.639 minutes.</p><p> Step 2: Preparation of 4-fluoro-1- (pyridine-2-ylmethyl) -1H-pyrazole-3-carboxylic acid Sodium hydride (60%, 506 mg, 12.7 mmol), 4-fluoro-1H-pyrazole-3 -Ethyl carboxylate (500 mg, 3.2 mmol) was added to a solution of N, N-dimethylformamide (10 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 0.5 hours and then 2- (bromomethyl) pyridine (600 mg, 3.5 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours and quenched by the addition of water (10 mL). The resulting solution was stirred at room temperature for 5 hours. The pH was adjusted to 7 with aqueous hydrochloric acid (1N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (360 mg, 72%). LC-MS (Method I): m / z = 221.9 [M + H]⁺, 0.320 minutes.</p><p> Step 3: (S) -4-Fluoro-N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -1-( Preparation of Pyridine-2-ylmethyl) -1H-Pyrazole-3-Carboxamide The crude product obtained using amide coupling procedure C is subjected to the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B ~ 45% B; 254/220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.56-8.55 (m, 1H), 8.16-8.15 (d, J = 4.4 Hz, 1H), 8.11-8.09 (m, 1H), 7.83-7.82 (m, 1H), 7.51-7.49 (m, 1H) ), 7.34-7.28 (m, 3H), 7.24-7.20 (m, 2H), 5.46 (s, 2H), 4.91-4.78 (m, 1H), 4.58-4.53 (m, 1H), 4.41-4.37 (m) , 1H), 3.33 (s, 3H) .LC-MS (Method F): m / z = 396.1 [M + H]⁺, 0.924 minutes.</p><p> Example 56: (S) -5-benzyl-N- (9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl )-2H-1,2,4-triazole-3-carboxamide<chemistry num="158"><img file="JP6974331B2_D0192.tif" /></chemistry> Step 1: 9-Cyano-5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-ylcarbamic acid (S) -tert-butyl 9-chloro -5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-ylcarbamic acid (S) -tert-butyl (200 mg, 0.61 mmol) and cyanide To a mixture of zinc (300 mg, 2.59 mmol) in tetrahydrofuran (2 mL) and water (10 mL), tBuXPhos precatalyst 3rd generation (244 mg, 0.31 mmol) and t-BuXPhos (130 mg, 0.31 mmol) were added under a nitrogen atmosphere. bottom. The reaction mixture was diluted with water (50 mL) stirred overnight at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/6) to give the title compound (150 mg, 78%) as a white solid. LC-MS (Method E): m / z = 262.0 [M + H-56]⁺, 0.853 minutes.</p><p> Step 2: Preparation of (S) -3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-9-carbonitrile hydrochloride of hydrogen chloride 1,4-Dioxane solution (4N, 10 mL), 9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-ylcarbamic acid It was added to a solution of (S) -tert-butyl (90 mg, 0.28 mmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated under vacuum to give the title compound (55 mg) as a white solid. LC-MS (Method E): m / z = 218.0 [M + H]⁺, 0.551 minutes.</p><p> Step 3: (S) -5-benzyl-N- (9-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) Preparation of -4H-1,2,4-triazole-3-carboxamide The crude product obtained using amide coupling procedure C is subjected to the following conditions: column, Xbridge Phenyl OBD column, 5 μm, 19 × 150 mm; Mobile phase, water (10 mmol / L NH)₄HCO₃) And ACN (50.0% ACN ~ 70.0% over 7 minutes); purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 14.20 (s, 1H), 8.55 (s, 1H), 7.81 (dd, J = 8.2, 1.5 Hz, 1H), 7.72 (dd, J = 7.8, 1.5 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.35-7.14 (m, 5H), 4.94-4.74 (m, 2H), 4.58-4.47 (m, 1H), 4.10 (s, 2H), 3.30 (s, 3H) .LC-MS (Method F): m / z = 403.0 [M + H]⁺, 1.069 minutes.</p><p> Example 57: (S) -1-benzyl-4-fluoro-N- (4-oxo-2,3,4,5-tetrahydropyrazole [3,2-b] [1,4] oxazepine-3- Ill) -1H-pyrazole-3-carboxamide<chemistry num="159"><img file="JP6974331B2_D0193.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: X Bridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (0.1% formic acid), Mobile phase B : ACN; Flow rate: 20 mL / min; Gradient: Purification by preparative HPLC using 25% B-60% B; UV254 &amp; 220 nm; over 7 minutes to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.17-8.13 (m, 2H), 7.56 (dd, J = 7.6, 1.2 Hz, 1H), 7.41-7.31 (m, 3H), 7.30-7.27 (m, 2H), 7.19-7.15 (m, 1H), 5.35 (s, 2H), 4.83-4.77 (m, 1H), 4.53-4.42 (m, 2H) .LC-MS ( Method V): m / z = 382.1 [M + H]⁺, 2.321 minutes. Example 58: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (1-Phenyl) Cyclopropyl) -1,3,4-thiadiazole-2-carboxamide<chemistry num="160"><img file="JP6974331B2_D0194.tif" /></chemistry></p><p> Step 1: Preparation of 5- (1-phenylcyclopropyl) -1,3,4-thiadiazole-2-amine 1-Phenylcyclopropanecarboxylic acid (1.6 g, 10 mmol) and N-aminothiourea (0.91 g, 10 mmol) The mixture in phosphoryl trichloride (10 mL) was heated at 70 ° C. for 1 hour and then cooled to room temperature. Water (100 mL) was added. The reaction mixture was heated to 70 ° C and stirred for 5 hours. The pH value of the resulting solution was adjusted to 8 with saturated aqueous sodium hydroxide (30 mL). The solid was collected by filtration to give the title compound (1.9 g, 87%) as a white solid. LC-MS (Method Q): m / z = 218.1 [M + H]⁺, 0.817 minutes.</p><p> Step 2: Preparation of 2-bromo-5- (1-phenylcyclopropyl) -1,3,4-thiadiazole 2- (1-phenylcyclopropyl) -1,3,4-thiadiazole-2-amine (1.1 g) , 5.0 mmol) to the mixture in acetonitrile (20 mL) was added cupric bromide (2.2 g, 10 mmol). The resulting mixture was stirred at room temperature for 15 minutes and then tert-butyl nitrite (1.5 mL, 10 mmol) was added dropwise at room temperature over 15 minutes. The reaction mixture was heated at 60 ° C., stirred for 16 hours and then water (50 mL) was added. The solid was removed by filtration and the filtrate was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/10) to give the title compound (1.0 g, 70%) as a yellow solid. LC-MS (Method K): m / z = 281.0 [M + H]⁺, 1.107 minutes.</p><p> Step 3: Preparation of 5- (1-phenylcyclopropyl) -1,3,4-thiadiazole-2-ethyl carboxylate bis (triphenylphosphine) palladium (II) (277 mg, 0.395 mmol), 2-bromo -5- (1-Phenylcyclopropyl) -1,3,4-thiadiazole (1.0 g, 3.57 mmol) and triethylamine (879 mg, 8.70 mmol) were added to the mixture in methanol (20 mL). After stirring at 100 ° C for 16 hours under a carbon monoxide atmosphere (50 atm), the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/20) to give the title compound (600 mg, 61%) as a yellow solid. LC-MS (Method E): m / z = 261.1 [M + H]⁺, 0.923 minutes.</p><p> Step 4: Preparation of 5- (1-Phenylcyclopropyl) -1,3,4-Thiadiazol-2-carboxylic acid Lithium hydroxide (5.4 mg, 2.0 mmol), 5- (1-phenylcyclopropyl) -1 , 3,4-Thiadiazol-2-carboxylate ethyl (100 mg, 0.41 mmol) was added to a solution of tetrahydrofuran (9 mL) and water (3 mL). The resulting mixture was stirred at room temperature for 2 hours. After removing tetrahydrofuran under reduced pressure, the pH value of the solution was adjusted to 3-4 with aqueous hydrochloric acid (1N, 20 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (80 mg, 76%) as a yellow oil. LC-MS (Method C): m / z = 247.0 [M + H]⁺, 1.288 minutes.</p><p> Step 5: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (1-Phenylcyclo) Preparation of propyl) -1,3,4-thiadiazole-2-carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: Xbridge Prep C18, 19 × 150 mm 5 μm; Mobile phase : Water (10 mmol / L NH₄HCO₃) And ACN (20% -80% in 12 minutes); purified by preparative HPLC using a detector, UV220 &amp; 254nm; to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 9.20 (s, 1H), 7.49-7.18 (m, 9H), 4.77-4.75 (m, 1H), 4.69-4.62 (m, 1H), 4.41-4.35 (m, 1H), 3.27 (s, 3H) ), 1.82-1.76 (m, 2H), 1.66-1.57 (m, 2H) .LC-MS (Method V): m / z = 421.1 [M + H]⁺, 3.918 minutes.</p><p> Example 59: 5-Benzyl-N-[(3S) -1-methyl-2-oxo-1,2,3,4-tetrahydrospiro [1-benzazepine-5,1-cyclopropane] -3-yl] -1H-pyrazole-3-carboxamide<chemistry num="161"><img file="JP6974331B2_D0195.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: column, Xbridge Phenyl OBD column, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol / L NH).₄HCO₃) And ACN (50.0% ACN ~ 70.0% over 7 minutes); purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 13.15 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.45-7.36 (m, 2H), 7.35-7.18 (m, 7H), 6.34 (s, 1H), 4.46-4.36 ( m, 1H), 3.97 (s, 2H), 3.29 (s, 3H), 2.72-2.64 (m, 1H), 1.51 (t, J = 12.0 Hz, 1H), 1.10-1.04 (m, 1H), 0.74 -0.66 (m, 2H), 0.43-0.37 (m, 1H) .LC-MS (Method D): m / z = 401.2 [M + H]⁺, 1.994 minutes.</p><p> Examples 60A and 60B: 5-benzyl-N-((1aS, 2S, 8bR) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] ] Azepine-2-yl) -1H-pyrazole-3-carboxamide (60A) and 5-benzyl-N-((1aR, 2R, 8bS) -4-methyl-3-oxo-1,1a, 2,3, 4,8b-Hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) -1H-pyrazole-3-carboxamide (60B)<chemistry num="162"><img file="JP6974331B2_D0196.tif" /></chemistry> Step 1: 5-Benzyl-N- (4-Methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) -1H-pyrazole -3-Preparation of carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (0.05% TFA) , Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 35% B to 65% B; 254/220 nm; purified by preparative HPLC over 7 minutes to give the title compound. LC-MS (Method I): m / z = 387.2 [M + H]⁺, 1.405 minutes.</p><p> Step 2: 5-benzyl-N-((1aS, 2S, 8bR) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine- 2-yl) -1H-pyrazole-3-carboxamide (first elution isomer) and 5-benzyl-N-((1aR, 2R, 8bS) -4-methyl-3-oxo-1,1a, 2,3 , 4,8b-Hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) -1H-pyrazole-3-carboxamide (second elution isomer) preparation 5-benzyl-N- {7-methyl-6 -Oxo-7-azatricyclo [6.4.0.0 ^ {2,4}] dodeca-1 (8), 9,11-triene-5-yl} -1H-pyrazole-3-carboxamide (30 mg, 0.077 mmol), The following conditions: Column: CHIRALPAK IC, 2.0 cm × 25 cm (5 μm); Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 50% B to 50% B over 30 minutes Separation by preparative chiral HPLC using 254/220 nm; RT1: 10.478 min; RT2: 13.826 min; to give the title compound:</p><p> Example 60A (first elution isomer):¹1 H NMR (300 MHz, chloroform-d) δ 8.47 (d, J = 7.7 Hz, 1H), 7.41-7.08 (m, 9H), 6.57 (s, 1H), 4.85 (d, J = 7.6 Hz, 1H) , 4.04 (s, 2H), 3.32 (s, 3H), 2.18-1.92 (m, 2H), 1.16-0.88 (m, 2H) .LC-MS (Method J): m / z = 387.2 [M + H ]⁺, 2.043 minutes.</p><p> Example 60B (second elution isomer):¹1 H NMR (300 MHz, chloroform-d) δ 8.29 (s, 1H), 7.39-7.05 (m, 9H), 6.53 (s, 1H), 4.85 (d, J = 7.6 Hz, 1H), 4.04 (s, 2H), 3.31 (s, 3H), 2.18-1.92 (m, 2H), 1.16-1.07 (m, 1H), 1.02-0.89 (m, 1H). LC-MS (Method J): m / z = 387.2 [M + H]⁺, 1.409 minutes.</p><p> Example 61: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -2- (1-Phenyl) Cyclopropyl) Oxazole-4-Carboxamide<chemistry num="163"><img file="JP6974331B2_D0197.tif" /></chemistry> Step 1: Preparation of 1-Phenylcyclopropanecarboxamide Thionyl chloride (6 g, 50.0 mmol) was added dropwise at 0 ° C to a stirred solution of 1-phenylcyclopropanecarboxylic acid (1.62 g, 10.0 mmol) in dichloromethane (10 mL). The resulting solution was stirred at room temperature for 5 hours and the reaction mixture was concentrated under high vacuum. The residue was then added dropwise to ammonium hydroxide (28%, 50 mL) at 0 ° C. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (1.50 g, 93%) as a yellow solid. LC-MS (Method I): m / z = 162.1 [M + H]⁺, 0.725 minutes.</p><p> Step 2: Preparation of 2- (1-phenylcyclopropyl) oxazole-4-ethyl carboxylate ethyl 3-bromo-2-oxopropanoate (970 mg, 5.0 mmol) and 1-phenylcyclo-propanecarboxamide (810 mg, 5.0 mmol) ) In ethanol (10 mL) was heated at 80 ° C for 16 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium carbonate (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/10) to give the title compound (420 mg, 33%) as a white solid. LC-MS (Method C): m / z = 258.1 [M + H]⁺, 1.527 minutes.</p><p> Step 3: Preparation of 2- (1-phenylcyclopropyl) oxazole-4-carboxylic acid Lithium hydroxide (5.4 mg, 2.02 mmol), 2- (1-phenylcyclopropyl) oxazole-4-carboxylate (100 mg) , 0.39 mmol) to a mixture of tetrahydrofuran (9 mL) and water (3 mL). The reaction mixture was stirred at room temperature for 16 hours. After removing tetrahydrofuran under reduced pressure, the pH value of the solution was adjusted to 6 with aqueous hydrochloric acid (1N, 5 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (67 mg, 76%) as a yellow oil. LC-MS (Method C): m / z = 230.1 [M + H]⁺, 1.291 minutes.</p><p> Step 4: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -2- (1-Phenylcyclo) Preparation of propyl) Oxazole-4-Carboxamide The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: Xbridge Prep C18, 19 × 150 mm, 5 μm; Mobile phase: Phase A: Water ( 10 mmol / L NH₄HCO₃); Phase B: ACN (20% -80% over 12 minutes); Purified by preparative HPLC using a detector, UV220 &amp; 254nm; to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.49-7.19 (m, 9H), 4.85-4.76 (m, 1H), 4.57-4.50 (m, 1H), 4.39- 4.33 (m, 1H), 3.29 (s, 3H), 1.61-1.58 (m, 2H), 1.42-1.38 (m, 2H) .LC-MS (Method D): m / z = 404.2 [M + H]⁺, 2.148 minutes.</p><p> Example 62: (S) -N- (4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl) -5- (1- Phenylcyclopropyl) Isoxazole-3-Carboxamide<chemistry num="164"><img file="JP6974331B2_D0198.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: X Select CSH Prep C18OBD Column, 5 μm, 19 × 150 mm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B : ACN; Flow rate: 20 mL / min; Gradient: 35% B ~ 70% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 10.54 (s, 1H), 8.93 (d, J = 8.0 Hz, 1H), 8.15 (dd, J = 4.4, 1.2 Hz, 1H), 7.55 (dd, J = 8.0, 1.2 Hz, 1H), 7.41 -7.29 (m, 5H), 7.17 (dd, J = 8.0, 4.8 Hz, 1H), 6.41 (s, 1H), 4.85-4.78 (m, 1H), 4.53-4.42 (m, 2H), 1.58-1.43 (m, 4H) .LC-MS (Method D): m / z = 391.1 [M + H]⁺, 1.981 minutes.</p><p> Example 63: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -5 -(1-Phenylcyclopropyl) Thiazole-2-Carboxamide<chemistry num="165"><img file="JP6974331B2_D0199.tif" /></chemistry> Step 1: Preparation of (1-phenylcyclopropyl) methanol A solution of borane in tetrahydrofuran (1M, 60 mL, 60 mmol) to a solution of 1-phenylcyclopropanecarboxylic acid (6.5 g, 40 mmol) in tetrahydrofuran (40 mL) at 0 ° C. Added slowly. The reaction mixture was stirred at room temperature for 2 hours, quenched with water (50 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (5.5 g, 93%) as a colorless oil. LC-MS (Method C): m / z = 131.2 [MH₂O + H]⁺, 1.125 minutes.</p><p> Step 2: Preparation of 1-Phenylcyclopropanecarbaldehyde Dess-Martin peryodinane (35.6 g, 84 mmol) at 0 ° C in a solution of (1-phenylcyclopropyl) methanol (5.4 g, 42 mmol) in dichloromethane (40 mL). Was added in. The resulting mixture was stirred at 0 ° C for 1.5 hours. The solid was removed by filtration and the filtrate was concentrated under vacuum. The obtained residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/10) to give the title compound (4.4 g, 72%) as a colorless oil. LC-MS (Method C): m / z = 147.2 [M + H]⁺, 1.215 minutes.</p><p> Step 3: Preparation of (E)-(1- (2-methoxyvinyl) cyclopropyl) benzene Potassium 2-methylpropane-2 in a solution of triphenylphosphonium (22.4 g, 65 mmol) in tetrahydrofuran (30 mL) -A solution of olate in tetrahydrofuran (1M, 65mL, 65 mmol) was added at 0 ° C. The resulting mixture was stirred at 0 ° C. for 0.5 hours, followed by the addition of 1-phenylcyclopropanecarbaldehyde (4.2 g, 29 mmol). The reaction mixture was stirred at room temperature for 1 hour, quenched by the addition of water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (20 g, crude) as a yellow oil, which was then refined without further purification. Used directly in the step.</p><p> Step 4: Preparation of 2-bromo-2- (1-phenylcyclopropyl) acetaldehyde (E)-(1- (2-Methoxyvinyl) cyclopropyl) benzene (3.8 g, 22 mmol) in tetrahydrofuran (20 mL) and water ( To the 2 mL) solution was added N-bromosuccinimide (4.3 g, 24 mmol) at -20 ° C. The solution was stirred at -20 ° C for 1 hour and concentrated to give the title compound (8 g, crude) as a yellow oil, which was used directly in the next step without further purification.</p><p> Step 5: Preparation of ethyl 5- (1-phenylcyclopropyl) thiazole-2-carboxylate 2-amino in ethanol (20 mL) solution of 2-bromo-2- (1-phenylcyclopropyl) acetaldehyde (2 g, 8 mmol) -2-Ethyl thioxoacetate (1.1 g, 8 mmol) was added. The reaction mixture was stirred at 80 ° C. for 4 hours and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/5) to give the title compound (310 mg, 14%) as a yellow oil. LC-MS (Method I): m / z = 274.0 [M + H]⁺, 1.034 minutes.</p><p> Step 6: Preparation of 5- (1-phenylcyclopropyl) thiazole-2-carboxylic acid Lithium hydroxide (52.8 mg, 2.2 mmol), 5- (1-phenylcyclopropyl) thiazole-2-carboxylate (100 mg) , 0.36 mmol) in tetrahydrofuran (2 mL) and water (1 mL). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure and diluted with water (10 mL). The resulting mixture was adjusted to pH = 5 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (49 mg, 56%) as a yellow oil, which without further purification. , Used directly in the next step. LC-MS (Method C): m / z = 246.1 [M + H]⁺, 1.200 minutes.</p><p> Step 7: S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -5-( The crude product obtained using the 1-phenylcyclopropyl) thiazole-2-carboxamide amide coupling procedure C was subjected to the following conditions: Column: Xbridge Prep C18, 19 × 250 mm, 5 μm; Mobile phase: Phase A: Water (10 mmol / L NH₄HCO₃); Phase B: ACN (45% -65% over 7 minutes); Purified by preparative HPLC using a detector, UV220 &amp; 254nm; to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.95 (d, J = 7.5 Hz, 1H), 8.36 (dd, J = 4.7, 1.6 Hz, 1H), 7.74 (s, 1H), 7.70 (dd, J = 7.9, 1.6 Hz, 1H), 7.40 -7.23 (m, 6H), 4.88-4.71 (m, 2H), 4.52 (dd, J = 9.1, 6.7 Hz, 1H), 3.35 (s, 3H), 1.47 (s, 4H) .LC-MS (method) T): m / z = 421.3 [M + H]⁺, 1.729 minutes.</p><p> Example 64: (S) -1-benzyl-4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl ) -1H-Pyrazole-3-carboxamide<chemistry num="166"><img file="JP6974331B2_D0200.tif" /></chemistry> Step 1: Preparation of 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid Sodium hydride (60%, 1 g, 25 mmol), 4-fluoro-1H-pyrazole-3-carboxylate (1.2 g) , 7.6 mmol) to a solution of N, N-dimethylformamide (20 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 0.5 hours, followed by the addition of benzyl bromide (1.36 g, 8.0 mmol). The resulting mixture was stirred at room temperature for 2 hours. Water (20 mL) was added dropwise. The resulting solution was then stirred at room temperature for 5 hours. The pH value of the solution was adjusted to 7 with aqueous hydrochloric acid (1N, 20 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue, then the following conditions: Column: XBridge C18OBD preparative column, 5 μm, 19 mm × 250 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30% B-60% B over 7 minutes; Purification by preparative HPLC using 254 nm; gave the title compound (370 mg, 22%) as a white solid. LC-MS (Method D): m / z = 221.1 [M + H]⁺, 1.206 minutes.</p><p> Step 2: (S) -1-benzyl-4-fluoro-N- (5-methyl-4-oxo-2,3,4,5, tetrahydrobenzo [b] [1,4] oxazepine-3-yl)- Preparation of 1H-pyrazole-3-carboxamide The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: Xbridge Prep C18OBD Column 19 × 150 mm, 5 μm; Mobile phase A: Water (0.05%) NH₃H₂O), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 25% B to 55% B over 7 minutes; detector, purified by preparative HPLC using UV220 &amp; 254 nm; to obtain the title compound. rice field.¹H NMR (400 MHz, chloroform-d) δ 7.66 (d, J = 6.8 Hz, 1H), 7.43-7.40 (m, 3H), 7.39-7.21 (m, 6H), 5.26 (s, 2H), 5.13- 5.07 (m, 1H), 4.83-4.81 (m, 1H), 4.31-4.26 (m, 1H), 3.47 (s, 3H) .LC-MS (Method J): m / z = 395.2 [M + H]⁺, 1.474 minutes.</p><p> Example 65: N-[(4S, 9aR) -5-oxo-octahydropyrrolo [2,1-c] [1,4] oxazepine-4-yl] -5-benzyl-4H-1,2,4 -Triazole-3-carboxamide<chemistry num="167"><img file="JP6974331B2_D0201.tif" /></chemistry> The title compound was prepared from N-Boc-D-prolinol using the procedure described in Example 27.</p><p> The crude product is purified by column chromatography on KP-NH modified silica gel (CH).₂Cl₂-MeOH, 97: 3 ~ 90: 10), the title compound was obtained.¹H NMR (400MHz, CDCl₃) δ 8.31 (d, J = 6.3 Hz, 1H), 7.37-7.23 (m, 5H), 4.90 (ddd, J = 9.3, 6.3, 2.8 Hz, 1H), 4.21 (s, 2H), 4.17 (dd, J = 11.7, 2.6 Hz, 1H), 4.09 (q, J = 8.8 Hz, 1H), 3.98 (d, J = 12.5 Hz, 1H), 3.93-3.82 (m, 1H), 3.52-3.39 (m, 2H) ), 3.24 (dd, J = 12.8, 9.3 Hz, 1H), 2.33-2.17 (m, 1H), 2.01-1.90 (m, 1H), 1.87-1.70 (m, 1H), 1.66-1.51 (m, 1H) ). LC-MS (Method A): m / z = 356.4 [M + H]⁺, 0.71 minutes.</p><p> Example 66: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -5 -(1-Phenylcyclopropyl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="168"><img file="JP6974331B2_D0202.tif" /></chemistry> Step 1: Preparation of 1-Phenylcyclopropane Carbohydrazide Triethylamine (93.5 g, 925.5 mmol) was added to a stirred mixture of hydrazine dihydrochloride (32.1 g, 308.6 mmol) in N, N-dimethylformamide (300 mL). .. The resulting mixture was mixed with 1-phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol), O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexa. Fluorophosphate (28.2 g, 74.0 mmol) and N, N-diisopropylethylamine (23.9 g, 185.1 mmol) were added to the mixture in N, N-dimethylformamide (100 mL). The reaction mixture was stirred at room temperature for 2 hours, diluted with water (500 mL) and extracted with ethyl acetate (5 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (6 g, 55.2%) as a white solid. LC-MS (Method E): m / z = 177.0 [M + H]⁺, 1.139 minutes.</p><p> Step 2: Preparation of 2-oxo-2- (2- (1-phenylcyclopropanecarbonyl) hydrazide) ethyl acetate 2-chloro-2-oxoethyl acetate (1.56 g, 11.4 mmol), 1-phenylcyclopropanecarbocarbonate Hydrazide (2.00 g, 11.4 mmol) and triethylamine (3.44 g, 34.1 mmol) were added to a stirring solution of dichloromethane (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 hours, quenched by the addition of water (40 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (3 g, 96.7%) as a yellow oil. LC-MS (Method E): m / z = 277.0 [M + H]⁺, 0.676 minutes.</p><p> Step 3: Preparation of ethyl 5- (1-phenylcyclopropyl) -1,3,4-oxadiazole-2-carboxylate Tosyl chloride (0.80 g, 3.62 mmol), 2-oxo-2- (2-oxo-2-) (1-Phenylcyclopropanecarbonyl) Hydradinyl) Ethyl acetate (1.0 g, 3.62 mmol) and triethylamine (1.1 g, 6.6 mmol) were added to a stirred solution of dichloromethane (25 mL). The reaction mixture was stirred at room temperature for 12 hours, quenched by the addition of water (20 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (0.80 g, 85.6%) as a yellow oil. LC-MS (Method C): m / z = 259.0 [M + H]⁺, 1.457 minutes.</p><p> Step 4: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -5- Preparation of (1-Phenylcyclopropyl) -1,3,4-oxadiazole-2-carboxamide The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase, water (10 mmol / L NH)₄HCO₃), ACN (40% ACN ~ 70% B in 7 minutes); Purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.37-8.35 (m, 1H), 7.71-7.69 (m, 1H), 7.42-7.30 (m, 6H), 4.82-4.80 (m, 1H), 4.75-4.73 (m) , 1H), 4.54-4.50 (m, 1H), 3.33 (s, 3H), 1.70-1.69 (m, 2H), 1.54-1.50 (m, 2H). LC-MS (Method T): m / z = 406.3 [M + H]⁺, 2.463 minutes.</p><p> Examples 67A and 67B: 5-Benzyl-N-((1aR, 2S, 8bS) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] ] Azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide (67A) and 5-benzyl-N-((1aS, 2R, 8bR) -4-methyl-3-oxo-1, 1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide (67B)<chemistry num="169"><img file="JP6974331B2_D0203.tif" /></chemistry> Step 1: Preparation of tert-butyl carbamic acid (trans-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) Sis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) tert-butyl carbamic acid (100 mg, 0.33 mmol) The 1,8-diazabicyclo [5.4.0] undec-7-ene solution was stirred at 90 ° C overnight. The solution was purified by TLC (ethyl acetate / petroleum ether, 1/8) to give the title compound (60 mg, 60%) as a yellow solid. LC-MS (Method E): m / z = 325.0 [M + Na]⁺, 0.930 minutes.</p><p> Step 2: Preparation of trans-2-amino-4-methyl-1,1a,2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one hydrochloride (trans-4-methyl-3) -Oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) tert-butyl carbamic acid (60 mg, 0.20 mmol) 1,4-dioxane (2 mL) ) A solution of hydrogen chloride in 1,4-dioxane (4M, 5 mL, 20 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours and concentrated under high vacuum to give the title compound (40 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS (Method S): m / z = 203.3 [M + H]⁺, 0.592 minutes.</p><p> Step 3: Trans-5-benzyl-N- (4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) -4H Preparation of -1,2,4-triazole-3-carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase A: Water (0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 35% B to 65% B over 7 minutes; 254/220 nm; purified by preparative HPLC. , The title compound was obtained. LC-MS (Method J): m / z = 388.2 [M + H]⁺, 1.305 minutes.</p><p> Step 7: 5-benzyl-N-((1aR, 2S, 8bS) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine- 2-yl) -4H-1,2,4-triazole-3-carboxamide (first elution isomer) and 5-benzyl-N-((1aS, 2R, 8bR) -4-methyl-3-oxo-1) , 1a,2,3,4,8b-Hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide (second elution isomer) Trans-5-benzyl-N- (4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) -4H-1, Enantiomer of 2,4-triazole-3-carboxamide (25 mg, 0.065 mmol) under the following conditions: Column: Chilarpak ID-2, 2 × 25 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 17 mL / min; Gradient: 50% B ~ 50% B over 22 minutes; UV254 &amp; 220 nm; RT1: 11.72 min Separation by preparative chiral HPLC using RT2: 18.02 min; to give the title compound.</p><p> Example 67A (first elution isomer):¹1 H NMR (300 MHz, Methanol-d₄) δ 7.56 (d, J = 7.5 Hz, 1H), 7.42-7.19 (m, 9H), 4.23-4.13 (m, 3H), 3.43 (s, 3H), 2.25-2.15 (m, 1H), 1.72- 1.58 (m, 1H), 1.25-1.13 (m, 1H), 0.79-0.65 (m, 1H) .LC-MS (Method D): m / z = 388.2 [M + H]⁺, 1.806 minutes.</p><p> Example 67B (second elution isomer):¹1 H NMR (300 MHz, Methanol-d₄) δ 7.56 (d, J = 7.5 Hz, 1H), 7.42-7.19 (m, 9H), 4.23-4.13 (m, 3H), 3.43 (s, 3H), 2.25-2.15 (m, 1H), 1.72- 1.58 (m, 1H), 1.25-1.13 (m, 1H), 0.79-0.65 (m, 1H) .LC-MS (Method D): m / z = 388.2 [M + H]⁺, 1.812 minutes.</p><p> Example 68A: (R) -5-benzyl-N- (4,5-dihydrobenzo [b] imidazole [1,2-d] [1,4] oxazepine-4-yl) -4H-1,2, 4-Triazole-3-Carboxamide<chemistry num="170"><img file="JP6974331B2_D0204.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: Xbridge Prep C18OBD Column 19 × 150 mm 5 μm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; flow rate: 30 mL / min; gradient: 25% B to 55% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 14.42 (s, 1H), 8.80 (br. S, 1H), 7.70-7.64 (m, 2H), 7.43-7.25 (m, 8H), 7.07 (d, J = 1.2 Hz, 1H), 5.40- 5.29 (m, 1H), 4.64-4.49 (m, 2H), 4.14 (s, 2H) .LC-MS (Method D): m / z = 387.1 [M + H]⁺, 1.322 minutes.</p><p> Example 68 B: (S) -5-benzyl-N- (4,5-dihydrobenzo [b] imidazole [1,2-d] [1,4] oxazepine-4-yl) -4H-1,2, 4-Triazole-3-Carboxamide<chemistry num="171"><img file="JP6974331B2_D0205.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: Xbridge Prep C18OBD Column 19 × 150 mm 5 μm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; flow rate: 30 mL / min; gradient: 25% B to 55% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 14.39 (s, 1H), 8.80 (s, 1H), 7.70-7.65 (m, 2H), 7.41-7.22 (m, 8H), 7.07 (d, J = 1.2 Hz, 1H), 5.40-5.31 ( m, 1H), 4.64-4.49 (m, 2H), 4.14 (s, 2H) .LC-MS (Method D): m / z = 387.1 [M + H]⁺, 1.325 minutes.</p><p> Examples 69A and 69B: (S) -5-benzyl-N- (5,6-dihydro-4H-benzo [f] [1,2,4] triazolo [4,3-a] azepine-4-yl) -4H-1,2,4-triazole-3-carboxamide (69A) and (R) -5-benzyl-N- (5,6-dihydro-4H-benzo [f] [1,2,4] triazolo [ 4,3-a] Azepine-4-yl) -4H-1,2,4-triazole-3-carboxamide (69B)<chemistry num="172"><img file="JP6974331B2_D0206.tif" /></chemistry> Step 1: (5,6-dihydro-4H-benzo [f] [1,2,4] triazolo [4,3-a] azepine-4-yl) Preparation of benzyl carbamate Formylhydrazine (0.54 g, 9 mmol) In a stirred solution of (S) -benzyl (2-thioxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-ylcarbamate (1.00 g, 3 mmol) in 1-butanol (15 mL). Added. After stirring at 60 ° C for 1 hour and 150 ° C for 15 hours, the reaction mixture was concentrated under high vacuum, diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with salt water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (1/3). 0.64 g, 63%) was obtained as a white solid. LC-MS (Method E): m / z = 335.1 [M + H]⁺, 0.746 minutes.</p><p> Step 2: Preparation of 5,6-dihydro-4H-benzo [f] [1,2,4] triazolo [4,3-a] azepine-4-amine in methanol (20 mL), (5,6-dihydro- 4H-benzo [f] [1,2,4] triazolo [4,3-a] azepine-4-yl) benzyl carbamate (0.63 g, 1.9 mmol) under hydrogen atmosphere (2 to 3 atmospheres), palladium Hydrogenated in the presence of carrying carbon (10%, 0.2 g). The reaction mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The solid was removed by filtration and the filtrate was concentrated under high vacuum to give the title compound (0.36 g, 95%) as a colorless oil. LC-MS (Method C): m / z = 201.1 [M + H]⁺, 0.848 minutes.</p><p> Step 3: (S) -5,6-dihydro-4H-benzo [f] [1,2,4] triazolo [4,3-a] azepine-4-amine and (R) -5,6-dihydro- Preparation of 4H-benzo [f] [1,2,4] triazolo [4,3-a] azepine-4-amine 5,6-dihydro-4H-benzo [f] [1,2,4] triazolo [4] , 3-a] Azepine-4-amine (0.36 g, 1.8 mmol) enantiomer, under the following conditions: Column: Chiral pak IC, 2 × 25 cm, 5 μm; Mobile phase A: MTBE, Mobile phase B: EtOH; Flow rate: Separation by preparative chiral HPLC using 15 mL / min; gradient: 60% B to 60% B over 23 minutes; 220/254 nm; RT1: 12.04 min; RT2: 20.81 min; to give the title compound. ..</p><p> (S) -5,6-dihydro-4H-benzo [f] [1,2,4] triazolo [4,3-a] azepine-4-amine (first elution isomer): 110 mg (62%) Obtained as a white solid. LC-MS (Method C): m / z = 201.1 [M + H]⁺, 0.848 minutes.</p><p> (R) -5,6-dihydro-4H-benzo [f] [1,2,4] triazolo [4,3-a] azepine-4-amine (second elution isomer): 110 mg (62%) Obtained as a white solid. LC-MS (Method C): m / z = 201.1 [M + H]⁺, 0.848 minutes.</p><p> Step 4: (S) -5-benzyl-N- (5,6-dihydro-4H-benzo [f] [1,2,4] triazolo [4,3-a] azepine-4-yl) -4H- Preparation of 1,2,4-Triazole-3-Carboxamide The crude product obtained using amide coupling procedure C is subjected to the following conditions: Column: XBridge C18OBD preparative column, 100 Å, 5 μm, 19 mm × 250 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B ~ 40% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 14.39 (s, 1H), 8.93 (m, 2H), 7.62-7.59 (m, 1H), 7.56-7.43 (m, 3H), 7.38-7.23 (m, 5H), 5.02-4.92 (m, 1H) ), 4.14 (s, 2H), 2.84-2.77 (m, 1H), 2.60-2.55 (m, 1H), 2.48-2.40 (m, 2H). LC-MS (Method D): m / z = 386.2 [ M + H]⁺, 1.489 minutes.</p><p> Example 69B: (R) -5-benzyl-N- (5,6-dihydro-4H-benzo [f] [1,2,4] triazolo [4,3-a] azepine-4-yl) -4H -1,2,4-triazole-3-carboxamide<chemistry num="173"><img file="JP6974331B2_D0207.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: X Bridge C18OBD preparative column, 100 Å, 5 μm, 19 mm × 250 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B ~ 40% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 14.39 (s, 1H), 8.93 (m, 2H), 7.62-7.59 (m, 1H), 7.56-7.43 (m, 3H), 7.37-7.22 (m, 5H), 5.02-4.92 (m, 1H) ), 4.14 (s, 2H), 2.84-2.73 (m, 1H), 2.58-2.54 (m, 1H), 2.48-2.41 (m, 2H). LC-MS (Method D): m / z = 386.2 [ M + H]⁺, 1.486 minutes.</p><p> Example 70A: (R) -5-benzyl-N- (4,5-dihydrobenzo [b] imidazole [1,2-d] [1,4] oxazepine-4-yl) isoxazole-3-carboxamide<chemistry num="174"><img file="JP6974331B2_D0208.tif" /></chemistry> Step 1: Preparation of (4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) carbamic acid (S) -benzyl of potassium carbonate (4.8 g, 35 mmol) A solution of water (9 mL), (S) -3-amino-2,3-dihydrobenzo [b] [1,4] oxazepine-4 (5H) -on hydrochloride (1.5 g, 7 mmol) in dichloromethane (70 mL) It was added to the solution and then benzyl chloronate (1.8 g, 10.5 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was collected by filtration, washed with water (20 mL) and dried under high vacuum to give the title compound (1.44 g, 66%) as a white solid. LC-MS (Method C): m / z = 313.1 [M + H]⁺, 1.365 minutes.</p><p> Step 2: Preparation of 4-thioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-ylcarbamic acid (S) -benzyl Lawesson's reagent (2.43 g, 6 mmol), 4 -Oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-ylcarbamic acid (S) -benzyl (1.9 g, 6 mmol) added to a solution of tetrahydrofuran (50 mL) and reacted. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (1.85 g, crude) as a pale yellow solid. LC-MS (Method E): m / z = 351.0 [M + Na]⁺, 0.946 minutes.</p><p> Step 3: Preparation of 4- (2,2-dimethoxyethylamino) -2,3-dihydrobenzo [b] [1,4] -oxazepine-3-ylcarbamic acid (R) -benzyl 2,2-dimethoxyethane Amine (2.37 g, 22.6 mmol), 4-thioxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-ylcarbamic acid (S) -benzyl (1.85 g, 5.65 mmol) ) And ferric chloride (2.0 g, 7.35 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at 55 ° C. for 2 hours and cooled to room temperature. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (2.20 g, 98%) as a pale yellow oil. LC-MS (Method C): m / z = 400.2 [M + H]⁺, 1.157 minutes.</p><p> Step 4: Preparation of (4,5-dihydrobenzo [b] imidazole [1,2-d] [1,4] oxazepine-4-yl) benzyl carbamate 4- (2,2-dimethoxyethylamino) -2 , 3-Dihydrobenzo [b] [1,4] -oxazepine-3-ylcarbamic acid (R) -benzyl (2.2 g, 5.5 mmol) formic acid (15 mL, 96%) solution stirred at 100 ° C for 2 hours. bottom. The black precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with water (50 mL), basified to pH = 6 with aqueous sodium hydroxide (1N, 30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (0.45 g, 24%) as a white solid. LC-MS (Method E): m / z = 336.0 [M + H]⁺, 0.655 minutes.</p><p> Step 5: (S)-(4,5-dihydrobenzo [b] imidazo [1,2-d] [1,4] oxazepine-4-yl) benzyl carbamate (first elution isomer) and (R) -(4,5-Dihydrobenzo [b] imidazo [1,2-d] [1,4] oxazepine-4-yl) Preparation of benzyl carbamate (second elution isomer) (4,5-dihydrobenzo [4,5-dihydrobenzo [, b] Imidazo [1,2-d] [1,4] oxazepine-4-yl) benzyl carbamate (450 mg, 1.35 mmol) enantiomer, under the following conditions: Column: CHIRALPAK-IC-SFC, 5 cm x 25 cm (5 cm x 25 mmol) 5 μm); Mobile phase A: CO₂ 50%, mobile phase B: MeOH: 50%; flow rate: 150 mL / min; 220 nm; RT1: 5.65 min; RT2: 6.91 min; separated by SFC to give the title compound:</p><p> (S)-(4,5-Dihydrobenzo [b] imidazole [1,2-d] [1,4] oxazepine-4-yl) benzyl carbamate: (250 mg, 56%) was obtained as a white solid. LC-MS (Method E): m / z = 336.0 [M + H]⁺, 0.655 minutes.</p><p> (R)-(4,5-dihydrobenzo [b] imidazole [1,2-d] [1,4] oxazepine-4-yl) benzyl carbamate (second elution isomer): (200 mg, 45%) Was obtained as a white solid. LC-MS (Method E): m / z = 336.0 [M + H]⁺, 0.655 minutes.</p><p> Step 6: Preparation of (R) -4,5-dihydrobenzo [b] imidazole [1,2-d] [1,4] oxazepine-4-amine in methanol (20 mL), (R)-(4,5) -Dihydrobenzo [b] imidazo [1,2-d] [1,4] oxazepine-4-yl) benzyl carbamate (0.25 g, 0.75 mmol) under hydrogen atmosphere (2 to 3 atmospheres), palladium-bearing carbon Hydrogenated in the presence of (10%, 0.5 g). The reaction mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The solid was removed by filtration and the filtrate was concentrated under high vacuum to give the title compound (0.14 g, 93%) as a white solid. LC-MS (Method C): m / z = 202.1 [M + H]⁺, 0.758 minutes.</p><p> Step 7: Preparation of (R) -5-benzyl-N- (4,5-dihydrobenzo [b] imidazole [1,2-d] [1,4] oxazepine-4-yl) isooxazole-3-carboxamide The crude product obtained using amide coupling procedure C was subjected to the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B ~ 65% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 9.24 (d, J = 8.7 Hz, 1H), 7.71-7.65 (m, 2H), 7.40-7.28 (m, 8H), 7.07 (d, J = 1.2 Hz, 1H), 6.59 (s, 1H) , 5.43-5.34 (m, 1H), 4.61-4.46 (m, 2H), 4.24 (s, 2H) .LC-MS (Method D): m / z = 387.1 [M + H]⁺, 1.579 minutes.</p><p> Example 70B: (S) -5-benzyl-N- (4,5-dihydrobenzo [b] imidazole [1,2-d] [1,4] oxazepine-4-yl) isoxazole-3-carboxamide<chemistry num="175"><img file="JP6974331B2_D0209.tif" /></chemistry> Step 1: Preparation of (S) -4,5-dihydrobenzo [b] imidazole [1,2-d] [1,4] oxazepine-4-amine in methanol (20 mL), (S)-(4,5) -Dihydrobenzo [b] imidazo [1,2-d] [1,4] oxazepine-4-yl) benzyl carbamate (0.2 g, 0.6 mmol) under hydrogen atmosphere (2 to 3 atmospheres), palladium-bearing carbon Hydrogenated in the presence of (10%, 0.2 g). The reaction mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. The solid was removed by filtration and the filtrate was concentrated under high vacuum to give the title compound (0.11 g, 92%) as a white solid. LC-MS (Method C): m / z = 202.1 [M + H]⁺, 0.758 minutes.</p><p> Step 2: Preparation of (S) -5-benzyl-N- (4,5-dihydrobenzo [b] imidazole [1,2-d] [1,4] oxazepine-4-yl) isooxazole-3-carboxamide The crude product obtained using amide coupling procedure C was subjected to the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 45% B to 57% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 9.24 (d, J = 8.4 Hz, 1H), 7.71-7.65 (m, 2H), 7.42-7.28 (m, 8H), 7.07 (d, J = 1.5 Hz, 1H), 6.59 (s, 1H) , 5.43-5.34 (m, 1H), 4.62-4.45 (m, 2H), 4.24 (s, 2H) .LC-MS (Method V): m / z = 387.1 [M + H]⁺, 2.491 minutes.</p><p> Example 71A: (S) -5-benzyl-N- (5,6-dihydro-4H-benzo [f] [1,2,4] triazolo [4,3-a] azepine-4-yl) isooxazole -3-Carboxamide<chemistry num="176"><img file="JP6974331B2_D0210.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B ~ 58% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 9.36 (d, J = 8.4 Hz, 1H), 8.93 (s, 1H), 7.62-7.59 (m, 1H), 7.55-7.43 (m, 3H), 7.40-7.26 (m, 5H), 6.58 ( s, 1H), 5.01-4.92 (m, 1H), 4.24 (s, 2H), 2.86-2.77 (m, 1H), 2.49-2.39 (m, 3H) .LC-MS (Method D): m / z = 386.2 [M + H]⁺, 1.805 minutes.</p><p> Example 71B: (R) -5-benzyl-N- (5,6-dihydro-4H-benzo [f] [1,2,4] triazolo [4,3-a] azepine-4-yl) isooxazole -3-Carboxamide<chemistry num="177"><img file="JP6974331B2_D0211.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B-60% B over 7 minutes; UV254 &amp; 220 nm; purified by preparative HPLC to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 9.36 (d, J = 8.1 Hz, 1H), 8.93 (s, 1H), 7.63-7.59 (m, 1H), 7.55-7.43 (m, 3H), 7.40-7.26 (m, 5H), 6.58 ( s, 1H), 5.01-4.92 (m, 1H), 4.24 (s, 2H), 2.86-2.77 (m, 1H), 2.49-2.38 (m, 3H) .LC-MS (Method D): m / z = 386.2 [M + H]⁺, 1.809 minutes.</p><p> Example 72: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (1-Phenyl) Cyclopropyl) -1H-pyrazole-3-carboxamide<chemistry num="178"><img file="JP6974331B2_D0212.tif" /></chemistry> Step 1: Preparation of N-methoxy-N-methyl-1-phenylcyclopropanecarboxamide N, N-diisopropylethylamine (47.2 g, 219.6 mmol), 1-phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol), O , N-dimethylhydroxylamine hydrochloride (6.5 g, 67.8 mmol), N- (3-dimethylaminopropyl))-N'-ethylcarboxamide hydrochloride (14.2 g, 73.9 mmol) and 1-hydroxybenzotriazole (10.0 g) , 73.9 mmol) to the mixture in N, N-dimethylformamide (60 mL). The resulting mixture was stirred at room temperature overnight, diluted with water (300 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/20) to give the title compound (11.2 g, 89.6%) as a colorless oil. LC-MS (Method K): m / z = 206.0 [M + H]⁺, 1.489 minutes.</p><p> Step 2: Preparation of 1- (1-Phenylcyclopropyl) Etanone In a solution of methylmagnesium bromide (3M, 14 mL, 42 mmol) in tetrahydrofuran, N-methoxy-N-methyl-1-phenylcyclopropanecarboxamide (11.2 g, 24.4). A solution of mmol) in tetrahydrofuran (50 mL) was added at 0 ° C. The resulting mixture was stirred at room temperature overnight, quenched with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/20) to give the title compound (7.4 g, 85%) as a colorless oil. LC-MS (Method E): m / z = 161.0 [M + H]⁺, 0.889 minutes.</p><p> Step 3: Preparation of ethyl 2,4-dioxo-4- (1-phenylcyclopropyl) butanoate 1- (1-phenylcyclopropyl) etanone (1.92 g, 12 mmol) and diethyl oxalate (2.1 g, 14.4 mmol) To the mixture in toluene (8 mL) was added potassium 2-methylpropan-2-olate (1.7 g, 15.6 mmol) at 0 ° C. The resulting mixture was stirred at room temperature for 4 hours and concentrated under vacuum. The residue was diluted with water (20 mL). The resulting mixture was neutralized to pH = 6 with aqueous hydrochloric acid (1N) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/10) to give the title compound (1.95 g, 61%) as a yellow solid. LC-MS (Method S): m / z = 261.2 [M + H]⁺, 1.076 minutes.</p><p> Step 4: Preparation of 5- (1-phenylcyclopropyl) -1H-pyrazole-3-ethyl carboxylate Ethanol 2,4-dioxo-4- (1-phenylcyclopropyl) ethyl butanoate (800 mg, 3.0 mmol) Hydrazin hydrate (80% aqueous solution, 200 mg, 3.0 mmol) was added to the (8 mL) solution. The reaction mixture was stirred at 80 ° C. for 1.5 hours and concentrated under vacuum. The obtained residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (550 mg, 70%) as a yellow solid. LC-MS (Method K): m / z = 256.7 [M + H]⁺, 1.640 minutes.</p><p> Step 5: Preparation of 5- (1-phenylcyclopropyl) -1H-pyrazole-3-carboxylic acid Ethyl 5- (1-phenylcyclopropyl) -1H-pyrazole-3-carboxylate (470 mg, 1.8 mmol) in methanol Sodium hydroxide (432 mg, 10.8 mmol) was added to the (4.5 mL) and water (1.5 mL) solutions. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was diluted with water (20 mL), adjusted to pH = 5 using aqueous hydrochloric acid (1N) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (280 mg, crude) as a yellow solid, which was the next step without further purification. Used directly in. LC-MS (Method K): m / z = 228.7 [M + H]⁺, 1.434 minutes.</p><p> Step 6: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (1-Phenylcyclo) Preparation of propyl) -1H-pyrazole-3-carboxamide The crude product obtained using amide coupling procedure C is subjected to the following conditions: Column: XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase, water. (10 mmol / L NH₄HCO₃), ACN (40% ACN ~ 65% B over 7 minutes); Purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) 13.16 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.55-7.46 (m, 1H), 7.38-7.17 (m, 8H), 6.34 (s, 1H), 4.93-4.75 (m) , 1H), 4.60-4.28 (m, 2H), 3.31 (s, 3H), 1.39-1.16 (m, 4H) .LC-MS (Method O): m / z = 403.05 [M + H]⁺, 1.511 minutes.</p><p> Example 73: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -5 -(1-Phenylcyclopropyl) -1H-pyrazole-3-carboxamide<chemistry num="179"><img file="JP6974331B2_D0213.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: X Bridge C18OBD preparative column, 100 Å, 5 μm, 19 mm × 250 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B ~ 50% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 13.18 (s, 1H), 8.38-8.35 (m, 1H), 8.24 (d, J = 7.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.36-7.20 (m, 6H), 6.54- 6.35 (m, 1H), 4.90-4.80 (m, 1H), 4.70-4.62 (m, 1H), 4.53-4.46 (m, 1H), 3.35 (s, 3H), 1.34-1.30 (m, 4H). LC-MS (Method D): m / z = 404.2 [M + H]⁺, 1.872 minutes.</p><p> Example 74: (S) -4-Fluoro-N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3- Il) -1- (pyridin-2-ylmethyl) -1H-pyrazole-3-carboxamide<chemistry num="180"><img file="JP6974331B2_D0214.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 5% B to 57% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.56 (d, J = 4.8 Hz, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 4.4 Hz, 1H) ), 7.87-7.77 (m, 1H), 7.70 (dd, J = 8.0, 1.6 Hz, 1H), 7.38-7.31 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H), 5.47 (s, 2H), 4.88-4.80 (m, 1H), 4.71-4.64 (m, 1H), 4.52-4.47 (m, 1H), 3.35 (s, 3H) .LC-MS (Method V): m / z = 397.1 [M + H]⁺, 2.159 minutes.</p><p> Examples 75A and 75B: 5-Benzyl-N-((1aS, 2S, 8bR) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido] 2,3-b] Azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide (75A) and 5-benzyl-N-((1aR, 2R, 8bS) -4-methyl-3 -Oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide (75B)<chemistry num="181"><img file="JP6974331B2_D0215.tif" /></chemistry> Step 1: 5-Benzyl-N- (cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2 -Il) -4H-1,2,4-Triazole-3-Carboxamide preparation Crude products obtained using amide coupling procedure C under the following conditions: Column: Xbridge Prep C18, 19 × 150 mm, 5 μm; mobile phase: phase A: water (10 mmol / L NH)₄HCO₃); Phase B: ACN (20% -80% over 12 minutes); Purified by preparative HPLC using a detector, UV220 &amp; 254 nm; to give the title compound (55 mg, 44.3%) as a white solid. LC-MS (Method C): m / z = 389.2 [M + H]⁺, 1.111 minutes.</p><p> Step 2: 5-benzyl-N-((1aR, 2R, 8bS) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3] -b] Azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide (first elution isomer) and 5-benzyl-N-((1aS, 2S, 8bR) -4-methyl- 3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) -4H-1,2,4-triazole-3- Preparation of carboxamide (second elution isomer)<chemistry num="182"><img file="JP6974331B2_D0216.tif" /></chemistry> 5-benzyl-N- (cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepin-2-yl) -4H-1,2,4-triazole-3-carboxamide (55 mg, 0.14 mmol) enantiomer, under the following conditions: Column: Chiralpak IC, 2 × 25 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: EtOH Flow: 19 mL / min; Gradient: 35% B to 35% B over 18.5 min; UV220 &amp; 254 nm; RT1: 13.00 min; RT2: 15.67 min; rice field:</p><p> Example 75B (first elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 14.37 (s, 1H), 8.46 (d, J = 7.2 Hz, 1H), 8.40-8.38 (m, 1H), 8.02-7.98 (m, 1H), 7.35-7.25 (m, 6H), 4.46 ( d, J = 7.2 Hz, 1H), 4.16 (s, 2H), 3.30 (s, 3H), 2.33-2.26 (m, 1H), 2.05-1.99 (m, 1H), 1.21-1.14 (m, 1H) , 1.11-1.04 (m, 1H) .LC-MS (Method D): m / z = 389.2 [M + H]⁺, 1.651 minutes.</p><p> Example 75A (second elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, J = 7.2 Hz, 1H), 8.40-8.38 (m, 1H), 8.02-7.98 (m, 1H), 7.38-7.23 (m, 6H), 4.46 (d, J = 7.2 Hz, 1H), 4.14 (s, 2H), 3.30 (s, 3H), 2.32-2.26 (m, 1H), 2.06-1.99 (m, 1H), 1.20-1.15 (m, 1H), 1.10-1.04 (m, 1H) .LC-MS (Method D): m / z = 389.2 [M + H]⁺, 1.656 minutes. Example 76: (S) -1-benzyl-4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyridol [3,2-b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="183"><img file="JP6974331B2_D0217.tif" /></chemistry></p><p> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: Purified by preparative HPLC using 32% B ~ 54% B; UV254 &amp; 220 nm; over 7 minutes to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.37 (dd, J = 4.5, 1.5 Hz, 1H), 8.26 (d, J = 7.5 Hz, 1H), 8.15 (d, J = 4.5 Hz, 1H), 7.71 (dd, J = 8.1, 1.8 Hz) , 1H), 7.43-7.27 (m, 6H), 5.36 (s, 2H), 4.90-4.80 (m, 1H), 4.73-4.65 (m, 1H), 4.55-4.48 (m, 1H), 3.36 (s) , 3H) .LC-MS (Method D): m / z = 396.1 [M + H]⁺, 1.893 minutes.</p><p> Example 77: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -5 -(1-Phenylcyclopropyl) Isoxazole-3-Carboxamide<chemistry num="184"><img file="JP6974331B2_D0218.tif" /></chemistry> Step 1: Preparation of ethyl 5- (1-phenylcyclopropyl) isoxazole-3-carboxylate 2,4-Dioxo-4- (1-phenylcyclopropyl) Ethyl butanoate (970 mg, 3.7 mmol) in ethanol (10 mL) ) Was added hydroxylamine hydrochloride (255 mg, 3.7 mmol). The reaction mixture was heated to reflux and stirred for 4 hours. Upon concentration under reduced pressure, the residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/5) to give the title compound (260 mg, 27%) as a yellow solid. LC-MS (Method K): m / z = 258.1 [M]⁺, 1.603 minutes.</p><p> Step 2: Preparation of 5- (1-phenylcyclopropyl) isoxazole-3-carboxylic acid Ethyl 5- (1-phenylcyclopropyl) isoxazole-3-carboxylate (100 mg, 0.39 mmol) in methanol (3 mL) and Sodium hydroxide (93 mg, 2.33 mmol) was added to the water (1 mL) solution. The resulting mixture was stirred at room temperature overnight, concentrated to dryness and diluted with water (10 mL). The reaction mixture was adjusted to pH = 5 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (80 mg, crude) as a yellow solid. LC-MS (Method E): m / z = 229.9 [M + H]⁺, 0.840 minutes.</p><p> Step 3: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -5- Preparation of (1-Phenylcyclopropyl) Isoxazole-3-Carboxamide The crude product obtained using amide coupling procedure C is transferred to the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B ~ 75% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.95 (d, J = 8.1 Hz, 1H), 8.37 (dd, J = 4.8, 1.5 Hz, 1H), 7.70 (dd, J = 7.8, 1.5 Hz, 1H), 7.43-7.29 (m, 6H) , 6.38 (s, 1H), 4.90-4.80 (m, 1H), 4.70-4.62 (m, 1H), 4.55-4.48 (m, 1H), 3.35 (s, 3H), 1.58-1.51 (m, 2H) , 1.50-1.42 (m, 2H) .LC-MS (Method D): m / z = 405.1 [M + H]⁺, 2.134 minutes.</p><p> Example 78: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (1-Phenyl) Cyclopropyl) -1H-imidazol-2-carboxamide<chemistry num="185"><img file="JP6974331B2_D0219.tif" /></chemistry> Step 1: Preparation of 2-bromo-1- (1-phenylcyclopropyl) etanone A solution of 1- (1-phenylcyclopropyl) etanone (4.0 g, 25.0 mmol) and triethylamine (5.0 g, 50 mmol) in dichloromethane (100 mL). To trimethylsilyl trifluoromethanesulfonate (5.55 g, 25.0 mmol) was added at 0 ° C. After stirring for 0.5 hours, 1-bromopyrrolidine-2,5-dione (4.9 g, 27.5 mmol) was added in portions at 0 ° C. The reaction mixture was stirred for an additional 2 hours, quenched with 100 mL of water and extracted with dichloromethane (3 x 80 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/20) to give the title compound (3.4 g, 57%) as a yellow oil. LC-MS (Method E): m / z = 238.8 [M + H]⁺, 0.971 minutes.</p><p> Step 2: Preparation of 5- (1-phenylcyclopropyl) -1H-ethyl imidazole-2-carboxylate 2-bromo-1- (1-phenylcyclopropyl) etanone (3.4 g, 14.2 mmol), 2-amino- A solution of 2-iminoacetate ethyl (1.65 g, 14.2 mmol) and triethylamine (4.3 g, 42.6 mmol) in ethanol (50 mL) was heated under reflux for 5 hours. Upon concentration under reduced pressure, the obtained residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/5) to give the title compound (520 mg, 14%) as a yellow solid. LC-MS (Method C): m / z = 257.0 [M + H]⁺, 1.000 minutes.</p><p> Step 3: Preparation of 5- (1-phenylcyclopropyl) -1H-imidazol-2-carboxylic acid Ethyl 5- (1-phenylcyclopropyl) -1H-imidazol-2-carboxylate (300 mg, 1.2 mmol) in methanol Sodium hydroxide (288 mg, 7.2 mmol) was added to the (9 mL) and water (3 mL) solutions. The mixture was stirred at room temperature overnight. The solution was adjusted to pH = 5 and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (130 mg, crude) as a yellow solid. LC-MS (Method C): m / z = 229.1 [M + H]⁺, 0.906 minutes.</p><p> Step 4: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -5- (1-Phenylcyclo) Preparation of propyl) -1H-imidazol-2-carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase, water. (10 mmol / L NH₄HCO₃), ACN (40% ACN ~ 70% B over 7 minutes); Purified by preparative HPLC using a detector, UV254 &amp; 220 nm; to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 13.11-12.79 (m, 1H), 8.32-8.17 (m, 1H), 7.51 (dd, J = 7.6, 1.9 Hz, 1H), 7.37-7.16 (m, 8H), 6.85-6.44 (m, 1H) ), 4.88-4.74 (m, 1H), 4.66-4.50 (m, 1H), 4.45-4.35 (m, 1H), 3.32 (s, 3H), 1.38-1.27 (m, 2H), 1.25-1.12 (m) , 2H) .LC-MS (Method Q): m / z = 403.3 [M + H]⁺, 1.533 minutes.</p><p> Example 79: (S) -7- (2-fluorophenyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3- Il) Benzo [d] Thiazole-2-carboxamide<chemistry num="186"><img file="JP6974331B2_D0220.tif" /></chemistry> Step 1: (S) -7-bromo-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) benzo [d] Preparation of Thiazole-2-Carboxamide Using the procedure described in Example 54, the title compound (370 mg) was obtained as a yellow solid, which was used in the next step without purification. LC-MS (Method S): m / z = 432.2 [M + H]⁺, 1.102 minutes.</p><p> Step 2: 7- (2-Fluorophenyl) -N-((S) -5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl ) Preparation of benzo [d] thiazole-2-carboxamide [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (29 mg, 0.04 mmol), (S) -7-bromo-N-(S) 5-Methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) benzo [d] thiazole-2-carboxamide (170 mg, 0.39 mmol), 2- A mixture of fluorophenylboronic acid (85 mg, 0.59 mmol) and potassium carbonate (109 mg, 0.79 mmol) in dioxane (2 mL) and water (0.5 mL) was added under a nitrogen atmosphere. The resulting mixture was stirred at 80 ° C overnight. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. Residues under the following conditions: Column: XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 3% B ~ 38% B over 7 minutes; 254 &amp; 220 nm; Purification by preparative HPLC using Rt: 6.33 min; gave the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 9.31-9.29 (d, J = 7.5 Hz, 1H), 8.29-8.26 (d, J = 8.1 Hz, 1H), 7.79-7.77 (m, 1H), 7.68-7.60 (m, 2H), 7.60- 7.51 (m, 2H), 7.43-7.26 (m, 5H), 4.89-4.72 (m, 2H), 4.50-4.44 (m, 1H), 3.33 (s, 3H) .LC-MS (Method T): m / z = 448.3 [M + H]⁺, 1.884 minutes.</p><p> Examples 80A and 80B: 5-Benzyl-N-((1aS, 2S, 8bR) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido] 2,3-b] Azepine-2-yl) -1H-pyrazole-3-carboxamide (80A) and 5-benzyl-N-((1aR, 2R, 8bS) -4-methyl-3-oxo-1,1a , 2,3,4,8b-Hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) -1H-pyrazole-3-carboxamide (80B)<chemistry num="187"><img file="JP6974331B2_D0221.tif" /></chemistry> Step 1: 5-Benzyl-N- (cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2 -Il) -1H-Preparation of pyrazole-3-carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: XBridge C18OBD preparative column, 100 Å, 5 μm, 19 mm × 250 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B ~ 50% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound. LC-MS (Method D): m / z = 388.2 [M + H]⁺, 1.757 minutes.</p><p> Step 2: 5-benzyl-N-((1aS, 2S, 8bR) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3] -b] Azepine-2-yl) -1H-pyrazole-3-carboxamide (first elution isomer) and 5-benzyl-N-((1aR, 2R, 8bS) -4-methyl-3-oxo-1, Preparation of 1a, 2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) -1H-pyrazole-3-carboxamide (second elution isomer) 5- Benzyl-N- (cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) -1H -Pyrazol-3-carboxamide (60 mg, 0.16 mmol) isomer compound under the following conditions: Column: Chiral IC, 2 x 25 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 60% B to 60% B at 16.5 min; UV254 &amp; 220 nm; RT1: 8.27 min; RT2: 13.00 min;</p><p> Example 80A (first elution isomer):¹1 H NMR (300 MHz, Methanol-d₄) δ 8.38 (dd, J = 4.8, 1.8 Hz, 1H), 7.94 (dd, J = 7.8, 1.8 Hz, 1H), 7.35-7.21 (m, 6H), 6.52 (s, 1H), 4.65 (s, 1H), 4.05 (s, 2H), 3.40 (s, 3H), 2.31-2.23 (m, 1H), 2.12-2.03 (m, 1H), 1.32-1.26 (m, 1H), 1.22-1.13 (m, 1H) .LC-MS (Method D): m / z = 388.2 [M + H]⁺, 1.757 minutes.</p><p> Example 80B (second elution isomer):¹1 H NMR (300 MHz, Methanol-d₄) δ 8.38 (dd, J = 4.5, 1.8 Hz, 1H), 7.94 (dd, J = 7.8, 1.5 Hz, 1H), 7.35-7.21 (m, 6H), 6.52 (s, 1H), 4.65 (s, 1H), 4.06 (s, 2H), 3.40 (s, 3H), 2.31-2.23 (m, 1H), 2.12-2.04 (m, 1H), 1.33-1.26 (m, 1H), 1.22-1.13 (m, 1H) .LC-MS (Method D): m / z = 388.2 [M + H]⁺, 1.757 minutes.</p><p> Examples 81A and 81B: 5-Benzyl-N-((1aS, 2S, 8bR) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyridode [d] 2,3-b] Azepin-2-yl) Isoxazole-3-carboxamide (81A) and 5-benzyl-N-((1aR, 2R, 8bS) -4-methyl-3-oxo-1,1a, 2 , 3,4,8b-Hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) isoxazole-3-carboxamide (81B)<chemistry num="188"><img file="JP6974331B2_D0222.tif" /></chemistry> Step 1: 5-Benzyl-N- (cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2 -Il) Preparation of isooxazole-3-carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 55% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound. LC-MS (Method D): m / z = 389.1 [M + H]⁺, 2.036 minutes.</p><p> Step 2: 5-benzyl-N-((1aR, 2R, 8bS) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3] -b] Azepine-2-yl) Isoxazole-3-carboxamide (first elution isomer) and 5-benzyl-N-((1aS, 2S, 8bR) -4-methyl-3-oxo-1,1a, 2,3,4,8b-Hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) Isoxazole-3-Carboxamide (second elution isomer) preparation 5-benzyl-N- (Cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) Isoxazole-3-carboxamide (60 mg, 0.15 mmol) isomer compound under the following conditions: Column: Chiralpak IC, 2 × 25 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 18 mL / min; gradient: 50% B to 50% B over 17 minutes; UV254 &amp; 220 nm; RT1: 12.098 minutes; RT2 Separation by preparative chiral HPLC using: 14.358 min; to give the title compound:</p><p> Example 81B (first elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 8.98 (d, J = 7.5 Hz, 1H), 8.40 (dd, J = 4.5, 1.8 Hz, 1H), 7.98 (dd, J = 7.5, 1.8 Hz, 1H), 7.40-7.26 (m, 6H) , 6.62 (s, 1H), 4.45 (d, J = 7.2 Hz, 1H), 4.24 (s, 2H), 3.29 (s, 3H), 2.34-2.25 (m, 1H), 2.02-1.94 (m, 1H) ), 1.25-1.06 (m, 2H) .LC-MS (Method D): m / z = 389.1 [M + H]⁺, 2.036 minutes.</p><p> Example 81A (second elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 8.98 (d, J = 7.2 Hz, 1H), 8.40 (dd, J = 4.5, 1.8 Hz, 1H), 7.98 (dd, J = 7.5, 1.8 Hz, 1H), 7.40-7.26 (m, 6H) , 6.62 (s, 1H), 4.45 (d, J = 7.2 Hz, 1H), 4.24 (s, 2H), 3.29 (s, 3H), 2.34-2.25 (m, 1H), 2.02-1.94 (m, 1H) ), 1.22-1.06 (m, 2H) .LC-MS (Method D): m / z = 389.1 [M + H]⁺, 2.027 minutes.</p><p> Examples 82A and 82B: 1-benzyl-4-fluoro-N-((1aS, 2S, 8bR) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [ d] Pyrido [2,3-b] azepine-2-yl) -1H-pyrazole-3-carboxamide (82A) and 1-benzyl-4-fluoro-N-((1aR, 2R, 8bS) -4-methyl -3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) -1H-pyrazole-3-carboxamide (82B)<chemistry num="189"><img file="JP6974331B2_D0223.tif" /></chemistry> Step 1: 1-Benzyl-4-fluoro-N- (cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] ] Preparation of azepine-2-yl) -1H-pyrazole-3-carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: X Bridge C18OBD preparative column, 100 Å, 5 μm , 19mm × 250mm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 35% B to 65% B over 7 minutes; Purified by preparative HPLC using UV254 &amp; 220 nm; Title compound (58 mg, 50%) Was obtained as a white solid. LC-MS (Method V): m / z = 406.1 [M + H]⁺, 2.852 minutes.</p><p> Step 2: 1-benzyl-4-fluoro-N-((1aR, 2R, 8bS) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] Azepine-2-yl) -1H-pyrazole-3-carboxamide (first elution isomer) and 1-benzyl-4-fluoro-N-((1aS, 2S, 8bR) -4- Methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) -1H-pyrazole-3-carboxamide (second) Preparation of elution isomers 1-benzyl-4-fluoro-N- (cis-4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,, 3-b] Azepine-2-yl) -1H-pyrazole-3-carboxamide (58 mg, 0.15 mmol) isomer compound under the following conditions: Column: Chilarpak IC, 2 × 25 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 18 mL / min; gradient: 50% B to 50% B over 23 minutes; UV254 &amp; 220 nm; RT1: 10.936 minutes; RT2 Separation by preparative chiral HPLC using: 16.976 min; to give the title compound:</p><p> Example 82B (first elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 8.39 (dd, J = 4.8, 1.8 Hz, 1H), 8.17-8.12 (m, 2H), 8.00 (dd, J = 7.8, 1.8 Hz, 1H), 7.44-7.28 (m, 6H), 5.36 ( s, 2H), 4.46 (d, J = 6.9 Hz, 1H), 3.30 (s, 3H), 2.33-2.24 (m, 1H), 2.06-1.98 (m, 1H), 1.26-1.14 (m, 1H) , 1.12-1.03 (m, 1H) .LC-MS (Method V): m / z = 406.1 [M + H]⁺, 2.852 minutes.</p><p> Example 82A (second elution isomer):¹1 H NMR (300 MHz, Methanol-d₄) δ 8.38 (dd, J = 4.8, 1.8 Hz, 1H), 7.94 (dd, J = 7.5, 1.8 Hz, 1H), 7.77 (d, J = 4.5 Hz, 1H), 7.44-7.27 (m, 6H) , 5.35 (s, 2H), 4.66 (s, 1H), 3.41 (s, 3H), 2.32-2.23 (m, 1H), 2.15-2.03 (m, 1H), 1.33-1.26 (m, 1H), 1.22 -1.14 (m, 1H) .LC-MS (Method D): m / z = 406.1 [M + H]⁺, 1.923 minutes.</p><p> Example 83A: 5-Benzyl-N-((1aS, 2S, 8bR) -5,7-difluoro-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] ] Azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="190"><img file="JP6974331B2_D0224.tif" /></chemistry><chemistry num="191"><img file="JP6974331B2_D0225.tif" /></chemistry> Step 1: Preparation of 2,4-difluoro-6-vinylbenzoenamine Tributyl (ethenyl) in a solution of 2-bromo-4,6-difluoroaniline (10.0 g, 48.0 mmol) in N, N-dimethylformamide (50 mL). Stannane (18.0 g, 56.7 mmol) and tetrakis (triphenylphosphine) palladium (2.2 g, 1.90 mmol) were added under a nitrogen atmosphere. The resulting mixture was stirred at 80 ° C for 16 hours. After cooling to room temperature, the reaction mixture was quenched by the addition of water (200 mL) and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 3/17) to give the title compound (6.0 g, 80%) as a yellow oil. LC-MS (Method C): m / z = 156.0 [M + H]⁺, 1.216 minutes.</p><p> Step 2: Preparation of N- (2,4-difluoro-6-vinylphenyl) porcine-3-enamide Thionyl chloride (9.3 g, 46.46 mmol) in pig-3-enoic acid (4.0 g, 46.46 mmol) in dichloromethane ( 20 mL) Dropped into the solution. After stirring at room temperature for 1 hour, the resulting mixture was added to a solution of triethylamine (11.8 g, 116.6 mmol) and 2-ethenyl-4,6-difluoroaniline (6.0 g, 38.67 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 3 hours, quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 3/17) to give the title compound (5.7 g, 66%) as a yellow oil. LC-MS (Method C): m / z = 224.0 [M + H]⁺, 1.145 minutes.</p><p> Step 3: Preparation of (Z) -7,9-difluoro-1H-benzo [b] azepine-2 (3H) -one [1,3-bis (2,4,6-trimethylphenyl) imidazolidine-2- Iridene] Dichloro (Phenylmethylidene) Ruthenium Tricyclohexylphosphin (3.4 g, 4.0 mmol), N- (5-ethenyl-2,4-difluorophenyl) But-3-enamide (4.4 g, 19.9 mmol) in toluene ( 150 mL) added to the solution. The resulting solution was stirred at 80 ° C. for 16 hours and then concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (2.8 g, 69%) as a yellow oil. LC-MS (Method S): m / z = 196.0 [M + H]⁺, 0.754 minutes.</p><p> Step 4: Preparation of 5,7-difluoro-1,1a, 2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one Potassium hydroxide (40 g, 714 mmol) in water (60 mL) 1-Methyl-1-nitrosourea (20.6 g, 199.8 mmol) in ether (150 mL) was added dropwise at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at 0 ° C. for 1 hour, then the organic phase was separated to give a solution of diazomethane (150 mL). A solution of diazomethane (150 mL) was added dropwise to a solution of 7,9-difluoro-2,3-dihydro-1H-1-benzazepine-2-one (2.0 g, 10.25 mmol) in tetrahydrofuran (60 mL), followed by A mixture of palladium diacetate (224.5 mg, 1.00 mmol) in tetrahydrofuran (10 mL) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature overnight. The solid was removed by filtration and the filtrate was concentrated under vacuum to give the title compound (1.2 g, crude) as a yellow oil. LC-MS (Method C): m / z = 210.0 [M + H]⁺, 1.117 minutes.</p><p> Step 5: Trans-5,7-difluoro-2-iodo-1,1a,2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one preparation 5,7-difluoro-1, 1a, 2,8b-Tetrahydrobenzo [b] Cyclopropa [d] Azepine-3 (4H) -one (1.2 g, 6.0 mmol) in dichloromethane (60 mL) to a mixture of N, N, N', N'- Tetramethylethylenediamine (2.1 g, 18.0 mmol) was added, followed by iodotrimethylsilane (3.6 g, 18.0 mmol) at 0 ° C. After stirring at 0 ° C for 2 hours, iodine (2.3 g, 9.0 mmol) was added. The reaction mixture was stirred at 0 ° C. for 1 hour, quenched with aqueous sodium thiosulfate (5%, 40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (1.32 g, crude) as a yellow oil. LC-MS (Method C): m / z = 336.0 [M + H]⁺, 1.213 minutes.</p><p> Step 6: Preparation of cis-2-azido-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one Sodium azide (250 mg, 3.84 mmol) ), Trans-5,7-difluoro-2-iodo-1,1a,2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one (860 mg, 2.56 mmol) N, N -Added to dimethylformamide (40 mL) solution. The resulting mixture was stirred at room temperature for 16 hours, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (520 mg, crude) as a yellow oil. LC-MS (Method C): m / z = 251.0 [M + H]⁺, 1.176 minutes.</p><p> Step 7: Preparation of cis-2-amino-5,7-difluoro-1,1a, 2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one Triphenylphosphine (629 mg, 2.40 mmol) ), Sis-2-azido-5,7-difluoro-1,1a,2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one (400 mg, 1.60 mmol) in tetrahydrofuran (10 mL). ) And water (1 mL) solution. The resulting mixture was stirred at room temperature for 16 hours, diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 3/97) to give the title compound (310 mg, 86%) as a yellow oil. LC-MS (Method C): m / z = 225.0 [M + H] +, 0.776 minutes.</p><p> Step 8: (1aR, 2R, 8bS) -2-amino-5,7-difluoro-1,1a, 2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one (first elution) (Isoisomer) and (1aS, 2S, 8bR) -2-amino-5,7-difluoro-1,1a, 2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one (second) Preparation of elution isomer) cis-2-amino-5,7-difluoro-1,1a, 2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one (310 mg, 1.38 mmol) The following conditions: column: Chiralpak IA, 2 × 25 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 15 mL / min; gradient: 50% B ~ 50% over 28 minutes B; 254/220 nm; RT1: 10.247 min; RT2: 20.789 min; was separated by preparative chiral HPLC to give the title compound:</p><p> (1aR, 2R, 8bS) -2-amino-5,7-difluoro-1,1a, 2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one (first elution isomer) : (150 mg, 48%) was obtained as a white solid. LC-MS (Method C): m / z = 225.0 [M + H]⁺, 0.776 minutes.</p><p> (1aS, 2S, 8bR) -2-amino-5,7-difluoro-1,1a, 2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one (second elution isomer) : (140 mg, 45%) was obtained as a white solid. LC-MS (Method C): m / z = 225.0 [M + H]⁺, 0.776 minutes.</p><p> Step 9: 5-Benzyl-N-((1aS, 2S, 8bR) -5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] Azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide N, N-diisopropylethylamine (50 mg, 0.39 mmol), (1aS, 2S, 8bR) -2-amino-5,7-difluoro-1,1a, 2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine -3 (4H) -one (30 mg, 0.13 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (32 mg, 0.16 mmol), N- (3-dimethylaminopropyl) -N '-Ethylcarbodiimide hydrochloride (31 mg, 0.16 mmol) and 1-hydroxybenzotriazole (22 mg, 0.16 mmol) were added to a mixture of N, N-dimethylformamide (5 mL). The resulting mixture was stirred at room temperature for 2 hours, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. Residues under the following conditions: column, XBridge C18OBD preparative column, 5 μm, 19 mm × 250 mm; mobile phase, water (10 mmoL / L NH)₄HCO₃) And ACN (30.0% ACN ~ 60.0% over 7 minutes); detector, UV254nm; purified by preparative HPLC to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 14.30 (br. S, 1H), 9.96 (br. S, 1H), 8.43 (d, J = 6.8 Hz, 1H), 7.36-7.19 (m, 7H), 4.61 (d, J = 6.8 Hz, 1H), 4.14 (s, 2H), 2.32-2.26 (m, 1H), 2.07-2.01 (m, 1H), 1.43-1.39 (m, 1H), 1.12-1.07 (m, 1H) .LC-MS (Method Q): m / z = 410.3 [M + H]⁺, 1.144 minutes.</p><p> Example 83 B: 5-Benzyl-N-((1aR, 2R, 8bS) -5,7-difluoro-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] ] Azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="192"><img file="JP6974331B2_D0226.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: column, XBridge C18OBD preparative column, 5 μm, 19 mm × 250 mm; mobile phase, water (10 mmoL / L NH).₄HCO₃) And ACN (30.0% ACN at 7 minutes up to 60.0%); purified by preparative HPLC using a detector, UV254 nm; to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 14.41 (s, 1H), 9.95 (s, 1H), 8.42 (d, J = 6.8 Hz, 1H), 7.35-7.19 (m, 7H), 4.61 (d, J = 6.8 Hz, 1H), 4.14 (s, 2H), 2.32-2.26 (m, 1H), 2.07-2.01 (m, 1H), 1.43-1.39 (m, 1H), 1.12-1.07 (m, 1H) .LC-MS (Method Q): m / z = 410.30 [M + H]⁺, 1.143 minutes.</p><p> Example 84: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -7-Phenylbenzo [d] ] Thiazole-2-carboxamide<chemistry num="193"><img file="JP6974331B2_D0227.tif" /></chemistry> [1,1'-Bis (diphenylphosphino) ferrocene] Dichloropalladium (II) (34 mg, 0.05 mmol), (S) -7-bromo-N- (5-methyl-4-oxo-2,3,, 4,5-Tetrahydrobenzo [b] [1,4] oxazepine-3-yl) benzo [d] thiazole-2-carboxamide (200 mg, 0.47 mmol), phenylboronic acid (85 mg, 0.70 mmol) and potassium carbonate (128 mg) , 0.93 mmol) to the mixture in dioxane (2 mL) and water (0.5 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 80 ° C overnight. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. Residues under the following conditions: Column: XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 3 over 7 minutes Purification by preparative HPLC using% B to 38% B; 254 &amp; 220 nm; Rt: 6.33 min; gave the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 9.30 (d, J = 7.8 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 7.79-7.60 (m, 4H), 7.60-7.49 (m, 4H), 7.34-7.26 (m, 3H), 4.96-4.68 (m, 2H), 4.50-4.45 (m, 1H), 3.33 (s, 3H) .LC-MS (Method T): m / z = 430.3 [M + H]⁺, 1.906 minutes.</p><p> Example 85: (S) -5-Benzyl-N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3- Il) -1,3,4-thiadiazole-2-carboxamide<chemistry num="194"><img file="JP6974331B2_D0228.tif" /></chemistry> Step 1: Preparation of 2-oxo-2- (2- (2-phenylacetyl) hydrazinyl) ethyl acetate Stirring 2-phenylacetohydrazide (2 g, 13.3 mmol) and triethylamine (4.04 g, 39.9 mmol) in dichloromethane (30 mL) Ethyl 2-chloro-2-oxoacetate (1.8 g, 13.4 mmol) was added dropwise to the solution at 0 ° C. The resulting solution was stirred at room temperature for 12 hours, diluted with water (20 mL) and extracted with dichloromethane (5 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (1.2 g, 36%) as a white solid. LC-MS (Method I): m / z = 251.0 [M + H]⁺, 0.944 minutes.</p><p> Step 2: Preparation of ethyl 5-benzyl-1,3,4-thiazyl-2-carboxylate 2-oxo-2- (2- (2-phenylacetyl) hydrazinyl) ethyl acetate (0.65 g, 2.6 mmol) in tetrahydrofuran Lawesson's reagent (1.89 g, 4.7 mmol) was added to the mixture in (8 mL). The resulting mixture was stirred at 70 ° C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL). The phases were separated and the organic layer was washed with aqueous sodium bicarbonate (10%, 3 x 20 mL) and brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (500 mg, 78%) as a yellow oil. LC-MS (Method I): m / z = 249.0 [M + H]⁺, 0.991 minutes.</p><p> Step 3: Preparation of 5-benzyl-1,3,4-thiadiazole-2-carboxylic acid in tetrahydrofuran (6 mL) of ethyl 5-benzyl-1,3,4-thiadiazole-2-carboxylate (500 mg, 2.01 mmol) and Lithium hydroxide (97 mg, 4.04 mmol) was added to the mixture in water (2 mL). The resulting solution was stirred at room temperature for 12 hours and concentrated under vacuum. The residue was diluted with water (10 mL) and the pH value of the solution was adjusted to 6 with aqueous hydrochloric acid (1N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (250 mg, crude) as a white solid. LC-MS (Method I): m / z = 221.0 [M + H]⁺, 0.574 minutes.</p><p> Step 4: (S) -5-benzyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl ) -1,3,4-Thiadiazole-2-carboxamide preparation The crude product obtained using amide coupling procedure C is transferred under the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 38% B ~ 70% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 9.46 (d, J = 6.6 Hz, 1H), 8.37 (dd, J = 4.8, 1.8 Hz, 1H), 7.71 (dd, J = 7.8, 1.5 Hz, 1H), 7.38-7.26 (m, 6H) , 4.91-4.75 (m, 2H), 4.58-4.52 (m, 3H), 3.36 (s, 3H) .LC-MS (Method D): m / z = 396.1 [M + H]⁺, 1.912 minutes.</p><p> Example 86: (S) -5-Benzyl-N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3- Il) Thiazole-2-carboxamide<chemistry num="195"><img file="JP6974331B2_D0229.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 38% B ~ 70% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.95 (d, J = 7.2 Hz, 1H), 8.37 (dd, J = 4.8, 1.5 Hz, 1H), 7.88 (s, 1H), 7.71 (dd, J = 8.1, 1.5 Hz, 1H), 7.37 -7.23 (m, 6H), 4.89-4.72 (m, 2H), 4.56-4.50 (m, 1H), 4.28 (s, 2H), 3.36 (s, 3H) .LC-MS (Method D): m / z = 395.1 [M + H]⁺, 2.096 minutes.</p><p> Example 87: (S) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl) -1- (1-phenyl) Cyclopropyl) -1H-1,2,3-triazole-4-carboxamide<chemistry num="196"><img file="JP6974331B2_D0230.tif" /></chemistry> Step 1: Preparation of tert-butyl phenylcyclopropylcarbamate 1-to a stirred mixture of phenylcyclopropanecarboxylic acid (10.0 g, 61.7 mmol) and diphenyl azidolate (17.0 g, 61.7 mmol) in toluene (100 mL). , Triethylamine (18.6 g, 185 mmol) was added. The reaction mixture was stirred at 100 ° C. for 5 hours, cooled to room temperature, and then 2-methylpropan-2-ol (33.7 mg, 0.216 mmol) was added. The reaction mixture was stirred at room temperature overnight and concentrated under high vacuum. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/5) to give the title compound (4.00 g, 28%) as a yellow solid. LC-MS (Method C): m / z = 234.2 [M + H]⁺, 1.345 minutes.</p><p> Step 2: Preparation of 1-phenylcyclopropaneamine hydrochloride tert-butyl 1-phenylcyclopropylcarbamate (4.0 g, 17.2 mmol) was added to a dioxane solution of hydrogen chloride (4N, 50 mL, 200 mmol). The reaction mixture was stirred at room temperature for 3 hours and concentrated under high vacuum to give the title compound (2.00 g, 88%) as a white solid. LC-MS (Method C): m / z = 134.2 [M + H]⁺, 0.775 minutes.</p><p> Step 3: Preparation of (1-azidocyclopropyl) benzene 1-Ether (10 mL) of phenylcyclopropaneamine hydrochloride (320 mg, 1.89 mmol) Stir solution to ether solution of methylmagnesium bromide (3M, 1.89 mL, 5.67 mmol) ) Was added at -60 ° C under an argon atmosphere. After stirring at -60 ° C for 30 minutes, 4-methylbenzenesulfonyl azide (745 mg, 3.78 mmol) was added. The reaction mixture was stirred at -60 ° C for 1 hour, quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (500 mg, crude) as a yellow solid.</p><p> Step 4: Preparation of ethyl 1- (1-phenylcyclopropyl) -1H-1,2,3-triazole-4-carboxylate Copper acetate (468 mg, 3.14 mmol) with (1-azidocyclopropyl) benzene propiolic acid It was added to an ethyl (5 mL) solution. The reaction mixture was stirred at room temperature overnight and concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (100 mg, 12%) as a yellow oil. LC-MS (Method C): m / z = 258.1 [M + H]⁺, 1.250 minutes.</p><p> Step 5: Preparation of 1- (1-phenylcyclopropyl) -1H-1,2,3-triazole-4-carboxylic acid Lithium hydroxide (18.7 mg, 0.78 mmol), 1- (1-phenylcyclopropyl) -1H-1,2,3-Triazole-4-ethyl carboxylate (100 mg, 0.39 mmol) was added to a solution of tetrahydrofuran (3 mL) and water (1 mL). The resulting solution was stirred at room temperature overnight, concentrated under vacuum and diluted with water (5 mL). The pH of the solution was adjusted to 5 with aqueous hydrochloric acid (1N, 5 mL). The resulting solution was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (30 mg, crude) as a white solid. LC-MS (Method D): m / z = 230.2 [M + H]⁺, 0.532 minutes.</p><p> Step 6: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -1- (1-Phenylcyclo) Preparation of propyl) -1H-1,2,3-triazole-4-carboxamide The crude product obtained using amide coupling procedure C is subjected to the following conditions: Column: XBridge Shield RP18 OBD Column, 5 μm, 19 × 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 35% B to 65% B over 7 minutes; 220 nm; Rt: 6 minutes; Purified by preparative HPLC using the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.58 (d, J = 8.1 Hz, 1H), 7.53-7.49 (m, 1H), 7.39-7.20 (m, 5H), 7.07-7.04 (m, 2H), 4.89- 4.81 (m, 1H), 4.65-4.55 (m, 1H), 4.43-4.30 (m, 1H), 3.32 (s, 3H), 1.79-1.78 (m, 2H), 1.73-1.64 (m, 2H). LC-MS (Method D): m / z = 404.1 [M + H]⁺, 1.992 minutes. Example 88: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -2- (1-Phenyl) Cyclopropyl) -1H-imidazole-5-carboxamide<chemistry num="197"><img file="JP6974331B2_D0231.tif" /></chemistry><chemistry num="198"><img file="JP6974331B2_D0232.tif" /></chemistry></p><p> Step 1: Preparation of (Z) -N'-hydroxy-1-phenylcyclopropanecarboxyimideamide Hydroxylamine hydrochloride (1.4 g, 20.3 mmol), 1-phenylcyclopropanecarbonitrile (1.5 g, 10.5 mmol) and Sodium carbonate (2.2 g, 20.7 mmol) was added to the mixture in ethanol (20 mL) and water (10 mL). The resulting mixture was stirred at 80 ° C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/20) to give the title compound (1.2 g, 68%) as a white solid. LC-MS (Method E): m / z = 176.8 [M + H]⁺, 0.371 minutes.</p><p> Step 2: Preparation of 2- (1-phenylcyclopropyl) -1H-imidazole-5-ethyl carboxylate (Z) -N'-hydroxy-1-phenylcyclopropanecarboxyimideamide (1.2 g, 6.8 mmol) and propiol A solution of ethyl acid (1.0 g, 10.2 mmol) in ethanol (50 mL) was stirred at 80 ° C. overnight and concentrated under vacuum. The residue was dissolved in oxydibenzene (20 mL) and the mixture was stirred at 200 ° C. for 2 hours. The resulting mixture was concentrated and purified by column chromatography (ethyl acetate / petroleum ether, 1/5) to give the title compound (0.7 g, 40%) as a yellow solid. LC-MS (Method C): m / z = 257.0 [M + H]⁺, 1.200 minutes.</p><p> Step 3: Preparation of 2- (1-phenylcyclopropyl) -1H-imidazole-5-carboxylic acid Lithium hydroxide (288 mg, 7.2 mmol), 2- (1-phenylcyclopropyl) -1H-imidazole-5- Carboxylate (300 mg, 1.2 mmol) was added to a solution of tetrahydrofuran (9 mL) and water (3 mL). The reaction mixture was stirred overnight at room temperature, diluted with water (20 mL), adjusted to pH 5 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (130 mg, crude) as a yellow solid. LC-MS (Method C): m / z = 229.1 [M + H]⁺, 0.906 minutes.</p><p> Step 4: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -2- (1-Phenylcyclo) Preparation of propyl) -1H-imidazole-5-carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: Xbridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 35% B-60% B over 7 minutes; UV254 &amp; 220 nm; purified by preparative HPLC to give the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 12.28 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.52-7.49 (m, 2H), 7.37-7.19 (m, 8H), 4.89-4.79 (m, 1H), 4.54- 4.38 (m, 2H), 3.33 (s, 3H), 1.48-1.40 (m, 2H), 1.28-1.20 (m, 2H) .LC-MS (Method O): m / z = 403.1 [M + H]⁺, 1.389 minutes.</p><p> Example 89A: 5-Benzyl-N-((1aR, 2R, 8bS) -5,7-difluoro-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] ] Azepine-2-yl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="199"><img file="JP6974331B2_D0233.tif" /></chemistry> Step 1: Preparation of 2-oxo-2- (2- (2-phenylacetyl) hydrazinyl) ethyl acetate 2-chloro-2-oxoethyl acetate (603 mg, 4.4 mmol), 2-phenylacetohydrazide (660 mg, 4.4) Ethyl) and triethylamine (1.33 g, 13.2 mmol) were added to a stirring solution of dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 5 hours, quenched by the addition of water (20 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (550 mg, 50%) as a yellow oil. LC-MS (Method S): m / z = 251.0 [M + H]⁺, 0.679 minutes.</p><p> Step 2: Preparation of 5-benzyl-1,3,4-oxadiazole-2-ethyl carboxate Tosyl chloride (840 mg, 4.4 mmol), 2-oxo-2- (2- (2-phenylacetyl) hydrazinyl) ) Ethyl acetate (666 mg, 6.6 mmol) was added to a stirred solution of tetrahydrofuran (25 mL). The reaction mixture was stirred at room temperature overnight, quenched by the addition of water (20 mL) and extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (500 mg, 98%) as a yellow oil. LC-MS (Method C): m / z = 233.0 [M + H]⁺, 1.200 minutes.</p><p> Step 3: Preparation of 5-benzyl-1,3,4-oxadiazole-2-carboxylic acid Lithium hydroxide (103 mg, 4.3 mmol), 5-benzyl-1,3,4-oxadiazole-2- Ethyl carboxate (500 mg, 2.15 mmol) was added to a stirred solution of tetrahydrofuran (5 mL) and water (2 mL). The reaction mixture was stirred at room temperature overnight, concentrated under vacuum and diluted with water (20 mL). The pH value of the mixture was adjusted to pH = 6 with aqueous hydrochloric acid (1N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (250 mg, crude) as a yellow semi-solid. LC-MS (Method I): m / z = 205.0 [M + H]⁺, 0.058 minutes.</p><p> Step 4: 5-Benzyl-N-((1aR, 2R, 8bS) -5,7-difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] Preparation of azepine-2-yl) -1,3,4-oxadiazole-2-carboxamide The crude product obtained using amide coupling procedure C was subjected to the following conditions: column, XBridge C18OBD preparative column. , 5 μm, 19 mm × 250 mm; mobile phase, water (10 mmol / L NH)₄HCO₃) And ACN (30.0% ACN over 7 minutes up to 60.0%); purified by preparative HPLC using a detector, UV254 nm; to give the title compound.¹1 H NMR (400 MHz, CD₃OD) δ 7.38-7.29 (m, 5H), 7.12-7.08 (m, 1H), 6.98-6.93 (m, 1H), 4.82 (d, J = 0.8 Hz, 1H), 4.36 (s, 2H), 2.31-2.25 (m, 1H), 2.12-2.07 (m, 1H), 1.67-1.63 (m, 1H), 1.23-1.17 (m, 1H) .LC-MS (Method V): m / z = 411.05 [M + H]⁺, 2.915 minutes.</p><p> Example 89B: 5-Benzyl-N-((1aS, 2S, 8bR) -5,7-difluoro-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] ] Azepine-2-yl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="200"><img file="JP6974331B2_D0234.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: column, XBridge C18OBD preparative column, 5 μm, 19 mm × 250 mm; mobile phase, water (10 mmol / L NH).₄HCO₃) And ACN (30.0% ACN ~ 60.0% over 7 minutes); detector, UV254nm; purified by preparative HPLC to give the title compound.¹1 H NMR (400 MHz, CD₃OD) δ 7.39-7.28 (m, 5H), 7.11-7.08 (m, 1H), 6.98-6.93 (m, 1H), 4.81 (d, J = 0.8 Hz, 1H), 4.36 (s, 2H), 2.31-2.25 (m, 1H), 2.12-2.07 (m, 1H), 1.67-1.63 (m, 1H), 1.23-1.17 (m, 1H) .LC-MS (Method Q): m / z = 411.30 [M + H]⁺, 0.965 minutes.</p><p> Examples 90A: 1-benzyl-N-((1aR, 2R, 8bS) -5,7-difluoro-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] ] Azepine-2-yl) -1H-1,2,3-triazole-4-carboxamide<chemistry num="201"><img file="JP6974331B2_D0235.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: column, XBridge C18OBD preparative column, 5 μm, 19 mm × 250 mm; mobile phase, water (10 mmol / L NH).₄HCO₃) And ACN (30.0% ACN over 7 minutes up to 60.0%); purified by preparative HPLC using a detector, UV254 nm; to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 9.90 (br. S, 1H), 8.77 (s, 1H), 8.51 (d, J = 7.0 Hz, 1H), 7.43-7.33 (m, 5H), 7.32-7.26 (m, 1H), 7.24- 7.19 (m, 1H), 5.67 (s, 2H), 4.63 (d, J = 6.9 Hz, 1H), 2.32-2.26 (m, 1H), 2.06-2.00 (m, 1H), 1.44-1.40 (m, 1H), 1.14-1.08 (m, 1H) .LC-MS (Method D): m / z = 410.10 [M + H]⁺, 1.876 minutes.</p><p> Example 90 B: 1-benzyl-N-((1aS, 2S, 8bR) -5,7-difluoro-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] ] Azepine-2-yl) -1H-1,2,3-triazole-4-carboxamide<chemistry num="202"><img file="JP6974331B2_D0236.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: column, XBridge C18OBD preparative column, 5 μm, 19 mm × 250 mm; mobile phase, water (10 mmol / L NH).₄HCO₃) And ACN (30.0% ACN ~ 60.0% over 7 minutes); detector, UV254nm; purified by preparative HPLC to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 9.90 (s, 1H), 8.77 (s, 1H), 8.51 (d, J = 7.0 Hz, 1H), 7.46-7.33 (m, 5H), 7.30-7.26 (m, 1H), 7.24-7.19 ( m, 1H), 5.67 (s, 2H), 4.63 (d, J = 6.9 Hz, 1H), 2.32-2.26 (m, 1H), 2.05-2.00 (m, 1H), 1.45-1.40 (m, 1H) , 1.14-1.08 (m, 1H) .LC-MS (Method J): m / z = 410.15 [M + H]⁺, 1.269 minutes.</p><p> Example 91: (S) -N- (4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl) -5- (1- Phenylcyclopropyl) -1H-pyrazole-3-carboxamide<chemistry num="203"><img file="JP6974331B2_D0237.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: X Bridge Prep Phenyl OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (0.1% formic acid), Mobile phase B : ACN; Flow rate: 20 mL / min; Gradient: Purification by preparative HPLC using 25% B-60% B; UV254 &amp; 220 nm; over 7 minutes to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H), 10.53 (s, 1H), 8.24-8.14 (m, 2H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.34-7.15 (m, 6H), 6.38 ( s, 1H), 4.84-4.77 (m, 1H), 4.52-4.41 (m, 2H), 1.35-1.30 (m, 4H) .LC-MS (Method D): m / z = 390.1 [M + H]⁺, 1.537 minutes.</p><p> Examples 92: 1-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrazole [3,2-b] [1,4] Oxazepine-3-yl) -4-fluoro-1H-pyrazole-3-carboxamide<chemistry num="204"><img file="JP6974331B2_D0238.tif" /></chemistry> Step 1: Preparation of (2S, 3R) -2- (tert-butoxycarbonylamino) -3- (2-nitropyridin-3-yloxy) -butanoic acid Sodium hydride (60%, 9.2 g, 230 mmol), Add (2S, 3R) -2- (tert-butoxycarbonylamino) -3-hydroxybutanoic acid (25 g, 115 mmol) to a stirred solution of N, N-dimethylformamide (500 mL) and add the reaction mixture at 0 ° C to 1 Stirred for hours. After the addition of 3-fluoro-2-nitropyridine (16.4 g, 115 mmol), the reaction mixture was stirred at room temperature for an additional 2 hours and then quenched with hydrochloric acid (3N, 20 mL). The pH value of the reaction solution was adjusted to 3 to 4 with hydrogen chloride (3N, 20 mL). The resulting solution was extracted with ethyl acetate (3 x 150 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (acetonitrile / water, 1/2) to give the title compound (3.8 g, 10%) as a pale yellow oil. LC-MS (Method C): m / z = 286.1 [M + H-56]⁺, 1.167 minutes.</p><p> Step 2: Preparation of (2S, 3R) -3- (2-aminopyridine-3-yloxy) -2- (tert-butoxycarbonylamino) -butanoic acid in methanol (30 mL), (2S, 3R) -2- (tert-Butoxycarbonylamino) -3- (2-nitropyridine-3-yloxy) butanoic acid (3.77 g, 11 mmol) under hydrogen atmosphere (2-3 atm), palladium carbon (10%, 1.0 g) Hydrogenated in the presence. The reaction mixture was stirred at room temperature for 6 hours. The solid was removed by filtration and the filtrate was concentrated under vacuum to give the title compound (3.12 g, 91%) as a colorless oil. LC-MS (Method C): m / z = 312.1 [M + H]⁺, 0.887 minutes.</p><p> Step 3: (2R, 3S) -2-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] tert-butyl oxazepine-3-ylcarbamate Preparation of N, N-diisopropylethylamine (1.43 g, 11 mmol), (2S, 3R) -3- (2-aminopyridine-3-yloxy) -2- (tert-butoxycarbonylamino) butanoic acid (3.0 g, 10 mmol) and N, N-dimethylformamide (50 mL) of N, N, N', N'-tetramethyl-O- (7-azabenzotriazole-1-yl) uronium hexafluorophosphate (4.18 g, 11 mmol) It was added to the stirred solution. The reaction mixture was stirred at room temperature for 5 hours, quenched by the addition of water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/20) to give the title compound (2.2 g, 78%) as a white solid. LC-MS (Method C): m / z = 294.1 [M + H]⁺, 1.136 minutes.</p><p> Step 4: (2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-ylcarbamic acid tert -Preparation of butyl Iodomethane (388 mg, 2.73 mmol), (2R, 3S) -2-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-ylcarbamate tert-butyl (800 mg, 2.73 mmol) and cesium carbonate (890 mg, 2.73 mmol) were added dropwise to a stirred solution of N, N-dimethylformamide (15 mL). The reaction mixture was stirred at 0 ° C for 1 hour and at room temperature for 3 hours, diluted with water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (670 mg, 80%) as a white solid. LC-MS (Method C): m / z = 308.2 [M + H]⁺, 1.250 minutes.</p><p> Step 5: Preparation of (2R, 3S) -3-amino-2,5-dimethyl-2,3-dihydropyrido [3,2-b] [1,4] oxazepine-4 (5H) -one hydrochloride (2R) , 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-ylcarbamic acid tert-butyl (670 mg,) 2.18 mmol) was added to a dioxane solution of hydrogen chloride (4 M, 10 mL, 40 mmol). The reaction mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure to give the title compound (460 mg, crude) as a white solid. LC-MS (Method E): m / z = 207.90 [M + H]⁺, 0.432 minutes.</p><p> Step 6: 1-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine -3-yl) -4-Fluoro-1H-Pyrazole-3-Carboxamide preparation The crude product obtained using amide coupling procedure C is subjected to the following conditions: Column: X Bridge C18OBD preparative column, 5 μm , 19mm × 250mm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B-60% B; UV254 &amp; 220 nm; purified by preparative HPLC at 7 min to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.36 (dd, J = 4.4, 1.6 Hz, 1H), 8.15 (d, J = 4.4 Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.61 (d, J = 6.4 Hz) , 1H), 7.42-7.31 (m, 4H), 7.31-7.27 (m, 2H), 5.37 (s, 2H), 5.00-4.93 (m, 1H), 4.92-4.88 (m, 1H), 3.40 (s) , 3H), 1.32 (d, J = 6.0 Hz, 3H). LC-MS (Method F): m / z = 409.9 [M + H]⁺, 1.336 minutes.</p><p> Example 93: 1-Benzyl-N-((2S, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrazole [3,2-b] [1,4] Oxazepine-3-yl) -4-fluoro-1H-pyrazole-3-carboxamide<chemistry num="205"><img file="JP6974331B2_D0239.tif" /></chemistry> The title compound was prepared from (2S, 3S) -2- (tert-butoxycarbonylamino) -3-hydroxybutanoic acid using the procedure described in Example 92.</p><p> The obtained crude product was subjected to the following conditions: Column: Xbridge Prep C18OBD Column 19 × 150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 55% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J = 8.4 Hz, 1H), 8.38 (dd, J = 4.8, 1.2 Hz, 1H), 8.14 (d, J = 4.4 Hz, 1H), 7.63 (dd, J = 8.0, 1.6 Hz) , 1H), 7.42-7.27 (m, 6H), 5.36 (s, 2H), 5.10-5.01 (m, 1H), 4.45-4.40 (m, 1H), 3.34 (s, 3H), 1.26 (d, J) = 6.0 Hz, 3H) .LC-MS (Method D): m / z = 410.1 [M + H]⁺, 1.923 minutes.</p><p> Example 94: 5-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="206"><img file="JP6974331B2_D0240.tif" /></chemistry> N, N-diisopropylethylamine (95 mg, 0.73 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (50 mg, 0.24 mmol), (2R, 3S) -3-amino-2 , 5-Dimethyl-2,3-dihydropyrido [3,2-b] [1,4] Oxazepine-4 (5H) -on hydrochloride (50 mg, 0.24 mmol), N- (3-dimethylaminopropyl))- It was added to the mixture of N'-ethylcarbodiimide hydrochloride (60 mg, 0.32 mmol) and 1-hydroxybenzotriazole (43 mg, 0.32 mmol) in N, N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature overnight, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product obtained using amide coupling procedure C is subjected to the following conditions: Column: X Bridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 5% B ~ 5% B over 4 minutes; UV254 &amp; 220 nm; Purified by preparative HPLC using the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 14.46 (s, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.38 -7.23 (m, 6H), 5.01-4.94 (m, 1H), 4.93-4.89 (m, 1H), 4.14 (s, 2H), 3.40 (s, 3H), 1.31 (d, J = 6.0 Hz, 3H ). LC-MS (Method D): m / z = 393.1 [M + H]⁺, 1.725 minutes.</p><p> Example 95: 5-Benzyl-N-((2S, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="207"><img file="JP6974331B2_D0241.tif" /></chemistry> Example 96: 5-Benzyl-N-((2R, 3S) -2-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine- 3-Il) -4H-1,2,4-triazole-3-carboxamide<chemistry num="208"><img file="JP6974331B2_D0242.tif" /></chemistry> Step 1: Preparation of (2R, 3S) -3-amino-2-methyl-2,3-dihydropyrido [3,2-b] [1,4] oxazepine-4 (5H) -one hydrochloride (2R, 3S) )-2-Methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-ylcarbamate tert-butyl (100 mg, 0.34 mmol) , Added to a dioxane solution of hydrogen chloride (4M, 5mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give the title compound (100 mg, crude) as a white solid. LC-MS (Method E): m / z = 194.0 [M + H]⁺, 0.432 minutes.</p><p> Step 2: 5-Benzyl-N-((2R, 3S) -2-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3 -Il) -4H-1,2,4-Triazole-3-Carboxamide preparation The crude product obtained using amide coupling procedure C is subjected to the following conditions: Column: X Bridge C18OBD preparative column, 10 μm , 19 mm x 250 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20% B ~ 35% B over 7 minutes, UV254 &amp; 220 nm; Purification by taking HPLC gave the title compound.¹1 H NMR (300 MHz, DMSO-d₆) δ 14.41 (s, 1H), 10.84 (s, 1H), 8.19-8.08 (m, 2H), 7.62 (dd, J = 8.1, 1.2 Hz, 1H), 7.37-7.20 (m, 6H), 4.98- 4.86 (m, 2H), 4.15 (s, 2H), 1.30 (d, J = 6.0 Hz, 3H). LC-MS (Method D): m / z = 379.1 [M + H]⁺, 1.546 minutes. Example 97: 5-Benzyl-N-((2S, 3S) -2-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine- 3-Il) -4H-1,2,4-triazole-3-carboxamide<chemistry num="209"><img file="JP6974331B2_D0243.tif" /></chemistry></p><p> Step 1: Preparation of (2S, 3S) -3-amino-2-methyl-2,3-dihydropyrido [3,2-b] [1,4] oxazepine-4 (5H) -one hydrochloride (2S, 3S) )-2-Methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-ylcarbamate tert-butyl (50 mg, 0.17 mmol) It was added to a dioxane solution of hydrogen chloride (4M, 5 mL, 20 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated under vacuum to give the title compound (35 mg, crude) as a white solid. LC-MS (Method E): m / z = 194.0 [M + H]⁺, 0.432 minutes.</p><p> Step 2: 5-Benzyl-N-((2S, 3S) -2-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3 -Il) -4H-1,2,4-Triazole-3-Carboxamide preparation The crude product obtained using amide coupling procedure C is subjected to the following conditions: Column: X Select CSH prep C18OBD Preparative column , 5 μm, 19 mm × 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 15% B-60% B over 7 minutes; UV254 &amp; 220 nm; Purified by preparative HPLC to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 14.36 (s, 1H), 10.56 (s, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.23-8.20 (m, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.39 -7.17 (m, 6H), 5.11-4.90 (m, 1H), 4.44 (m, 1H), 4.16 (s, 2H), 1.32 (d, J = 6.0 Hz, 3H). LC-MS (Method F) : m / z = 378.95 [M + H]⁺, 0.932 minutes.</p><p> Examples 98A and 98B: (R) -5-benzyl-N- (8'-oxo-6', 7', 8', 9'-tetrahydrospiro [cyclopropane-1,5'-pyrid [2,3] -b] Azepine] -7'-yl) -4H-1,2,4-triazole-3-carboxamide (98A) and (S) -5-benzyl-N- (8'-oxo-6', 7' , 8', 9'-tetrahydrospiro [cyclopropane-1,5'-pyrido [2,3-b] azepine] -7'-yl) -4H-1,2,4-triazole-3-carboxamide (98B) )<chemistry num="210"><img file="JP6974331B2_D0244.tif" /></chemistry> Step 1: 7'-Amino-6', 7'-dihydrospiro [cyclopropane-1,5'-pyrido [2,3-b] azepine] -8'(9'H) -preparation of on-chloride chloride A solution of hydrogen in 1,4-dioxane (4N, 10 mL, 40 mmol) was added to (8'-oxo-6', 7', 8', 9'-tetrahydrospiro [cyclopropane-1,5'-pyrido [2,, 3-b] Azepine] -7'-yl) Carbamic acid tert-butyl (100 mg, 0.34 mmol) was added to a solution of 1,4-dioxane (4 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated under high vacuum to give the title compound (80 mg, crude) as a white solid. LC-MS (Method C): m / z = 204.1 [M + H]⁺, 0.677 minutes.</p><p> Step 2: 5-benzyl-N- (8'-oxo-6', 7', 8', 9'-tetrahydrospiro [cyclopropane-1,5'-pyrido [2,3-b] azepine] -7 '-Il) -4H-1,2,4-Triazole-3-Carboxamide Preparation The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 35% B to 65% B over 7 minutes; 254/220 nm; Purification by preparative HPLC gave the title compound (50 mg, 56%) as a white solid. LC-MS (Method V): m / z = 389.2 [M + H]⁺, 0.982 minutes.</p><p> Step 2: (R) -5-benzyl-N- (8'-oxo-6', 7', 8', 9'-tetrahydrospiro [cyclopropane-1,5'-pyrido [2,3-b]] Azepine] -7'-yl) -4H-1,2,4-triazole-3-carboxamide (first elution isomer) and (S) -5-benzyl-N- (8'-oxo-6', 7 ', 8', 9'-Tetrahydrospiro [cyclopropane-1,5'-pyrido [2,3-b] azepine] -7'-yl) -4H-1,2,4-triazole-3-carboxamide ( Preparation of second-eluting isomer) 5-benzyl-N- (8'-oxo-6', 7', 8', 9'-tetrahydrospiro [cyclopropane-1,5'-pyrido [2,3-b] ] Azepine] -7'-yl) -4H-1,2,4-triazole-3-carboxamide (50 mg, 0.128 mmol) with the following conditions: Column: Chiralpak ID-2, 2 × 25 cm, 5 μm; Mobile phase A: Hexane / DCM 4.5: 1, Mobile phase B: EtOH; Flow rate: 17 mL / min; Gradient: 50% B to 50% B over 22 minutes; Separation by preparative chiral HPLC using UV254 &amp; 220 nm; RT1: 11.72 min; RT2: 18.02 min; to give the title compound:</p><p> Example 98A (first elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 14.28 (s, 1H), 10.37 (s, 1H), 8.27 (dd, J = 4.8, 1.8 Hz, 1H), 7.69 (dd, J = 7.6, 1.8 Hz, 1H), 7.34-7.08 (m, 6H), 4.42-4.33 (m, 1H), 3.30 (s, 3H), 2.82-2.68 (m, 1H), 1.72 (s, 1H), 1.23-1.05 (m, 1H), 0.88-0.78 (m, 1H), 0.70-0.65 (m, 1H), 0.40-0.25 (m, 1H) .LC-MS (Method D): m / z = 389.2 [M + H]⁺, 1.499 minutes.</p><p> Example 98B (second elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 10.38 (d, J = 2.8 Hz, 1H), 8.37-8.22 (m, 2H), 7.71-7.67 (m, 1H), 7.44-7.08 (m, 6H), 4.43-4.34 (m, 1H), 4.06 (s, 2H), 2.78-2.71 (m, 1H), 1.73 (t, J = 12.3 Hz, 1H), 1.23-1.05 (m, 2H), 0.86-0.79 (m, 1H), 0.71-0.64 ( m, 1H), 0.27 (s, 1H) .LC-MS (Method D): m / z = 389.2 [M + H]⁺, 1.503 minutes.</p><p> Example 99: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -5 -(1-Phenylcyclopropyl) -1H-imidazol-2-carboxamide<chemistry num="211"><img file="JP6974331B2_D0245.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: Xbridge Prep C18, 19 × 150 mm, 5 μm; Mobile phase: Phase A: Water (10 mmol / L NH)₄HCO₃); Phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 55% B over 7 minutes; Detector, UV220 &amp; 254 nm; Rt: 6.32 min; Purified by preparative HPLC using, title The compound was obtained.¹1 H NMR (300 MHz, DMSO-d₆) δ 12.80 (s, 1H), 8.50-8.32 (m, 2H), 7.72-7.70 (m, 1H), 7.39-7.15 (m, 6H), 6.78-6.65 (m, 1H), 4.92-4.63 (m) , 2H), 4.52-4.48 (m, 1H), 3.36 (s, 3H), 1.35-1.30 (m, 2H), 1.28-1.11 (m, 2H) .LC-MS (Method O): m / z = 404.0 [M + H]⁺, 1.412 minutes.</p><p> Examples 100A and 100B: 4- (2-fluorophenoxy) -N-((1aS, 2S, 8bR) -4-methyl-3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) picoline amide (100A) and 4- (2-fluorophenoxy) -N-((1aR, 2R, 8bS) -4-methyl-3-oxo -1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) picoline amide (100B)<chemistry num="212"><img file="JP6974331B2_D0246.tif" /></chemistry> Step 1: 4- (2-Fluorophenoxy) -N- (cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-] b] Preparation of azepin-2-yl) picoline amide The crude product obtained using the amide coupling procedure C was purified by preparative TLC (ethyl acetate / petroleum ether, 1/3) and the title racemic compound. Got LC-MS (Method J): m / z = 419.1 [M + H]⁺, 1.330 minutes.</p><p> Step 2: 4- (2-Fluorophenoxy) -N-((1aS, 2S, 8bR) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] Pyrid [2,3-b] azepine-2-yl) picoline amide (first elution isomer) and 4- (2-fluorophenoxy) -N-((1aR, 2R, 8bS) -4-methyl-3- Preparation of oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) picoline amide (second elution isomer) 4- (2) -Fluorophenoxy) -N- (cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl ) Picoline amide (25 mg, 0.096 mmol) isomer compound under the following conditions: Column: Chilarpak IA, 2 × 25 cm, 5 μm; Mobile phase A: hexane, Mobile phase B: EtOH; Flow rate: 16 mL / min; Gradient: 19 Separation by preparative chiral HPLC using 50% B to 50% B in minutes; 220/254 nm; RT1: 13.609 minutes; RT2: 15.738 minutes; gave the title compound:</p><p> Example 100A (first elution isomer):¹1 H NMR (300 MHz, Methanol-d₄) δ 8.59 (d, J = 5.6 Hz, 1H), 8.39 (dd, J = 4.7, 1.8 Hz, 1H), 7.95 (dd, J = 7.7, 1.8 Hz, 1H), 7.55 (d, J = 2.5 Hz) , 1H), 7.42 -7.27 (m, 5H), 7.15 (dd, J = 5.6, 2.6 Hz, 1H), 4.66 (s, 1H), 3.42 (s, 3H), 2.32-2.26 (m, 1H), 2.17-2.06 (m, 1H), 1.36-1.32 (m, 1H), 1.23-1.14 (m, 1H) .LC-MS (Method J): m / z = 419.2 [M + H]⁺, 1.467 minutes.</p><p> Example 100B (second elution isomer):¹1 H NMR (300 MHz, Methanol-d₄) δ 8.58 (d, J = 5.6 Hz, 1H), 8.38 (dd, J = 4.7, 1.8 Hz, 1H), 7.95 (dd, J = 7.7, 1.8 Hz, 1H), 7.55 (d, J = 2.6 Hz) , 1H), 7.41-7.28 (m, 5H), 7.14 (dd, J = 5.6, 2.6 Hz, 1H), 4.65 (s, 1H), 3.42 (s, 3H), 2.35-2.25 (m, 1H), 2.15-2.03 (m, 1H), 1.37-1.25 (m, 1H), 1.24-1.16 (m, 1H) .LC-MS (Method T): m / z = 419.3 [M + H]⁺, 2.774 minutes.</p><p> Examples 101A and 101B: (R) -5-benzyl-N- (1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo [4,3-b]] Azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide (101A) and (S) -5-benzyl-N- (1,4-dimethyl-5-oxo-1,4,5 , 6,7,8-Hexahydropyrazolo [4,3-b] Azepine-6-yl) -4H-1,2,4-Triazole-3-carboxamide (101B)<chemistry num="213"><img file="JP6974331B2_D0247.tif" /></chemistry> Step 1: Preparation of ethyl 4- (1-methyl-4-nitro-1H-pyrazole-5-yl) butanoate 5-bromo-1-methyl-4-nitro-1H-pyrazole (2.0 g, 9.76 mmol), (4-ethoxy-4-oxobutyl) zinc (II) bromide (0.5 M in tetrahydrofuran) (29.2 mL, 14.6 mmol) and dicyclohexyl (2', 6'-dimethoxybiphenyl-2-yl) phosphine (402.3 mg, 0.98 mmol) ) In Tetrahydrofuran (100 mL), a solution of palladium diacetate (109.8 mg, 0.49 mmol) in tetrahydrofuran was added dropwise under a nitrogen atmosphere while stirring. The resulting mixture was heated at 40 ° C overnight. The reaction mixture was concentrated under high vacuum and the residue was purified by column chromatography (methanol / dichloromethane, 1/99) to give the title compound (445 mg, 18.9%) as a yellow oil. LC-MS (Method C): m / z = 242.1 [M + H]⁺, 1.156 minutes.</p><p> Step 2: Preparation of 4- (4-amino-1-methyl-1H-pyrazol-5-yl) ethyl butanoate 4- (1-methyl-4-nitro-1H-pyrazol-5-yl) ethyl butanoate ( 405 mg, 1.68 mmol) was hydrogenated in methanol (20 mL) under a hydrogen atmosphere (2-3 atm) and in the presence of palladium-bearing carbon (10%, 41 mg). The reaction mixture was stirred at room temperature for 2 hours. The solid was then removed by filtration and the solvent was evaporated under vacuum to give the title compound (320 mg, crude) as a yellow solid. LC-MS (Method C): m / z = 212.2 [M + H]⁺, 0.768 minutes.</p><p> Step 3: Preparation of 4- (4-amino-1-methyl-1H-pyrazole-5-yl) butanoic acid 4- (4-amino-1-methyl-1H-pyrazole-5-yl) ethyl butanoate (320 mg) , 1.51 mmol) and lithium hydroxide (108.9 mg, 4.53 mmol) in tetrahydrofuran / water = 3/1 (4 mL) were stirred at room temperature for 3 hours. The pH value of the solution was adjusted to 6-7 with hydrochloric acid (1N). The resulting solution was concentrated under vacuum to give the title compound (220 mg, crude) as a yellow solid. LC-MS (Method C): m / z = 184.1 [M + H]⁺, 0.318 minutes.</p><p> Step 4: Preparation of 1-methyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (1H, 4H, 6H) -one N, N-diisopropylethylamine (465.2 mg, 3.6 mmol), 4- (4-Amino-1-methyl-1H-pyrazole-5-yl) butanoic acid (220 mg, 1.2 mmol) and N, N, N', N'-tetramethyl-O- (7-azabenzotriazole-) 1-Il) Uronium hexafluorophosphate (548.2 mg, 1.44 mmol) was added to a stirred solution of N, N-dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 2 hours, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (160 mg, 80.8%) as a yellow solid. LC-MS (Method C): m / z = 166.2 [M + H]⁺, 0.751 minutes.</p><p> Step 5: 1,4-Dimethyl-7,8-dihydropyrazolo [4,3-b] Azepine-5 (1H, 4H, 6H) -On Preparation Iodomethane (150.5 mg, 1.06 mmol), 1-methyl -7,8-Dihydropyrazolo [4,3-b] Azepine-5 (1H, 4H, 6H) -one (160 mg, 0.96 mmol) and sodium hydride (60%) (42.4 mg, 1.06 mmol) N , N-Dimethylformamide (5 mL) was added dropwise to the stirred solution with stirring. The reaction mixture was stirred at room temperature for 2 hours, quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate, 3/1) to give the title compound (140 mg, 81.5%) as a yellow solid. LC-MS (Method C): m / z = 180.2 [M + H]⁺, 0.816 minutes.</p><p> Step 6: Preparation of 6-iodine-1,4-dimethyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (1H, 4H, 6H) -one N¹, N¹, N², N²-Tetramethylethane-1,2-diamine (271.4 mg, 2.34 mmol), 1,4-dimethyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (1H, 4H, 6H)- On (140 mg, 0.78 mmol) in dichloromethane (5 mL) was added at 0 ° C. followed by trimethylsilane (468 mg, 2.34 mmol). The reaction mixture was stirred at 0 ° C for 1 hour. After adding iodine (137.2 mg, 0.54 mmol), the reaction mixture was stirred at 0 ° C for an additional hour and quenched with aqueous sodium thiosulfate (5%, 15 mL). The reaction mixture was stirred for an additional 15 minutes and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (214 mg, crude) as a yellow solid, which was not further purified. Used directly in the next step. LC-MS (Method C): m / z = 306.0 [M + H]⁺, 0.953 minutes.</p><p> Step 7: 6-Amino-1,4-dimethyl-7,8-dihydropyrazolo [4,3-b] Azepine-5 (1H, 4H, 6H) -On Preparation 6-Iodo-1,4-dimethyl -7,8-dihydropyrazolo [4,3-b] azepine-5 (1H, 4H, 6H) -one (214 mg, 0.70 mmol) in N, N-dimethylformamide (4 mL) solution with sodium azide (4 mL) 136.9 mg, 2.1 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (6 mL) and water (2 mL), and triphenylphosphine (551.8 mg, 2.1 mmol) was added in portions. The reaction mixture was stirred at 50 ° C. overnight, diluted with water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (100 mg, 73.6%) as a yellow solid. LC-MS (Method C): m / z = 195.1 [M + H]⁺, 0.386 minutes.</p><p> Step 8: 5-Benzyl-N- (1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl)- Preparation of 4H-1,2,4-triazole-3-carboxamide The crude product obtained using amide coupling procedure C is subjected to the following conditions: Column: Xbridge Prep C18, 19 × 150 mm, 5 μm; mobile phase : Phase A: Water (10 mmol / L NH₄HCO₃); Phase B: ACN (20% -80% over 12 minutes); Purified by preparative HPLC using a detector, UV220 &amp; 254nm; to give the title compound. LC-MS (Method C): m / z = 380.2 [M + H]⁺, 1.290 minutes.</p><p> Step 9: (R) -5-benzyl-N- (1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6 -Il) -4H-1,2,4-triazole-3-carboxamide (first elution isomer) and (S) -5-benzyl-N- (1,4-dimethyl-5-oxo-1,4, Preparation of 5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide (second elution isomer) 5- Benzyl-N- (1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl) -4H-1,2 , 4-Triazole-3-Carboxamide (50 mg, 0.13 mmol) isomer compound under the following conditions: Column: Chiralpak IA, 2 × 25 cm, 5 μm; Mobile phase A: Hex, Mobile phase B: EtOH; Flow rate: 15 mL / Minutes; Gradient: 60% B to 60% B over 21 minutes; 220/254 nm; RT 1: 12.12 minutes; RT 2: 18.44 minutes; separated by preparative chiral HPLC.</p><p> Example 101A (first elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 7.51 (s, 1H), 7.34-7.22 (m, 5H), 4.60 (dd, J = 2.0, 10.0 Hz, 1H), 4.17 (s, 2H), 3.80 (s, 3H), 3.36 (s, 3H), 3.20-3.11 (m, 1H), 2.99-2.91 (m, 1H), 2.48-2.41 (m, 1H), 2.25-2.14 (m, 1H) .LC-MS (Method V): m / z = 380.1 [M + H]⁺, 2.240 minutes.</p><p> Example 101B (second elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 7.51 (s, 1H), 7.35-7.22 (m, 5H), 4.60 (dd, J = 2.4, 10.4 Hz, 1H), 4.17 (s, 2H), 3.80 (s, 3H), 3.36 (s, 3H), 3.20-3.11 (m, 1H), 2.99-2.91 (m, 1H), 2.49-2.41 (m, 1H), 2.25-2.14 (m, 1H) .LC-MS (Method D): m / z = 380.2 [M + H]⁺, 1.471 minutes.</p><p> Examples 102A &amp; 102B: 5-((R) -2,3-dihydro-1H-inden-1-yl) -N-((S) -4-oxo-2,3,4,5-tetrahydropyrido [3] , 2-b] [1,4] Oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide and 5-((S) -2,3-dihydro-1H-inden-1- Il) -N-((S) -4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl) -4H-1,2, 4-Triazole-3-Carboxamide<chemistry num="214"><img file="JP6974331B2_D0248.tif" /></chemistry> Step 1: 5- (2,3-dihydro-1H-inden-1-yl) -N-((S) -4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Preparation of oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide The crude product obtained using the procedure described in Example 54 is as follows. Conditions: Column: XBridge C18OBD preparative column, 5 μm, 19 mm × 250 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B ~ 36% B over 7 minutes; 254 nm; Rt: 7 min; Obtained. LC-MS (Method D): m / z = 391.1 [M + H]⁺, 1.593 minutes.</p><p> Step 2: 5-((R) -2,3-dihydro-1H-inden-1-yl) -N-((S) -4-oxo-2,3,4,5-tetrahydropyrido [3, 2-b] [1,4] Oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide and 5-((S) -2,3-dihydro-1H-inden-1-yl) )-N-((S) -4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl) -4H-1,2,4 -Preparation of triazole-3-carboxamide 5- (2,3-dihydro-1H-inden-1-yl) -N-((S) -4-oxo-2,3,4,5-tetrahydropyrido [3] , 2-b] [1,4] Oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide (10 mg) with the following conditions: Column: CHIRALPAK IA, 2.12 × 15 cm , 5 μm; Mobile phase A: Hex: DCM 4.5: 1, mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 50% B to 50% B at 17.5 min; 220/254 nm; RT1: 10.95 min; RT2: 15.02 min; Separation was performed by taking chiral HPLC to obtain the title compound.</p><p> Example 102A (first elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 8.14-8.13 (m, 1H), 7.57-7.55 (m, 1H), 7.33-7.31 (m, 1H), 7.31-7.10 (m, 3H), 7.09-7.07 (m, 1H), 5.04-4.91 (m, 1H), 4.69-4.61 (m, 2H), 4.47-4.42 (m, 1H), 3.18-3.15 (m, 1H), 3.07-3.03 (m, 1H), 2.65-2.63 (m, 1H) , 2.44-2.39 (m, 1H) .LC-MS (Method T): m / z = 391.3 [M + H]⁺, 1.133 minutes.</p><p> Example 102B (second elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 8.14-8.13 (m, 1H), 7.57-7.55 (m, 1H), 7.33-7.31 (m, 1H), 7.31-7.10 (m, 3H), 7.09-7.07 (m, 1H), 5.04-4.91 (m, 1H), 4.69-4.61 (m, 2H), 4.47-4.42 (m, 1H), 3.18-3.15 (m, 1H), 3.07-3.03 (m, 1H), 2.65-2.63 (m, 1H) , 2.44-2.39 (m, 1H) .LC-MS (Method T): m / z = 391.3 [M + H]⁺, 1.135 minutes.</p><p> Examples 103A and 103B: (R) -5-benzyl-N- (7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro [benzo [b] azepine-5,1'-cyclo Propane] -3-yl) -4H-1,2,4-triazole-3-carboxamide and (S) -5-benzyl-N- (7,9-difluoro-2-oxo-1,2,3,4 -Tetrahydrospiro [benzo [b] azepine-5,1'-cyclopropane] -3-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="215"><img file="JP6974331B2_D0249.tif" /></chemistry><chemistry num="216"><img file="JP6974331B2_D0250.tif" /></chemistry> Step 1: Preparation of 2- (3,5-difluoro-2-nitrophenyl) dimethyl malonate Dimethyl malonate (15 g, 114 mmol), 1,3,5-trifluoro-2-nitrobenzene (10 g, 56 mmol) and Potassium carbonate (23 g, 168 mmol) was added dropwise to a stirred mixture of N, N-dimethylformamide (150 mL). The reaction mixture was stirred at 70 ° C. overnight and quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/8) to give the title compound (15 g, 92%) as a yellow oil. LC-MS (Method C): m / z = 290.0 [M + H]⁺, 1.235 minutes.</p><p> Step 2: Preparation of 2- (3,5-difluoro-2-nitrophenyl) methyl acetate A solution of lithium chloride (6.3 g, 150 mmol) in water (20 mL), 2- (3,5-difluoro-2-nitrophenyl) ) Dimethyl malonate (15 g, 52 mmol) was added to a solution of dimethyl sulfoxide (50 mL). The reaction mixture was stirred at 100 ° C. overnight and quenched by the addition of water (250 mL). The resulting solution was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (11 g, crude) as a yellow oil, which was then refined without further purification. Used directly in the step.</p><p> Step 3: Preparation of methyl 1,2- (3,5-difluoro-2-nitrophenyl) cyclopropanecarboxylate 1,2-dibromoethane (13 g, 70 mmol), 2- (3,5-difluoro-2-nitrophenyl) ) Methyl acetate (11 g, 48 mmol) and potassium carbonate (20 g, 145 mmol) were added dropwise to a stirred solution of N, N-dimethylformamide (50 mL). The reaction mixture was stirred at 70 ° C. overnight and quenched by the addition of water (250 mL). The resulting solution was extracted with ethyl acetate (3 x 250 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/8) to give the title compound (1.1 g, 9%) as a yellow oil. LC-MS (Method C): m / z = 258.1 [M + H]⁺, 1.291 minutes.</p><p> Step 4: Preparation of (1- (3,5-difluoro-2-nitrophenyl) cyclopropyl) Diisobutylaluminum hydride in toluene (1M, 9.4 mL, 9.4 mmol) 1- (3,5-difluoro) -2-Nitrophenyl) Methyl cyclopropanecarboxylate (1.1 g, 4.3 mmol) was added dropwise to a stirred solution of toluene (30 mL) at -78 ° C under a nitrogen atmosphere. The reaction mixture was stirred at 78 ° C. for 2 hours, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/6) to give the title compound (0.92 g, 94%) as a yellow oil. LC-MS (Method C): m / z = 230.1 [M + H]⁺, 1.192 minutes.</p><p> Steps 5: 1-Preparation of (3,5-difluoro-2-nitrophenyl) cyclopropanecarbaldehyde Dess-Martin peryodinane (3.4 g, 8 mmol), (1- (3,5-difluoro-2-nitro) It was added to a stirring solution of phenyl) cyclopropyl) methanol (0.92 g, 4 mmol) in dichloromethane (30 mL). The reaction mixture was stirred at 0 ° C. for 2 hours, quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/6) to give the title compound (0.85 mg, 92%) as a yellow oil.</p><p> Step 6: Preparation of 3- (1- (3,5-difluoro-2-nitrophenyl) cyclopropyl) acrylic acid (E) -ethyl (triphenylphosphoraniridene) ethyl acetate (1.5 g, 4.3 mmol), It was added to a stirred solution of 1- (3,5-difluoro-2-nitrophenyl) cyclopropanecarbaldehyde (800 mg, 3.5 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at 50 ° C. overnight, quenched by the addition of water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/8) to give the title compound (0.64 g, 61%) as a yellow oil. LC-MS (Method C): m / z = 298.0 [M + H]⁺, 1.382 minutes.</p><p> Step 7: Preparation of ethyl 3- (1- (2-amino-3,5-difluorophenyl) cyclopropyl) ethyl propanoate in methanol (30 mL), 3- (1- (3,5-difluoro-2-nitrophenyl) ) Cyclopropyl) Acrylic acid (E) -ethyl (640 mg, 2.2 mmol) was hydrogenated in a hydrogen atmosphere (2-3 atm) in the presence of palladium-bearing carbon (10%, 65 mg). After stirring overnight at room temperature under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum to give the title compound (400 mg, crude) as a yellow oil. LC-MS (Method C): m / z = 270.1 [M + H]⁺, 1.361 minutes.</p><p> Step 8: Preparation of 3- (1- (2-amino-3,5-difluorophenyl) cyclopropyl) propanoic acid Lithium hydroxide (180 mg, 7.5 mmol), 3- (1- (2-amino-3,,) It was added to a solution of ethyl 5-difluorophenyl) cyclopropyl) ethyl propanoate (400 mg, 1.5 mmol) in tetrahydrofuran (30 mL) and water (10 mL). The reaction mixture was stirred at room temperature overnight. After removing tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH = 7 with aqueous hydrochloric acid (1N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (320 mg, crude) as a yellow oil. LC-MS (Method C): m / z = 242.1 [M + H]⁺, 1.143 minutes.</p><p> Step 9: 7,9-Difluoro-3,4-dihydrospiro [benzo [b] azepine-5,1'-cyclopropane] -2 (1H) -one preparation N, N-diisopropylethylamine (515 mg, 4.0 mmol) ), 3- (1- (2-Amino-3,5-difluorophenyl) cyclopropyl) propanoic acid (320 mg, 1.3 mmol) and N, N, N', N'-tetramethyl-O- (7-). Azabenzotriazole-1-yl) uronium hexafluorophosphate (608 mg, 1.6 mmol) was added to the mixture in N, N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 2 hours and quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/6) to give the title compound (270 mg, 91%) as a yellow oil. LC-MS (Method C): m / z = 224.1 [M + H]⁺, 1.303 minutes.</p><p> Step 10: 7,9-Difluoro-3-iodo-3,4-dihydrospiro [benzo [b] azepine-5,1'-cyclopropane] -2 (1H) -on preparation N, N, N', N'-tetramethylethylenediamine (418 mg, 3.6 mmol), 7,9-difluoro-3,4-dihydrospiro [benzo [b] azepine-5,1'-cyclopropane] -2 (1H) -one (270 mg) , 1.2 mmol) was added to a solution of dichloromethane (40 mL) at 0 ° C., followed by the addition of imidazole trimethylsilane (720 mg, 3.6 mmol) over 20 minutes. The mixture was stirred at 0 ° C. for 1 hour, then iodine (457 mg, 1.8 mmol) was added to the mixture. After stirring at 0 ° C for an additional hour, the reaction mixture was quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (410 mg, crude) as a yellow oil. LC-MS (Method C): m / z = 350.1 [M + H]⁺, 1.262 minutes.</p><p> Step 11: 3-Azide-7,9-difluoro-3,4-dihydrospiro [benzo [b] azepine-5,1'-cyclopropane] -2 (1H) -one preparation Sodium azide (117 mg, 1.8) mmol) to 7,9-difluoro-3-iodo-3,4-dihydrospiro [benzo [b] azepine-5,1'-cyclopropane] -2 (1H) -one (410 mg, 1.2 mmol) N , N-dimethylformamide (20 mL) was added to the solution. The resulting mixture was stirred overnight at room temperature and quenched by the addition of water (40 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (260 mg, crude) as a yellow oil. LC-MS (Method E): m / z = 265.1 [M + H]⁺, 0.875 minutes.</p><p> Step 12: Preparation of 3-amino-7,9-difluoro-3,4-dihydrospiro [benzo [b] azepine-5,1'-cyclopropane] -2 (1H) -one Triphenylphosphine (393 mg, 1.5) mmol), 3-azido-7,9-difluoro-3,4-dihydrospiro [benzo [b] azepine-5,1'-cyclopropane] -2 (1H) -one (260 mg, 1.0 mmol) in THF Added to (10 mL) and water (1 mL) solutions. The resulting mixture was stirred at room temperature overnight, diluted with water (20 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 5/1) to give the title compound (210 mg, 90%) as a yellow oil. LC-MS (Method C): m / z = 239.1 [M + H]⁺, 0.814 minutes.</p><p> Step 13: 5-Benzyl-N- (7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro [benzo [b] azepine-5,1'-cyclopropane] -3-yl) -4H-1,2,4-Triazole-3-Carboxamide Preparation The crude product obtained using amide coupling procedure C is transferred under the following conditions: Column: XBridge Prep C18OBD Column 19 × 150 mm, 5 μm; Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 30 mL / min; Gradient: Purified by preparative HPLC using 25% B ~ 55% B; UV254 &amp; 220 nm; over 7 minutes, title compound (30 mg, 26%) Was obtained as a white solid. LC-MS (Method O): m / z = 423.9 [M + H]⁺, 1.204 minutes.</p><p> Step 14: (R) -5-benzyl-N- (7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro [benzo [b] azepine-5,1'-cyclopropane]- 3-Il) -4H-1,2,4-triazole-3-carboxamide (Example 103A) and (S) -5-benzyl-N- (7,9-difluoro-2-oxo-1,2,3) , 4-Tetrahydrospiro [benzo [b] azepine-5,1'-cyclopropane] -3-yl) -4H-1,2,4-triazole-3-carboxamide (Example 103B) preparation 5-benzyl- N- (7,9-difluoro-2-oxo-1,2,3,4-tetrahydrospiro [benzo [b] azepine-5,1'-cyclopropane] -3-yl) -4H-1,2, The rasemi compound of 4-triazole-3-carboxamide under the following conditions: Column: Chiralpak IA, 2 × 25 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 16 mL / min; gradient: 55% B ~ 55% B over 27 minutes; UV220 &amp; 254 nm; Rt1: 13.94 min; Rt2 Separation by preparative chiral HPLC using: 21.44 min; gave two title compounds.</p><p> Example 103A (first elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 7.33-7.26 (m, 5H), 7.10-6.99 (m, 2H), 4.72-4.62 (m, 1H), 4.17 (s, 2H), 3.08-2.99 (m, 1H), 1.63-1.57 (m) , 1H), 1.25-1.18 (m, 1H), 1.07-1.01 (m, 1H), 0.85-0.77 (m, 1H), 0.59-0.52 (m, 1H) .LC-MS (Method O): m / z = 423.9 [M + H]⁺, 1.204 minutes.</p><p> Example 103B (second elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 7.36-7.23 (m, 5H), 7.07-6.98 (m, 2H), 4.73-4.64 (m, 1H), 4.23 (s, 2H), 3.07-2.96 (m, 1H), 1.68-1.53 (m) , 1H), 1.25-1.18 (m, 1H), 1.06-0.99 (m, 1H), 0.84-0.77 (m, 1H), 0.59-0.52 (m, 1H) .LC-MS (Method V): m / z = 424.2 [M + H]⁺, 2.031 minutes.</p><p> Examples 104A and 104B: (R) -5-benzyl-N- (2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine- 6-yl) -4H-1,2,4-triazole-3-carboxamide and (S) -5-benzyl-N- (2-methyl-5-oxo-2,4,5,6,7,8- Hexahydropyrazolo [4,3-b] azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="217"><img file="JP6974331B2_D0251.tif" /></chemistry><chemistry num="218"><img file="JP6974331B2_D0252.tif" /></chemistry> Step 1: Preparation of 4- (1-methyl-4-nitro-1H-pyrazol-3-yl) ethyl butanoate (4-ethoxy-4-oxobutyl) zinc (II) bromide in tetrahydrofuran (0.5 M, 41.5 mL, 20.7 mmol) solution to 3-iodo-1-methyl-4-nitro-1H-pyrazole (4.32 g, 17.1 mmol) and dicyclohexyl (2', 6'-dimethoxybiphenyl-2-yl) phosphine (864 mg, 2.1 mmol). ) Was added to a stirred mixture in tetrahydrofuran (50 mL) under a nitrogen atmosphere, followed by the addition of a mixture of palladium diacetate (432 mg, 1.9 mmol) in tetrahydrofuran. The resulting mixture was stirred overnight at room temperature and concentrated under high vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/99) to give the title compound (1.7 g, 41.3%) as a yellow oil. LC-MS (Method E): m / z = 242.1 [M + H]⁺, 0.852 minutes.</p><p> Step 2: Preparation of 4- (1-methyl-4-nitro-1H-pyrazol-3-yl) butanoic acid Lithium hydroxide (339 mg, 14.1 mmol), 4- (1-methyl-4-nitro-1H-) Pyrazole-3-yl) Ethyl butanoate (1.7 g, 7.05 mmol) was added to the mixture in tetrahydrofuran (30 mL) and water (10 mL). The reaction mixture was stirred at room temperature for 2 hours. After removing tetrahydrofuran under reduced pressure, the pH value of the solution was adjusted to 6-7 with aqueous hydrochloric acid (1N, 20 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under high vacuum to give the title compound (1.2 g, crude) as a yellow solid. LC-MS (Method E): m / z = 213.9 [M + H]⁺, 0.617 minutes.</p><p> Step 3: Preparation of 4- (4-amino-1-methyl-1H-pyrazol-3-yl) butanoic acid in methanol (20 mL), 4- (1-methyl-4-nitro-1H-pyrazol-3-yl) ) A solution of butanoic acid (1.2 g, 5.61 mmol) was hydrogenated in a hydrogen atmosphere (2-3 atm) in the presence of palladium-bearing carbon (10%, 120 mg). After stirring at room temperature for 5 hours under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum to give the title compound (1 g, crude) as a yellow solid. LC-MS (Method C): m / z = 184.1 [M + H]⁺, 0.304 minutes.</p><p> Step 4: Preparation of 2-methyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (2H, 4H, 6H) -one N, N-diisopropylethylamine (2.2 g, 17.05 mmol), 4- (4-Amino-1-methyl-1H-pyrazole-3-yl) butanoic acid (1.0 g, 5.46 mmol) and N, N, N', N'-tetramethyl-O- (7-azabenzotriazole) -1-yl) Uronium hexafluorophosphate (2.5 g, 6.58 mmol) was added to the stirred mixture in N, N-dimethylformamide (20 mL). The reaction mixture was stirred at room temperature for 3 hours and diluted with water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (560 mg, 62.1%) as a yellow solid. LC-MS (Method C): m / z = 166.2 [M + H]⁺, 0.331 minutes.</p><p> Step 5: 6-iodo-2-methyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (2H, 4H, 6H) -on preparation N¹, N¹, N², N²-Tetramethylethane-1,2-diamine (1.01 g, 8.73 mmol), 2-methyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (2H, 4H, 6H) -on ( 0.48 g, 2.91 mmol) was added to the stirred mixture in dichloromethane (30 mL) at 0 ° C, followed by the addition of trimethylsilyl iodide (1.16 g, 5.82 mmol) over 20 minutes. The reaction mixture was stirred at 0 ° C for 1 hour. Iodine (1.11 g, 4.37 mmol) was added to the mixture. The reaction mixture was stirred at 0 ° C for an additional hour and quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL). The resulting solution was stirred for 15 minutes and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (550 mg, crude) as a yellow solid. LC-MS (Method I): m / z = 291.9 [M + H]⁺, 0.522 minutes.</p><p> Step 6: Preparation of 6-azido-2-methyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (2H, 4H, 6H) -one Sodium azide (246 mg, 3.78 mmol), 6-iodo-2-methyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (2H, 4H, 6H) -one (550 mg, 1.89 mmol) N, N-dimethylformamide (4 mL) Added to the solution. The reaction mixture was stirred at 40 ° C. overnight, diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (480 mg, crude) as a brown solid, which was not further purified. Used directly in the next step. LC-MS (Method I): m / z = 207.0 [M + H]⁺, 0.481 minutes.</p><p> Step 7: Preparation of 6-amino-2-methyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (2H, 4H, 6H) -one Triphenylphosphine (1.5 g, 7.28 mmol) , 6-Azido-2-methyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (2H, 4H, 6H) -one (0.48 g, 2.18 mmol) in tetrahydrofuran (10 mL) and water (10 mL) 1 mL) Added to the solution. The resulting mixture was stirred at room temperature for 16 hours, diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 3/97) to give the title compound (300 mg, 70.9%) as a yellow oil. LC-MS (Method R): m / z = 181.3 [M + H]⁺, 0.655 minutes.</p><p> Step 8: 5-benzyl-N- (2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl) -4H- Preparation of 1,2,4-Triazole-3-Carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: XSelect CSH Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase A: Water (0.05% TFA), mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 5% B to 47% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6.22 min; The title compound (50 mg, 26.8%) was obtained as a white solid. LC-MS (Method Y): m / z = 366.0 [M + H]⁺, 0.779 minutes.</p><p> Step 9: (R) -5-benzyl-N- (2-methyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl ) -4H-1,2,4-triazole-3-carboxamide (Example 104A) and (S) -5-benzyl-N- (2-methyl-5-oxo-2,4,5,6,7, Preparation of 8-hexahydropyrazolo [4,3-b] azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide (Example 104B) 5-benzyl-N- (2-methyl) -5-oxo-2,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide (50 mg) , 0.13 mmol) racemic compound under the following conditions: Column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; Mobile phase A: hexane, Mobile phase B: i-PrOH; Flow rate: 20 mL / min; Gradient: 21 Separation by preparative chiral HPLC using 50% B to 50% B; UV254 &amp; 220 nm; Rt1: 9.68 minutes; Rt2: 14.84 minutes; to give the title compound:</p><p> Example 104A (first elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 14.37 (br. S, 1H), 9.86 (s, 1H), 8.39 (br. S, 1H), 7.40 (s, 1H), 7.34-7.22 (m, 5H), 4.40-4.35 (m, 1H) ), 4.11 (s, 2H), 3.74 (s, 3H), 2.90-2.81 (m, 2H), 2.26-2.20 (m, 1H), 2.11-1.97 (m, 1H) .LC-MS (Method X) : m / z = 366.2 [M + H]⁺, 2.165 minutes.</p><p> Example 104B (second elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 14.37 (br. S, 1H), 9.86 (s, 1H), 8.39 (br. S, 1H), 7.40 (s, 1H), 7.34-7.22 (m, 5H), 4.40-4.35 (m, 1H) ), 4.11 (s, 2H), 3.74 (s, 3H), 2.89-2.84 (m, 2H), 2.25-2.21 (m, 1H), 2.11-1.97 (m, 1H). LC-MS (Method T) : m / z = 366.3 [M + H]⁺, 0.858 minutes.</p><p> Examples 105A and 105B: (S) -5-benzyl-N- (2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo [4,3-b]] Azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide and (R) -5-benzyl-N- (2,4-dimethyl-5-oxo-2,4,5,6,, 7,8-Hexahydropyrazolo [4,3-b] azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="219"><img file="JP6974331B2_D0253.tif" /></chemistry> Step 1: Preparation of 6-azido-2,4-dimethyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (2H, 4H, 6H) -one Iodomethane (664 mg, 4.68 mmol), 6-Azido-2-methyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (2H, 4H, 6H) -one (480 mg, 2.33 mmol) and cesium carbonate (1.5 g, 4.66 mmol) Was added dropwise to the stirred mixture in N, N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 2 hours and quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (480 mg, crude) as a brown solid. LC-MS (Method I): m / z = 221.0 [M + H]⁺, 0.565 minutes.</p><p> Step 2: Preparation of 6-amino-2,4-dimethyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (2H, 4H, 6H) -one Triphenylphosphine (2.44 g, 9.31 mmol) ), 6-Azido-2,4-dimethyl-7,8-dihydropyrazolo [4,3-b] azepine-5 (2H, 4H, 6H) -one (480 mg, 2.18 mmol) in tetrahydrofuran (10 mL). And added to a solution of water (1 mL). The resulting mixture was stirred at room temperature for 16 hours, diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 3/97) to give the title compound (300 mg, 71%) as a yellow oil. LC-MS (Method I): m / z = 195.0 [M + H]⁺, 0.168 minutes.</p><p> Step 3: 5-benzyl-N-(2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl)- Preparation of 4H-1,2,4-triazole-3-carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: XBridge C18OBD preparative column, 100 Å, 5 μm, 19 mm × 250 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 15% B to 30% B over 10 minutes; UV254 &amp; 220 nm; Rt: 7 minutes; The mixture was purified by preparative HPLC to give the title compound (50 mg, 26.8%) as a white solid. LC-MS (Method Q): m / z = 380.4 [M + H]⁺, 0.786 minutes.</p><p> Step 4: (S) -5-benzyl-N- (2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6 -Il) -4H-1,2,4-triazole-3-carboxamide (Example 105A) and (R) -5-benzyl-N- (2,4-dimethyl-5-oxo-2,4,5, Preparation of 6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide (Example 105B) 5-benzyl-N- (2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl) -4H-1,2,4-triazole -3-Carboxamide (50 mg, 0.13 mmol) racemic compound under the following conditions: Column: CHIRALPAK IC, 2 × 25 cm, 5 μm; Mobile phase A: hexane: DCM = 4.5: 1, Mobile phase B: EtOH; Flow rate: Separation by preparative chiral HPLC using 16 mL / min; gradient: 50% B to 50% B over 21 min; UV220 &amp; 254 nm; Rt1: 8.88 min; Rt2: 16.76 min; to give the title compound. ::</p><p> Example 105A (first elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 14.35 (br. S, 1H), 8.32 (br. S, 1H), 7.83 (s, 1H), 7.34-7.22 (m, 5H), 4.53-4.45 (m, 1H), 4.11 (s, 2H) ), 3.79 (s, 3H), 3.19 (s, 3H), 2.85-2.66 (m, 2H), 2.35-2.31 (m, 1H), 2.30-2.26 (m, 1H) .LC-MS (Method T) : m / z = 380.2 [M + H]⁺, 0.958 minutes.</p><p> Example 105B (second elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 14.29 (br. S, 1H), 8.30 (br. S, 1H), 7.83 (s, 1H), 7.34-7.22 (m, 5H), 4.52-4.46 (m, 1H), 4.11 (s, 2H) ), 3.79 (s, 3H), 3.19 (s, 3H), 2.85-2.68 (m, 2H), 2.35-2.31 (m, 1H), 2.30-2.27 (m, 1H) .LC-MS (Method T) : m / z = 380.2 [M + H]⁺, 0.953 minutes.</p><p> Example 106: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -5 -(1-Phenylcyclopropyl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="220"><img file="JP6974331B2_D0254.tif" /></chemistry> The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: Column: XSelect CSH Prep C18OBD Column, 5 μm, 19 × 150 mm; Mobile Phase A: Water (0.1% Formic Acid); Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B-60% B over 7 minutes; Detector, UV254 &amp; 220 nm; Rt: 5.47 min; purified by preparative HPLC using title compound Got¹1 H NMR (400 MHz, DMSO-d₆) δ 14.11 (s, 1H), 8.49 (d, J = 7.9 Hz, 1H), 8.37 (dd, J = 4.8, 1.5 Hz, 1H), 7.71 (dd, J = 8.0, 1.5 Hz, 1H), 7.40 -7.22 (m, 6H), 4.92-4.66 (m, 2H), 4.56-4.55 (m, 1H), 3.36 (s, 3H), 1.52-1.27 (m, 4H) .LC-MS (Method O): m / z = 405.0 [M + H]⁺, 1.126 minutes ...</p><p> Examples 107A and 107B: (R) -5-benzyl-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl ) -4H-1,2,4-triazole-3-carboxamide and (S) -5-benzyl-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2] , 3-b] Azepine-7-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="221"><img file="JP6974331B2_D0255.tif" /></chemistry> Step 1: Preparation of (E) -6,7-dihydroquinoline-8 (5H) -onoxime Hydrolamine hydrochloride (1.4 g, 20.3 mmol), 6,7-dihydroquinoline-8 (5H) -on (1.5) g, 10.2 mmol) and sodium hydroxide (1.2 g, 30.0 mmol) were added to ethanol (20 mL) and water (10 mL) solutions. The resulting mixture was stirred at 80 ° C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3 x 80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/20) to give the title compound (1.4 g, 86.4%) as a white solid. LC-MS (Method E): m / z = 163.1 [M + H]⁺, 0.362 minutes.</p><p> Step 2: Preparation of (E) -6,7-dihydroquinoline-8 (5H) -one O-methylsulfonyl oxime Triethylamine (3.5 g, 30.6 mmol) and methanesulfonyl chloride (0.74 g, 6.4 mmol), (E) )-6,7-Dihydroquinoline-8 (5H) -one oxime (1.4 g, 8.64 mmol) was added to a solution of dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 2 hours, diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/5) to give the title compound (1.7 g, 82%) as a yellow solid. LC-MS (Method C): m / z = 241.0 [M + H]⁺, 0.810 minutes.</p><p> Step 3: Preparation of 6,7-dihydro-5H-pyrido [2,3-b] azepine-8 (9H) -one Potassium acetate (5g, 51 mmol), (E) -6,7-dihydroquinoline-8 It was added to a solution of (5H) -one O-methylsulfonyl oxime (1.7 g, 7 mmol) in ethanol (40 mL) and water (20 mL). The reaction mixture was stirred at 110 ° C. overnight and concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/5) to give the title compound (1.0 g, 87%) as a yellow solid. LC-MS (Method C): m / z = 162.8 [M + H]⁺, 0.612 minutes.</p><p> Step 4: Preparation of 9-methyl-6,7-dihydro-5H-pyrido [2,3-b] azepine-8 (9H) -one Iodomethane (1.0 g, 0.70 mmol), 6,7-dihydro-5H -Pyrido [2,3-b] azepine-8 (9H) -one (1.0 g, 0.60 mmol) and cesium carbonate (3.0 g, 0.92 mmol) in N, N-dimethylformamide (20 mL) droplets on a stirred mixture. Added. The reaction mixture was stirred overnight at room temperature, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/30) to give the title compound (0.97 g, 89.8%) as a yellow solid. LC-MS (Method C): m / z = 177.1 [M + H]⁺, 1.192 minutes.</p><p> Step 5: 7-Iodine-9-Methyl-6,7-Dihydro-5H-Pyrido [2,3-b] Azepine-8 (9H) -On Preparation N¹, N¹, N², N²-Tetramethylethane-1,2-diamine (1.9 g, 16.4 mmol), 9-methyl-6,7-dihydro-5H-pyrido [2,3-b] azepine-8 (9H) -one (0.97 g) , 5.5 mmol) to the stirred mixture in dichloromethane (100 mL) at 0 ° C, followed by addition of trimethylsilyl iodide (3.3 g, 16.5 mmol) over 20 minutes. The reaction mixture was stirred at 0 ° C for 1 hour. After adding iodine (4.2 g, 16.5 mmol), the reaction mixture was stirred at room temperature for an additional 4 hours and then quenched by the addition of aqueous sodium thiosulfate (5%, 30 mL). The resulting solution was stirred for 15 minutes and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/30) to give the title compound (1.5 g, 89.8%) as a white solid. LC-MS (Method C): m / z = 303.0 [M + H]⁺, 1.350 minutes.</p><p> Step 6: Preparation of 7-azido-9-methyl-6,7-dihydro-5H-pyrido [2,3-b] azepine-8 (9H) -one Sodium azide (650 mg, 10.0 mmol), 7- Addition of iodo-9-methyl-6,7-dihydro-5H-pyrido [2,3-b] azepine-8 (9H) -one (1.5 g, 4.9 mmol) to N, N-dimethylformamide (10 mL) solution bottom. The reaction mixture was stirred at room temperature for 5 hours, diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (900 mg, 84%) as a white solid. LC-MS (Method C): m / z = 218.2 [M + H]⁺, 0.586 minutes.</p><p> Step 7: Preparation of 7-amino-6,7-dihydro-5H-pyrido [2,3-b] azepine-8 (9H) -one Triphenylphosphine (1.6 g, 6.1 mmol), 7-azido-9 -Methyl-6,7-dihydro-5H-pyrido [2,3-b] azepine-8 (9H) -one (0.9 g, 4.1 mmol) was added to a solution in tetrahydrofuran (10 mL) and water (10 mL). The reaction mixture was stirred at room temperature overnight, diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (0.65 g, 82%) as a white solid. LC-MS (Method C): m / z = 192.1 [M + H]⁺, 0.386 minutes.</p><p> Step 8: 5-Benzyl-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) -4H-1,2 Preparation of 4-triazole-3-carboxamide</p><p> N, N-diisopropylethylamine (201.2 mg, 1.56 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (104.6 mg, 0.52 mmol), 7-amino-9-methyl-6 , 7-Dihydro-5H-pyrido [2,3-b] azepine-8 (9H) -one (100 mg, 0.52 mmol), N- (3-dimethylaminopropyl))-N'-ethylcarbodiimide hydrochloride (119.6) mg, 0.62 mmol) and 1-hydroxybenzotriazole (84.2 mg, 0.62 mmol) were added to the mixture in N, N-dimethylformamide (4 mL). The reaction mixture was stirred at room temperature overnight, diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residues under the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 10% B ~ 35% B over 11 minutes; UV254 &amp; 220 nm; Rt: 10 min; 50 mg, 25%) was obtained as a white solid. LC-MS (Method D): m / z = 377.2 [M + H]⁺, 1.551 minutes.</p><p> Step 9: (R) -5-benzyl-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) -4H -1,2,4-Triazole-3-carboxamide (Example 107A) and (S) -5-benzyl-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido) [2,3-b] Preparation of azepine-7-yl) -4H-1,2,4-triazole-3-carboxamide (Example 107B) 5-benzyl-N- (9-methyl-8-oxo-6) , 7,8,9-Tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) -4H-1,2,4-triazole-3-carboxamide (50 mg, 0.14 mmol). The following conditions: Column: Chiralpak ID-2, 2 × 25 cm, 5 μm; Mobile phase A: hexane, Mobile phase B: MeOH: EtOH = 1: 1; Flow rate: 17 mL / min; Gradient: 60% over 23 minutes Separation by preparative chiral HPLC using B ~ 60% B; UV220 &amp; 254nm; Rt1: 8.53 min; Rt2: 18.27 min; to give the title compound:</p><p> Example 107A (first elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 14.35 (br. S, 1H), 8.52-8.42 (m, 2H), 7.82-7.79 (m, 1H), 7.34-7.21 (m, 6H), 4.35-4.26 (m, 1H), 4.10 (s) , 2H), 3.34 (s, 3H), 2.75-2.62 (m, 2H), 2.41-2.16 (m, 2H) .LC-MS (Method D): m / z = 377.2 [M + H]⁺, 1.551 minutes.</p><p> Example 107B (second elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 14.35 (br. S, 1H), 8.45-8.41 (m, 2H), 7.83-7.79 (m, 1H), 7.35-7.15 (m, 6H), 4.35-4.23 (m, 1H), 4.10 (s) , 2H), 3.34 (s, 3H), 2.75-2.61 (m, 2H), 2.50-2.20 (m, 2H) .LC-MS (Method D): m / z = 377.2 [M + H]⁺, 1.546 minutes.</p><p> Example 108: (S) -2-Benzyl-N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3- Ill) -1H-imidazole-5-carboxamide<chemistry num="222"><img file="JP6974331B2_D0256.tif" /></chemistry> Step 1: Preparation of (Z) -N'-hydroxy-2-phenylacetimideamide Sodium bicarbonate (1.44 g, 17.1 mmol), 2-phenyl acetonitrile (1.0 g, 8.54 mmol) and hydroxylamine hydrochloride (1.19). g, 17.1 mmol) was added to the mixture in ethanol (15 mL) and water (5.0 mL). The reaction mixture was stirred at 80 ° C. overnight, diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 5/95) to give the title compound (1.15 g, 90%) as a white solid. MS (Method I): m / z = 151.1 [M + H]⁺, 0.194 minutes.</p><p> Step 2: Preparation of 2-benzyl-1H-imidazole-5-ethyl carboxylate (Z) -N'-hydroxy-2-phenylacetoimideamide (1.0 g, 6.67 mmol) and ethyl propiolic acid (1.96 g, 20 mmol) The reaction mixture in ethanol (20 mL) was stirred overnight at 80 ° C. Diphenyl ether (50 mL) was added to the mixture and stirred at 130 ° C. for 2 hours. The reaction mixture was quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/99) to give the title compound (650 mg, 43%) as a gray solid. LC-MS (Method L): m / z = 231.1 [M + H]⁺, 1.197 minutes.</p><p> Step 3: (S) -2-Benzyl-N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl ) -1H-Preparation of imidazole-5-carboxamide The crude product obtained using the procedure described in Example 54 is subjected to the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; Mobile phase A: water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B ~ 45% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6 min; Obtained.¹1 H NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 8.0, 1.6 Hz, 1H), 7.57 (d, J = 2.1 Hz, 1H), 7.38-7.17 (m, 6H), 4.90-4.76 (m, 1H), 4.64 (dd, J = 11.5, 9.8 Hz, 1H), 4.54-4.45 (m, 1H) ), 4.02 (s, 2H), 3.36 (s, 3H). LC-MS (Method O): m / z = 378.0 [M + H]⁺, 1.047 minutes.</p><p> Examples 109A and 109B: (S) -1-benzyl-N- (2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo [4,3-b]] Azepine-6-yl) -4-fluoro-1H-pyrazole-3-carboxamide and (R) -1-benzyl-N- (2,4-dimethyl-5-oxo-2,4,5,6,7, 8-Hexahydropyrazolo [4,3-b] Azepine-6-yl) -4-Fluoro-1H-Pyrazole-3-Carboxamide<chemistry num="223"><img file="JP6974331B2_D0257.tif" /></chemistry> Step 1: 1-Benzyl-N- (2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl)- Preparation of 4-Fluoro-1H-Pyrazole-3-Carboxamide The crude product obtained using amide coupling procedure C is subjected to the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase A: Water (10 mmol / L NH₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B ~ 50% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6 min; 80 mg, 55.6%) was obtained as a white solid. LC-MS (Method Q): m / z = 397.4 [M + H]⁺, 1.115 minutes.</p><p> Step 2: (S) -1-benzyl-N- (2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6 -Il) -4-fluoro-1H-pyrazole-3-carboxamide (Example 109A) and (R) -1-benzyl-N- (2,4-dimethyl-5-oxo-2,4,5,6,, Preparation of 7,8-hexahydropyrazolo [4,3-b] azepine-6-yl) -4-fluoro-1H-pyrazole-3-carboxamide (Example 109B). 1-Benzyl-N- (2,4-dimethyl-5-oxo-2,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl) -4-fluoro The racemic compound of -1H-pyrazole-3-carboxamide (80 mg, 0.20 mmol) was prepared under the following conditions: Column: Lux 5u Cellulose-3, AXIA Packed, 2.12 × 25 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 40% B-40% B over 15 minutes; UV254 &amp; 220 nm; Rt1: 9.89 min; Rt2 Separation by preparative chiral HPLC using: 12.58 min; to give the title compound:</p><p> Example 109A (first elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 8.13 (d, J = 4.4 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.40-7.31 (m, 3H), 7.31-7.28 (m, 2H) , 5.33 (s, 2H), 4.50-4.44 (m, 1H), 3.78 (s, 3H), 3.18 (s, 3H), 2.84-2.77 (m, 1H), 2.75-2.67 (m, 1H), 2.33 -2.24 (m, 1H), 2.16-2.04 (m, 1H) .LC-MS (Method T): m / z = 397.2 [M + H]⁺, 1.155 minutes.</p><p> Example 109B (second elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 8.13 (d, J = 4.4 Hz, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.83 (s, 1H), 7.40-7.31 (m, 3H), 7.31-7.26 (m, 2H) , 5.33 (s, 2H), 4.51-4.42 (m, 1H), 3.78 (s, 3H), 3.18 (s, 3H), 2.87-2.63 (m, 2H), 2.35-2.21 (m, 1H), 2.18 -2.03 (m, 1H) .LC-MS (method T): m / z = 397.2 [M + H]⁺, 1.154 minutes.</p><p> Examples 110A and 110B: 5-Benzyl-N-((1aR, 2R, 8bS) -3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-] b] Azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide and 5-benzyl-N-((1aS, 2S, 8bR) -3-oxo-1,1a, 2,3, 4,8b-Hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="224"><img file="JP6974331B2_D0258.tif" /></chemistry> Step 1: 5-benzyl-N- (cis-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepin-2-yl)- Preparation of 4H-1,2,4-triazole-3-carboxamide The crude product obtained using amide coupling procedure C was purified by preparative TLC (ethyl acetate / petroleum ether, 1/3). , The title compound (20 mg, 26.7%) was obtained as a yellow solid. LC-MS (Method I): m / z = 375.2 [M + H]⁺, 1.007 minutes.</p><p>Step 2: 5-benzyl-N-((1aR, 2R, 8bS) -3-oxo-1,1a, 2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine -2-yl) -4H-1,2,4-triazole-3-carboxamide (Example 110A) and 5-benzyl-N-((1aS, 2S, 8bR) -3-oxo-1,1a, 2, Preparation of 3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide (Example 110B) 5- Benzyl-N- (cis-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) -4H-1,2 , 4-Triazole-3-Carboxamide (20 mg, 0.053 mmol) racemic compound under the following conditions: Column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 30% B to 30% B over 20 minutes; UV254 &amp; 220 nm; Rt1: 12.8 min Separation by preparative chiral HPLC using Rt2: 16.08 min; to give the title compound:</p><p> Example 110A (first elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.24 (dd, J = 4.8, 1.6 Hz, 1H), 7.91 (dd, J = 7.6, 1.6 Hz, 1H), 7.38-7.16 (m, 6H), 4.84 (s, 1H), 4.17 (s, 2H), 2.25-2.21 (m, 1H), 2.15-2.09 (m, 1H), 1.62-1.57 (m, 1H), 1.16-1.12 (m, 1H). LC-MS (Method J): m / z = 375.2 [M + H]⁺, 1.007 minutes.</p><p> Example 110B (second elution isomer):¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.23 (dd, J = 4.8, 1.8 Hz, 1H), 7.90 (dd, J = 7.5, 1.8 Hz, 1H), 7.39-7.13 (m, 6H), 4.84 (s, 1H), 4.18 (s, 2H), 2.19-2.09 (m, 2H), 1.64-1.55 (m, 1H), 1.17-1.10 (m, 1H) .LC-MS (Method F): m / z = 374.9 [M + H]⁺, 0.919 minutes.</p><p> Examples 111A and 111B: (R) -1-benzyl-4-fluoro-N-(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyridol [2,3-b] azepine -7-yl) -1H-pyrazole-3-carboxamide and (S) -1-benzyl-4-fluoro-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido) [2,3-b] Azepine-7-yl) -1H-pyrazole-3-carboxamide<chemistry num="225"><img file="JP6974331B2_D0259.tif" /></chemistry> Step 1: 1-Benzyl-4-fluoro-N- (9-Methyl-8-oxo-6,7,8,9-Tetrahydro-5H-Pyrazole [2,3-b] Azepine-7-yl) -1H -Preparation of pyrazole-3-carboxamide N, N-diisopropylethylamine (201.2 mg, 1.56 mmol), 1-benzyl-4-fluoro-1H-pyrazol-3-carboxylic acid (104.6 mg, 0.52 mmol), 7-amino-9-methyl-6,7 -Dihydro-5H-pyrido [2,3-b] azepine-8 (9H) -one (100 mg, 0.52 mmol), N- (3-dimethylaminopropyl))-N'-ethylcarbodiimide hydrochloride (119.6 mg, 0.62 mmol) and 1-hydroxybenzotriazole (84.2 mg, 0.62 mmol) were added to the mixture in N, N-dimethylformamide (3 mL). The reaction mixture was stirred at room temperature overnight, diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product obtained using amide coupling procedure C is subjected to the following conditions: Column: XSelect CSH Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 35% B ~ 55% B over 7 minutes; UV254 &amp; 220 nm; Purification by preparative HPLC using Rt: 5.6 min; gave the title compound (32 mg, 25.4%) as a white solid. LC-MS (Method D): m / z = 394.2 [M + H]⁺, 1.571 minutes.</p><p> Step 2: (R) -1-benzyl-4-fluoro-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrazole [2,3-b] azepine-7- Il) -1H-pyrazole-3-carboxamide (Example 111A) and (S) -1-benzyl-4-fluoro-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H) -Preparation of pyrido [2,3-b] azepine-7-yl) -1H-pyrazole-3-carboxamide (Example 111B) 1-benzyl-4-fluoro-N- (9-methyl-8-oxo-6) , 7,8,9-Tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) -1H-pyrazole-3-carboxamide (32 mg, 0.081 mmol) with the following conditions: Column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; Mobile phase A: hexane, Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 30% B ~ 30% B over 15 minutes; UV254 &amp; 220 nm; Rt1: Separation by preparative chiral HPLC using 11.47 min; Rt2: 13.24 min; to give the title compound:</p><p> Example 111A (first elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 8.42-8.40 (m, 1H), 8.10-8.02 (m, 2H), 7.80-7.77 (m, 1H), 7.39-7.24 (m, 6H), 5.31 (s, 2H), 4.32-4.23 (m) , 1H), 3.33 (s, 3H), 2.78-2.60 (m, 2H), 2.38-2.25 (m, 2H) .LC-MS (Method D): m / z = 394.2 [M + H]⁺, 1.571 minutes.</p><p> Example 111B (second elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 8.42-8.40 (m, 1H), 8.10-8.02 (m, 2H), 7.80-7.77 (m, 1H), 7.39-7.24 (m, 6H), 5.31 (s, 2H), 4.32-4.23 (m) , 1H), 3.32 (s, 3H), 2.72-2.66 (m, 2H), 2.39-2.26 (m, 2H) .LC-MS (Method D): m / z = 394.2 [M + H]⁺, 1.570 minutes.</p><p> Example 112: 5-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) Isoxazole-3-carboxamide<chemistry num="226"><img file="JP6974331B2_D0260.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: XBridge C18OBD preparative column, 5 μm, 19 × 250 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B-60% B at 7 min; UV254 &amp; 220 nm; Rt: 7 min; Obtained.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.35 (dd, J = 4.7, 1.5 Hz, 1H), 8.27 (d, J = 7.0 Hz, 1H), 7.73 (dd, J = 7.9, 1.5 Hz, 1H), 7.39-7.23 (m, 6H) , 6.61 (s, 1H), 4.99-4.87 (m, 2H), 4.22 (s, 2H), 3.39 (s, 3H), 1.36 (d, J = 6.2 Hz, 3H). LC-MS (Method X) : m / z = 393.2 [M + H]⁺, 3.187 minutes.</p><p> Example 113: (S) -N- (1-Methyl-2-oxo-1,2,3,4-Tetrahydropyrido [3,4-b] [1,4] Oxazepine-3-yl) -5 -(1-Phenylcyclopropyl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="227"><img file="JP6974331B2_D0261.tif" /></chemistry> The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: Column: XBridge Shield RP18 OBD Column, 5 μm, 19 × 150 mm; Mobile Phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 10% B-40% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6 min; purified by preparative HPLC to give the title compound. ..¹1 H NMR (400 MHz, DMSO-d₆) δ 14.11 (s, 1H), 8.91-8.36 (m, 3H), 7.53 (d, J = 5.3 Hz, 1H), 7.33 (m, 5H), 4.94-4.82 (m, 1H), 4.82-4.70 ( m, 1H), 4.51 (dd, J = 9.6, 7.2 Hz, 1H), 3.32 (s, 3H), 1.59-1.20 (m, 4H) .LC-MS (Method O): m / z = 405.0 [M + H]⁺, 1.127 minutes.</p><p> Examples 114A and 114B: (S) -1-benzyl-N- (1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo [4,3-b]] Azepine-6-yl) -4-fluoro-1H-pyrazole-3-carboxamide and (R) -1-benzyl-N- (1,4-dimethyl-5-oxo-1,4,5,6,7, 8-Hexahydropyrazolo [4,3-b] Azepine-6-yl) -4-Fluoro-1H-Pyrazole-3-Carboxamide<chemistry num="228"><img file="JP6974331B2_D0262.tif" /></chemistry> Step 1: 1-Benzyl-N- (1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl)- Preparation of 4-Fluoro-1H-Pyrazole-3-Carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: XBridge Prep Phenyl OBD Column 19 × 150 mm 5 μm; Mobile phase A: Water (10 mmol / L NH₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 50% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6 min; purified by preparative HPLC using the title compound ( 50 mg, 48.6%) was obtained as a white solid. LC-MS (Method C): m / z = 397.2 [M + H]⁺, 1.512 minutes.</p><p> Step 2: (S) -1-benzyl-N- (1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6 -Il) -4-fluoro-1H-pyrazole-3-carboxamide (Example 114A) and (R) -1-benzyl-N- (1,4-dimethyl-5-oxo-1,4,5,6, Preparation of 7,8-hexahydropyrazolo [4,3-b] azepine-6-yl) -4-fluoro-1H-pyrazole-3-carboxamide (Example 114B). 1-benzyl-N- (1,4-dimethyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl) -4-fluoro The racemic compound of -1H-pyrazole-3-carboxamide (50 mg, 0.13 mmol) was prepared under the following conditions: Column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate. Separation by preparative chiral HPLC using: 20 mL / min; gradient: 50% B ~ 50% B over 18 minutes; UV254 &amp; 220 nm; Rt1: 12.54 min; Rt2: 15.41 min; rice field:</p><p> Example 114A (first elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 8.14 (d, J = 4.0 Hz, 1H), 8.07 (d, J = 6.4 Hz, 1H), 7.50 (s, 1H), 7.41-7.27 (m, 5H), 5.34 (s, 2H), 4.43 -4.37 (m, 1H), 3.74 (s, 3H), 3.24 (s, 3H), 3.06-2.96 (m, 1H), 2.91-2.84 (m, 1H), 2.30-2.23 (m, 1H), 2.10 -1.99 (m, 1H) .LC-MS (Method D): m / z = 397.1 [M + H]⁺, 1.500 minutes.</p><p> Example 114B (second elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 8.14 (d, J = 4.4 Hz, 1H), 8.07 (d, J = 6.8 Hz, 1H), 7.50 (s, 1H), 7.41-7.26 (m, 5H), 5.34 (s, 2H), 4.43 -4.37 (m, 1H), 3.74 (s, 3H), 3.24 (s, 3H), 3.06-2.96 (m, 1H), 2.91-2.83 (m, 1H), 2.30-2.22 (m, 1H), 2.10 -1.99 (m, 1H) .LC-MS (Method D): m / z = 397.1 [M + H]⁺, 1.514 minutes.</p><p> Example 115: (S) -4-Fluoro-1- (4-Fluorobenzyl) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrazole [3,2-b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="229"><img file="JP6974331B2_D0263.tif" /></chemistry> Step 1: Preparation of 4-fluoro-1- (4-fluorobenzyl) -1H-pyrazole-3-carboxylic acid Sodium hydride (60%, 152 mg, 3.8 mmol), 4-fluoro-1H-pyrazole-3- It was added to a solution of methyl carboxylate (200 mg, 1.27 mmol) in N, N-dimethylformamide (10 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 0.5 hours, followed by the addition of 1- (bromomethyl) -4-fluorobenzene (264 mg, 1.40 mmol). The reaction mixture was stirred at room temperature for an additional 1.5 hours and quenched by the addition of water (20 mL). The resulting solution was then stirred at room temperature for 5 hours. The pH value of the solution was adjusted to 7 with aqueous hydrochloric acid (1N, 10 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residues under the following conditions: Column: XBridge C18OBD preparative column, 100 Å, 5 μm, 19 mm × 250 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 40% B-60% over 9 minutes Purification by preparative HPLC using B; UV254 &amp; 220 nm; Rt: 7 min; to give the title compound (100 mg, 33.2%). LC-MS (Method S): m / z = 239.2 [M + H]⁺, 1.093 minutes.</p><p> Step 2: (S) -4-fluoro-1- (4-fluorobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [ 1,4] Oxazepine-3-yl) -1H-Pyrazole-3-Carboxamide preparation The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: XBridge Prep C18OBD Column 19 × 150 mm 5 μm; mobile phase A: water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 55% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6.32 min; Obtained.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.37-8.35 (m, 1H), 8.27 (d, J = 8 Hz, 1H), 8.14 (d, J = 4.4 Hz, 1H), 7.71-7.69 (m, 1H), 7.36-7.32 (m, 3H), 7.25-7.20 (m, 2H), 5.33 (s, 2H), 4.87-4.81 (m, 1H), 4.70-4.65 (m, 1H), 4.52-4.48 (m, 1H), 3.35 (s, 3H) .LC-MS (Method X): m / z = 414.2 [M + H]⁺, 2.606 minutes.</p><p> Example 116: (S) -N- (5,6-dihydro-4H-benzo [f] imidazole [1,2-a] azepine-4-yl) -5- (2-fluorophenoxy) pyridazine-3- Carboxamide<chemistry num="230"><img file="JP6974331B2_D0264.tif" /></chemistry> Step 1: Preparation of 3-chloro-5- (2-fluorophenoxy) pyridazine 2-fluorophenol (2 g, 17.8 mmol), 3,5-dichloropyridazine (3.17 g, 21.4 mmol) and cesium carbonate (8.7 g,) 26.9 mmol) was added dropwise to the stirred mixture in acetonitrile (40 mL). The reaction mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The solid was removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether) to give the title compound (2.8 g, 70%) as a white solid. LC-MS (Method X): m / z = 225.1 [M + H]⁺, 0.919 minutes.</p><p> Step 2: Preparation of 5- (2-fluorophenoxy) pyridazine-3-carboxylate ethyl 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane (0.95 g, 1.16 mmol), 3- Chloro-5- (2-fluorophenoxy) pyridazine (2.6 g, 11.6 mmol) and sodium acetate (1.9 g, 23.2 mmol) were added to the mixture in ethanol (125 mL) and N, N-dimethylformamide (25 mL). The reaction mixture was stirred under a carbon monoxide atmosphere (1 MPa) at 90 ° C. overnight. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/10) to give the title compound (2.4 g, 79%) as a colorless oil. LC-MS (Method X): m / z = 263.1 [M + H]⁺, 0.905 minutes.</p><p> Step 3: Preparation of 5- (2-fluorophenoxy) pyridazine-3-carboxylic acid Lithium hydroxide (48 mg, 2 mmol), 5- (2-fluorophenoxy) pyridazine-3-carboxylate ethyl (131 mg, 0.5 mmol) Was added to a stirring solution of tetrahydrofuran (8 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 1 hour. After removing the tetrahydrofuran under reduced pressure, the residue was diluted with water (20 mL). The pH of the resulting solution was adjusted to 4 with aqueous hydrochloric acid (2N, 5 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (100 mg, crude) as a white solid. LC-MS (Method R): m / z = 235.2 [M + H]⁺, 0.507 minutes.</p><p> Step 4: (S) -N- (5,6-dihydro-4H-benzo [f] imidazole [1,2-a] azepine-4-yl) -5- (2-fluorophenoxy) pyridazine-3-carboxamide Preparation of crude product obtained using amide coupling procedure C under the following conditions: Column: XBridge Prep C18OBD Column 19 × 150 mm 5 μm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN, flow rate: 30 mL / min; gradient: 45% B ~ 50% B; UV254 &amp; 220 nm; purified by preparative HPLC over 5 minutes to give the title compound.¹1 H NMR (400 MHz, Methanol-d₄) δ 9.25 (d, J = 2.8 Hz, 1H), 7.51-7.32 (m, 10H), 7.08 (d, J = 1.2 Hz, 1H), 5.11-5.06 (m, 1H), 2.88-2.81 (m, 1H), 2.80-2.71 (m, 1H), 2.66-2.57 (m, 1H), 2.51-2.42 (m, 1H) .LC-MS (Method D): m / z = 416.1 [M + H]⁺, 1.337 minutes.</p><p> Example 117: N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3- Il) -4- (2-fluorophenoxy) picoline amide<chemistry num="231"><img file="JP6974331B2_D0265.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (0.1% formic acid), Mobile phase B: Purification by preparative HPLC using ACN; flow rate: 20 mL / min; gradient: 35% B to 85% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6.35 min; to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.75 (d, J = 6.8 Hz, 1H), 8.64 (d, J = 5.6 Hz, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz) , 1H), 7.54-7.39 (m, 3H), 7.38-7.33 (m, 3H), 7.27-7.29 (m, 1H), 5.02-4.95 (m, 1H), 4.94-4.89 (m, 1H), 3.41 (s, 3H), 1.32 (d, J = 6.0 Hz, 3H). LC-MS (Method Q): m / z = 423.0 [M + H]⁺, 2.88 5 minutes.</p><p> Examples 118A &amp; 118B: (R) -5-benzyl-N- (1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6- Il) -4H-1,2,4-triazole-3-carboxamide and (S) -5-benzyl-N- (1-methyl-5-oxo-1,4,5,6,7,8-hexahydro) Pyrazolo [4,3-b] azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="232"><img file="JP6974331B2_D0266.tif" /></chemistry> Step 1: 5-benzyl-N- (1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl) -4H- Preparation of 1,2,4-Triazole-3-Carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: XBridge Prep Phenyl OBD Column 19 × 150 mm 5 μm; Mobile phase A: Purified by preparative HPLC using water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 5% B to 35% B over 10 minutes; UV254 &amp; 220 nm; Rt: 9 min; The title compound (50 mg, 38.1%) was obtained as a white solid. LC-MS (Method C): m / z = 366.2 [M + H]⁺, 1.174 minutes.</p><p> Step 2: (R) -5-benzyl-N- (1-methyl-5-oxo-1,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl ) -4H-1,2,4-triazole-3-carboxamide (Example 118A) and (S) -5-benzyl-N- (1-methyl-5-oxo-1,4,5,6,7, 8-Hexahydropyrazolo [4,3-b] azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide (Example 118B) 5-benzyl-N- (1-methyl-5) -Oxo-1,4,5,6,7,8-hexahydropyrazolo [4,3-b] azepine-6-yl) -4H-1,2,4-triazole-3-carboxamide (50 mg, 0.14) The following conditions: column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 50 over 12 minutes. Separation by preparative chiral HPLC using% B to 50% B; 254/220 nm; Rt1: 8.84 min; Rt2: 10.81 min; to give the title compound:</p><p> Example 118A (first elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 10.00 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7.41-7.29 (m, 5H), 7.17 (s, 1H), 4.41-4.37 (m, 1H), 4.18 (s, 2H), 3.76 (s, 3H), 3.05-3.00 (m, 2H), 2.34-2.30 (m, 1H), 2.10-2.05 (m, 1H). LC-MS (Method D): m / z = 366.1 [M + H]⁺, 1.180 minutes.</p><p> Example 118B (second elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 9.94 (s, 1H), 8.46 (d, J = 6.0 Hz, 1H), 7.35-7.10 (m, 5H), 7.10 (s, 1H), 4.35-4.30 (m, 1H), 4.12 (s, 2H), 3.69 (s, 3H), 3.00-2.92 (m, 2H), 2.27-2.23 (m, 1H), 2.04-1.98 (m, 1H) .LC-MS (Method D): m / z = 366.1 [M + H]⁺, 1.177 minutes.</p><p> Examples 119A &amp; 119B: 5-benzyl-N-((7R, 7aR, 8aS) -5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydro-cyclopropa [d] pyrazino [2,3] -b] Azepine-7-yl) -4H-1,2,4-triazole-3-carboxamide and 5-benzyl-N-((7S, 7aS, 8aR) -5-methyl-6-oxo-5,6 , 7,7a,8,8a-hexahydrocyclopropa [d] pyrazino [2,3-b] azepine-7-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="233"><img file="JP6974331B2_D0267.tif" /></chemistry><chemistry num="234"><img file="JP6974331B2_D0268.tif" /></chemistry> Step 1: Preparation of 3-bromopyrazine-2-amine In a solution of 3-bromopyrazine-2-amine (10 g, 57 mmol) in N, N-dimethylformamide (50 mL), tributyl (ethenyl) stannane (20 g, 63 mmol) and Tetrakis (triphenylphosphine) palladium (2.7 g, 2.3 mmol) was added under a nitrogen atmosphere. The resulting mixture was stirred at 80 ° C. for 16 hours, quenched by the addition of water (200 mL) and extracted with dichloromethane (3 x 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 3/97) to give the title compound (6.0 g, 86%) as a yellow solid. LC-MS (Method C): m / z = 122.1 [M + H]⁺, 0.658 minutes.</p><p> Step 2: Preparation of N- (3-vinylpyrazine-2-yl) porcine-3-enamide Thionyl chloride (9.3 g, 46.5 mmol) in dichloromethane (20 mL) of porcine-3-enoic acid (4.0 g, 46.5 mmol) It was added dropwise to the solution. After stirring at room temperature for 1 hour, the resulting mixture was added to a solution of triethylamine (11.8 g, 116.6 mmol) and 3-vinylpyrazine-2-amine (4.7 g, 38.7 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 2 hours, quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 3/1) to give the title compound (5.7 g, 78%) as a yellow oil. LC-MS (Method C): m / z = 190.1 [M + H]⁺, 0.881 minutes.</p><p> Step 3: Preparation of (Z) -5H-pyrazino [2,3-b] azepine-6 (7H) -one [1,3-bis (2,4,6-trimethylphenyl) imidazolidine-2-iriden] Dichloro (Phenylmethylidene) ruthenium tricyclohexylphosphin (340 mg, 0.4 mmol) was added to a toluene (50 mL) solution of N- (3-vinylpyrazine-2-yl) porcine-3-enamide (380 mg, 2 mmol). The resulting solution was stirred at 80 ° C. for 16 hours and then concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 5/1) to give the title compound (210 mg, 65%) as a yellow oil. LC-MS (Method C): m / z = 162.1 [M + H]⁺, 0.762 minutes.</p><p> Step 4: Preparation of (Z) -5-methyl-5H-pyrazino [2,3-b] azepine-6 (7H) -one Iodomethane (180 mg, 1.3 mmol), (Z) -5H-pyrazino [2,, 3-b] Azepine-6 (7H) -one (210 mg, 1.3 mmol) and cesium carbonate (1.3 g, 3.9 mmol) were added dropwise to a stirred solution of N, N-dimethylformamide (30 mL). The reaction mixture was stirred at room temperature for 4 hours, diluted with water (60 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 4/1) to give the title compound (200 mg, 88%) as a yellow solid. LC-MS (Method E): m / z = 176.1 [M + H]⁺, 0.776 minutes.</p><p> Step 5: 5-Methyl-7,7a,8,8a-Tetrahydrocyclopropa [d] Pyrazineno [2,3-b] Azepine-6 (5H) -Preparation of on Potassium hydroxide (4g, 71.4 mmol) water A solution of 1-methyl-1-nitrosourea (2.1 g, 20 mmol) in ether (30 mL) was added dropwise to the (6 mL) solution at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at 0 ° C. for 1 hour, then the organic phase was separated to give a solution of diazomethane (30 mL). Add a solution of diazomethane (30 mL) to a solution of (Z) -5-methyl-5H-pyrazino [2,3-b] azepine-6 (7H) -one (200 mg, 1.1 mmol) in tetrahydrofuran (10 mL). , Subsequently, a mixture of palladium diacetate (25 mg, 0.11 mmol) in tetrahydrofuran (5 mL) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature overnight. The solid was removed by filtration and the filtrate was concentrated under vacuum to give the title compound (110 mg, crude) as a yellow oil. LC-MS (Method E): m / z = 190.1 [M + H]⁺, 0.825 minutes.</p><p> Step 6: Trans-7-iodo-5-methyl-7,7a,8,8a-tetrahydrocyclopropa [d] pyrazino [2,3-b] azepine-6 (5H) -one preparation 5-methyl-7 , 7a,8,8a-tetrahydrocyclopropa [d] pyrazino [2,3-b] azepine-6 (5H) -one (110 mg, 0.6 mmol) in dichloromethane (20 mL), N, N, N ', N'-Tetramethylethylene-diamine (210 mg, 1.8 mmol) was added, followed by iodotrimethylsilane (360 mg, 1.8 mmol) at 0 ° C. After stirring at 0 ° C for 2 hours, iodine (230 mg, 0.9 mmol) was added. The reaction mixture was stirred at 0 ° C. for 1 hour, quenched with aqueous sodium thiosulfate (5%, 40 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (132 mg, crude) as a yellow oil. LC-MS (Method E): m / z = 316.1 [M + H]⁺, 0.840 minutes.</p><p> Step 7: Preparation of cis-7-azido-5-methyl-7,7a,8,8a-tetrahydrocyclopropa [d] pyrazino [2,3-b] azepine-6 (5H) -one Sodium azide (39 mg) , 0.6 mmol), trans-7-iodo-5-methyl-7,7a,8,8a-tetrahydrocyclopropa [d] pyrazino [2,3-b] azepine-6 (5H) -one (132 mg, 0.4) Methyl) was added to the mixture in N, N-dimethylformamide (10 mL). The resulting mixture was stirred at room temperature for 16 hours, quenched by the addition of water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (60 mg, crude) as a yellow oil. LC-MS (Method C): m / z = 231.1 [M + H]⁺, 1.036 minutes.</p><p> Step 8: Preparation of cis-7-amino-5-methyl-7,7a,8,8a-tetrahydrocyclopropa [d] pyrazino [2,3-b] azepine-6 (5H) -one</p><p> Triphenylphosphine (102 mg, 0.39 mmol), cis-7-azido-5-methyl-7,7a,8,8a-tetrahydrocyclopropa [d] pyrazino [2,3-b] azepine-6 (5H)- On (60 mg, 0.26 mmol) was added to the mixture in tetrahydrofuran (10 mL) and water (1 mL). The resulting mixture was stirred at room temperature for 16 hours, diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/19) to give the title compound (40 mg, 75%) as a yellow oil. LC-MS (Method E): m / z = 205.1 [M + H]⁺, 0.406 minutes.</p><p> Step 9: 5-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa [d] pyrazino [2,3-b] azepine-7- Il) Preparation of -4H-1,2,4-triazole-3-carboxamide N, N-diisopropylethylamine (93 mg, 0.72 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (51 mg, 0.24 mmol), cis-7-amino-5-methyl-7,7a,8,8a-tetrahydrocyclopropa [d] pyrazino [2,3-b] azepine-6 (5H) -one (40 mg, 40 mg,) 0.20 mmol), N- (3-dimethylamino-propyl))-N'-ethylcarbodiimide hydrochloride (46 mg, 0.24 mmol) and 1-hydroxybenzotriazole (32 mg, 0.24 mmol) N, N-dimethylformamide (4 mL) ) Was added to the mixture. The reaction mixture was stirred at room temperature overnight, diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residues under the following conditions: Column: XBridge Prep C18OBD column 19 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 30 mL / min; Gradient: Purified by preparative HPLC using 25% B ~ 55% B; UV254 &amp; 220 nm; over 7 minutes, title compound (20 mg, 26%) Was obtained as a white solid. LC-MS (Method D): m / z = 390.2 [M + H]⁺, 1.386 minutes.</p><p> Step 10: 5-benzyl-N-((7R, 7aR, 8aS) -5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydro-cyclopropa [d] pyrazino [2,3-] b] Azepine-7-yl) -4H-1,2,4-triazole-3-carboxamide (Example 119A) and 5-benzyl-N-((7S, 7aS, 8aR) -5-methyl-6-oxo -5,6,7,7a,8,8a-hexahydrocyclopropa [d] -pyrazino [2,3-b] azepine-7-yl) -4H-1,2,4-triazole-3-carboxamide ( Preparation of Example 119B) 5-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa [d] -pyrazino [2,3-b] Azepine-7-yl) -4H-1,2,4-triazole-3-carboxamide (20 mg, 0.05 mmol) lasemi compound under the following conditions: Column: Chiralpak IA, 2 × 25 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 16 mL / min; gradient: 55% B to 55% B over 27 minutes; 220/254 nm; Rt1: 13.94 min Separation by preparative chiral HPLC using Rt2: 21.44 min; to give the title compound:</p><p> Example 119A (first elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 8.44-8.40 (m, 2H), 7.36-7.21 (m, 5H), 4.81 (s, 1H), 4.18 (s, 2H), 3.42 (s, 3H), 2.66-2.58 (m, 1H), 2.29-2.18 (m, 1H), 1.57-1.48 (m, 1H), 1.36-1.25 (m, 1H) .LC-MS (Method D): m / z = 390.1 [M + H]⁺, 1.389 minutes.</p><p> Example 119B (second elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 8.46-8.38 (m, 2H), 7.39-7.21 (m, 5H), 4.81 (s, 1H), 4.18 (s, 2H), 3.42 (s, 3H), 2.66-2.58 (m, 1H), 2.30-2.22 (m, 1H), 1.57-1.50 (m, 1H), 1.35-1.26 (m, 1H) .LC-MS (Method D): m / z = 390.2 [M + H]⁺, 1.384 minutes.</p><p> Examples 120A and 120B: 5-benzyl-N-((1aS, 2S, 8bR) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyridode [d] 2,3-b] Azepine-2-yl) -1,3,4-thiadiazole-2-carboxamide and 5-benzyl-N-((1aR, 2R, 8bS) -4-methyl-3-oxo-1, 1a,2,3,4,8b-hexahydrocyclopropa- [d] pyrido [2,3-b] azepine-2-yl) -1,3,4-thiadiazole-2-carboxamide<chemistry num="235"><img file="JP6974331B2_D0269.tif" /></chemistry> Step 1: 5-Benzyl-N- (cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2 -Il) -1,3,4-Thiadiazole-2-carboxamide preparation The crude product obtained using amide coupling procedure C is transferred under the following conditions: Column: XBridge Prep C18OBD Column 19 × 150 mm 5 μm; Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 55% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6.32 min; 20 mg, 32.9%) was obtained as a white solid. LC-MS (Method I): m / z = 406.2 [M + H]⁺, 1.001 minutes.</p><p>Step 2: 5-benzyl-N-((1aS, 2S, 8bR) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3] -b] Azepine-2-yl) -1,3,4-thiadiazole-2-carboxamide (Example 120A) and 5-benzyl-N-((1aR, 2R, 8bS) -4-methyl-3-oxo- 1,1a,2,3,4,8b-hexahydrocyclopropa- [d] pyrido [2,3-b] azepine-2-yl) -1,3,4-thiadiazole-2-carboxamide (Example 120B) ) Preparation 5-benzyl-N- (cis-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa- [d] -pyrido [2,3-b] azepine -2-yl) -1,3,4-thiadiazole-2-carboxamide (20 mg, 0.049 mmol) lasemi compound under the following conditions: Column: Lux Cellulose-4, 0.46 × 5 cm, 3 μm; Mobile phase A: Hexane; Mobile phase B: EtOH; Flow rate: 1.0 mL / min; Gradient: 50% B to 50% B over 8 minutes; UV254 &amp; 220 nm; Rt1: 4.09 Separation by preparative chiral separation using min; Rt2: 6.43 min; gave the title compound:</p><p> Example 120A (first elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 8.38 (dd, J = 4.8, 2.0 Hz, 1H), 7.94 (dd, J = 7.6, 2.0 Hz, 1H), 7.41-7.26 (m, 6H), 4.64 (s, 1H), 4.53 (s, 2H), 3.41 (s, 3H), 2.33-2.25 (m, 1H), 2.15-2.06 (m, 1H), 1.34-1.28 (m, 1H), 1.21-1.12 (m, 1H). LC-MS ( Method D): m / z = 406.1 [M + H]⁺, 1.703 minutes.</p><p> Example 120B (second elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 8.36 (dd, J = 4.8, 2.0 Hz, 1H), 7.91 (dd, J = 7.6, 2.0 Hz, 1H), 7.38-7.24 (m, 6H), 4.62 (s, 1H), 4.50 (s, 2H), 3.38 (s, 3H), 2.29-2.24 (m, 1H), 2.12-2.06 (m, 1H), 1.32-1.26 (m, 1H), 1.22-1.14 (m, 1H). LC-MS ( Method V): m / z = 406.1 [M + H]⁺, 2.915 minutes.</p><p> Examples 121A &amp; 121B: (R) -4- (2,4-difluorophenoxy) -N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] Azepine-7-yl) picoline amide and (S) -4- (2,4-difluorophenoxy) -N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2] , 3-b] Azepine-7-il) Picoline amide<chemistry num="236"><img file="JP6974331B2_D0270.tif" /></chemistry> Step 1: Preparation of 4- (2,4-difluorophenoxy) methyl picolinate In a closed tube, methyl 4-chloropicolinate (1 g, 5.85 mmol), 2,4-difluorophenol (1.14 g, 8.77 mmol), carbonate. Cesium (5.7 g, 17.5 mmol), copper powder (0.38 g, 5.94 mmol) and N, N-dimethylformamide (10 mL) were added. The resulting mixture was heated at 100 ° C. by microwave irradiation, stirred for 3 hours, diluted with water (20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (0.5 g, crude) as a white solid. LC-MS (Method I): m / z = 265.9 [M + H]⁺, 0.926 minutes.</p><p> Step 2: Preparation of 4- (2,4-difluorophenoxy) picolinic acid Lithium hydroxide (260 mg, 10.8 mmol), methyl 4-phenoxypicolinate (500 mg, 1.89 mmol) in tetrahydrofuran (10 mL) and water (5 mL) Added to the stirring mixture in. The resulting solution was stirred at room temperature overnight. After removing tetrahydrofuran under reduced pressure, the pH of the aqueous solution was adjusted to 6 with aqueous hydrochloric acid (1N, 10 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (200 mg, crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method X): m / z = 252.2 [M + H]⁺, 0.639 minutes.</p><p> Step 3: 4- (2,4-difluorophenoxy) -N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl ) Preparation of picoline amide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: XBridge Shield RP18 OBD column, 19 × 150 mm 5 μm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B ~ 70% B over 7 minutes; 254 &amp; 220 nm; Rt: 5.590 min; 80 mg, 40.1%) was obtained as a white solid. LC-MS (Method R): m / z = 425.3 [M + H]⁺, 1.442 minutes.</p><p> Step 4: (R) -4- (2,4-difluorophenoxy) -N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine -7-yl) Picoline amide (Example 121A) and (S) -4- (2,4-difluorophenoxy) -N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H) -Preparation of pyrido [2,3-b] azepine-7-yl) picoline amide (Example 121B) 4- (2,4-difluorophenoxy) -N- (9-methyl-8-oxo-6,7, A racemic compound of 8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) picoline amide (80 mg, 0.19 mmol) under the following conditions: Column: Chiralpak ID-2, 2 × 25 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 15 mL / min; gradient: 55% B to 55% B over 23 minutes; UV220 &amp; 254 nm; Rt1: 14.83 min; Rt2: 18.87 min; And separated by preparative chiral HPLC to give the title compound:</p><p> Example 121A (first elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 8.88 (d, J = 8.0 Hz, 1H), 8.60 (d, J = 5.6 Hz, 1H), 8.44-8.43 (m, 1H), 7.84-7.81 (m, 1H), 7.65-7.48 (m, 2H), 7.36-7.22 (m, 4H), 4.36-4.29 (m, 1H), 3.36 (s, 3H), 2.81-2.70 (m, 2H), 2.50-2.44 (m, 1H), 2.35-2.21 ( m, 1H) .LC-MS (method T): m / z = 425.25 [M + H]⁺, 1.432 minutes.</p><p> Example 121B (second elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 8.88 (d, J = 7.6 Hz, 1H), 8.60 (d, J = 5.6 Hz, 1H), 8.44-8.43 (m, 1H), 7.84-7.81 (m, 1H), 7.61-7.50 (m, 2H), 7.34-7.24 (m, 4H), 4.34-4.31 (m, 1H), 3.36 (s, 3H), 2.77-2.73 (m, 2H), 2.51-2.50 (m, 1H), 2.31-2.21 ( m, 1H) .LC-MS (Method X): m / z = 425.25 [M + H]⁺, 1.437 minutes.</p><p> Example 122: 3-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) Isoxazole-5-carboxamide<chemistry num="237"><img file="JP6974331B2_D0271.tif" /></chemistry> Step 1: Preparation of (E) -2-phenylacetaldehyde oxime Sodium hydroxide (1.2 g, 30.0 mmol) with 2-phenylacetaldehyde (1.2 g, 10.0 mmol) and hydroxylamine hydrochloride (1.4 g, 20.3 mmol) It was added to the mixture in ethanol (40 mL) and water (20 mL). The resulting mixture was stirred at room temperature for 5 hours, diluted with water (50 mL) and extracted with dichloromethane (3 x 80 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/20) to give the title compound (400 mg, 29.6%) as a white solid. LC-MS (Method E): m / z = 136.0 [M + H]⁺, 0.371 minutes.</p><p> Step 2: Preparation of 3-benzylisooxazole-5-ethyl carboxylate Ethyl propiolic acid (2.7 g, 27.5 mmol), (E) -2-phenylacetaldehyde oxime (400 mg, 2.9 mmol) and chromium oxide (2.5 g, 2.5 g,) 29.7 mmol) was added to the mixture in acetonitrile (50 mL). The reaction mixture was stirred at 80 ° C for 5 hours. The solid was removed by filtration and the filtrate was evaporated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/2) to give the title compound (200 mg, 40%) as a yellow solid. LC-MS (Method C): m / z = 232.0 [M + H]⁺, 1.200 minutes.</p><p> Step 3: 3-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine -3-Il) Preparation of isooxazole-5-carboxamide The crude product obtained using the procedure described in Example 54 is subjected to the following conditions: Column: XBridge C18OBD preparative column, 100 Å, 19 × 250mm 5μm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 35% B to 55% B over 7 minutes; UV254 &amp; 220 nm; Rt: 7 min; Obtained.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.73 (d, J = 7.6 Hz, 1H), 8.34-8.33 (m, 1H), 7.71-7.69 (m, 1H), 7.36-7.24 (m, 6H), 7.18 (s, 1H), 5.03- 4.99 (m, 1H), 4.84-4.78 (m, 1H), 4.06 (s, 2H), 3.40 (s, 3H), 1.37 (d, J = 6.4 Hz, 3H) .LC-MS (Method D): m / z = 393.1 [M + H]⁺, 1.787 minutes.</p><p> Example 123: (S) -5-benzyl-N- (4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl) thiazole- 2-Carboxamide<chemistry num="238"><img file="JP6974331B2_D0272.tif" /></chemistry> The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: Column: XBridge C18OBD preparative column, 100 Å, 5 μm, 19 mm × 250 mm; Mobile phase A: Water (10 mmol / L) NH₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B ~ 40% B over 7 minutes; UV254 &amp; 220 nm; Rt: 7 min; Obtained.¹1 H NMR (300 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.92 (d, J = 7.9 Hz, 1H), 8.15 (dd, J = 4.7, 1.5 Hz, 1H), 7.88 (s, 1H), 7.56 (dd, J = 8.0, 1.5 Hz, 1H), 7.41-7.12 (m, 6H), 4.88-4.74 (m, 1H), 4.62-4.41 (m, 2H), 4.28 (s, 2H) .LC-MS (Method O): m / z = 381.0 [M + H]⁺, 1.290 minutes.</p><p> Example 124: 5-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) Thiazole-2-carboxamide<chemistry num="239"><img file="JP6974331B2_D0273.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: XBridge C18OBD preparative column, 19 × 150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B-60% B over 7 minutes; Purified by preparative HPLC using UV254 &amp; 220 nm; Title compound (18.8 mg, 9%) ) Was obtained as a white semi-solid.¹1 H NMR (400 MHz, Methanol-d₄) δ 8.36-8.30 (m, 1H), 7.76-7.65 (m, 2H), 7.37-7.22 (m, 6H), 5.04-4.96 (m, 2H), 4.26 (s, 2H), 3.50 (s, 3H) ), 1.42 (d, J = 6.0 Hz, 3H). LC-MS (Method D): m / z = 409.2 [M + H]⁺, 1.638 minutes.</p><p> Examples 125A &amp; 125B: (R) -5-benzyl-N- (9'-methyl-8'-oxo-6', 7', 8', 9'-tetrahydrospiro [cyclopropane-1,5'-pyrido] 2,3-b] Azepine] -7'-yl) -4H-1,2,4-triazole-3-carboxamide (125A) and (S) -5-benzyl-N- (9'-methyl-8' -Oxo-6', 7', 8', 9'-Tetrahydrospiro [cyclopropane-1,5'-pyrido [2,3-b] azepine] -7'-yl) -4H-1,2,4 -Triazole-3-Carboxamide (125B)<chemistry num="240"><img file="JP6974331B2_D0274.tif" /></chemistry> Step 1: Preparation of 2- (2-nitropyridine-3-yl) dimethyl malonate Dimethyl malonate (14 g, 105.6 mmol), 3-fluoro-2-nitropyridine (10 g, 70.4 mmol) and potassium carbonate (19.5 mmol) g, 140.8 mmol) was added dropwise to the stirred mixture in N, N-dimethylformamide (25 mL) at room temperature. The reaction mixture was stirred at 70 ° C. overnight, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (18 g, 89.8%) as a brown oil. LC-MS (Method R): m / z = 255.1 [M + H]⁺, 0.762 minutes.</p><p> Step 2: Preparation of 2- (2-nitropyridin-3-yl) methyl acetate Add a solution of lithium chloride (8 g, 189 mmol) in water (10 mL) to dimethyl 2- (2-nitropyridin-3-yl) malonate. 16 g, 63 mmol) was added to the mixture in dimethyl sulfoxide (50 mL). The reaction mixture was stirred at 100 ° C. overnight, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (12 g, crude) as a brown oil. LC-MS (Method R): m / z = 197.1 [M + H]⁺, 0.673 minutes.</p><p> Step 3: Preparation of 1- (2-nitropyridine-3-yl) methyl cyclopropanecarboxylate 1,2-dibromoethane (17 g, 91.8 mmol), 3-fluoro-2-nitropyridine (12 g, 61.2 mmol) And a stirring mixture of potassium carbonate (25.3 g, 183.6 mmol) in N, N-dimethylformamide (25 mL) was added dropwise at room temperature. The reaction mixture was stirred at 70 ° C. overnight, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, anhydrous sulfuric diisocyanato dried over potassium, filtered, and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (5 g, 36.8%) as a red oil. LC-MS (Method R): m / z = 223.1 [M + H]⁺, 0.802 minutes.</p><p> Step 4: Preparation of (1- (2-nitropyridin-3-yl) cyclopropyl) Toluene solution of diisobutylaluminum hydride (1M, 45 mL, 45 mmol), 1- (2-nitropyridin-3-yl) Methyl cyclopropanecarboxylate (5 g, 22.5 mmol) was added dropwise to a stirred solution of toluene (50 mL) at -78 ° C. The reaction mixture was stirred at 78 ° C. for 2 hours, quenched by the addition of water (2 mL) and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (3 g, 68.6%) as a yellow solid. LC-MS (Method C): m / z = 195.1 [M + H]⁺, 0.975 minutes.</p><p> Steps 5: 1-Preparation of (2-nitropyridin-3-yl) cyclopropanecarbaldehyde Dess-Martin peryodinane (13 g, 30.9 mmol), (1- (2-nitropyridin-3-yl) cyclopropyl ) Methanol (3 g, 15.5 mmol) was added to a stirring solution of dichloromethane (100 mL). The reaction mixture was stirred at 0 ° C. for 2 hours, quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (2.5 g, 84.2%) as a yellow oil. LC-MS (Method C): m / z = 193.0 [M + H]⁺, 1.002 minutes.</p><p> Step 6: Preparation of 2- (tert-butoxycarbonylamino) -3-(1- (2-nitropyridin-3-yl) cyclopropyl) acrylic acid (Z) -methyl 1,8-diazabicyclo [5.4.0] Undeca-7-ene (4 g, 26 mmol) was added to a stirred solution of 2-{[(tert-butoxy) carbonyl] amino} -2- (dimethoxyphosphoryl) methyl acetate (7.7 g, 26 mmol) in tetrahydrofuran (50 mL). .. The reaction mixture was stirred at 70 ° C. for 1 hour, followed by the addition of a solution of 1- (2-nitropyridin-3-yl) cyclopropanecarbaldehyde (2.5 g, 13 mmol) in tetrahydrofuran (50 mL). The reaction mixture was then stirred at 70 ° C. overnight, quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (3 g, 63.5%) as a yellow solid. LC-MS (Method E): m / z = 364.0 [M + H]⁺, 0.860 minutes.</p><p> Step 7: Preparation of methyl 3- (1- (2-aminopyridine-3-yl) cyclopropyl) -2- (tert-butoxycarbonyl-amino) propanoate in methanol (50 mL), 2- (tert-butoxycarbonyl) Amino) -3- (1- (2-nitropyridine-3-yl) cyclopropyl) acrylic acid (Z) -methyl (3 g, 8.26 mmol) under a hydrogen atmosphere (2 to 3 atmospheres), palladium-supported carbon ( Hydrogenated in the presence of 10%, 0.3 g). The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. The solid was removed by filtration and the filtrate was concentrated under high vacuum to give the title compound (2.5 g, crude) as a white solid. LC-MS (Method C): m / z = 336.1 [M + H]⁺, 0.926 minutes.</p><p> Step 8: Preparation of 3- (1- (2-aminopyridine-3-yl) cyclopropyl) -2- (tert-butoxycarbonylamino) propanoic acid Lithium hydroxide (358 mg, 14.9 mmol), 3- (1) -(2-Aminopyridine-3-yl) cyclopropyl) -2- (tert-butoxycarboxyamino) methyl propanoate (2.5 g, 7.46 mmol) was added to a solution of methyl propanate (2.5 g, 7.46 mmol) in tetrahydrofuran (15 mL) and water (5 mL). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was diluted with water (20 mL), adjusted to pH = 7 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (1 g, crude) as a white solid. LC-MS (Method R): m / z = 322.1 [M + H]⁺, 0.580 minutes.</p><p> Step 9: (8'-oxo-6', 7', 8', 9'-tetrahydrospiro [cyclopropane-1,5'-pyrido [2,3-b] azepine] -7'-yl) carbamic acid Preparation of tert-butyl N, N-diisopropylethylamine (1.2 g, 9.34 mmol), 3- (1- (2-aminopyridine-3-yl) cyclopropyl) -2- (tert-butoxycarbonylamino) propanoic acid N, N of (1 g, 3.11 mmol), 2- (7-aza-1H-benzotriazole-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (1.59 g, 3.73 mmol) -Added to the mixture in dimethylformamide (20 mL). The reaction mixture was stirred at room temperature for 2 hours, quenched by the addition of water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (500 mg, 53%) as a yellow solid. LC-MS (Method R): m / z = 304.0 [M + H]⁺, 0.842 minutes.</p><p> Step 10: (9'-methyl-8'-oxo-6', 7', 8', 9'-tetrahydrospiro [cyclopropane-1,5'-pyrido [2,3-b] azepine] -7' -Preparation of tert-butyl carbamic acid iodomethane (52 mg, 0.36 mmol), (8'-oxo-6', 7', 8', 9'-tetrahydrospiro [cyclopropane-1,5'-pyrido] 2,3-b] Azepine] -7'-yl) tert-butyl carbamic acid (110 mg, 0.36 mmol) and cesium carbonate (119 mg, 0.36 mmol) in N, N-dimethylformamide (5 mL) stirred solution at 0 ° C. Dropped in. The reaction mixture was stirred at room temperature for 2 hours, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (110 mg, 95.6%) as a white solid. LC-MS (Method C): m / z = 218.1 [M + H-100]⁺, 1.613 minutes.</p><p> Step 11: 7'-Amino-9'-Methyl-6', 7'-Dihydrospiro [cyclopropane-1,5'-pyrido [2,3-b] azepine] -8'(9'H) -on Preparation of Hydrochloride A 1,4-dioxane solution of hydrogen chloride (4M, 10 mL, 40 mmol) was added to (9'-methyl-8'-oxo-6', 7', 8', 9'-tetrahydrospiro [cyclopropane]. It was added to a solution of tert-butyl -1,5'-pyrido [2,3-b] azepine] -7'-yl) carbamic acid (110 mg, 0.34 mmol) in 1,4-dioxane (4 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated under high vacuum to give the title compound (80 mg, crude) as a white solid. LC-MS (Method C): m / z = 218.1 [M + H]⁺, 0.777 minutes.</p><p> Step 12: 5-Benzyl-N- (9'-methyl-8'-oxo-6', 7', 8', 9'-tetrahydrospiro- [cyclopropane-1,5'-pyrid [2,3-] b] Preparation of azepine] -7'-yl) -4H-1,2,4-triazole-3-carboxamide N, N-diisopropylethylamine (107 mg, 0.828 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (62 mg, 0.304 mmol), 7'-amino-9'-methyl-6 ', 7'-Dihydrospiro [cyclopropane-1,5'-pyrido [2,3-b] azepine] -8'(9'H) -on hydrochloride (60 mg, 0.276 mmol), N- (3- (3- Dimethylaminopropyl))-N'-ethylcarbodiimide hydrochloride (69 mg, 0.359 mmol) and 1-hydroxybenzotriazole (49 mg, 0.359 mmol) in N, N-dimethylformamide (4 mL) were added to the mixture. The reaction mixture was stirred at room temperature overnight, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residues under the following conditions: Column: Xbridge Prep C18OBD Column 19 × 150 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; flow rate: 30 mL / min; gradient: 25% B to 55% B; UV254 &amp; 220 nm; purified by preparative HPLC over 7 minutes to give the title compound. LC-MS (Method D): m / z = 403.1 [M + H]⁺, 1.460 minutes.</p><p> Step 13: (R) -5-benzyl-N- (9'-methyl-8'-oxo-6', 7', 8', 9'-tetrahydrospiro- [cyclopropane-1,5'-pyrid [ 2,3-b] Azepine] -7'-yl) -4H-1,2,4-triazole-3-carboxamide (first elution isomer) and (S) -5-benzyl-N- (9'- Methyl-8'-oxo-6', 7', 8', 9'-tetrahydrospiro [cyclopropane-1,5'-pyrido [2,3-b] azepine] -7'-yl) -4H-1 , 2,4-Triazole-3-carboxamide (second elution isomer) 5-benzyl-N- (9'-methyl-8'-oxo-6', 7', 8', 9'-tetrahydrospiro -[Cyclopropane-1,5'-pyrido [2,3-b] azepine] -7'-yl) -4H-1,2,4-triazole-3-carboxamide (60 mg, 0.149 mmol) is a racemic compound. , The following conditions: Column: Chiralpak ID-2, 2 × 25 cm, 5 μm; Mobile phase A: Hexane / DCM (4.5 / 1), Mobile phase B: EtOH; Flow rate: 17 mL / min; Gradient: 50% B to 50% B over 22 minutes Separation by preparative chiral HPLC using UV254 &amp; 220 nm; RT1: 11.72 min; RT2: 18.02 min; to give the title compound:</p><p> Example 125A (first elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 14.27 (s, 1H), 8.41 (dd, J = 4.8, 1.8 Hz, 2H), 7.75 (dd, J = 7.6, 1.8 Hz, 1H), 7.34-7.18 (m, 6H), 4.42-4.33 ( m, 1H), 4.09 (s, 2H), 3.31 (s, 3H), 2.73-2.63 (m, 1H), 1.73-1.62 (m, 1H), 1.09-1.05 (m, 1H), 0.70 (d, J = 5.4 Hz, 2H), 0.36 (d, J = 10.0 Hz, 1H). LC-MS (Method D): m / z = 403.1 [M + H]⁺, 1.661 minutes.</p><p> Example 125B (second elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 14.27 (s, 1H), 8.41 (dd, J = 4.8, 1.8 Hz, 2H), 7.75 (dd, J = 7.6, 1.8 Hz, 1H), 7.35-7.18 (m, 6H), 4.40-4.33 ( m, 1H), 4.09 (s, 2H), 3.30 (s, 3H), 2.69 (t, J = 10.6 Hz, 1H), 1.68 (t, J = 12.3 Hz, 1H), 1.07 (d, J = 10.0 Hz, 1H), 0.70 (d, J = 5.5 Hz, 2H), 0.36 (d, J = 9.9 Hz, 1H). LC-MS (Method D): m / z = 403.1 [M + H]⁺, 1.673 minutes.</p><p> Example 126: (S) -5-benzyl-4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) Thiazole-2-carboxamide<chemistry num="241"><img file="JP6974331B2_D0275.tif" /></chemistry> Step 1: Preparation of Methyl 4-Fluoro-5-Methylthiazole-2-carboxylate 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] Octanebis (Tetrafluoroborate) (7.0 g, 19.8 mmol) was added to a mixture of methyl 4-fluoro-5-methylthiazole-2-carboxylate (1.6 g, 10.2 mmol) in acetonitrile (50 mL) under a nitrogen atmosphere. The reaction mixture was heated to reflux, stirred overnight, diluted with water (50 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (600 mg, 33.7%) as a white solid. LC-MS (Method C): m / z = 176.1 [M + H]⁺, 1.240 minutes.</p><p> Step 2: Preparation of Methyl 5- (bromomethyl) -4-fluorothiazole-2-carboxylate Benzoyl peroxide (10 mg, 0.04 mmol), N-bromosuccinimide (650 mg, 3.6 mmol) and 4-fluoro-5-methyl Methyl thiazole-2-carboxylate (600 mg, 3.4 mmol) was added to the mixture in carbon tetrachloride (20 mL). The reaction mixture was stirred at 75 ° C overnight. The solid was removed by filtration. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated sodium bicarbonate (20 mL) and brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/2) to give the title compound (600 mg, 68.9%) as a yellow solid. LC-MS (Method F): m / z = 254 [M + H]⁺, 1.490 minutes.</p><p> Step 3: Preparation of Methyl 5-benzyl-4-fluorothiazole-2-carboxylate Tetrax (triphenylphosphine) palladium (147 mg, 0.13 mmol), methyl 5- (bromomethyl) -4-fluorothiazole-2-carboxylate It was added to a mixture of (582 mg, 2.3 mmol), phenylboronic acid (402 mg, 3.3 mmol) and sodium carbonate (1 g, 9.4 mmol) in toluene (20 mL) and ethanol (10 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 80 ° C. overnight, quenched by the addition of water (20 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/2) to give the title compound (400 mg, 66.6%) as a yellow solid. LC-MS (Method C): m / z = 252.2 [M + H]⁺, 1.971 minutes.</p><p> Step 4: (S) -5-benzyl-4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine -3-yl) Thiazole-2-carboxamide The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: Column: XBridge Prep C18OBD column, 19 × 150 mm, 5 μm; mobile phase. A: Water (10 mmol / L NH₄HCO₃), Mobile phase B: ACN; purified by preparative HPLC using 40% ACN ~ 70% B; UV254 &amp; 220 nm; over 7 minutes to give the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 9.14 (d, J = 7.6 Hz, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 7.70 (dd, J = 8.0, 1.6 Hz, 1H), 7.39-7.21 (m, 6H) , 4.88-4.71 (m, 2H), 4.51 (t, J = 5.6 Hz, 1H), 4.17 (s, 2H), 3.34 (s, 3H). LC-MS (Method V): m / z = 413.00 [ M + H]⁺, 2.480 minutes.</p><p> Examples 127: 1- (4-cyanobenzyl) -N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrazole [3,2-b] [1,4] Oxazepine-3-yl) -4-fluoro-1H-pyrazole-3-carboxamide<chemistry num="242"><img file="JP6974331B2_D0276.tif" /></chemistry> Step 1: Preparation of 1- (4-cyanobenzyl) -4-fluoro-1H-pyrazole-3-carboxylic acid Sodium hydride (60%, 144 mg, 6 mmol), 4-fluoro-1H-pyrazole-3-carboxylic acid It was added to a stirred mixture of ethyl acid (474 mg, 3 mmol) in N, N-dimethylformamide (20 mL). The resulting mixture was stirred at room temperature for 2 hours, followed by the addition of 4- (bromomethyl) benzonitrile (585 mg, 3 mmol). The resulting mixture was stirred at room temperature for 2 hours. After the addition of water (20 mL), the reaction mixture was stirred overnight at room temperature, the pH was adjusted to 6 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residues under the following conditions: Column: XBridge C18OBD preparative column, 100 Å, 5 μm, 19 mm × 250 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30% B ~ 50% over 7 minutes Purification by preparative HPLC using B; UV254 &amp; 220 nm; Rt: 7 min; gave the title compound (250 mg, 34%) as a white solid. LC-MS (Method C): m / z = 246.1 [M + H]⁺, 0.969 minutes.</p><p> Step 2: 1: 1- (4-Cyanobenzyl) -N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5 tetrahydropyrido [3,2-b] [1 , 4] Preparation of oxazepine-3-yl) -4-fluoro-1H-pyrazole-3-carboxamide The crude product obtained using amide coupling procedure C was prepared under the following conditions: Column: XBridge C18OBD fractionation. Column, 100 Å, 5 μm, 19 mm × 250 mm; Mobile phase A: Water (0.1% formic acid), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 48% B over 12 minutes; UV254 &amp; 220 nm Purification by preparative HPLC using Rt: 7 min; gave the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.35 (dd, J = 4.8, 1.6 Hz, 1H), 8.20 (d, J = 4.4 Hz, 1H), 7.88-7.85 (m, 2H), 7.75 (dd, J = 8.0, 1.6 Hz, 1H) , 7.61 (d, J = 6.4 Hz, 1H), 7.44-7.41 (m, 2H), 7.36 (dd, J = 8.0, 4.8 Hz, 1H), 5.50 (s, 2H), 4.99-4.88 (m, 2H) ), 3.39 (s, 3H), 1.31 (d, J = 6.4 Hz, 3H). LC-MS (Method X): m / z = 435.2 [M + H]⁺, 1.355 minutes.</p><p> Examples 128: 1- (3-cyanobenzyl) -N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrazole [3,2-b] [1,4] Oxazepine-3-yl) -4-fluoro-1H-pyrazole-3-carboxamide<chemistry num="243"><img file="JP6974331B2_D0277.tif" /></chemistry> Step 1: Preparation of 1- (3-cyanobenzyl) -4-fluoro-1H-pyrazole-3-carboxylic acid Sodium hydride (60%, 144 mg, 6 mmol), 4-fluoro-1H-pyrazole-3-carboxylic acid It was added to a stirred mixture of ethyl acid (474 mg, 3 mmol) in N, N-dimethylformamide (20 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 2 hours, followed by the addition of 4- (bromomethyl) benzonitrile (585 mg, 3 mmol). The reaction mixture was stirred at room temperature for an additional 2 hours. After the addition of water (20 mL), the resulting mixture was stirred at room temperature overnight. The pH value of the solution was adjusted to 6 with aqueous hydrochloric acid (1N, 10 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residues under the following conditions: Column: XBridge Prep C18OBD column 19 × 150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20% B ~ 50% B over 7 minutes; UV254 &amp; 220 nm; Rt Purification by preparative HPLC using: 6 min; gave the title compound (230 mg, 31%) as a white solid. LC-MS (Method C): m / z = 246.1 [M + H]⁺, 1.236 minutes.</p><p> Step 2: 1: 1- (3-cyanobenzyl) -N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [ 1,4] Preparation of oxazepine-3-yl) -4-fluoro-1H-pyrazole-3-carboxamide The crude product obtained using the amide coupling procedure C was prepared under the following conditions: Column: XBridge C18OBD minutes. Tori column, 100 Å, 5 μm, 19 mm × 250 mm; Mobile phase A: Water (0.1% formic acid), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 48% B over 12 minutes; Purification by preparative HPLC using UV254 &amp; 220 nm; Rt: 7 min; gave the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 8.19 (d, J = 4.4 Hz, 1H), 7.86-7.79 (m, 2H), 7.75 (dd, J = 8.0, 1.6 Hz, 1H) , 7.62-7.60 (m, 3H), 7.36 (dd, J = 8.0, 4.4 Hz, 1H), 5.45 (s, 2H), 4.99-4.88 (m, 2H), 3.40 (s, 3H), 1.32 (d) , J = 6.0 Hz, 3H) .LC-MS (Method D): m / z = 435.1 [M + H]⁺, 1.695 minutes.</p><p> Examples 129A and 129B: (S) -5-benzyl-N- (2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] [1, 3] Diazepine-6-yl) -4H-1,2,4-triazole-3-carboxamide and (R) -5-benzyl-N- (2,4-dimethyl-5-oxo-5,6,7, 8-Tetrahydro-4H-pyrazolo [1,5-a] [1,3] diazepine-6-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="244"><img file="JP6974331B2_D0278.tif" /></chemistry> Step 1: Preparation of 4- (3-Methyl-5-Nitro-1H-Pyrazole-1-yl) Methyl Butane Sodium Hydride (60%, 2.5 g, 63 mmol), 3-Methyl-5-Nitro-1H -Pyrazole (8 g, 63 mmol) was added to the mixture in tetrahydrofuran (80 mL) at 0 ° C. The resulting mixture was stirred at 0 ° C. for 0.5 hours, followed by the addition of methyl 4-bromobutaneate (11.2 g, 63 mmol). The reaction mixture was stirred at 0 ° C. for 1 hour, quenched by the addition of water (40 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/10) to give the title compound (2.2 g, 15%) as a colorless oil. LC-MS (Method C): m / z = 228.1 [M + H]⁺, 1.180 minutes.</p><p> Step 2: Preparation of 4- (5-amino-3-methyl-1H-pyrazol-1-yl) methyl butanoate 4- (3-methyl-5-nitro-1H-pyrazol-1-yl) methyl butanoate ( A mixture of 2.2 g, 9.7 mmol) in methanol (50 mL) was hydrogenated in a hydrogen atmosphere (2-3 atm) in the presence of palladium-bearing carbon (10%, 0.2 g). After stirring at room temperature for 2 hours, the reaction mixture was filtered through Celite under a hydrogen atmosphere. The filtrate was concentrated under vacuum to give the title compound (1.8 g, 94%) as a yellow solid. LC-MS (Method C): m / z = 198.1 [M + H]⁺, 0.733 minutes.</p><p> Step 3: Preparation of 2-methyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one using the procedure described in Example 54. The crude product obtained was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (1.0 g, 66%) as a yellow solid. LC-MS (Method C): m / z = 166.1 [M + H]⁺, 0.755 minutes.</p><p> Step 4: Preparation of 2,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one Iodomethane (0.74 g, 5.4 mmol), 2-Methyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one (0.90 g, 5.4 mmol) and cesium carbonate (5.28 g, 16.2 mmol) Was added dropwise to the stirred mixture in N, N-dimethylformamide (15 mL). The reaction mixture was stirred at room temperature for 3 hours, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/20) to give the title compound (0.72 g, 74%) as a yellow solid. LC-MS (Method C): m / z = 180.1 [M + H]⁺, 0.865 minutes.</p><p> Step 5: 6-iodine-2,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -on preparation N¹, N¹, N², N²-Tetramethylethane-1,2-diamine (1.2 g, 12.0 mmol), 2,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 ( 6H) -on (720 mg, 4.0 mmol) was added to the stirred mixture in dichloromethane (10 mL) at 0 ° C, followed by the addition of iodotrimethylsilane (2.4 g, 12.0 mmol) over 20 minutes. The reaction mixture was stirred at 0 ° C for 1 hour. After the addition of iodine (2.0 g, 8.0 mmol), the reaction mixture was stirred at 0 ° C for an additional hour. The mixture was then quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL), stirred for an additional 15 minutes and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane) to give the title compound (500 mg, 41%) as a yellow solid. LC-MS (Method C): m / z = 306.0 [M + H]⁺, 1.033 minutes.</p><p> Step 6: Preparation of 6-azido-2,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one Sodium azide (137 mg, 2.10 mmol), 6-iodo-2,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one (500 mg, 1.64 mmol) Was added to the mixture in N, N-dimethylformamide (10 mL). The resulting mixture was stirred at room temperature for 2 hours, quenched by the addition of water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound (280 mg, crude) as a yellow oil. LC-MS (Method S): m / z = 221.3 [M + H]⁺, 0.763 minutes.</p><p> Step 7: Preparation of 6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one Triphenylphosphine (734 mg, 2.80 mmol), 6-azido-2,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one of tetrahydrofuran (10 mL) and Added to the stirred mixture in water (2 mL). The reaction mixture was stirred at room temperature overnight, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (200 mg, 62%) as a yellow oil. LC-MS (Method I): m / z = 195.0 [M + H]⁺, 0.263 minutes.</p><p> Step 8: 5-benzyl-N- (2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] [1,3] diazepine-6-yl ) -4H-1,2,4-Triazole-3-Carboxamide Preparation N, N-diisopropylethylamine (140 mg, 1.13 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid ( 73 mg, 0.36 mmol), 6-amino-2,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one (70 mg, 0.36 mmol) ), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (77 mg, 0.39 mmol) and 1-hydroxybenzotriazole (65 mg, 0.39 mmol) in N, N-dimethylformamide (2 mL). Was added to. The reaction mixture was stirred at room temperature overnight, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residues under the following conditions: Column: XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 15% B ~ 45% B over 7 minutes; UV254 &amp; 220 nm; Purification by preparative HPLC using Rt: 6 min; gave the title compound (50 mg, 36%) as a white solid. LC-MS (Method Y): m / z = 380.2 [M + H]⁺, 0.750 minutes.</p><p> Step 9: (S) -5-benzyl-N- (2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] [1,3] diazepine -6-yl) -4H-1,2,4-triazole-3-carboxamide (129A) and (R) -5-benzyl-N- (2,4-dimethyl-5-oxo-5,6,7, 8-Tetrahydro-4H-Pyrazolo [1,5-a] [1,3] Diazepine-6-yl) -4H-1,2,4-Triazole-3-Carboxamide (129B) Preparation 5-benzyl-N- (2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] [1,3] diazepine-6-yl) -4H-1,2,4 -The racemic compound of triazole-3-carboxamide under the following conditions: Column: Chilarpak IC, 2 × 25 cm, 5 μm; Mobile phase A: hexane, Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: Over 22 minutes Separation by preparative chiral HPLC using 50% B ~ 50% B; UV254 &amp; 220nm; RT1: 10.04 min; RT2: 18.12 min; to give the title compound:</p><p> Example 129A (first elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 14.31 (s, 1H), 8.55 (s, 1H), 7.40-7.18 (m, 5H), 6.13 (s, 1H), 4.41-4.20 (m, 2H), 4.20-4.02 (m, 3H), 3.23 (s, 3H), 2.65-2.26 (m, 2H), 2.18 (s, 3H) .LC-MS (Method D): m / z = 380.2 [M + H]⁺, 1.298 minutes.</p><p> Example 129B (second elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 14.30 (s, 1H), 8.46 (s, 1H), 7.38-7.20 (m, 5H), 6.13 (s, 1H), 4.41-4.20 (m, 2H), 4.20-4.02 (m, 3H), 3.23 (s, 3H), 2.61-2.37 (m, 2H), 2.17 (s, 3H) .LC-MS (Method D): m / z = 380.2 [M + H]⁺, 1.300 minutes.</p><p> Example 130: (S) -1- (3-cyano-5-fluorobenzyl) -4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrazole [3, 2-b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="245"><img file="JP6974331B2_D0279.tif" /></chemistry> Step 1: Preparation of 3-fluoro-5- (hydroxymethyl) benzonitrile Sodium borohydride (1.0 g, 6.71 mmol) and 3-fluoro-5-formylbenzonitrile (306 mg, 8.05 mmol) in ethanol (10 mL). And the stirring mixture in tetrahydrofuran (10 mL) was added at 0 ° C. under a nitrogen atmosphere. After stirring at 0 ° C for 1 hour, the reaction mixture was concentrated under vacuum, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (980 mg, crude) as a yellow solid. LC-MS (Method T): m / z = 152.3 [M + H]⁺, 0.671 minutes.</p><p> Step 2: Preparation of 3- (bromomethyl) -5-fluorobenzonitrile Tribromophosphine (2.9 g, 10.7 mmol) and 3-fluoro-5- (hydroxymethyl) benzonitrile (0.8 g, 5.30 mmol) dichloromethane ( 10 mL) was added to the stirred mixture. After stirring overnight at room temperature, the reaction mixture was concentrated under vacuum to give the title compound (0.8 g, crude) as a yellow solid, which was used directly in the next step without further purification.</p><p> Step 3: (S) -1- (3-cyano-5-fluorobenzyl) -4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2] -b] [1,4] Preparation of oxazepine-3-yl) -1H-pyrazole-3-carboxamide Potassium carbonate (55 mg, 0.40 mmol) was added to (S) -4-fluoro-N- (5-methyl-4). -Oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl) -1H-pyrazole-3-carboxamide (40 mg, 0.13 mmol) and 3- ( Bromomethyl) -5-fluorobenzonitrile (34 mg, 0.16 mmol) was added to the stirred mixture in N, N-dimethylformamide (2 mL). After stirring at room temperature for 2 hours, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residues under the following conditions: Column: XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 30 mL / min; Gradient: 35% B to 65% B over 5 minutes; UV254 &amp; 220 nm; Rt: 3.75 min; Obtained.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.37 (dd, J = 4.8, 1.6 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 4.4 Hz, 1H), 7.90-7.86 (m, 1H), 7.71 (dd, J = 7.6, 1.2 Hz, 1H), 7.66 (s, 1H), 7.56-7.52 (m, 1H), 7.36-7.32 (m, 1H), 5.44 (s, 2H), 4.89-4.81 (m) , 1H), 4.70-4.64 (m, 1H), 4.54-4.49 (m, 1H), 3.36 (s, 3H) .LC-MS (Method X): m / z = 439.2 [M + H]⁺, 1.291 minutes.</p><p> Examples 131A and 131B: (S) -5-benzyl-N- (3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] [1, 3] Diazepine-6-yl) -4H-1,2,4-triazole-3-carboxamide and (R) -5-benzyl-N- (3,4-dimethyl-5-oxo-5,6,7, 8-Tetrahydro-4H-pyrazolo [1,5-a] [1,3] diazepine-6-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="246"><img file="JP6974331B2_D0280.tif" /></chemistry> Step 1: Preparation of methyl 4- (4-methyl-5-nitro-1H-pyrazol-1-yl) butanoate Diisopropyl azodicarboxylate (3.4 g, 16.9 mmol), methyl 4-hydroxybutanoate (2 g, 16.9) Stirring mixture of 4-methyl-5-nitro-1H-pyrazole (1 g, 7.8 mmol) and triphenylphosphine (4.44 g, 16.9 mmol) in tetrahydrofuran (40 mL) at 0 ° C. Added slowly. After stirring overnight at room temperature, the reaction mixture was quenched by the addition of water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/10) to give the title compound (1.0 g, 56%) as a colorless oil. LC-MS (Method C): m / z = 228.1 [M + H]⁺, 1.130 minutes.</p><p> Step 2: Preparation of 4- (5-amino-4-methyl-1H-pyrazol-1-yl) methyl butanoate 4- (4-methyl-5-nitro-1H-pyrazol-1-yl) methyl butanoate ( A 1.0 g, 4.4 mmol) solution of methanol (30 mL) was hydrogenated in a hydrogen atmosphere (2-3 atm) in the presence of palladium-bearing carbon (10%, 0.1 g). After stirring at room temperature for 2 hours under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum to give the title compound (0.85 mg, 97%) as a yellow solid. LC-MS (Method I): m / z = 197.9 [M + H]⁺, 1.013 minutes.</p><p> Step 3: Preparation of 3-methyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one using the procedure described in Example 54. The crude product obtained was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (600 mg, 84%) as a yellow solid. LC-MS (Method C): m / z = 166.1 [M + H]⁺, 0.782 minutes.</p><p> Step 4: Preparation of 3,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one Iodomethane (511 mg, 3.6 mmol), 3 -Methyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one (600 mg, 3.6 mmol) and cesium carbonate (3.52 g, 10.8 mmol) N , N-dimethylformamide (15 mL) was added to the stirred mixture. The reaction mixture was stirred at room temperature for 3 hours, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/20) to give the title compound (480 mg, 78%) as a yellow solid. LC-MS (Method C): m / z = 180.1 [M + H]⁺, 0.876 minutes.</p><p> Step 5: 6-iodine-3,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -on preparation N¹, N¹, N², N²-Tetramethylethane-1,2-diamine (0.82 mg, 8.02 mmol), 3,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 ( 6H) -On (0.48 mg, 2.67 mmol) was added to the stirred mixture in dichloromethane (10 mL) at 0 ° C, followed by addition of iodotrimethylsilane (1.6 g, 8.01 mmol). After stirring at 0 ° C for 1 hour, iodine (1.36 g, 5.35 mmol) was added. The reaction mixture was stirred at 0 ° C for an additional hour and quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL). The resulting mixture was stirred for an additional 15 minutes and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane) to give the title compound (0.427 g, 52%) as a yellow solid. LC-MS (Method I): m / z = 305.9 [M + H]⁺, 0.756 minutes.</p><p> Step 6: Preparation of 6-azido-3,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one Sodium azide (137 mg, 2.1 mmol), 6-iodo-3,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one (427 mg, 1.39 mmol) Was added to the stirred mixture in N, N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 2 hours, quenched with water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (400 mg, crude) as a yellow oil. LC-MS (Method C): m / z = 220.7 [M + H]⁺, 1.383 minutes.</p><p> Step 7: Preparation of 6-amino-3,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one Triphenylphosphine (734 mg, 2.80 mmol), 6-azido-3,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one (400 mg, 1.80 mmol) Was added to the stirred mixture in tetrahydrofuran (10 mL) and water (2 mL). After stirring overnight at room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (232 mg, 86%) as a yellow oil. LC-MS (Method C): m / z = 194.7 [M + H]⁺, 0.378 minutes.</p><p> Step 8: 5-benzyl-N- (3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] [1,3] diazepine-6-yl ) -4H-1,2,4-Triazole-3-Carboxamide Preparation N, N-diisopropylethylamine (140 mg, 1.13 mmol), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid ( 73 mg, 0.36 mmol), 6-amino-3,4-dimethyl-7,8-dihydro-4H-pyrazolo [1,5-a] [1,3] diazepine-5 (6H) -one (70 mg, 0.36 mmol) ), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (77 mg, 0.39 mmol) and 1-hydroxybenzotriazole (65 mg, 0.39 mmol) in N, N-dimethylformamide (2 mL). Was added to. After stirring overnight at room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residues under the following conditions: Column: XBridge C18OBD preparative column 100 Å, 10 μm, 19 mm × 250 mm; mobile phase A: water (0.05% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 22% B ~ 43% B over 7 minutes Purification by preparative HPLC using UV254 &amp; 220 nm; Rt: 7 min; gave the title compound (50 mg, 36%) as a white solid. LC-MS (Method T): m / z = 380.3 [M + H]⁺, 1.041 minutes.</p><p> Step 9: (S) -5-benzyl-N- (3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] [1,3] diazepine -6-yl) -4H-1,2,4-triazole-3-carboxamide (131A) and (R) -5-benzyl-N- (3,4-dimethyl-5-oxo-5,6,7, 8-Tetrahydro-4H-Pyrazolo [1,5-a] [1,3] Diazepine-6-yl) -4H-1,2,4-Triazole-3-Carboxamide (131B) Preparation 5-benzyl-N- (3,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] [1,3] diazepine-6-yl) -4H-1,2,4 -Triazole-3-carboxamide (50 mg, 0.13 mmol) racemic compound under the following conditions: Column: Chilarpak IF, 2 × 25 cm, 5 μm; Mobile phase A: hexane, Mobile phase B: EtOH; Flow rate: 17 mL / min; Gradient: 40% B to 40% B over 24 minutes; UV254 &amp; 220 nm; RT1: 7.35 minutes; RT2: 8.28 minutes; separated by preparative chiral HPLC to give the title compound:</p><p> Example 131A (first elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 14.31 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 7.40-7.18 (m, 6H), 4.36-4.09 (m, 5H), 3.22 (s, 3H), 2.61-2.23 ( m, 2H), 2.02 (s, 3H) .LC-MS (Method D): m / z = 380.2 [M + H]⁺, 1.312 minutes.</p><p> Example 131B (second elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 14.31 (s, 1H), 8.34 (d, J = 7.6 Hz, 1H), 7.38-7.20 (m, 6H), 4.30-4.14 (m, 5H), 3.22 (s, 3H), 2.60-2.27 ( m, 2H), 2.02 (s, 3H) .LC-MS (Method D): m / z = 380.2 [M + H]⁺, 1.312 minutes.</p><p> Example 132: 1-Benzyl-4-chloro-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrazole [3,2-b] [ 1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="247"><img file="JP6974331B2_D0281.tif" /></chemistry> Step 1: Preparation of ethyl 4-chloro-1H-pyrazole-3-carboxylate 1-chloropyrrolidin-2,5-dione (5.75 g, 42.9 mmol), 1H-ethyl pyrazole-3-carboxylate (5.00 g, 5.00 g,) 35.7 mmol) was added to the stirred mixture in N, N-dimethylformamide (40 mL). The reaction mixture was stirred at room temperature overnight and diluted with water (100 mL). The solid was removed by filtration and the filtrate was concentrated under vacuum to give the title compound (6.0 g, crude) as a yellow oil. LC-MS (Method S): m / z = 175.2 [M + H]⁺, 0.695 minutes.</p><p> Step 2: Preparation of ethyl 1-benzyl-4-chloro-1H-pyrazol-3-carboxylate Potassium carbonate (7.1 g, 51.4 mmol), (4-chloro-1H-pyrazol-3-carboxylate ethyl (3.0 g) , 17.1 mmol) and (bromomethyl) benzene (3.6 g, 21.1 mmol) added to the stirred mixture in N, N-dimethylformamide (10 mL). The reaction mixture was stirred overnight at room temperature and diluted with water (30 mL). The combined organic layers were washed with salt water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under vacuum. The residue was purified by column chromatography. (Ethyl acetate / petroleum ether, 1/3), the title compound (2.0 g, 44%) was obtained as a colorless oil. LC-MS (Method S): m / z = 265.2 [M + H]⁺, 1.040 minutes.</p><p> Step 3: 1-Benzyl-4-chloro-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrazole [3,2-b] [1 , 4] Preparation of oxazepine-3-yl) -1H-pyrazole-3-carboxamide The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: Column: XBridge C18OBD fractionation. Column, 100 Å, 5 μm, 19 mm × 250 mm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B ~ 65% B over 7 minutes; UV254 &amp; 220 nm; Rt: 7 min; Obtained.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 8.26 (s, 1H), 7.76-7.71 (m, 2H), 7.42-7.29 (m, 6H), 5.42 (s, 2H), 4.99- 4.88 (m, 2H), 3.40 (s, 3H), 1.32 (d, J = 6.0 Hz, 3H). LC-MS (Method T): m / z = 426.2 [M + H]⁺, 1.518 minutes.</p><p> Example 133: (S) -4-Fluoro-1- (2-Fluorobenzyl) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrazole [3,2-b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="248"><img file="JP6974331B2_D0282.tif" /></chemistry> Potassium carbonate (34 mg, 0.25 mmol), (S) -4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1, 4] Oxazepine-3-yl) -1H-pyrazol-3-carboxamide (25 mg, 0.08 mmol) and 1- (bromomethyl) -2-fluorobenzene (19 mg, 0.10 mmol) in N, N-dimethylformamide (2 mL). Was added to the mixture of. After stirring at room temperature for 3 hours, the reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. Residues under the following conditions: Column: XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 30 mL / min; Gradient: 35% B to 65% B over 5 minutes; UV254 &amp; 220 nm; Rt: 3.75 min; Obtained.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.37 (dd, J = 4.8, 1.6 Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 4.4 Hz, 1H), 7.71 (dd, J = 8.0, 1.6 Hz) , 1H), 7.46-7.40 (m, 1H), 7.35-7.21 (m, 4H), 5.43 (s, 2H), 4.88-4.80 (m, 1H), 4.70-4.64 (m, 1H), 4.53-4.48 (m, 1H), 3.35 (s, 3H) .LC-MS (Method T): m / z = 414.2 [M + H]⁺, 1.346 minutes.</p><p> Example 134: 5-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="249"><img file="JP6974331B2_D0283.tif" /></chemistry> The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: Column: XBridge Shield RP18 OBD Column, 5 μm, 19 × 150 mm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 15% B-60% B over 15 minutes; UV254 &amp; 220 nm; Rt: 14.5 min; Purified by preparative HPLC using the title compound ( 13.3 mg, 17%) was obtained as a white solid.¹1 H NMR (400 MHz, Methanol-d₄) δ 8.33-8.31 (m, 1H), 7.71-7.67 (m, 1H), 7.37-7.28 (m, 6H), 5.07-4.97 (m, 2H), 4.34 (s, 2H), 3.50 (s, 3H) ), 1.44 (d, J = 6.0 Hz, 3H). LC-MS (Method J): m / z = 394.15 [M + H]⁺, 2.483 minutes.</p><p> Example 135: (S) -4-Fluoro-1- (3-Fluorobenzyl) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrazole [3,2-b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="250"><img file="JP6974331B2_D0284.tif" /></chemistry> Step 1: Preparation of 4-Fluoro-1H-Pyrazole-3-Carboxylic Acid Sodium hydroxide (253 mg, 6.33 mmol) in methanol (500 mg, 3.16 mmol) in ethyl 4-fluoro-1H-pyrazole-3-carboxylate (500 mg, 3.16 mmol) 10 mL) and added to the mixture in water (4 mL). The resulting solution was heated to 40 ° C and stirred overnight. After removing methanol under reduced pressure, the resulting solution was adjusted to pH = 6 with aqueous hydrochloric acid (1N, 20 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (400 mg, 97.2%) as a white solid. LC-MS (Method T): m / z = 131.4 [M + H]⁺, 0.567 minutes.</p><p> Step 2: (S) -4-Fluoro-N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrazole [3,2-b] [1,4] Oxazepine-3-yl )-1 Preparation of H-pyrazole-3-carboxamide N, N-diisopropylethylamine (993 mg, 7.70 mmol), (S) -3-amino-5-methyl-2,3-dihydropyrido [3,2-b] [1,4] oxazepine-4 (5H)- On hydrochloride (354 mg, 1.54 mmol), 4-fluoro-1H-pyrazole-3-carboxylic acid (200 mg, 1.54 mmol), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (355 mg, 1.85) It was added to the mixture in N, N-dimethylformamide (10 mL) of mmol) and 1-hydroxybenzotriazole (250 mg, 1.85 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative TLC (ethyl acetate) to give the title compound (200 mg, 42.6%) as a white solid. LC-MS (Method T): m / z = 306.3 [M + H]⁺, 0.696 minutes.</p><p> Step 3: (S) -4-fluoro-1- (3-fluorobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido- [3,2-b] [1,4] Preparation of Oxazepine-3-yl) -1H-Pyrazole-3-Carboxamide Potassium carbonate (68 mg, 0.49 mmol) was added to (S) -4-fluoro-N- (5-methyl-4-oxo-). 2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide (50 mg, 0.16 mmol) and 1- (bromomethyl)- 3-Fluorobenzene (38 mg, 0.20 mmol) was added to the mixture in N, N-dimethylformamide (5 mL). After stirring at room temperature for 3 hours, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residues under the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 35% B to 78% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6.5 min; Obtained.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.36 (d, J = 4.0 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 4.4 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.49-7.38 (m, 1H), 7.38-7.28 (m, 1H), 7.22-6.98 (m, 3H), 5.38 (s, 2H), 4.92-4.78 (m, 1H), 4.78-4.61 (m, 1H) ), 4.61-4.41 (m, 1H), 3.36 (s, 3H) .LC-MS (Method T): m / z = 414.2 [M + H]⁺, 1.347 minutes.</p><p> Example 136: 1-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -1H-1,2,4-triazole-3-carboxamide<chemistry num="251"><img file="JP6974331B2_D0285.tif" /></chemistry> Step 1: Preparation of methyl 1-benzyl-1H-1,2,4-triazole-3-carboxylate Sodium hydride (60%, 192 mg, 8 mmol), 1H-1,2,4-triazole-3-carboxylic acid Methyl acid (508 mg, 4 mmol) was added to the stirred mixture in N, N-dimethylformamide (10 mL). The resulting mixture was stirred at room temperature for 2 hours, followed by the addition of (bromomethyl) benzene (680 mg, 4 mmol) under a nitrogen atmosphere. After stirring for an additional 2 hours, the reaction mixture was quenched by the addition of water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/2) to give the title compound (400 mg, 46%) as a white solid. LC-MS (Method E): m / z = 217.9 [M + H]⁺, 0.661 minutes.</p><p> Step 2: Preparation of 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid Lithium hydroxide (48 mg, 2 mmol), 1-benzyl-1H-1,2,4-triazole-3-carboxylic acid Methyl acid (108 mg, 0.5 mmol) was added to the stirred mixture in tetrahydrofuran (3 mL) and water (1 mL). After stirring at 0 ° C for 2 hours, the pH of the reaction mixture was adjusted to 6 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (80 mg, 79%) as a white solid. LC-MS (Method E): m / z = 203.9 [M + H]⁺, 0.560 minutes.</p><p> Step 3: 1-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-pyrido [3,2-b] [1,4] oxazepine -3-Il) -1H-1,2,4-Triazole-3-Carboxamide preparation The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: XBridge C18OBD preparative column, 100 Å, 5 μm, 19 mm × 250 mm; mobile phase A: water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 75% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6.3 minutes; Purified by preparative HPLC using the title compound ( 31.5 mg, 40%) was obtained as a white solid.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.86 (s, 1H), 8.36 (dd, J = 4.4, 1.2 Hz, 1H), 8.01 (d, J = 6.4 Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.41 -7.31 (m, 6H), 5.50 (s, 2H), 5.00-4.88 (m, 2H), 3.40 (s, 3H), 1.31 (d, J = 6.4 Hz, 3H). LC-MS (Method D) : m / z = 393.15 [M + H]⁺, 1.553 minutes.</p><p> Example 137: (S) -4-fluoro-1-((5-fluoropyridin-3-yl) methyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido) [3,2-b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="252"><img file="JP6974331B2_D0286.tif" /></chemistry> Step 1: Preparation of 3- (bromomethyl) -5-fluoropyridine Tribromophosphine (853 mg, 3.15 mmol) in dichloromethane (2 mL) solution of (5-fluoropyridine-3-yl) methanol (200 mg, 1.57 mmol). Added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum to give the title compound (150 mg, crude). LC-MS (Method S): m / z = 190.1 [M + H]⁺, 0.787 minutes.</p><p> Step 2: (S) -4-fluoro-1-((5-fluoropyridin-3-yl) methyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [ 3,2-b] [1,4] Oxazepine-3-yl) -1H-Preparation of pyrazole-3-carboxamide Potassium carbonate (181 mg, 1.31 mmol) was added to (S) -4-fluoro-N- (5-). Methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl) -1H-pyrazole-3-carboxamide (80 mg, 0.26 mmol) and 3- (Bromomethyl) -5-fluoropyridine (107 mg, 0.39 mmol) was added to the mixture in N, N-dimethylformamide (2 mL). The resulting mixture was stirred at room temperature for 3 hours, diluted with water (2 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under vacuum. Residues under the following conditions: Column: XBridge C18OBD preparative column, 100 Å, 5 μm, 19 mm × 250 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃); Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 15% B to 35% B over 7 minutes; UV254 &amp; 220 nm; Rt: 7 min; Obtained.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.59 (d, J = 2.8 Hz, 1H), 8.46 (s, 1H), 8.37 (dd, J = 4.8, 1.6 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 8.20 (d) , J = 4.4 Hz, 1H), 7.72-7.67 (m, 2H), 7.36-7.32 (m, 1H), 5.46 (s, 2H), 4.88-4.81 (m, 1H), 4.70-4.64 (m, 1H) ), 4.54-4.49 (m, 1H), 3.36 (s, 3H) .LC-MS (Method T): m / z = 415.2 [M + H]⁺, 1.057 minutes.</p><p> Example 138: N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3- Il) -5- (1-phenylcyclopropyl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="253"><img file="JP6974331B2_D0287.tif" /></chemistry> The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: Column: XBridge C18OBD preparative column, 100 Å, 5 μm, 19 mm × 250 mm; Mobile phase A: Water (10 mmol / L) NH₄HCO₃); Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B-60% B at 7 min; UV254 &amp; 220 nm; Rt: 7 min; Obtained.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.36 (dd, J = 4.5, 1.5 Hz, 1H), 7.74 (dd, J = 8.1, 1.5 Hz, 1H), 7.44-7.29 (m, 6H), 4.96-4.90 ( m, 2H), 3.40 (s, 3H), 1.72-1.68 (m, 2H), 1.56-1.52 (m, 2H), 1.39-1.36 (m, 3H). LC-MS (Method D): m / z = 420.15 [M + H]⁺, 1.777 minutes.</p><p> Example 139: N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyridazine [3,2-b] [1,4] oxazepine-3- Il) -5- (2-fluorophenoxy) pyridazine-3-carboxamide<chemistry num="254"><img file="JP6974331B2_D0288.tif" /></chemistry> The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: Column: XBridge Shield RP18 OBD Column, 5 mm, 19 × 150 mm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃); Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 50% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6.5 min; Obtained.¹1 H NMR (300 MHz, DMSO-d₆) δ 9.48 (d, J = 3.0 Hz, 1H), 8.89 (d, J = 6.3 Hz, 1H), 8.36 (dd, J = 4.8, 1.8 Hz, 1H), 7.77 (dd, J = 7.8, 1.5 Hz) , 1H), 7.58-7.34 (m, 5H), 7.27 (dd, J = 3.0, 0.9 Hz, 1H), 5.05-4.93 (m, 2H), 3.42 (s, 3H), 1.35 (d, J = 5.7) Hz, 3H) .LC-MS (Method D): m / z = 424.1 [M + H]⁺, 1.747 minutes.</p><p> Examples 140: 1-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -1H-imidazole-4-carboxamide<chemistry num="255"><img file="JP6974331B2_D0289.tif" /></chemistry> Step 1: Preparation of 1-benzyl-1H-ethyl imidazole-4-carboxylate Sodium hydride (60%, 0.51 g, 21.3 mmol) with 1H-ethyl imidazole-4-carboxylate (2.0 g, 14.3 mmol) N, N-Dimethylformamide (15 mL) was added to the stirred solution. The resulting mixture was stirred at 0 ° C. for 30 minutes, followed by the addition of (bromomethyl) benzene (2.93 g, 17.13 mmol). After stirring at room temperature for 1.5 hours, the reaction mixture was quenched by the addition of water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/1) to give the title compound (1.0 g, 30%) as a yellow oil. LC-MS (Method C): m / z = 231.1 [M + H]⁺, 0.985 minutes.</p><p> Step 2: 1-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine -3-yl) -1H-Imidazole-4-Carboxamide Preparation The crude product obtained using the procedure described in Example 54 is subjected to the following conditions: column, XBridge Shield RP18 OBD, 5 μm, 19 × 150mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃); Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 30% B to 55% B over 7 minutes; Detector: UV254 &amp; 220 nm; purified by preparative HPLC to give the title compound ..¹1 H NMR (400 MHz, DMSO-d₆) δ 8.33 (dd, J = 4.4, 1.2 Hz, 1H), 7.89 (d, J = 1.2 Hz, 1H), 7.78-7.71 (m, 3H), 7.37-7.27 (m, 6H), 5.21 (s, 2H), 4.92-4.84 (m, 2H), 3.37 (s, 3H), 1.28 (d, J = 6.0 Hz, 3H) .LC-MS (Method F): m / z = 392.0 [M + H]⁺, 1.029 minutes.</p><p> Examples 141A and 141B: (S) -5-benzyl-N- (6,7-dihydroimidazole [1,2-d] pyrido [3,2-b] [1,4] oxazepine-7-yl)- 4H-1,2,4-triazole-3-carboxamide and (R) -5-benzyl-N- (6,7-dihydroimidazole [1,2-d] pyridod [3,2-b] [1,4 ] Oxazepine-7-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="256"><img file="JP6974331B2_D0290.tif" /></chemistry><chemistry num="257"><img file="JP6974331B2_D0291.tif" /></chemistry> Step 1: Preparation of 2-chloro-1- (1-trityl-1H-imidazol-2-yl) etanone A hexane solution of n-butyllithium (2.5M, 13.2mL, 33.0 mmol), 1-trityl-1H- A stirred mixture of imidazole (9.3 g, 30.0 mmol) in tetrahydrofuran (190 mL) was added dropwise at -78 ° C under a nitrogen atmosphere. After the addition was complete, the reaction mixture was slowly warmed to -10 ° C and stirred for 1 hour. The mixture was then cooled again to -78 ° C and a solution of tert-butyl 2-chloroacetate (5.4 g, 36.0 mol) in tetrahydrofuran (10 mL) was added in small portions. The resulting mixture was warmed to room temperature with stirring over 2-3 hours, quenched with ice water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (900 mg, 7.8%) as a yellow solid.</p><p> Step 2: Preparation of 2- (2-bromopyridin-3-yloxy) -1- (1-trityl-1H-imidazol-2-yl) etanone 2-chloro-1- (1-trityl-1H-imidazol-2) -Il) Ethanone (772.0 mg, 2.0 mmol) in a stirring mixture of 2-bromopyridin-3-ol (346.0 mg, 2.0 mmol) and potassium carbonate (414.0 mg, 3.0 mmol) in acetonitrile (10 mL) in a nitrogen atmosphere. Added below. The resulting mixture was heated to reflux and stirred for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (700 mg, 66.9%) as a yellow solid. LC-MS (Method C): m / z = 524.1 [M + H]⁺, 1.490 minutes.</p><p> Step 3: Preparation of 2- (2-bromopyridin-3-yloxy) -1- (1H-imidazol-2-yl) etanone 2- (2-bromopyridin-3-yloxy) -1- (1-trityl-) The mixture of 1H-imidazol-2-yl) etanone (700 mg, 1.34 mmol) in methanol / acetic acid (5 mL / 1 mL) was heated to reflux and stirred overnight. After cooling to room temperature, the resulting mixture was concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/1) to give the title compound (300 mg, 79.7%) as a yellow solid. LC-MS (Method R): m / z = 282.2 [M + H]⁺, 0.628 minutes.</p><p> Step 4: Preparation of imidazole [1,2-d] pyridin [3,2-b] [1,4] oxazepine-7 (6H) -one ferrous iodide (19 mg, 0.1 mmol), 2- ( 2-bromopyridin-3-yloxy) -1- (1H-imidazol-2-yl) Ethanone (281 mg, 1.0 mmol), L-proline (23.1 mg, 0.2 mmol) and potassium carbonate (345 mg, 2.50 mmol) toluene It was added to the mixture in (10 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 100 ° C overnight. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous ammonium chloride (20 mL) and extracted with dichloromethane / methanol (10/1) (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/40) to give the title compound (70 mg, 34.8%) as a yellow solid. LC-MS (Method R): m / z = 202.3 [M + H]⁺, 0.540 minutes.</p><p> Step 5: Preparation of 6,7-dihydroimidazole [1,2-d] pyrido [3,2-b] [1,4] oxazepine-7-amine Sodium cyanoborohydride (11.0 mg, 0.17 mmol), Imidazo [1,2-d] pyrido [3,2-b] [1,4] oxazepine-7 (6H) -one (50.0 mg, 0.29 mmol) and ammonium acetate (383.0 mg, 4.98 mmol) in methanol (5 mL) ) Was added to the stirring mixture. The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/15) to give the title compound (30 mg, 59.4%) as a yellow solid. LC-MS (Method C): m / z = 203.1 [M + H]⁺, 0.778 minutes.</p><p> Step 7: 5-benzyl-N- (6,7-dihydroimidazole [1,2-d] pyrido [3,2-b] [1,4] oxazepine-7-yl) -4H-1,2,4 -Preparation of triazole-3-carboxamide The crude product obtained using amide coupling procedure C was purified by preparative TLC (ethyl acetate / petroleum ether, 3/1) and the title compound (16 mg, 27.6). %) Was obtained as a white solid. LC-MS (Method C): m / z = 388.1 [M + H]⁺, 0.921 minutes.</p><p> Step 7: (S) -5-benzyl-N- (6,7-dihydroimidazole [1,2-d] pyrido [3,2-b] [1,4] oxazepine-7-yl) -4H-1 , 2,4-Triazole-3-carboxamide (141A) and (R) -5-benzyl-N- (6,7-dihydroimidazole [1,2-d] pyridod [3,2-b] [1,4 ] Preparation of oxazepine-7-yl) -4H-1,2,4-triazole-3-carboxamide (141B). 5-benzyl-N- (6,7-dihydroimidazole [1,2-d] pyrido [3,2-b] [1,4] oxazepine-7-yl) -4H-1,2,4-triazole- The racemic compound of 3-carboxamide (16 mg, 0.041 mmol) was prepared under the following conditions: Column: Chilarpak IC, 2 × 25 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 16 mL / min; Gradient: 30 Separation by preparative chiral HPLC using 50% B to 50% B; UV254 &amp; 220nm; RT1: 16.881; RT2: 24.391; over minutes to give the title compound:</p><p> Example 141A (first elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.43 (s, 1H), 8.31 (dd, J = 4.4, 1.2 Hz, 1H), 7.70 (dd, J = 8.0, 1.2 Hz, 1H), 7.42 (dd, J = 8.0, 4.4 Hz, 1H) , 7.33-7.22 (m, 6H), 5.86 (s, 1H), 4.59-4.48 (m, 2H), 4.15 (s, 2H) .LC-MS (Method D): m / z = 388.1 [M + H] ]⁺, 1.139 minutes.</p><p> Example 141B (second elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.37 (s, 1H), 8.29 (dd, J = 4.4, 1.6 Hz, 1H), 7.67 (dd, J = 8.0, 1.2 Hz, 1H), 7.38 (dd, J = 8.0, 4.4 Hz, 1H) , 7.32-7.20 (m, 6H), 5.83 (s, 1H), 4.57-4.47 (m, 2H), 4.10 (s, 2H) .LC-MS (Method D): m / z = 388.1 [M + H ]⁺, 1.139 minutes.</p><p> Example 142: (S) -5-benzyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3- Il) Isoxazole-3-carboxamide<chemistry num="258"><img file="JP6974331B2_D0292.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 50% B over 7 minutes; UV254 &amp; 220 nm; Rt: 5.6 min; Obtained.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.94 (d, J = 7.8 Hz, 1H), 8.33 (dd, J = 4.8, 1.5 Hz, 1H), 7.66 (dd, J = 7.8, 1.5 Hz, 1H), 7.35-7.21 (m, 6H) , 6.52 (s, 1H), 4.86-4.77 (m, 1H), 4.67-4.59 (m, 1H), 4.51-4.44 (m, 1H), 4.19 (s, 2H), 3.31 (s, 3H) .LC -MS (Method D): m / z = 379.1 [M + H]⁺, 1.719 minutes.</p><p> Example 143: N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3- Il) -4-fluoro-1- (4-fluorobenzyl) -1H-pyrazole-3-carboxamide<chemistry num="259"><img file="JP6974331B2_D0293.tif" /></chemistry> The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: Column: XBridge Shield RP18 OBD Column, 5 μm, 19 × 150 mm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 65% B over 7 minutes; UV254 &amp; 220 nm; Rt: 5 min; purified by preparative HPLC using the title compound ( 26.2 mg, 28%) was obtained as a white solid.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.32 (dd, J = 4.8, 1.5 Hz, 1H), 8.10 (d, J = 4.5 Hz, 1H), 7.71 (dd, J = 7.8, 1.5 Hz, 1H), 7.56 (d, J = 6.6 Hz) , 1H), 7.35-7.29 (m, 3H), 7.22-7.14 (m, 2H), 5.31 (s, 2H), 4.94-4.83 (m, 2H), 3.36 (s, 3H), 1.27 (d, J) = 6.3 Hz, 3H) .LC-MS (Method D): m / z = 428.1 [M + H]⁺, 1.771 minutes.</p><p> Example 144: (S) -1- (3-cyanobenzyl) -4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyridol [3,2-b]] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="260"><img file="JP6974331B2_D0294.tif" /></chemistry> The crude product obtained using amide coupling procedure C was subjected to the following conditions: Column: XBridge Shield RP 18 OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 50% B over 7 minutes; UV254 &amp; 220 nm; Rt: 5.5 min; Obtained.¹1 H NMR (300 MHz, DMSO-d₆) δ 8.32 (dd, J = 4.8, 1.5 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 4.2 Hz, 1H), 7.81-7.74 (m, 2H), 7.68 -7.64 (m, 1H), 7.61-7.55 (m, 2H), 7.32-7.27 (m, 1H), 5.39 (s, 2H), 4.85-4.76 (m, 1H), 4.67-4.59 (m, 1H) , 4.50-4.44 (m, 1H), 3.32 (s, 3H) .LC-MS (Method D): m / z = 421.1 [M + H]⁺, 1.550 minutes.</p><p> Examples 145A and 145B: (S) -N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) -5- (1-Phenylcyclopropyl) -1,3,4-oxadiazole-2-carboxamide and (R) -N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido) [2,3-b] Azepine-7-yl) -5- (1-Phenylcyclopropyl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="261"><img file="JP6974331B2_D0295.tif" /></chemistry> Step 1: N- (9-Methyl-8-oxo-6,7,8,9-Tetrahydro-5H-pyrido [2,3-b] Azepine-7-yl) -5- (1-Phenylcyclopropyl) Preparation of -1,3,4-oxadiazole-2-carboxamide Preparative HPLC: Column: XBridge Shield RP18 OBD, 19 × 150 mm, 5 μm; mobile phase: phase A: water (10 mmol / L NH)₄HCO₃); Phase B: ACN (35.0% ACN ~ 41.0% over 7 minutes); detector, UV220 &amp; 254nm; Rt: 5.88 minutes; purified to give the title compound (45 mg, 25.4%) as a white solid. LC-MS (Method E): m / z = 404.00 [M + H]⁺, 0.833 minutes.</p><p> Step 2: (S) -N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) -5- (1- Phenylcyclopropyl) -1,3,4-oxadiazole-2-carboxamide (first elution isomer) and (R) -N- (9-methyl-8-oxo-6,7,8,9-tetrahydro Preparation of -5H-pyrido [2,3-b] azepine-7-yl) -5- (1-phenylcyclopropyl) -1,3,4-oxadiazole-2-carboxamide (second elution isomer) .. N- (9-Methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) -5- (1-phenylcyclopropyl) -1, Racemic compound of 3,4-oxadiazole-2-carboxamide (45 mg, 0.11 mmol) under the following conditions: Column: Chilarpak IA, 5 μm, 2.12 × 15 cm; mobile phase A: hexane, mobile phase B: IPA; flow rate: 20 mL / min; gradient: 50% B ~ 50% B over 13.5 minutes; UV220 &amp; 254 nm; RT1: 8.78; RT2: Separation by preparative chiral HPLC using 11.03; gave the title compound:</p><p> Example 145A (first elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 8.41 (dd, J = 4.9, 1.8 Hz, 1H), 7.78 (dd, J = 7.5, 1.8 Hz, 1H), 7.45-7.42 (m, 2H), 7.38-7.25 (m, 4H), 4.48- 4.44 (m, 1H), 3.45 (s, 3H), 2.91-2.76 (m, 2H), 2.60-2.49 (m, 1H), 2.37-2.28 (m, 1H), 1.77-1.74 (m, 2H), 1.55-1.53 (m, 2H) .LC-MS (Method X): m / z = 404.10 [M + H]⁺, 1.180 minutes.</p><p> Example 145B (second elution isomer):¹1 H NMR (400 MHz, Methanol-d₄) δ 8.41 (dd, J = 4.9, 1.8 Hz, 1H), 7.79 (dd, J = 7.6, 1.8 Hz, 1H), 7.46-7.42 (m, 2H), 7.38-7.25 (m, 4H), 4.49- 4.44 (m, 1H), 3.45 (s, 3H), 2.90-2.77 (m, 2H), 2.60-2.49 (m, 1H), 2.37-2.28 (m, 1H), 1.77-1.74 (m, 2H), 1.55-1.53 (m, 2H) .LC-MS (Method X): m / z = 404.00 [M + H]⁺, 1.179 minutes.</p><p> Example 146: (S) -5-Benzyl-N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3- Il) -1,3,4-oxadiazole-2-carboxamide<chemistry num="262"><img file="JP6974331B2_D0296.tif" /></chemistry> The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: Column: XBridge Shield RP18 OBD Column, 5 mm, 19 × 150 mm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 35% B to 65% B over 7 minutes; UV254 &amp; 220 nm; Rt: 5 min; Obtained.¹1 H NMR (300 MHz, DMSO-d₆) δ 9.50 (s, 1H), 8.33 (dd, J = 4.8, 1.5 Hz, 1H), 7.69-7.65 (m, 1H), 7.38-7.24 (m, 6H), 4.84-4.65 (m, 2H), 4.53-4.47 (m, 1H), 4.34 (s, 2H), 3.31 (s, 3H) .LC-MS (Method D): m / z = 380.1 [M + H]⁺, 1.531 minutes.</p><p> Example 147: 5-Benzyl-N-((2R, 3S) -2,5-dimethyl-8- (methylsulfonyl) -4-oxo-2,3,4,5-tetrahydropyrido [3,2- b] [1,4] Oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="263"><img file="JP6974331B2_D0297.tif" /></chemistry><chemistry num="264"><img file="JP6974331B2_D0298.tif" /></chemistry> Step 1: (2R, 3S) -8-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-ylcarbamine Preparation of tert-butyl acid Bromide (1.63 g, 10.2 mmol), (2R, 3S) -2-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1 , 4] Oxazepine-3-ylcarbamic acid tert-butyl (1.0 g, 3.4 mmol) was added to the stirred mixture in N, N-dimethylformamide (30 mL). The reaction mixture was stirred at room temperature for 4 hours and quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (900 mg, 71%) as a white solid. LC-MS (Method C): m / z = 372.0 [M + H]⁺, 1.283 minutes.</p><p> Step 2: (2R, 3S) -8-bromo-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-pyrido [3,2-b] [1,4] oxazepine-3- Preparation of tert-butyl carbamic acid Iodomethane (306 mg, 2.2 mmol), (2R, 3S) -8-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2] -b] [1,4] Oxazepine-3-ylcarbamate tert-butyl (800 mg, 2.2 mmol) and cesium carbonate (703 mg, 2.2 mmol) added to a stirred mixture in N, N-dimethylformamide (20 mL). .. The reaction mixture was stirred at room temperature for 2 hours, diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/6) to give the title compound (650 mg, 79%) as a white solid. LC-MS (Method C): m / z = 330.0 [M + H-56]⁺, 1.408 minutes.</p><p> Step 3: (2R, 3S) -2,5-dimethyl-8- (methylsulfonyl) -4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine -3-Preparation of tert-butyl ylcarbamate Tetrahydrofuran (2.0M, 0.52mL, 1.04 mmol) solution of isopropylmagnesium chloride, (2R, 3S) -8-bromo-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [ 3,2-b] [1,4] Oxazepine-3-ylcarbamate tert-butyl (200 mg, 0.52 mmol) was added to a stirred mixture in tetrahydrofuran (5 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hour, followed by the addition of methanesulfonyl chloride (60 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for an additional 2 hours, diluted with water (15 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (55 mg, 28%) as a white solid. LC-MS (Method C): m / z = 330.1 [M + H-56]⁺, 1.208 minutes.</p><p> Step 4: (2R, 3S) -3-amino-2,5-dimethyl-8- (methylsulfonyl) -2,3-dihydropyrido- [3,2-b] [1,4] oxazepine-4 (5H) -Preparation of on hydrochloride (2R, 3S) -2,5-dimethyl-8- (methylsulfonyl) -4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1, 4] A stirred mixture of tert-butyl oxazepine-3-ylcarbamic acid (55 mg, 0.15 mmol) in 1,4-dioxane (5 mL) with a solution of 1,4-dioxane of hydrogen chloride (4M, 2 mL, 8 mmol). Added. The reaction mixture was stirred at room temperature for 2 hours and concentrated under high vacuum to give the title compound (46 mg, crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method C): m / z = 286.1 [M + H]⁺, 0.783 minutes.</p><p> Step 5: 5-Benzyl-N-((2R, 3S) -2,5-dimethyl-8- (methylsulfonyl) -4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] ] [1,4] Oxazepine-3-yl) -4H-1,2,4-Triazole-3-Carboxamide preparation The crude product obtained using the amide coupling procedure C is subjected to the following conditions: column: : XBridge C18OBD preparative column, 100 Å, 5 μm, 19 mm × 250 mm; mobile phase A: water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B-60% B over 7 minutes; UV254 &amp; 220 nm; Rt: 7 min; Obtained.¹1 H NMR (400 MHz, DMSO-d₆) δ 14.40 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.01 (br s, 1H), 7.36-7.21 (m, 5H), 5.15-5.04 (m, 2H), 4.16 (s, 2H), 3.45 (s, 3H), 3.39 (s, 3H), 1.35 (d, J = 6.4 Hz, 3H). LC-MS (Method D): m / z = 471.1 [M + H]⁺, 1.519 minutes.</p><p> Examples 148A and 148B: (S) -5-benzyl-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl ) -1,3,4-Oxadiazole-2-carboxamide and (R) -5-benzyl-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2] , 3-b] Azepine-7-yl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="265"><img file="JP6974331B2_D0299.tif" /></chemistry> Step 1: 5-benzyl-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) -1,3,4 -Preparation of Oxadiazole-2-Carboxamide The crude product obtained using the procedure described in Example 54 is transferred to the following conditions: Column: XSelect CSH Prep C18OBD Column, 5 mm, 19 x 150 mm; Phase A: water (0.1% formic acid); mobile phase B: ACN; flow rate: 20 mL / min; gradient: 40% B to 52% B over 4 minutes; UV254 &amp; 220 nm; Rt: 4 min; Purification by HPLC gave the title compound (20 mg, 14.2%) as a white solid. LC-MS (Method D): m / z = 378.1 [M + H]⁺, 1.492 minutes.</p><p> Step 2: (S) -5-benzyl-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) -1 , 3,4-Oxadiazole-2-carboxamide (first elution isomer) and (R) -5-benzyl-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H) -Preparation of pyrido [2,3-b] azepine-7-yl) -1,3,4-oxadiazole-2-carboxamide (second elution isomer) 5-benzyl-N- (9-methyl-8) -Oxo-6,7,8,9-Tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) -1,3,4-oxadiazole-2-carboxamide (20 mg) lasemi compound , Columns: CHIRALPAK IA, 2.12 × 15 cm, 5 μm; Mobile phase A: hexane; Mobile phase B: IPA; Flow rate: 20 mL / min; Gradient: 50% B to 50% B over 12 minutes; Separation by preparative chiral HPLC using UV254 &amp; 220 nm; RT1: 7.106; RT2: 9.363 min; gave the title compound:</p><p> Example 148A (first elution isomer):¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.44 (dd, J = 5.1, 1.8 Hz, 1H), 7.81 (dd, J = 7.5, 1.5 Hz, 1H), 7.38-7.26 (m, 6H), 4.54-4.46 (m, 1H), 4.34 ( s, 2H), 3.48 (s, 3H), 2.90-2.78 (m, 2H), 2.65-2.51 (m, 1H), 2.41-2.97 (m, 1H) .LC-MS (Method D): m / z = 378.1 [M + H]⁺, 1.492 minutes.</p><p> Example 148B (second elution isomer):¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.41 (dd, J = 4.8, 1.8 Hz, 1H), 7.78 (dd, J = 7.2, 1.5 Hz, 1H), 7.39-7.21 (m, 6H), 4.52-4.41 (m, 1H), 4.31 ( s, 2H), 3.45 (s, 3H), 2.91-2.75 (m, 2H), 2.64-2.45 (m, 1H), 2.41-2.25 (m, 1H) .LC-MS (Method D): m / z = 378.1 [M + H]⁺, 1.494 minutes.</p><p> Example 149: (S) -5- (2-fluorophenoxy) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyridazine [3,2-b] [1,4 ] Oxazepine-3-yl) pyridazine-3-carboxamide<chemistry num="266"><img file="JP6974331B2_D0300.tif" /></chemistry> The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: Column: XBridge C18OBD preparative column, 100 Å, 5 mm, 19 mm × 250 mm; Mobile phase A: Water (10 mmol / L) NH₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 40% B-60% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6.5 min; Obtained.¹1 H NMR (300 MHz, DMSO-d₆) δ 9.45-9.42 (m, 2H), 8.34-8.31 (m, 1H), 7.69-7.65 (m, 1H), 7.53-7.38 (m, 3H), 7.37-7.27 (m, 2H), 7.22 (d) , J = 3.6 Hz, 1H), 4.91-4.74 (m, 2H), 4.56-4.50 (m, 1H), 3.32 (s, 3H) .LC-MS (Method V): m / z = 410.1 [M + H]⁺, 2.765 minutes.</p><p> Example 150: 5-Benzyl-N-((2R, 3S) -8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [ 1,4] Oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="267"><img file="JP6974331B2_D0301.tif" /></chemistry> Step 1: (2R, 3S) -8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido- [3,2-b] [1,4] oxazepine-3 -Preparation of tert-butyl carbamic acid Tetrax (triphenylphosphanyl) palladium (60 mg, 0.052 mmol), zinc cyanide (80 mg, 0.68 mmol) and (2R, 3S) -8-bromo-2,5-dimethyl -4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-ylcarbamic acid tert-butyl (200 mg, 0.52 mmol) N, N-dimethyl It was added to the formamide (2 mL) suspension under a nitrogen atmosphere. The reaction mixture was heated at 140 ° C. under microwaves and stirred for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (110 mg, 64%) as a white solid. LC-MS (Method C): m / z = 277.1 [M + H-56]⁺, 1.300 minutes.</p><p> Step 2: (2R, 3S) -3-amino-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-8- Preparation of Carbonitrile Hydrochloride (2R, 3S) -8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-pyrido [3,2-b] [1,4] Oxazepine A solution of hydrogen chloride in 1,4-dioxane (4M, 2mL, 8 mmol) was added to a solution of tert-butyl ylcarbamate (68 mg, 0.21 mmol) in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature for 2 hours and concentrated under high vacuum to give the title compound (55 mg, crude) as a white solid, which was used directly in the next step without further purification. LC-MS (Method C): m / z = 233.1 [M + H]⁺, 0.825 minutes.</p><p> Step 3: 5-benzyl-N-((2R, 3S) -8-cyano-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-pyrido [3,2-b] [1 , 4] Preparation of oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: XSelect CSH Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30% B ~ 65% B over 7 minutes; UV254 &amp; 220 nm Purification by preparative HPLC using Rt: 6 min; gave the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 14.43 (s, 1H), 8.82 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 2.0 Hz, 1H), 8.00 (br s, 1H), 7.36-7.23 (m, 5H), 5.08-5.01 (m, 2H), 4.15 (s, 2H), 3.42 (s, 3H), 1.33 (d, J = 6.0 Hz, 3H). LC-MS (Method F): m / z = 418.0 [M + H]⁺, 1.187 minutes.</p><p> Example 151: (S) -5-benzyl-4-cyano-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) Thiazole-2-carboxamide<chemistry num="268"><img file="JP6974331B2_D0302.tif" /></chemistry> The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: Column: XBridge Prep C18OBD Column 5 μm, 19 × 150 mm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 55% B over 7 minutes; 254 nm; Rt: 6.32 min; Obtained.¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.35 (dd, J = 4.8, 1.6 Hz, 1H), 7.67 (dd, J = 8.0, 1.6 Hz, 1H), 7.43-7.26 (m, 6H), 4.98 (dd, J = 11.5, 7.4 Hz, 1H), 4.70-4.55 (m, 2H), 4.42 (s, 2H), 3.48 (s, 3H) .LC-MS (Method Q): m / z = 420.3 [M + H]⁺, 1.503 minutes.</p><p> Examples 152A and 152B: (R) -1- (3-cyanobenzyl) -4-fluoro-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrazole [2, 3-b] Azepine-7-yl) -1H-pyrazole-3-carboxamide and (S) -1- (3-cyanobenzyl) -4-fluoro-N- (9-methyl-8-oxo-6,7) , 8,9-Tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) -1H-pyrazole-3-carboxamide<chemistry num="269"><img file="JP6974331B2_D0303.tif" /></chemistry> Step 1: 1- (3-cyanobenzyl) -4-fluoro-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrazole [2,3-b] azepine-7 -Il) -1H-Preparation of pyrazole-3-carboxamide The crude product obtained using amide coupling procedure C is subjected to the following conditions: Column: XBridge C18OBD preparative column, 100 Å, 5 μm, 19 mm × 250 mm; Mobile phase A: water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 20% B ~ 50% B over 7 minutes; UV254 &amp; 220 nm; Rt: 7 min; 65 mg, 60%) was obtained as a white solid. LC-MS (Method D): m / z = 419.1 [M + H]⁺, 1.508 minutes.</p><p> Step 2: (R) -1- (3-cyanobenzyl) -4-fluoro-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrazole [2,3-b] ] Azepine-7-yl) -1H-pyrazole-3-carboxamide (first elution isomer) and (S) -1- (3-cyanobenzyl) -4-fluoro-N- (9-methyl-8-oxo) Preparation of -6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) -1H-pyrazole-3-carboxamide (second elution isomer) 1- (3-cyano) Benzyl) -4-fluoro-N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) -1H-pyrazole-3 -Carboxamide (65 mg, 0.16 mmol) isomer compound under the following conditions: Column: Chilarpak ID-2, 5 μm, 2 × 25 cm; Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 16 mL / min; Gradient: Separation by preparative chiral HPLC using 60% B ~ 60% B; UV254 &amp; 220nm; RT1: 12.92 minutes; RT2: 16.60 minutes; over 20 minutes to give the title compound:</p><p> Example 152A (first elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 8.16 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.85-7.78 (m, 3H), 7.64 -7.58 (m, 2H), 7.30-7.26 (m, 1H), 5.42 (s, 2H), 4.34-4.26 (m, 1H), 3.35 (s, 3H), 2.78-2.65 (m, 2H), 2.43 -2.25 (m, 2H) .LC-MS (Method F): m / z = 419.0 [M + H]⁺, 1.070 minutes.</p><p> Example 152B (second elution isomer):¹1 H NMR (400 MHz, DMSO-d₆) δ 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 8.16 (d, J = 4.4 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.85-7.78 (m, 3H), 7.64 -7.58 (m, 2H), 7.30-7.26 (m, 1H), 5.42 (s, 2H), 4.34-4.26 (m, 1H), 3.35 (s, 3H), 2.78-2.64 (m, 2H), 2.43 -2.24 (m, 2H) .LC-MS (Method F): m / z = 419.1 [M + H]⁺, 1.071 minutes.</p><p> Example 153: (S) -1- (2-cyanobenzyl) -4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyridol [3,2-b]] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="270"><img file="JP6974331B2_D0304.tif" /></chemistry> 2- (Bromomethyl) benzonitrile (39 mg, 0.20 mmol), (S) -4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2- b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide (50 mg, 0.16 mmol) and potassium carbonate (68 mg, 0.49 mmol) in N, N-dimethylformamide (4 mL) with stirring mixture. Was added to. The resulting mixture was stirred at room temperature for 3 hours, diluted with water (5 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and dried under vacuum. Residues under the following conditions: Column: XBridge Prep C18OBD Column 5 μm, 19 × 150 mm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B ~ 55% B over 7 minutes; 254 nm; Rt: 6.32 min; Obtained.¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.35 (dd, J = 4.8, 1.6 Hz, 1H), 7.88 (d, J = 4.5 Hz, 1H), 7.83 (dd, J = 7.7, 1.3 Hz, 1H), 7.73-7.66 (m, 2H) , 7.56 (td, J = 7.6, 1.1 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.32 (dd, J = 8.0, 4.8 Hz, 1H), 5.59 (s, 2H), 5.01 ( dd, J = 11.5, 7.2 Hz, 1H), 4.68 (dd, J = 9.8, 7.2 Hz, 1H), 4.50 (dd, J = 11.5, 9.9 Hz, 1H), 3.49 (s, 3H). LC-MS (Method Q): m / z = 421.3 [M + H]⁺, 1.201 minutes.</p><p> Examples 154A and 154B: (R) -1-benzyl-N- (6,7-dihydroimidazole [1,2-d] pyrido [3,2-b] [1,4] oxazepine-7-yl)- 4-Fluoro-1H-pyrazole-3-carboxamide and (S) -1-benzyl-N- (6,7-dihydroimidazole [1,2-d] pyrido [3,2-b] [1,4] oxazepine -7-yl) -4-fluoro-1H-pyrazole-3-carboxamide<chemistry num="271"><img file="JP6974331B2_D0305.tif" /></chemistry> Step 1: 1-benzyl-N- (6,7-dihydroimidazole [1,2-d] pyrido [3,2-b] [1,4] oxazepine-7-yl) -4-fluoro-1H-pyrazole -3-Preparation of Carboxamide The crude product obtained using amide coupling procedure C was purified by preparative TLC (ethyl acetate / petroleum ether, 3/1) and the title compound (16 mg, 33.0%). Was obtained as a white solid. LC-MS (Method S): m / z = 405.2 [M + H]⁺, 0.954 minutes.</p><p> Step 2: (S) -1-benzyl-N- (6,7-dihydroimidazole [1,2-d] pyrido [3,2-b] [1,4] oxazepine-7-yl) -4-fluoro -1H-pyrazole-3-carboxamide (first eluting isomer) and (R) -1-benzyl-N- (6,7-dihydroimidazole [1,2-d] pyridod [3,2-b] [1 , 4] Preparation of oxazepine-7-yl) -4-fluoro-1H-pyrazole-3-carboxamide (second elution isomer) 1-benzyl-N- (6,7-dihydroimidazole [1,2-d] A racemic compound of pyrido [3,2-b] [1,4] oxazepine-7-yl) -4-fluoro-1H-pyrazole-3-carboxamide (16 mg, 0.039 mmol) under the following conditions: Column: CHIRALPAK IC , 5 μm, 2 × 25 cm; mobile phase A: hexane: DCM = 5: 1, mobile phase B: EtOH; flow rate: 16 mL / min; gradient: 50% B to 50% B over 26 minutes; UV254 &amp; 220 nm; RT1 Separation by preparative chiral HPLC using: 3.96 min; RT 2: 6.18 min; to give the title compound:</p><p> Example 154A (first elution isomer):¹1 H NMR (300 MHz, Methanol-d₄) δ 8.25-8.22 (m, 2H), 7.70 (d, J = 4.5 Hz, 1H), 7.61 (dd, J = 8.1, 1.5 Hz, 1H), 7.34-7.22 (m, 6H), 7.07 (d, J = 1.5 Hz, 1H), 5.73-5.69 (m, 1H), 5.25 (s, 2H), 4.47-4.44 (m, 2H) .LC-MS (Method T): m / z = 405.2 [M + H] ]⁺, 1.063 minutes.</p><p> Example 154B (second elution isomer):¹1 H NMR (300 MHz, Methanol-d₄) δ 8.25-8.22 (m, 2H), 7.70 (d, J = 4.5 Hz, 1H), 7.61 (dd, J = 8.1, 1.5 Hz, 1H), 7.34-7.22 (m, 6H), 7.07 (d, J = 1.5 Hz, 1H), 5.73-5.69 (m, 1H), 5.25 (s, 2H), 4.47-4.44 (m, 2H) .LC-MS (Method T): m / z = 405.2 [M + H] ]⁺, 1.069 minutes.</p><p> Examples 155: 1-benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrazole [3,2-b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="272"><img file="JP6974331B2_D0306.tif" /></chemistry> Step 1: Preparation of 1-benzyl-1H-pyrazole-3-carboxylic acid Sodium hydride (96 mg, 4 mmol), N, N-dimethylformamide (20 mL) of 1H-pyrazole-3-carboxylate ethyl (280 mg, 2 mmol) ) Was added to the stirring mixture. The resulting mixture was stirred at room temperature for 2 hours, followed by the addition of (bromomethyl) benzene (340 mg, 2 mmol). After stirring for another 2 hours, the reaction mixture was diluted with water (5 mL). Lithium hydroxide (96 mg, 4 mmol) was added, the resulting mixture was stirred overnight at room temperature, the pH was adjusted to 6 with hydrochloric acid (2N, 20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residues under the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 30% B ~ 55% B over 7 minutes; UV254 &amp; 220 nm; Purification by preparative HPLC using Rt: 4.9 min; gave the title compound (220 mg, 54.4%) as a white solid. LC-MS (Method E): m / z = 202.9 [M + H]⁺, 0.855 minutes.</p><p> Step 2: 1-benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydro-pyrido [3,2-b] [1,4] oxazepine -3-yl) -1 Preparation of H-pyrazole-3-carboxamide The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; Mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 25% B to 75% B over 7 minutes; UV254 &amp; 220 nm; Rt: 3.3 min; Purification by taking HPLC gave the title compound.¹1 H NMR (400 MHz, DMSO-d₆) δ 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.76 (dd, J = 8.0, 1.6 Hz, 1H), 7.70 (d, J = 6.4 Hz) , 1H), 7.42-7.25 (m, 6H), 6.70 (d, J = 2.0 Hz, 1H), 5.46 (s, 2H), 4.99-4.89 (m, 2H), 3.40 (s, 3H), 1.32 ( d, J = 6.0 Hz, 3H) .LC-MS (Method V): m / z = 392.1 [M + H]⁺, 2.961 minutes.</p><p> Examples 156A and 156B: 4-fluoro-1- (4-fluorobenzyl) -N-((1aR, 2R, 8bS) -4-methyl-3-oxo-1,1a, 2,3,4,8b- Hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) -1H-pyrazole-3-carboxamide and 4-fluoro-1- (4-fluorobenzyl) -N-((1aS, 2S) , 8bR) -4-Methyl-3-oxo-1,1a,2,3,4,8b-Hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) -1H-pyrazole- 3-Carboxamide<chemistry num="273"><img file="JP6974331B2_D0307.tif" /></chemistry> The crude product obtained using amide coupling procedure C was purified by preparative TLC (methanol / dichloromethane, 1/20) to give the title compound as a white solid.</p><p> Racemic compounds, column: Chiralpak IC, 2 × 25 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 19 mL / min; gradient: 35% B ~ 35% over 18.5 minutes B; UV220 &amp; 254nm; Rt1: 13.00; Rt2: 15.67; was separated by preparative chiral HPLC to give the title compound:</p><p> Example 156A (first elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.35 (dd, J = 4.8, 2.0 Hz, 1H), 7.92 (dd, J = 7.6, 1.6 Hz, 1H), 7.77 (d, J = 4.4 Hz, 1H), 7.38-7.35 (m, 2H) , 7.27 (dd, J = 8.0, 4.8 Hz, 1H), 7.14-7.07 (m, 2H), 5.31 (s, 2H), 4.63 (s, 1H), 3.39 (s, 3H), 2.28-2.22 (m) , 1H), 2.10-2.05 (m, 1H), 1.27-1.20 (m, 1H), 1.18-1.12 (m, 1H) .LC-MS (Method D): m / z = 424.1 [M + H]⁺, 1.658 minutes.</p><p> Example 156B (second elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.35 (dd, J = 4.8, 2.0 Hz, 1H), 7.92 (dd, J = 8.0, 2.0 Hz, 1H), 7.76 (d, J = 4.4 Hz, 1H), 7.49 -7.35 (m, 2H) , 7.26 (dd, J = 7.6, 4.8 Hz, 1H), 7.12-7.08 (m, 2H), 5.31 (s, 2H), 4.63 (s, 1H), 3.39 (s, 3H), 2.28-2.22 (m) , 1H), 2.10-2.04 (m, 1H), 1.26-1.19 (m, 1H), 1.18-1.27 (m, 1H) .LC-MS (Method D): m / z = 424.1 [M + H]⁺, 1.664 minutes.</p><p> Examples 157A and 157B: 5-Benzyl-N-((1aR, 2R, 8bS) -4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido] 2,3-b] Azepine-2-yl) -1,3,4-oxadiazole-2-carboxamide and 5-benzyl-N-((1aS, 2S, 8bR) -4-methyl-3-oxo- 1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine-2-yl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="274"><img file="JP6974331B2_D0308.tif" /></chemistry> The crude product obtained using the procedure described in Example 54 was purified by column chromatography (ethyl acetate / petroleum ether, 1/1) to give the title compound as a white solid.</p><p> Racemic compound under the following conditions: Column: CHIRALPAK AS-H, 2.0 cm (inner diameter) x 25 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 16 mL / min; Gradient: 50 over 16 minutes Separation by preparative chiral HPLC using% B ~ 50% B; UV220 &amp; 254nm; Rt1: 8.212; Rt2: 10.554; gave the title compound:</p><p> Example 157A (first elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 9.48 (d, J = 6.6 Hz, 1H), 8.39 (dd, J = 4.8, 1.8 Hz, 1H), 7.99 (dd, J = 7.5, 1.8 Hz, 1H), 7.37-7.27 (m, 6H) , 4.42 (d, J = 6.3 Hz, 1H), 4.38 (s, 2H), 3.34 (s, 3H), 2.31-2.26 (m, 1H), 2.07-1.96 (m, 1H), 1.23-1.08 (m) , 2H) .LC-MS (Method X): m / z = 390.1 [M + H]⁺, 2.745 minutes.</p><p> Example 157B (second elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 9.47 (d, J = 6.0 Hz, 1H), 8.39 (dd, J = 6.6, 1.8 Hz, 1H), 7.97 (dd, J = 7.5, 1.8 Hz, 1H), 7.37-7.21 (m, 6H) , 4.43 (d, J = 6.3 Hz, 1H), 4.39 (s, 2H), 3.33 (s, 3H), 2.32-2.26 (m, 1H), 2.03-1.99 (m, 1H), 1.23-1.08 (m) , 2H) .LC-MS (Method D): m / z = 390.1 [M + H]⁺, 1.533 minutes.</p><p> Example 158: (S) -1-benzyl-5-cyano-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="275"><img file="JP6974331B2_D0309.tif" /></chemistry> Step 1: Preparation of ethyl 5-cyano-1H-pyrazole-3-carboxylate Sodium nitrite (10.56 g, 153 mmol), ethyl propiolic acid (5.00 g, 51.1 mmol) and 2-aminoacetonitrile hydrochloride (9.44 g, 102 mmol) was added to the mixture in chloroform (150 mL) and water (5 mL). The reaction mixture was stirred at room temperature for 12 hours, then heated to 60 ° C. and stirred for an additional 6 hours. After cooling to room temperature, the resulting mixture was filtered. The filtrate was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/9) to give the title compound (2.90 g, 35%) as a yellow solid. LC-MS (Method C): m / z = 166.1 [M + H]⁺, 1.032 minutes.</p><p> Step 2: Preparation of 5-cyano-1H-pyrazole-3-carboxylic acid Aqueous sodium hydroxide solution (2M, 30 mL, 60 mmol), ethyl 5-cyano-1H-pyrazole-3-carboxylate (1.5 g, 9.09 mmol) Was added to the mixture in ethanol (25 mL). The reaction mixture was stirred at room temperature for 4 hours. After removing ethanol under reduced pressure, the pH value of the solution was adjusted to 3-4 with aqueous hydrochloric acid (1M, 100 ml, 100 mmol). The resulting solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under high vacuum to give the title compound (400 mg, crude) as a yellow solid.¹1 H NMR (400 MHz, DMSO-d₆) δ 14.89 (s, 1H), 7.43 (s, 1H), 3.15 (s, 1H).</p><p> Step 3: (S) -5-cyano-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl )-1 Preparation of H-pyrazole-3-carboxamide The crude product obtained using amide coupling procedure C was purified by column chromatography (ethyl acetate / petroleum ether, 1/1) and the title compound (180 mg, 53). %) Was obtained as a yellow solid. LC-MS (Method S): m / z = 313.2 [M + H]⁺, 0.749 minutes.</p><p> Step 4: ((S) -1-benzyl-5-cyano-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4]] Preparation of Oxazepine-3-yl) -1H-Pyrazole-3-Carboxamide Cesium carbonate (80 mg, 0.25 mmol) was added to (S) -5-cyano-N- (5-methyl-4-oxo-2,3,4). , 5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide (60 mg, 0.19 mmol) and (bromomethyl) benzene (39 mg, 0.23 mmol) It was added to the mixture in N, N-dimethylformamide (3 mL). The reaction mixture was stirred at room temperature for 0.5 hours, diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was obtained. Washed with salt water, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was prepared under the following conditions: column, XBridge Shield RP18. OBD, 5 μm, 19 × 150 mm; mobile phase A: water (0.1% formic acid); mobile phase B: MeCN; flow rate: 20 mL / min; gradient: 20% B ~ 45% B over 7 minutes; UV254 &amp; 220 nm; Rt Purification by preparative HPLC using: 7 min; to give the title compound:¹1 H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J = 7.9 Hz, 1H), 8.35 (dd, J = 4.7, 1.6 Hz, 1H), 7.69 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (s, 1H), 7.44 -7.29 (m, 4H), 7.28-7.22 (m, 2H), 5.65 (s, 2H), 4.90-4.84 (m, 1H), 4.73-4.67 (m, 1H), 4.54-4.50 (m, 1H) , 3.35 (s, 3H) .LC-MS (Method T): m / z = 403.2 [M + H]⁺, 1.412 minutes.</p><p> Example 159: (S) -5-cyano-1- (4-fluorobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b]] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="276"><img file="JP6974331B2_D0310.tif" /></chemistry> The crude product obtained using the procedure described in Example 158, Step 4 was subjected to the following conditions: Column: XBridge Shield RP18 OBD, 5 μm, 19 × 150 mm; Mobile Phase A: Water (10 mmol / L). NH₄HCO₃); Phase B: ACN; Flow rate: 20 mL / min; Gradient: 35% B-60% B over 12 minutes; UV254 &amp; 220 nm; Rt: 6.5 min; rice field:¹1 H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J = 7.9 Hz, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 7.70 (dd, J = 7.9, 1.6 Hz, 1H), 7.59 (s, 1H), 7.36 -7.29 (m, 3H), 7.27-7.20 (m, 2H), 5.64 (s, 2H), 4.90-4.84 (m, 1H), 4.72-4.67 (m, 1H), 4.54-4.50 (m, 1H) , 3.36 (s, 3H) .LC-MS (Method T): m / z = 421.1 [M + H]⁺, 1.433 minutes.</p><p> Examples 160A and 160B: (S) -5-benzyl-N- (5'-methyl-4'-oxo-4', 5'-dihydro-3'H-spiro [cyclopropane-1,2'-pyrido) [3,2-b] [1,4] Oxazepine] -3'-yl) -1,3,4-oxadiazole-2-carboxamide and (R) -5-benzyl-N- (5'-methyl) -4'-oxo-4', 5'-dihydro-3'H-spiro [cyclopropane-1,2'-pyrido [3,2-b] [1,4] oxazepine] -3'-yl)- 1,3,4-oxadiazole-2-carboxamide<chemistry num="277"><img file="JP6974331B2_D0311.tif" /></chemistry><chemistry num="278"><img file="JP6974331B2_D0312.tif" /></chemistry> Step 1: Preparation of 2- (Triphenylphosphoranilidene) ethyl acetate (52 g, 149.42 mmol), (1-ethoxycyclopropoxy) trimethylsilane (20 g, 114.94 mmol) and benzoic acid (20 g, 114.94 mmol) 1.83 g, 14.95 mmol) was added to the mixture in toluene (150 mL). The reaction mixture was stirred at 80 ° C. overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / petroleum ether, 1/1) to give the title compound (2.1 g, 14%) as a colorless oil. LC-MS (Method S): m / z = 127.2 [M + H]⁺, 0.886 minutes.</p><p> Step 2: Preparation of 2- (1-((2-nitropyridine-3-yl) oxy) cyclopropyl) ethyl acetate 2-nitropyridin-3-ol (3.36 g, 24.00 mmol), 2-cyclopropanol It was added to a mixture of ethyl acetate (1.00 g, 7.93 mmol) and molecular sieves 4 Å (2.80 g) in dimethylacetamide (40 mL). The reaction mixture was stirred at 130 ° C. overnight under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with diethyl ether (150 mL) and washed with aqueous sodium hydroxide (0.2 M, 3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane / petroleum ether, 2/1) to give the title compound (450 mg, 21%) as a yellow oil. LC-MS (Method S): m / z = 267.2 [M + H]⁺, 0.935 minutes.</p><p> Step 3: Preparation of 2- (1-((2-aminopyridin-3-yl) oxy) cyclopropyl) ethyl acetate 2- (1-((2-Pyridine-3-yl) oxy) cyclopropyl) acetic acid A mixture of ethyl (800 mg, 3.00 mmol) in methanol (30 mL) was subjected to hydrogenation in a hydrogen atmosphere (2-3 atm) in the presence of palladium-bearing carbon (10%, 80 mg). The reaction mixture was stirred at room temperature for 2 hours. The mixture was filtered through Cerite and the filtrate was concentrated under high vacuum to give the title compound (650 mg, 92%) as a yellow oil. LC-MS (Method S): m / z = 237.1 [M + H]⁺, 0.587 minutes.</p><p> Step 4: Preparation of 3'H-spiro [cyclopropane-1,2'-pyrido [3,2-b] [1,4] oxazepine] -4'(5'H) -one Preparation of trimethylaluminum in toluene (toluene solution of trimethylaluminum) Drop 2M, 5.3 mL, 10.55 mmol) onto a stirred mixture of 2- (1-((2-aminopyridine-3-yl) oxy) cyclopropyl) ethyl acetate (500 mg, 2.11 mmol) in toluene (50 mL). Added. The resulting mixture was stirred at room temperature overnight, quenched by the addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/3) to give the title compound (290 mg, 72%) as a yellow oil. LC-MS (Method S): m / z = 191.1 [M + H]⁺, 0.704 minutes.</p><p> Step 5: 5'-Methyl-3'H-Spiro [Cyclopropane-1,2'-Pyrido [3,2-b] [1,4] Oxazepine] -4'(5'H) -On Preparation Iodomethane (178 mg, 1.26 mmol), 3'H-spiro [cyclopropane-1,2'-pyrido [3,2-b] [1,4] oxazepine] -4'(5'H) -one (200 mg, 200 mg, 1.05 mmol) and cesium carbonate (341 mg, 1.05 mmol) were added dropwise to a stirred mixture in N, N-dimethylformamide (10 mL). The reaction mixture was stirred at 0 ° C for 2 hours, diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 3/17) to give the title compound (150 mg, 69%) as a white solid. LC-MS (Method S): m / z = 205.1 [M + H]⁺, 0.767 minutes.</p><p> Step 6: 3'-Iodine-5'-Methyl-3'H-Spiro [Cyclopropane-1,2'-Pyrid [3,2-b] [1,4] Oxazepine] -4'(5'H) -On preparation N, N, N', N'-tetramethylethylenediamine (0.49 g, 4.25 mmol), 5'-methyl-3'H-spiro [cyclopropane-1,2'-pyrido [3,2-b] [ 1,4] Oxazepine] -4'(5'H) -one (0.18 g, 0.85 mmol) added to the mixture in dichloromethane (40 mL) at 0 ° C, followed by iodotrimethylsilane (1.70 g, 8.50). mmol) was added dropwise over 20 minutes. The mixture was stirred at 0 ° C for 1 hour, then a solution of iodine (0.32 g, 1.25 mmol) in dichloromethane (100 mL) was added to the mixture. The reaction mixture was stirred at 0 ° C for an additional hour, quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (280 mg, crude) as a yellow oil. LC-MS (Method C): m / z = 330.8 [M + H]⁺, 0.946 minutes.</p><p> Step 7: 3'-Azide-5'-Methyl-3'H-Spiro [Cyclopropane-1,2'-Pirido [3,2-b] [1,4] Oxazepine] -4'(5'H) -Preparation of on Sodium azide (109 mg, 1.68 mmol), 3'-iodo-5'-methyl-3'H-spiro [cyclopropane-1,2'-pyrido [3,2-b] [1, 4] Oxazepine] -4'(5'H) -one (280 mg, 0.84 mmol) added to the mixture in N, N-dimethylformamide (5 mL). The resulting mixture was stirred at room temperature for 2 hours, quenched by the addition of water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative TLC (ethyl acetate / petroleum ether, 1/2) to give the title compound (70 mg, 33%) as a yellow solid. LC-MS (Method C): m / z = 246.0 [M + H]⁺, 0.925 minutes.</p><p> Step 8: 3'-amino-5'-methyl-3'H-spiro [cyclopropane-1,2'-pyrido [3,2-b] [1,4] oxazepine] -4'(5'H) -Preparation of on 3'-Azido-5'-Methyl-3'H-Spiro [cyclopropane-1,2'-pyrido [3,2-b] [1,4] oxazepine] -4'(5'H )-On (70 mg, 0.28 mmol) in methanol (10 mL) was hydrogenated in a hydrogen atmosphere (2-3 atm) in the presence of palladium-bearing carbon (10%, 10 mg). After stirring at room temperature for 30 minutes, the reaction mixture was filtered through Cerite and the filtrate was concentrated under vacuum to give the title compound (50 mg, 78%) as a white solid. LC-MS (Method S): m / z = 220.2 [M + H]⁺, 0.690 minutes.</p><p> Step 9: 5-benzyl-N- (5'-methyl-4'-oxo-4', 5'-dihydro-3'H-spiro [cyclopropane-1,2'-pyrido [3,2-b]] [1,4] Oxazepine] -3'-Il) -1,3,4-Oxadiazole-2-Carboxamide Preparation of crude product obtained using the procedure described in Example 54. Purification by preparative TLC (ethyl acetate / petroleum ether, 1/1) gave the title compound (42 mg, 45%) as a white solid. LC-MS (Method S): m / z = 406.0 [M + H]⁺, 1.024 minutes.</p><p> Step 10: (S) -5-benzyl-N- (5'-methyl-4'-oxo-4', 5'-dihydro-3'H-spiro [cyclopropane-1,2'-pyrido [3,, 2-b] [1,4] Oxazepine] -3'-yl) -1,3,4-oxadiazole-2-carboxamide and (R) -5-benzyl-N- (5'-methyl-4' -Oxo-4', 5'-dihydro-3'H-spiro [cyclopropane-1,2'-pyrido [3,2-b] [1,4] oxazepine] -3'-yl) -1,3 , 4-Oxadiazole-2-Carboxamide 5-benzyl-N- (5'-methyl-4'-oxo-4', 5'-dihydro-3'H-spiro [cyclopropane-1,2' -Pyrido [3,2-b] [1,4] oxazepine] -3'-yl) -1,3,4-oxadiazole-2-carboxamide (42 mg, 0.10 mmol) with the following conditions. : Column: CHIRALPAK IA, 2.12 × 15 cm, 5 μm; mobile phase A: hexane, mobile phase B: IPA; flow rate: 20 mL / min; gradient: 50% B to 50% B over 14 minutes; UV254 &amp; 220 nm; RT1: 12.359; RT2: Separation by preparative chiral HPLC using 20.087; gave the title compound:</p><p> Example 160A (first elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 9.01 (d, J = 8.7 Hz, 1H), 8.39 (dd, J = 4.8, 1.5 Hz, 1H), 7.74 (dd, J = 8.1, 1.5 Hz, 1H), 7.39-7.27 (m, 6H) , 5.20 (d, J = 8.4 Hz, 1H), 4.35 (s, 2H), 3.40 (s, 3H), 1.36-1.28 (m, 1H), 1.16-1.02 (m, 1H), 1.00-0.94 (m) , 1H), 0.58-0.50 (m, 1H) .LC-MS (Method V): m / z = 406.1 [M + H]⁺, 2.745 minutes.</p><p> Example 160B (second elution isomer):¹1 H NMR (300 MHz, DMSO-d₆) δ 9.01 (d, J = 8.4 Hz, 1H), 8.39 (dd, J = 4.8, 1.5 Hz, 1H), 7.74 (dd, J = 8.1, 1.5 Hz, 1H), 7.39-7.27 (m, 6H) , 5.20 (d, J = 8.4 Hz, 1H), 4.35 (s, 2H), 3.40 (s, 3H), 1.36-1.31 (m, 1H), 1.16-1.03 (m, 1H), 1.00-0.94 (m) , 1H), 0.58-0.50 (m, 1H) .LC-MS (Method D): m / z = 406.1 [M + H]⁺, 1.652 minutes.</p><p> Example 161: (S) -5- (3-cyanobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4 ] Oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="279"><img file="JP6974331B2_D0313.tif" /></chemistry> Step 1: Preparation of 2- (3-cyanophenyl) methyl acetate Sulfuric acid (98%, 2.0 mL) in a mixture of 2- (3-cyanophenyl) acetic acid (3.5 g, 22.0 mmol) in methanol (80 mL). Added. The resulting mixture was stirred at room temperature for 3 hours and concentrated under vacuum. The residue was diluted with water (40 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (3.30 g, 87%) as a colorless oil. LC-MS (Method S): m / z = 176.2 [M + H]⁺, 0.504 minutes.</p><p> Step 2: Preparation of 2- (3-cyanophenyl) acetohydrazide Hydrazine hydrate (80%, 3.3 mL, 85.0 mmol) in a mixture of 2- (3-cyanophenyl) methyl acetate in methanol (50 mL). Added. The reaction mixture was stirred at 65 ° C. overnight and then concentrated under reduced pressure. The residue was diluted with water (40 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the crude title compound (2.4 g, 80%) as a white solid. LC-MS (Method S): m / z = 176.2 [M + H]⁺, 0.506 minutes.</p><p> Step 3: Preparation of 2- (2- (2- (3-cyanophenyl) Acetyl) Hydrazinyl) -2-Iminoacetate Ethyl 2-ethoxy-2-iminoacetate (1.82 g, 12.6 mmol), 2-( 3-Cyanophenyl) Acethydrazide (2.0 g, 11.5 mmol) was added to the stirred mixture in ethanol (20 mL) and diethyl ether (60 mL). The reaction mixture was stirred at room temperature overnight. The white solid was collected by filtration and rinsed with diethyl ether to give the title compound (2.88 g, 92%) as a white solid. LC-MS (Method C): m / z = 275.1 [M + H]⁺, 0.913 minutes.</p><p> Step 4: Preparation of 5- (3-cyanobenzyl) -4H-1,2,4-triazole-3-ethyl carboxylate Molecular sieve 4Å (50 mg), 2- (2- (2- (3-cyanophenyl)) -Acetyl) Hydradinyl) -2-imino Ethyl acetate (1.0 g, 3.65 mmol) was added to the mixture in xylene (10 mL). The reaction mixture was stirred in a closed tube at 160 ° C. overnight and concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/1) to give the title compound (500 mg, 54%) as a white solid. LC-MS (Method S): m / z = 257.2 [M + H]⁺, 0.767 minutes.</p><p> Step 5: Preparation of 5- (3-cyanobenzyl) -4H-1,2,4-triazole-3-carboxylic acid A solution of lithium hydroxide (94 mg, 4.0 mmol) in water (5 mL) was added to 5- (3- (3-cyanobenzyl). Cyanobenzyl) -4H-1,2,4-triazole-3-ethyl carboxylate (500 mg, 2.0 mmol) was added to a solution in tetrahydrofuran (15 mL). The resulting mixture was stirred at room temperature overnight. After removing tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH = 7 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (430 mg, crude) as a white solid. LC-MS (Method C): m / z = 229.1 [M + H]⁺, 0.816 minutes.</p><p> Step 6: (S) -5- (3-cyanobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Preparation of oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide The crude product obtained using amide coupling procedure C was prepared under the following conditions: Column: XBridge C18OBD preparative column , 100 Å, 5 μm, 19 mm × 250 mm; mobile phase A: water (0.1% formic acid), mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20% B ~ 45% B over 7 minutes; UV254 &amp; 220 nm; Purification by preparative HPLC using Rt: 7 min; to give the title compound:¹1 H NMR (400 MHz, DMSO-d₆) δ 14.53 (br s, 1H), 8.68 (s, 1H), 8.37 (dd, J = 4.4, 1.2 Hz, 1H), 7.79-7.69 (m, 3H), 7.64-7.61 (m, 1H), 7.58 -7.53 (m, 1H), 7.36-7.32 (m, 1H), 4.90-4.82 (m, 1H), 4.75-4.69 (m, 1H), 4.55-4.49 (m, 1H), 4.22 (s, 2H) , 3.36 (s, 3H) .LC-MS (Method T): m / z = 404.2 [M + H]⁺, 1.095 minutes.</p><p> Example 162: (S) -5- (3-cyano-5-fluorobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="280"><img file="JP6974331B2_D0314.tif" /></chemistry> Step 1: Preparation of methyl 2- (3-bromo-5-fluorophenyl) acetate Thionyl chloride (4.26 g, 35.8 mmol), methyl 2- (3-bromo-5-fluorophenyl) acetate (2.6 g, 11.93 mmol) ) Was added dropwise to the stirred mixture in methanol (30 mL), followed by the addition of N, N-dimethylformamide (2 drops). The reaction mixture was stirred at room temperature for 2 hours and concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/8) to give the title compound (2.79 g, 92.2%) as a yellow solid. LC-MS (Method S): m / z = 247.1 [M + H]⁺, 1.079 minutes.</p><p> Step 2: Preparation of 2- (3-cyano-5-fluorophenyl) methyl acetate Tetrakis (triphenylphosphine) palladium (1.2 g, 1.05 mmol), 2- (3-bromo-5-fluorophenyl) methyl acetate It was added to a mixture of (2.6 g, 10.5 mmol) and dicyanozinc (1.64 g, 14.17 mmol) in N, N-dimethylformamide (30 mL) under a nitrogen atmosphere. The reaction mixture was heated by microwave at 140 ° C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/10) to give the title compound (1.12 g, 54%) as a yellow solid. LC-MS (Method C): m / z = 194 [M + H]⁺, 0.914 minutes.</p><p> Step 3: Preparation of 2- (3-cyano-5-fluorophenyl) acetohydrazide Hydrazine hydrate (1.45 g, 29 mmol), 2- (3-cyano-5-fluorophenyl) methyl acetate (1.12 g, 5.80) mmol) was added to the mixture in methanol (20 mL). The resulting mixture was heated to reflux, stirred for 3 hours and concentrated under high vacuum. The residue was diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 3/1) to give the title compound (0.92 g, 82.2%) as a white solid. LC-MS (Method S): m / z = 194 [M + H]⁺, 0.30 minutes.</p><p> Step 4: Preparation of 2- (2- (2- (3-cyano-5-fluorophenyl) acetyl) hydrazinyl) -2-iminoacetate ethyl 2-ethoxy-2-iminoacetate ethyl (692 mg, 4.77 mmol), 2- (3-Cyano-5-fluorophenyl) acetohydrazide (910 mg, 4.77 mmol) was added to the stirred mixture in ethanol (5 mL) and diethyl ether (15 mL). The reaction mixture was stirred at room temperature for 4 hours. The solid was collected by filtration and dried under high vacuum to give the title compound (160 mg, 80.8%) as a white solid. LC-MS (Method C): m / z = 293 [M + H]⁺, 0.727 minutes.</p><p> Step 5: Preparation of ethyl 5- (3-cyano-5-fluorobenzyl) -4H-1,2,4-triazole-3-carboxylate 2- (2- (3-cyano-5-fluorophenyl) ) Acetyl) Hydradinyl) -2-Imino The mixture in ethyl acetate (1 g, 3.42 mmol) and xylene (20 mL) on a 4 Å molecular sieve was stirred at 160 ° C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated under high vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/1) to give the title compound (0.75 g, 79.5%) as a white solid. LC-MS (Method C): m / z = 275.0 [M + H]⁺, 0.811 minutes.</p><p> Step 6: Preparation of 5- (3-cyano-5-fluorobenzyl) -4H-1,2,4-triazole-3-carboxylic acid Lithium hydroxide (79.2 mg, 3.3 mmol), 5- (3-cyano) -5-Fluorobenzyl) -4H-1,2,4-triazole-3-ethyl carboxylate (140 mg, 0.78 mmol) was added to the stirred mixture in tetrahydrofuran (10 mL) and water (3 mL). The reaction mixture was stirred at room temperature overnight. After removing tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH = 6 with aqueous hydrochloric acid (1M, 20 mL, 20 mmol) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (250 mg, crude) as a yellow solid. LC-MS (Method C): m / z = 247.0 [M + H]⁺, 0.633 minutes.</p><p> Step 7: (S) -5- (3-cyano-5-fluorobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [ 1,4] Oxazepine-3-yl) -4H-1,2,4-Triazole-3-Carboxamide preparation The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: Xbridge. Prep C18, 19 × 150 mm, 5 μm; Mobile phase: Phase A: Water (10 mmol / L NH)₄HCO₃); Phase B: MeCN (20% -80% over 12 minutes); Purified by preparative HPLC using a detector, UV220 &amp; 254nm; to give the title compound:¹1 H NMR (300 MHz, DMSO-d₆) δ 14.37 (s, 1H), 8.56 (s, 1H), 8.37 (dd, J = 4.8, 1.5 Hz, 1H), 7.77-7.67 (m, 3H), 7.59-7.55 (m, 1H), 7.33 ( dd, J = 8.1, 4.8 Hz, 1H), 4.91-4.71 (m, 2H), 4.45-4.48 (m, 1H), 4.26 (s, 2H), 3.36 (s, 3H) .LC-MS (Method D) ): m / z = 422.1 [M + H]⁺, 1.376 minutes.</p><p> Example 163: (S) -5- (3-cyanobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3- Il) -4H-1,2,4-triazole-3-carboxamide<chemistry num="281"><img file="JP6974331B2_D0315.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: SunFire Prep C18OBD Column 19 × 150 mm 5 μm 10 nm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 75% B at 7 min; UV254 &amp; 220 nm; Rt: 6.34 min; Purified by preparative HPLC using:¹1 H NMR (400 MHz, DMSO-d₆) δ 8.48 (s, 1H), 7.78-7.73 (m, 2H), 7.64-7.61 (m, 1H), 7.57-7.49 (m, 2H), 7.36-7.22 (m, 3H), 4.87-4.79 (m) , 1H), 4.62-4.56 (m, 1H), 4.44-4.38 (m, 1H), 4.20 (s, 2H), 3.32 (s, 3H). LCMS (Method D): m / z = 403.1 [M + H]⁺, 1.376 minutes.</p><p> Example 164: (S) -5- (3-cyanobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3- Il) Thiazole-2-carboxamide<chemistry num="282"><img file="JP6974331B2_D0316.tif" /></chemistry> Step 1: Preparation of ethyl 5- (bromomethyl) thiazole-2 carboxylate Benzoyl peroxide (6 mg, 0.02 mmol), ethyl 5-methylthiazole-2-carboxylate (420 mg, 2.45 mmol) and N-bromosuccinimide (459 mg) , 2.58 mmol) added to the mixture in carbon tetrachloride (6 mL). The resulting mixture was stirred overnight at 75 ° C. under a nitrogen atmosphere, quenched by the addition of water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/2) to give the title compound (300 mg, 48.8%) as a yellow solid. LC-MS (Method S): m / z = 252.3 [M + H]⁺, 0.928 minutes.</p><p> Step 2: Preparation of 5- (3-cyanobenzyl) thiazole 2-carboxylic acid Tetraquis (triphenylphosphine) palladium (28 mg, 0.02 mmol), 5- (bromomethyl) thiazole-2 carboxylate ethyl (300 mg, 1.20 mmol) , (3-Cyanophenyl) boronic acid (194 mg, 1.32 mmol) and potassium carbonate (190 mg, 1.37 mmol) in toluene / ethanol (5 mL / 5 mL) were added under a nitrogen atmosphere. The resulting mixture was stirred at 90 ° C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was diluted with water (30 mL) and the pH value of the resulting solution was adjusted to 3 with aqueous hydrochloric acid (1 M, 50 mL, 50 mmol) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (100 mg, 34.1%) as a yellow oil. LC-MS (Method C): m / z = 245.2 [M + H]⁺, 1.208 minutes.</p><p> Step 3: (S) -5- (3-cyanobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine-3-yl ) Preparation of thiazole-2-carboxamide The crude product obtained using the amide coupling procedure B is subjected to the following conditions: Column: XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol) / L NH₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 65% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6.5 min; Obtained:¹1 H NMR (300 MHz, DMSO-d₆) δ 8.82 (d, J = 8.0 Hz, 1H), 7.93-7.90 (m, 1H), 7.84-7.80 (m, 1H), 7.78-7.71 (m, 1H), 7.70-7.63 (m, 1H), 7.62-7.44 (m, 2H), 7.40-7.20 (m, 3H), 4.88-4.75 (m, 1H), 4.73-4.60 (m, 1H), 4.48-4.37 (m, 1H), 4.34 (s, 2H) ), 3.30 (s, 3H) .LC-MS (Method V): m / z = 419.2 [M + H]⁺, 3.361 minutes.</p><p> Example 165: (S) -1-benzyl-5-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="283"><img file="JP6974331B2_D0317.tif" /></chemistry><chemistry num="284"><img file="JP6974331B2_D0318.tif" /></chemistry> Step 1: Preparation of 5-Fluoro-1H-pyrazole-3-carboxylic acid A solution of sodium hydroxide (2M, 0.63 mL, 1.26 mmol) to ethyl 5-fluoro-1H-pyrazole-3-carboxylate (100 mg, 0.63). mmol) was added to the stirred mixture in methanol (5 mL). The reaction mixture was stirred at room temperature overnight. After removing methanol under reduced pressure, the resulting solution was adjusted to pH = 5 with aqueous hydrochloric acid (1N, 2 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (80 mg, 97%) as a white solid.¹1 H NMR (300 MHz, DMSO-d₆) δ 13.67 (s, 1H), δ 13.49 (s, 1H), δ 6.47 (dd, J = 6.3, 2.2 Hz, 1H).</p><p> Step 2: (S) -5-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl )-1 Preparation of H-pyrazole-3-carboxamide The crude product obtained using amide coupling procedure C was purified by column chromatography (methanol / dichloromethane, 1/10) and the title compound (100 mg, 56.8%). Was obtained as a white solid. LC-MS (Method E): m / z = 306.1 [M + H]⁺, 0.898 minutes.</p><p> Step 3: (S) -1-benzyl-5-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine -3-Il) -1H-Pyrazole-3-Carboxamide Preparation Example 158, crude product obtained using the procedure described in step 4, under the following conditions: column, XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase: phase A: water (0.05% TFA), phase B: MeCN; flow rate: 20 mL / min; gradient: 25% B to 55% B at 7 minutes; detector, UV254 &amp; 220 nm Purified by preparative HPLC using; to give the title compound:¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.30 (dd, J = 4.7, 1.6 Hz, 1H), 7.63 (dd, J = 8.0, 1.6 Hz, 1H), 7.40-7.20 (m, 6H), 6.27 (d, J = 5.6 Hz, 1H) , 5.30 (s, 2H), 4.96 (dd, J = 11.6, 7.2 Hz, 1H), 4.62 (dd, J = 9.8, 7.2 Hz, 1H), 4.46 (dd, J = 11.6, 9.8 Hz, 1H), 3.44 (s, 3H) .LC-MS (Method D): m / z = 396.1 [M + H]⁺, 1.695 minutes.</p><p> Example 166: (S) -5-fluoro-1- (4-fluorobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b]] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="285"><img file="JP6974331B2_D0319.tif" /></chemistry> The crude product obtained using the procedure described in Example 158, step 4 was subjected to the following conditions: column, XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (0.05% TFA). ), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 5% B to 55% B over 7 minutes; Detector, purified by preparative HPLC using UV254 &amp; 220 nm; to give the title compound. ::¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.30 (dd, J = 4.8, 1.6 Hz, 1H), 7.63 (dd, J = 8.0, 1.6 Hz, 1H), 7.33-7.25 (m, 3H), 7.14-7.01 (m, 2H), 6.27 ( d, J = 5.6 Hz, 1H), 5.29 (s, 2H), 4.96 (dd, J = 11.5, 7.2 Hz, 1H), 4.62 (dd, J = 9.8, 7.2 Hz, 1H), 4.46 (dd, J = 11.5, 9.8 Hz, 1H), 3.44 (s, 3H) .LC-MS (Method D): m / z = 414.1 [M + H]⁺, 1.667 minutes.</p><p> Example 167: (S) -5-cyano-1- (3-cyanobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b]] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="286"><img file="JP6974331B2_D0320.tif" /></chemistry> The crude product obtained using the procedure described in Example 158, Step 4 was subjected to the following conditions: Column: XBridge Shield RP18 OBD, 5 μm, 19 × 150 mm; Mobile Phase A: Water (10 mmol / L). NH₄HCO₃); Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 25% B to 55% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6.32 min; Obtained:¹1 H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J = 7.9 Hz, 1H), 8.36 (dd, J = 4.7, 1.6 Hz, 1H), 7.87-7.82 (m, 1H), 7.80-7.75 (m, 1H), 7.69 (dd, J = 8.0, 1.6 Hz, 1H), 7.65-7.58 (m, 2H), 7.52-7.58 (m, 1H), 7.35-7.28 (m, 1H), 5.73 (s, 2H), 4.90-4.81 (m, 1H), 4.72-4.63 (m, 1H), 4.54-4.47 (m, 1H), 3.35 (s, 3H) .LC-MS (Method T): m / z = 428.1 [M + H]⁺, 1.320 minutes.</p><p> Example 168: (S) -1-((5-cyanopyridine-3-yl) methyl) -4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido) [3,2-b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="287"><img file="JP6974331B2_D0321.tif" /></chemistry> 5- (Bromomethyl) nicotinonitrile (35 mg, 0.18 mmol), (S) -4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2) -b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide (45 mg, 0.15 mmol) and potassium carbonate (62 mg, 0.45 mmol) in N, N-dimethylformamide (4 mL) with stirring. Added in the mixture. The resulting mixture was stirred at room temperature for 3 hours, diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product obtained using the procedure described in Example 158, Step 4 was subjected to the following conditions: Column: XBridge Shield RP18 OBD Column, 5 μm, 19 × 150 mm; Mobile Phase A: Water (10 mmol /) L NH₄HCO₃), Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient: 35% B to 50% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6.5 min; Obtained:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.91 (d, J = 1.9 Hz, 1H), 8.82 (d, J = 2.1 Hz, 1H), 8.35 (dd, J = 4.8, 1.6 Hz, 1H), 8.19 (t, J = 2.0 Hz, 1H) ), 7.92 (d, J = 4.4 Hz, 1H), 7.68 (dd, J = 8.0, 1.6 Hz, 1H), 7.32 (dd, J = 8.0, 4.8 Hz, 1H), 5.48 (s, 2H), 5.02 (dd, J = 11.5, 7.2 Hz, 1H), 4.69 (dd, J = 9.9, 7.2 Hz, 1H), 4.51 (dd, J = 11.5, 9.9 Hz, 1H), 3.50 (s, 3H) .LC- MS (Method D): m / z = 422.0 [M + H]⁺, 1.328 minutes.</p><p> Example 169: (S) -5-benzyl-N- (5-trizuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine -3-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="288"><img file="JP6974331B2_D0322.tif" /></chemistry> Step 1: (5-Trijuuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl) carbamic acid (S)- Preparation of tert-butyl Dehydrohydrate iodomethane (233.5 mg, 1.61 mmol), 4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl Carbamic acid (S) -tert-butyl (450 mg, 1.61 mmol) and cesium carbonate (629.2 mg, 1.93 mmol) were added to the stirred mixture in N, N-dimethylformamide (10 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 hours, diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (360 mg, 75.5%) as a white solid. LC-MS (Method E): m / z = 297.2 [M + H]⁺, 0.903 minutes.</p><p> Step 2: Preparation of (S) -3-amino-5-trijuuteriomethyl-2,3-dihydropyrido [3,2-b] [1,4] oxazepine-4 (5H) -one hydrochloride (5- Trijuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl) carbamic acid (S) -tert-butyl (200 mg, 0.68 mmol) was added to a 1,4-dioxane solution of hydrochloride (4M, 5 mL, 20 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated under vacuum to give the title compound (140 mg, crude) as a white solid. LC-MS (Method E): m / z = 197.1 [M + H]⁺, 0.761 minutes.</p><p> Step 3: (S) -5-Benzyl-N- (5-Trizuteriomethyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine- 3-Il) -4H-1,2,4-Triazole-3-Carboxamide preparation The crude product obtained using amide coupling procedure C is subjected to the following conditions: column, XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile Phase A: Water (10 mmol / L NH)₄CO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 25% B to 50% B over 7 minutes; Detector, purified by preparative HPLC using UV254 &amp; 220 nm; to give the title compound. ::¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.33 (dd, J = 4.8, 1.6 Hz, 1H), 7.66 (dd, J = 8.0, 1.6 Hz, 1H), 7.38-7.22 (m, 6H), 5.02 (dd, J = 11.6, 7.2 Hz, 1H), 4.67 (dd, J = 9.9, 7.2 Hz, 1H), 4.51 (dd, J = 11.5, 9.9 Hz, 1H), 4.16 (s, 2H). LC-MS (Method D): m / z = 382.1 [M + H]⁺, 1.371 minutes.</p><p> Examples 170A and 170B: 1- (3-cyanobenzyl) -N-((1aS, 2S, 8bR) -5,7-difluoro-3-oxo-1,1a, 2,3,4,8b-hexahydro Benzo [b] cyclopropa [d] azepine-2-yl) -4-fluoro-1H-pyrazole-3-carboxamide and 1- (3-cyanobenzyl) -N-((1aR, 2R, 8bS) -5,7 -Difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) -4-fluoro-1H-pyrazole-3-carboxamide<chemistry num="289"><img file="JP6974331B2_D0323.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was purified by preparative TLC (ethyl acetate / petroleum ether, 3/1) to give the title compound as a white solid.</p><p> Racemic compounds under the following conditions: Column: (R, R) WHELK-01 5 / 100Kromasil, 2.11 cm × 25 cm (5 μm); Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: Separation by preparative chiral HPLC using 60% B-60% B; UV254 &amp; 220nm; Rt1: 14.06; Rt2: 18.79; over 22 minutes gave the title compound:</p><p> Example 170A (first elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 7.88 (d, J = 4.4, Hz, 1H), 7.75-7.72 (m, 2H), 7.66-7.63 (m, 1H), 7.61-7.56 (m, 1H), 7.13-7.09 (m, 1H) , 6.99-6.92 (m, 1H), 5.23 (s, 2H), 4.82 (s, 1H), 2.31-2.24 (m, 1H), 2.15-2.09 (m, 1H), 1.66-1.61 (m, 1H) , 1.22-1.17 (m, 1H) .LC-MS (Method D): m / z = 452.1 [M + H]⁺, 1.627 minutes.</p><p> Example 170B (second elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 7.88 (d, J = 4.4 Hz, 1H), 7.74-7.72 (m, 2H), 7.67-7.63 (m, 1H), 7.61-7.56 (m, 1H), 7.13-7.09 (m, 1H), 6.99-6.92 (m, 1H), 5.43 (s, 2H), 4.82 (s, 1H), 2.29-2.25 (m, 1H), 2.15-2.11 (m, 1H), 1.66-1.60 (m, 1H), 1.22-1.15 (m, 1H) .LC-MS (Method V): m / z = 452.1 [M + H]⁺, 2.781 minutes.</p><p> Example 171: (S) -1- (3-cyanobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4 ] Oxazepine-3-yl) -1H-1,2,4-triazole-3-carboxamide<chemistry num="290"><img file="JP6974331B2_D0324.tif" /></chemistry> Step 1: Preparation of 1- (3-cyanobenzyl) -1H-1,2,4-triazole-3-methyl carboxylate Sodium hydride (60%, 0.38 g, 9.5 mmol), 1H-1,2, Methyl 4-triazole-3-carboxylate (1.0 g, 7.87 mmol) was added to the stirred mixture in N, N-dimethylformamide (20 mL). The resulting mixture was stirred at room temperature for 1 hour, followed by the addition of 3- (bromomethyl) benzonitrile (1.69 g, 8.67 mmol). The resulting mixture was stirred for an additional hour at room temperature, diluted with water (30 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (600 mg, 31.5%) as a white solid. LC-MS (Method C): m / z = 243.1 [M + H]⁺, 0.925 minutes.</p><p> Step 2: Preparation of 1- (3-cyanobenzyl) -1H-1,2,4-triazole-3-carboxylic acid A solution of lithium hydroxide (360 mg, 15.0 mmol) in water (10 ml) was added to 1- (3- (3-cyanobenzyl). Cyanobenzyl) -1H-1,2,4-triazole-3-carboxylate (600 mg, 2.48 mmol) was added to the stirred mixture in tetrahydrofuran (20 ml). The reaction mixture was stirred at room temperature for 2 hours. After removing tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH = 7 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (250 mg, 17.7%) as a white solid. LC-MS (Method X): m / z = 229.1 [M + H]⁺, 1.227 minutes.</p><p> Step 3: (S) -1- (3-cyanobenzyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Preparation of oxazepine-3-yl) -1H-1,2,4-triazole-3-carboxamide The crude product obtained using amide coupling procedure C was prepared under the following conditions: Column: XBridge Prep C18OBD Column 19 × 150 mm 5 μm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 20% B ~ 45% B over 7 minutes; 254 nm; Rt: 6 min; Obtained:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.64 (s, 1H), 8.33 (dd, J = 4.8, 1.6 Hz, 1H), 7.77-7.64 (m, 4H), 7.57 (t, J = 7.7 Hz, 1H), 7.30 (dd, J = 8.0, 4.8 Hz, 1H), 5.55 (s, 2H), 5.03 (dd, J = 11.7, 7.3 Hz, 1H), 4.69 (dd, J = 9.9, 7.1 Hz, 1H), 4.52 (dd, J = 11.2) , 9.6 Hz, 1H), 3.47 (s, 3H) .LC-MS (Method D): m / z = 404.2 [M + H]⁺, 1.371 minutes.</p><p> Examples 172: 1- (3-cyanobenzyl) -N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -1H-1,2,4-triazole-3-carboxamide<chemistry num="291"><img file="JP6974331B2_D0325.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 25% B to 75% B over 7 minutes; 254 nm; Rt: 6.25 min; Obtained:¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.66 (s, 1H), 8.33 (dd, J = 4.8, 1.6 Hz, 1H), 7.78-7.65 (m, 4H), 7.57 (t, J = 7.8 Hz, 1H), 7.32 (dd, J = 8.0, 4.8 Hz, 1H), 5.56 (s, 2H), 5.07-5.01 (m, 2H), 3.49 (s, 3H), 1.38 (d, J = 5.9 Hz, 3H). LC-MS (Method D) : m / z = 418.2 [M + H]⁺, 1.477 minutes.</p><p> Example 173: (S) -N- (5-trijuuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3-yl ) -5- (1-Phenylcyclopropyl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="292"><img file="JP6974331B2_D0326.tif" /></chemistry> The crude product obtained using the procedure described in Example 54 was subjected to the following conditions: column, XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase: phase A: water (10 mmol / L NH).₄HCO₃), Phase B: MeCN; Flow rate: 20 mL / min; Gradient: 25% B to 50% B over 7 minutes; Detector, UV254 nm; purified by preparative HPLC using Prescription HPLC to give the title compound:¹1 H NMR (300 MHz, DMSO-d₆) δ 9.49 (d, J = 7.6 Hz, 1H), 8.36 (dd, J = 4.7, 1.6 Hz, 1H), 7.70 (dd, J = 8.0, 1.6 Hz, 1H), 7.50-7.28 (m, 6H) , 4.87-4.62 (m, 2H), 4.50 (dd, J = 9.3, 7.1 Hz, 1H), 1.72-1.62 (m, 2H), 1.55-1.44 (m, 2H) .LC-MS (Method D): m / z = 409.1 [M + H]⁺, 1.624 minutes.</p><p> Example 174: 5-Benzyl-N-((2R, 3S) -2-methyl-5-trijuuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b]] [1,4] Oxazepine-3-yl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="293"><img file="JP6974331B2_D0327.tif" /></chemistry> Step 1: ((2R, 3S) -2-methyl-5-trijuuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine- 3-Il) Preparation of tert-butyl carbamate Dehydrohydrate iodomethane (124 mg, 0.85 mmol), (2R, 3S) -2-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3] , 2-b] [1,4] Oxazepine-3-ylcarbamate tert-butyl (250 mg, 0.85 mmol) and cesium carbonate (278 mg, 0.85 mmol) in N, N-dimethylformamide (30 mL) in a stirred mixture. Added. The reaction mixture was stirred at room temperature for 5 hours, diluted with water (20 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/20) to give the title compound (230 mg, 87.1%) as a white solid. LC-MS (Method C): m / z = 311.1 [M + H]⁺, 1.260 minutes.</p><p> Step 2: (2R, 3S) -3-amino-2-methyl-5-trihydrohydrogenated methyl-2,3-dihydropyrido [3,2-b] [1,4] oxazepine-4 (5H) -on Preparation of Hydrochloride ((2R, 3S) -2-Methyl-5-Trijuuteriomethyl-4-oxo-2,3,4,5 Tetrahydropyrido [3,2-b] [1,4] Oxazepine- 3-Il) tert-butyl carbamate (100 mg, 0.32 mmol) was added to a 1.4-dioxane solution of hydrogen chloride (4N, 6.0 mL, 24 mmol). The reaction mixture was stirred at room temperature for 3 hours and concentrated under vacuum to give the title compound (80 mg, 99%) as a white solid. LC-MS (Method C): m / z = 211.1 [M + H]⁺, 0.757 minutes.</p><p> Step 3: 5-Benzyl-N-((2R, 3S) -2-methyl-5-trijuuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [ 1,4] Preparation of oxazepine-3-yl) -1,3,4-oxadiazole-2-carboxamide The crude product obtained by using the procedure described in Example 54 is subjected to the following conditions. : Column: XBridge Prep OBD C18 Column 19 × 250mm, 5μm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 25% B to 75% B over 7 minutes; UV254 &amp; 220 nm; Rt: 6.85 min; Obtained:¹1 H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, 1H), 8.36 (dd, J = 4.8, 1.6 Hz, 1H), 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.40-7.28 (m, 6H), 4.98-4.90 ( m, 2H), 4.38 (s, 2H), 1.37 (d, J = 6.4 Hz, 3H). LC-MS (Method D): m / z = 397.2 [M + H]⁺, 1.680 minutes.</p><p> Example 175: (S) -1-benzyl-4-fluoro-N- (5-trijuuteriomethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1 , 4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="294"><img file="JP6974331B2_D0328.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: column, XBridge Prep C18OBD column, 5 μm, 19 × 150 mm; mobile phase: phase A: water (10 mmol / L NH).₄HCO₃), Phase B: MeCN; Flow rate: 20 mL / min; Gradient: 25% B to 65% B over 7 minutes; Detector, UV254 nm; purified by preparative HPLC using Prescription HPLC to give the title compound:¹1 H NMR (300 MHz, DMSO-d₆) δ 8.32 (dd, J = 4.7, 1.6 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.10 (d, J = 4.5 Hz, 1H), 7.66 (dd, J = 8.0, 1.6 Hz) , 1H), 7.42-7.19 (m, 6H), 5.31 (s, 2H), 4.85-4.76 (m, 1H), 4.64 (dd, J = 11.5, 9.7 Hz, 1H), 4.47 (dd, J = 9.6) , 7.4 Hz, 1H) .LC-MS (Method J): m / z = 399.3 [M + H]⁺, 1.331 minutes.</p><p> Example 176: 5-Benzyl-N-((1aR, 2S, 8bS) -5,7-difluoro-3-oxo-1,1a, 2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] ] Azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="295"><img file="JP6974331B2_D0329.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: Column: XBridge Prep OBD C18 Column 30 × 150 mm 5 μm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 25% B to 55% B over 7 minutes; 254 nm; Rt: 6.32 min; Obtained:¹1 H NMR (400 MHz, DMSO-d₆) δ 14.34 (br s, 1H), 9.72 (s, 1H), 8.62 (s, 1H), 7.35-7.18 (m, 7H), 4.12 (s, 2H), 3.98 (dd, J = 10.5, 7.5 Hz) , 1H), 2.26-2.17 (m, 1H), 1.87-1.77 (m, 1H), 1.13-1.04 (m, 1H), 0.60-0.57 (m, 1H) .LC-MS (Method Q): m / z = 410.5 [M + H]⁺, 1.77 3 minutes.</p><p> Examples 177A and 177B: 5-Benzyl-N-((7S, 7aS, 8aR) -5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa [d] pyradino [ 2,3-b] Azepine-7-yl) -1,3,4-oxadiazole-2-carboxamide and 5-benzyl-N-((7R, 7aR, 8aS) -5-methyl-6-oxo- 5,6,7,7a,8,8a-Hexahydrocyclopropa [d] pyrazino [2,3-b] azepine-7-yl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="296"><img file="JP6974331B2_D0330.tif" /></chemistry> The crude product obtained using the procedure described in Example 54 was purified by preparative TLC (ethyl acetate / petroleum ether, 3/1) to give the title compound as a white solid.</p><p> 5-benzyl-N- (cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa [d] pyrazino [2,3-b] azepine-7-yl) The racemic compound of -1,3,4-oxadiazole-2-carboxamide (40 mg, 0.10 mmol) was prepared under the following conditions: Column: CHIRAL ART Cellulose-SB S-5 μm, 250 × 20 mm, 5 μm; Mobile phase A: Hexane, mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 50% B to 50% B over 26 minutes; 220/254 nm; Rt1: 19.32; RT2: 23.55; Separation by: to give the title compound:</p><p> Example 177A (first elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.42-8.37 (m, 2H), 7.37-7.25 (m, 5H), 4.77 (s, 1H), 4.33 (s, 2H), 3.40 (s, 3H), 2.65-2.57 (m, 1H), 2.25-2.17 (m, 1H), 1.55-1.48 (m, 1H), 1.35-1.30 (m, 1H) .LCMS (Method D): m / z = 391.1 [M + H]⁺, 1.231 minutes.</p><p> Example 177B (second elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.42-8.37 (m, 2H), 7.36-7.25 (m, 5H), 4.77 (s, 1H), 4.33 (s, 2H), 3.39 (s, 3H), 2.64-2.56 (m, 1H), 2.24-2.16 (m, 1H), 1.54-1.46 (m, 1H), 1.34-1.28 (m, 1H) .LC-MS (Method D): m / z = 391.1 [M + H]⁺, 1.225 minutes.</p><p> Examples 178A and 178B: (S) -4-fluoro-1- (2-fluorobenzyl) -N- (5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2, 3-b] Azepine-7-yl) -1H-pyrazole-3-carboxamide and (R) -4-fluoro-1- (2-fluorobenzyl) -N- (5-methyl-6-oxo-6,7) , 8,9-Tetrahydro-5H-pyrazino [2,3-b] azepine-7-yl) -1H-pyrazole-3-carboxamide<chemistry num="297"><img file="JP6974331B2_D0331.tif" /></chemistry> Step 1: Preparation of ethyl 4- (3-aminopyrazine-2-yl) butanoate (4-ethoxy-4-oxobutyl) zinc (II) bromide in tetrahydrofuran (0.5 M, 26.0 mL, 13.0 mmol), 3 -Bromopyrazine-2-amine (1.0 g, 5.8 mmol) and tetrakis (triphenylphosphanyl) palladium (0.67 g, 0.58 mmol) were added to a mixture in tetrahydrofuran (60 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 70 ° C overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (0.45 g, 37.0%) as a pale yellow oil. LC-MS (Method S): m / z = 210.2 [M + H]⁺, 0.592 minutes.</p><p> Step 2: Preparation of 8,9-dihydro-5H-pyrazino [2,3-b] azepine-6 (7H) -one A toluene solution of trimethylaluminum (2M, 6.0mL, 12.0 mmol), 4- (3- (3-) Aminopyrazine-2-yl) ethyl butanoate (450 mg, 2.2 mmol) was added to a stirred mixture in toluene (20 mL). After stirring overnight at room temperature, the reaction mixture was quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (0.32 g, 91.0%) as a pale yellow solid. LC-MS (Method S): m / z = 16.42 [M + H]⁺, 0.473 minutes.</p><p> Step 3: Preparation of 5-methyl-8,9-dihydro-5H-pyrazino [2,3-b] azepine-6 (7H) -one Iodomethane (313 mg, 2.2 mmol), 8,9-dihydro-5H- Pyrazineno [2,3-b] azepine-6 (7H) -one (320 mg, 2.0 mmol) and cesium carbonate (717 mg, 2.2 mmol) were added dropwise to a stirred mixture in N, N-dimethylformamide (15 mL). After stirring overnight at room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (methanol / dichloromethane, 1/10) to give the title compound (300 mg, 87.0%) as a pale yellow solid. LC-MS (Method S): m / z = 178.1 [M + H]⁺, 0.570 minutes.</p><p> Step 4: 7-Iodo-5-Methyl-8,9-Dihydro-5H-Pyrazino [2,3-b] Azepine-6 (7H) -Preparation of On 5-Methyl-8,9-Dihydro-5H-Pyrazino [2,3-b] Azepine-6 (7H) -one (300 mg, 1.70 mmol) and N, N, N', N'-tetramethylethylenediamine (1.97 g, 17.0 mmol) in dichloromethane (80 mL). To, at 0 ° C, iodotrimethylsilane (2.38 g, 17.0 mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at 0 ° C. for 2 hours, followed by the addition of iodine (0.65 g, 2.6 mmol) in dichloromethane (100 mL) over 30 minutes. After stirring at room temperature for 1 hour, the reaction mixture was quenched by the addition of aqueous sodium thiosulfate (5%, 20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (450 mg, crude, 87.7%) as a yellow oil. LC-MS (Method S): m / z = 304.1 [M + H]⁺, 0.610 minutes.</p><p> Step 5: 7-Azide-5-Methyl-8,9-Dihydro-5H-Pyradino [2,3-b] Azepine-6 (7H) -Preparation of On Sodium Azide (290 mg, 4.47 mmol), 7- Stirring mixture of iodo-5-methyl-8,9-dihydro-5H-pyrazino [2,3-b] azepine-6 (7H) -one (450 mg, 1.49 mmol) in N, N-dimethylformamide (50 mL) Was added to. After stirring at room temperature for 3 hours, the reaction mixture was quenched by the addition of water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound (260 mg, crude) as a yellow oil. LC-MS (Method S): m / z = 219.1 [M + H]⁺, 0.600 minutes.</p><p> Step 6: Preparation of 7-amino-5-methyl-8,9-dihydro-5H-pyrazino [2,3-b] azepine-6 (7H) -one 7-azido-5-methyl in methanol (20 mL) -8,9-dihydro-5H-pyrazino [2,3-b] azepine-6 (7H) -one (260 mg, 1.2 mmol) under hydrogen atmosphere (2-3 atm), palladium-bearing carbon (10%, It was hydrogenated in the presence of 26 mg). After stirring at room temperature for 5 hours under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and dried under high vacuum to give the title compound (200 mg, 88%) as a colorless oil. LC-MS (Method S): m / z = 193.1 [M + H]⁺, 0.356 minutes.</p><p> Step 7: 4-Fluoro-1- (2-Fluorobenzyl) -N- (5-Methyl-6-oxo-6,7,8,9-Tetrahydro-5H-Pyrazineno [2,3-b] Azepine-7 -Il) -1H-Pyrazole-3-Carboxamide preparation The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: XBridge Shield C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A : Water (10 mmol / L NH₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 35% B ~ 50% B at 8 min; UV254 &amp; 220 nm; Rt: 6.82 min; 30 mg, 28%) was obtained as a white solid. LC-MS (Method O): m / z = 413.1 [M + H]⁺, 1.396 minutes.</p><p> Step 8: (S) -4-fluoro-1- (2-fluorobenzyl) -N- (5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2,3-b] ] Azepine-7-yl) -1H-pyrazole-3-carboxamide and (R) -4-fluoro-1- (2-fluorobenzyl) -N- (5-methyl-6-oxo-6,7,8, 9-Tetrahydro-5H-Pyrazino [2,3-b] Azepine-7-yl) -1H-Pyrazole-3-Carboxamide Preparation 4-Fluoro-1- (2-Fluorobenzyl) -N- (5-Methyl-) A racemic compound of 6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2,3-b] azepine-7-yl) -1H-pyrazole-3-carboxamide (30.0 mg, 0.07 mmol). Separated by preparative chiral HPLC, the following conditions: Column: CHIRALPAK IF, 2 × 25 cm, 5 μm; Mobile phase A: hexane, Mobile phase B: EtOH; Flow rate: 16 mL / min; Gradient: 50% at 30 min B ~ 50% of B; UV254 &amp; 220nm; Rt1: 17.00 min; Rt2: 24.16 min; was used to obtain the title compound:</p><p> Example 178A (first elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.48 (d, J = 2.8 Hz, 1H), 8.39 (d, J = 2.8 Hz, 1H), 7.77 (d, J = 4.4 Hz, 1H), 7.45-7.38 (m, 1H), 7.34-7.29 (m, 1H), 7.24-7.15 (m, 2H), 5.41 (s, 2H), 4.58-4.52 (m, 1H), 3.50 (s, 3H), 3.18-3.08 (m, 1H), 3.04-2.98 (m, 1H), 2.80-2.69 (m, 1H), 2.41-2.31 (m, 1H) .LC-MS (Method T): m / z = 413.1 [M + H]⁺, 1.198 minutes.</p><p> Example 178B (second elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.47 (d, J = 2.8 Hz, 1H), 8.38 (d, J = 2.8 Hz, 1H), 7.78 (d, J = 4.4 Hz, 1H), 7.45-7.38 (m, 1H), 7.34-7.29 (m, 1H), 7.25-7.15 (m, 2H), 5.41 (s, 2H), 4.58-4.52 (m, 1H), 3.50 (s, 3H), 3.19-3.08 (m, 1H), 3.05-2.98 (m, 1H), 2.81-2.69 (m, 1H), 2.41-2.32 (m, 1H) .LC-MS (Method X): m / z = 413.1 [M + H]⁺, 2.354 minutes.</p><p> Examples 179A and 179B: 4-Fluoro-1- (2-fluorobenzyl) -N-((7S, 7aS, 8aR) -5-Methyl-6-oxo-5,6,7,7a,8,8a- Hexahydrocyclopropa [d] pyrazino [2,3-b] azepine-7-yl) -1H-pyrazole-3-carboxamide and 4-fluoro-1- (2-fluorobenzyl) -N-((7R, 7aR) , 8aS) -5-Methyl-6-oxo-5,6,7,7a,8,8a-Hexahydrocyclopropa [d] Pyrazineno [2,3-b] Azepine-7-yl) -1H-Pyrazole- 3-Carboxamide<chemistry num="298"><img file="JP6974331B2_D0332.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was purified by preparative TLC (ethyl acetate / petroleum ether, 3/1) to give the title compound as a white solid.</p><p> Racemic compound under the following conditions: Column: CHIRALPAK IF, 2 × 25 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 16 mL / min; Gradient: 50% B ~ 50% at 38 min B; UV254 &amp; 220nm; Rt1: 22.995; Rt2: 30.882; was separated by preparative chiral HPLC to give the title compound:</p><p> Example 179A (first elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.30 (dd, J = 2.4, 6.4 Hz, 2H), 7.68 (d, J = 4.4 Hz, 1H), 7.34-7.27 (m, 1H), 7.25-7.20 (m, 1H), 7.13-7.04 ( m, 2H), 5.23 (s, 2H), 4.66 (s, 1H), 3.31 (s, 3H), 2.54-2.47 (m, 1H), 2.17-2.10 (m, 1H), 1.43-1.37 (m, 1H), 1.22-1.15 (m, 1H) .LC-MS (Method D): m / z = 425.0 [M + H]⁺, 1.679 minutes.</p><p> Example 179B (second elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.42 (dd, J = 3.2, 6.8 Hz, 2H), 7.80 (d, J = 4.4 Hz, 1H), 7.45-7.39 (m, 1H), 7.37-7.32 (m, 1H), 7.25-7.16 ( m, 2H), 5.44 (s, 2H), 4.78 (s, 1H), 3.42 (s, 3H), 2.65-2.58 (m, 1H), 2.28-2.22 (m, 1H), 1.54-1.49 (m, 1H), 1.33-1.27 (m, 1H) .LC-MS (Method D): m / z = 425.0 [M + H]⁺, 1.684 minutes.</p><p> Examples 180A and 180B: (S) -N- (5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2,3-b] azepine-7-yl) -5- (1-Phenylcyclopropyl) -1,3,4-oxadiazole-2-carboxamide and (R) -N- (5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino) [2,3-b] Azepine-7-yl) -5- (1-Phenylcyclopropyl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="299"><img file="JP6974331B2_D0333.tif" /></chemistry> The crude product obtained using amide coupling procedure C was purified by preparative TLC (ethyl acetate / petroleum ether, 1/1) to give the title compound.</p><p> N- (5-Methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2,3-b] azepine-7-yl) -5- (1-phenylcyclopropyl) -1, The racemic compound of 3,4-oxadiazole-2-carboxamide (30 mg, 0.08 mmol) was prepared under the following conditions: Column: CHIRALPAK IE, 2 × 25 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: MeOH; Flow rate. Separation by preparative chiral HPLC using: 20 mL / min; gradient: 100% B to 100% B over 16 minutes; UV254 &amp; 220 nm; Rt1: 10.459 mins; Rt2: 12.463 mins; to obtain the title compound. rice field:</p><p> Example 180A (first elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.49 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.48-7.46 (m, 2H), 7.41-7.31 (m, 3H), 4.57-4.51 (m, 1H), 3.49 (s, 3H), 3.18-3.09 (m, 1H), 3.05-2.99 (m, 1H), 2.74-2.63 (m, 1H), 2.50-2.41 (m, 1H), 1.80-1.77 ( m, 2H), 1.59-1.55 (m, 2H) .LC-MS (Method D): m / z = 405.0 [M + H]⁺, 1.260 minutes.</p><p> Example 180B (second elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.49 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.49-7.46 (m, 2H), 7.42-7.31 (m, 3H), 4.57-4.50 (m, 1H), 3.50 (s, 3H), 3.18-3.09 (m, 1H), 3.06-2.99 (m, 1H), 2.74-2.63 (m, 1H), 2.50-2.40 (m, 1H), 1.81-1.77 ( m, 2H), 1.60-1.55 (m, 2H) .LC-MS (Method D): m / z = 405.0 [M + H]⁺, 1.261 minutes.</p><p> Examples 181A and 181B: 5- (3-cyanobenzyl) -N-((1aR, 2R, 8bS) -5,7-difluoro-3-oxo-1,1a, 2,3,4,8b-hexahydro Benzo [b] cyclopropa [d] azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide and 5- (3-cyanobenzyl) -N-((1aS, 2S, 8bR) -5 , 7-Difluoro-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) -4H-1,2,4-triazole-3- Carboxamide<chemistry num="300"><img file="JP6974331B2_D0334.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: XBridge Shield C18OBD column, 5 μm, 19 × 150 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 30% B ~ 53% B over 8 minutes; 254 &amp; 220 nm, Rt: 7.43 min; Obtained as a white solid.</p><p> Racemic compound under the following conditions: Column: CHIRALPAK IE, 2 × 25 cm, 5 μm; Mobile phase A: Hexane: DCM = 5: 1, Mobile phase B: EtOH; Flow rate: 16 mL / min; Gradient: 50% over 23 minutes Separation by preparative chiral HPLC using B ~ 50% of B; 254 &amp; 220 nm; Rt1: 9.882; Rt2: 16.633; to give the title compound:</p><p> Example 181A (first elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 7.71 (s, 1H), 7.65-7.61 (m, 2H), 7.54-7.48 (m, 1H), 7.18-7.05 (m, 1H), 6.99-6.90 (m, 1H), 4.81 (s, 1H) ), 4.24 (s, 2H), 2.31-2.22 (m, 1H), 2.15-2.07 (m, 1H), 1.74-1.63 (m, 1H), 1.24-1.14 (m, 1H). LC-MS (Method) J): m / z = 435.4 [M + H]⁺, 1.200 minutes.</p><p> Example 181B (second elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 7.70 (s, 1H), 7.66-7.62 (m, 2H), 7.55-7.49 (m, 1H), 7.19-7.07 (m, 1H), 6.98-6.91 (m, 1H), 4.81 (s, 1H) ), 4.24 (s, 2H), 2.32-2.23 (m, 1H), 2.16-2.07 (m, 1H), 1.67-1.59 (m, 1H), 1.23-1.14 (m, 1H). LC-MS (Method) V): m / z = 435.1 [M + H]⁺, 3.354 minutes.</p><p> Examples 182A and 182B: (R) -4-fluoro-N- (5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2,3-b] azepine-7-yl )-1-((2-Methylpyridine-3-yl) methyl) -1H-pyrazole-3-carboxamide and (S) -4-fluoro-N- (5-methyl-6-oxo-6,7,8) , 9-Tetrahydro-5H-Pyrazole [2,3-b] Azepine-7-yl) -1-((2-Methylpyridine-3-yl) Methyl) -1H-Pyrazole-3-Carboxamide<chemistry num="301"><img file="JP6974331B2_D0335.tif" /></chemistry> Step 1: Preparation of 4-fluoro-1-((2-methylpyridine-3-yl) methyl) -1H-pyrazole-3-carboxylate ethyl 3- (bromomethyl) -2-methylpyridine (283 mg, 1.52 mmol) Was added to a stirred mixture of ethyl 4-fluoro-1H-pyrazole-3-carboxylate (200 mg, 1.27 mmol) and cesium carbonate (1.24 g, 3.80 mmol) in N, N-dimethylformamide (20 mL). The reaction mixture was stirred at room temperature for 3 hours, quenched by the addition of water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 1/4) to give the title compound (300 mg, 90.9%) as a white solid. LC-MS (Method C): m / z = 264.1 [M + H]⁺, 1.291 minutes.</p><p> Step 2: Preparation of 4-fluoro-1-((2-methylpyridine-3-yl) methyl) -1H-pyrazole-3-carboxylic acid Lithium hydroxide (82 mg, 3.42 mmol), 4-fluoro-1- ((2-Methylpyridine-3-yl) methyl) -1H-pyrazole-3-ethyl carboxylate (300 mg, 1.14 mmol) was added to the mixture in tetrahydrofuran (12 mL) and water (4 mL). The reaction mixture was stirred at room temperature overnight. After removing tetrahydrofuran under reduced pressure, the resulting solution was adjusted to pH = 6 with aqueous hydrochloric acid (1N, 10 mL) and extracted with ethyl acetate (3 × 60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (220 mg, crude) as a white solid. LC-MS (Method C): m / z = 236.0 [M + H]⁺, 0.365 minutes.</p><p> Step 3: 4-Fluoro-N- (5-Methyl-6-oxo-6,7,8,9-Tetrahydro-5H-Pyrazineno [2,3-b] Azepine-7-yl) -1-((2) -Preparation of Methylpyridin-3-yl) Methyl) -1H-Pyrazole-3-Carboxamide The crude product obtained using the amide coupling procedure C was prepared under the following conditions: Column: XBridge Shield C18OBD Column, 5 μm, 19 × 150 mm; Mobile Phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 20% B to 33% B over 8 minutes; UV254 &amp; 220 nm; Rt: 7.28 min; Obtained. LC-MS (Method Y): m / z = 410.2 [M + H]⁺, 0.841 minutes.</p><p> Step 4: (R) -4-Fluoro-N- (5-Methyl-6-oxo-6,7,8,9-Tetrahydro-5H-Pyrazino [2,3-b] Azepine-7-yl) -1 -((2-Methylpyridine-3-yl) methyl) -1H-pyrazole-3-carboxamide and (S) -4-fluoro-N- (5-methyl-6-oxo-6,7,8,9- Tetrahydro-5H-Pyrazole [2,3-b] Azepine-7-yl) -1-((2-Methylpyridine-3-yl) Methyl) -1H-Pyrazole-3-Carboxamide Preparation 4-Fluoro-N- (5-Methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2,3-b] azepine-7-yl) -1-((2-methylpyridine-3-yl) methyl) ) -1H-Pyrazole-3-Carboxamide (40 mg, 0.10 mmol) racemic compound under the following conditions: Column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 50% B to 50% B over 13 minutes; UV254 &amp; 220 nm; Rt1: 9.428 min Separation by preparative chiral HPLC using Rt2: 11.106 min; to give the title compound:</p><p> Example 182A (first elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.49 (d, J = 2.8 Hz, 1H), 8.42-8.39 (m, 2H), 7.80 (d, J = 4.4 Hz, 1H), 7.51-7.48 (m, 1H), 7.33-7.29 (m, 1H), 5.45 (s, 2H), 4.58-4.53 (m, 1H), 3.50 (s, 3H), 3.18-3.08 (m, 1H), 3.04-2.98 (m, 1H), 2.81-2.70 (m, 1H), 2.58 (s, 3H), 2.42-2.31 (m, 1H) .LC-MS (Method D): m / z = 410.0 [M + H]⁺, 0.715 minutes.</p><p> Example 182B (second elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.49 (d, J = 2.8 Hz, 1H), 8.42-8.39 (m, 2H), 7.80 (d, J = 4.4 Hz, 1H), 7.52-7.48 (m, 1H), 7.34-7.29 (m, 1H), 5.45 (s, 2H), 4.58-4.53 (m, 1H), 3.50 (s, 3H), 3.18-3.07 (m, 1H), 3.05-2.98 (m, 1H), 2.81-2.70 (m, 1H), 2.58 (s, 3H), 2.42-2.30 (m, 1H) .LC-MS (Method D): m / z = 410.0 [M + H]⁺, 0.720 minutes.</p><p> Examples 183A and 183B: 1-Benzyl-4-fluoro-N-((1aR, 2R, 8bS) -4-trijuuteriomethyl-7- (methylsulfonyl) -3-oxo-1,1a, 2,3 , 4,8b-Hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) -1H-pyrazole-3-carboxamide and 1-benzyl-4-fluoro-N-((1aS, 2S, 8bR) -4 -Trijuuteriomethyl-7- (methylsulfonyl) -3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) -1H-pyrazole- 3-Carboxamide<chemistry num="302"><img file="JP6974331B2_D0336.tif" /></chemistry><chemistry num="303"><img file="JP6974331B2_D0337.tif" /></chemistry> Step 1: Preparation of 7-bromo-4,5-dihydro-1H-benzo [b] azepine-2 (3H) -one with acetic acid (100 mL) solution of bromine (8 mL, 155 mmol), 4,5-dihydro-1H -Benzo [b] azepine-2 (3H) -one (10 g, 62 mmol) and sulfuric acid (5 mL) were added dropwise to a solution of acetic acid (100 mL) at 0 ° C. After stirring overnight at room temperature, the reaction mixture was poured into ice water (200 mL), neutralized with ammonium hydroxide (28%, 100 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 99/1) to give the title compound (11.5 g, 77%) as a colorless oil. LC-MS (Method C): m / z = 240.0 [M + H]⁺, 1.152 minutes.</p><p> Step 2: Preparation of 7-bromo-1-trijuuteriomethyl-4,5-dihydro-1H-benzo [b] azepine-2 (3H) -one deuterated iodomethane (5.9 g, 41 mmol), 7- Stirring mixture of bromo-4,5-dihydro-1H-benzo [b] azepine-2 (3H) -one (9 g, 38 mmol) and cesium carbonate (13.4 g, 41 mmol) in N, N-dimethylformamide (30 mL). Dropped into. The reaction mixture was stirred at room temperature for 2 hours, diluted with water (60 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/20) to give the title compound (7.2 g, 75%) as a yellow solid. LC-MS (Method C): m / z = 257.1 [M + H]⁺, 1.234 minutes.</p><p> Step 3: 1: Preparation of trijuuteriomethyl-7- (methylsulfonyl) -4,5-dihydro-1H-benzo [b] azepine-2 (3H) -one ferrous iodide (304 mg, 1.6 mmol) 7-bromo-1-trijuuteriomethyl-4,5-dihydro-1H-benzo [b] azepine-2 (3H) -one (4.1 g, 16 mmol), L-proline (368 mg, 3.2 mmol), Sodium hydroxide (64 mg, 1.6 mmol) and sodium methanesulfinate (8.16 g, 80 mmol) were added to a mixture in dimethylsulfoxide (20 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 120 ° C. overnight. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous ammonium chloride (40 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (methanol / dichloromethane, 1/20) to give the title compound (2.7 g, 66%) as a yellow solid. LC-MS (Method C): m / z = 257.1 [M + H]⁺, 0.907 minutes.</p><p> Step 4: Preparation of 3-iodo-1-trijuuteriomethyl-7- (methylsulfonyl) -4,5-dihydro-1H-benzo [b] azepine-2 (3H) -one N¹, N¹, N², N²-Tetramethylethane-1,2-diamine (3.8 g, 33 mmol), 1-trijuteriomethyl-7- (methylsulfonyl) -4,5-dihydro-1H-benzo [b] azepine-2 (3H) -A stirring mixture in on (2.7 g, 11 mmol) dichloromethane (40 mL) was added at 0 ° C, followed by the addition of iodotrimethylsilane (6.6 g, 33 mmol) over 30 minutes. After stirring at 0 ° C for 1 hour, a solution of iodine (4.2 g, 16.5 mmol) in dichloromethane (100 mL) was added. The reaction mixture was stirred at 0 ° C. for 2 hours, quenched by the addition of aqueous sodium thiosulfate (5%, 60 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane) to give the title compound (3.5 g, 88%) as a yellow solid. LC-MS (Method S): m / z = 382.9 [M + H]⁺, 0.826 minutes.</p><p> Step 5: 1-Tri-deuterated methyl-7- (methylsulfonyl) -1H-benzo [b] azepine-2 (3H) -one preparation 1,8-diazabicyclo [5.4.0] undeca-7-ene ( 3.8 g, 25.2 mmol), 3-iodo-1-tri deuterated methyl-7- (methylsulfonyl) -4,5-dihydro-1H-benzo [b] azepine-2 (3H) -one (3.2 g) , 8.4 mmol) was added to the stirred mixture in N, N-dimethylformamide (10 mL) at room temperature. The reaction mixture was stirred at 80 ° C. overnight, quenched by the addition of water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane) to give the title compound (1.8 g, 85%) as a yellow solid. LC-MS (Method T): m / z = 255.2 [M + H]⁺, 0.698 minutes.</p><p> Step 6: 4-Trijuuteriomethyl-7- (methylsulfonyl) -1,1a,2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one preparation 1-methyl-1- Nitrosourea (7.4 g, 70 mmol) was added to a solution of potassium hydroxide (14 g, 350 mmol) in water (21 mL) and ether (100 mL) at 0 ° C. The resulting mixture was stirred at 0 ° C. for 1 hour, then the organic phase was separated to give a solution of diazomethane in ether (100 mL). A solution of diazomethane (100 ml) in a mixture of 1-trijuuteriomethyl-7- (methylsulfonyl) -1H-benzo [b] azepine-2 (3H) -one (1.8 g, 7 mmol) in tetrahydrofuran (30 mL). Then a mixture of palladium diacetate (158 mg, 0.7 mmol) in tetrahydrofuran (10 mL) was added dropwise at 0 ° C. The reaction mixture was stirred at room temperature overnight. The solid was removed by filtration and the filtrate was concentrated under vacuum to give the title compound (1.5 g, crude) as a yellow oil. LC-MS (Method E): m / z = 268.9 [M + H]⁺, 0.757 minutes.</p><p> Step 7: Preparation of trans-2-iodo-4-trijuuteriomethyl-7- (methylsulfonyl) -1,1a,2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one N¹, N¹, N², N²-Tetramethylethane-1,2-diamine (1.95 g, 16.8 mmol), 4-trijuuteriomethyl-7- (methylsulfonyl) -1,1a, 2,8b-tetrahydrobenzo [b] cyclopropa [d] Azepine-3 (4H) -one (1.5 g, 5.6 mmol) was added to the stirred mixture in dichloromethane (30 mL) at 0 ° C, followed by iodotrimethylsilane (3.4 g, 16.8 mmol) over 30 minutes. Dropped. After stirring at 0 ° C for 1 hour, a solution of iodine (2.1 g, 8.4 mmol) in dichloromethane (50 mL) was added. The reaction mixture was stirred at 0 ° C. for 2 hours, quenched by the addition of aqueous sodium thiosulfate (5%, 40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give the title compound (1.6 g, crude) as a yellow oil. LC-MS (Method S): m / z = 394.9 [M + H]⁺, 0.892 minutes.</p><p> Step 8: Preparation of cis-2-azido-4-trijuuteriomethyl-7- (methylsulfonyl) -1,1a,2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one Sodium azide (390 mg, 6 mmol), trans-2-iodo-4-trijuuteriomethyl-7- (methylsulfonyl) -1,1a, 2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 It was added to the stirred mixture in (4H) -one (1.6 g, 4 mmol) N, N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature overnight, quenched with water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound (800 mg, crude) as a yellow oil. LC-MS (Method S): m / z = 309.9 [M + H]⁺, 0.855 minutes.</p><p> Step 9: Preparation of cis-2-amino-4-trijuuteriomethyl-7- (methylsulfonyl) -1,1a,2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one Sis-2-azido-4-trijuuteriomethyl-7- (methylsulfonyl) -1,1a,2,8b-tetrahydrobenzo [b] cyclopropa [d] azepine-3 (4H) -one (800 mg, 2.59 mmol) ) In methanol (30 mL) was hydrogenated in a hydrogen atmosphere (2-3 atm) in the presence of palladium-bearing carbon (10%, 100 mg). After stirring at room temperature for 2 hours under a hydrogen atmosphere, the reaction mixture was filtered through Celite. The filtrate was concentrated under vacuum and the resulting residue was purified by column chromatography (dichloromethane) to give the title compound (500 mg, 68%) as a yellow solid. LC-MS (Method F): m / z = 283.9 [M + H]⁺, 0.715 minutes.</p><p> Step 10: 1-Benzyl-4-fluoro-N- (cis-4-trijuuteriomethyl-7- (methylsulfonyl) -3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [ b] Cyclopropa [d] Azepine-2-yl) -1H-Pyrazole-3-Carboxamide preparation The crude product obtained using the amide coupling procedure C is subjected to the following conditions: Column: Xbridge Prep C18, 5 μm , 19 × 150mm; Mobile phase A: Water (0.1% NH)₄HCO₃), Mobile phase B: MeCN flow rate: 20 mL / min; Gradient: 32% B to 55% B over 8 minutes; 254 &amp; 220 nm; Rt: 7.38 min; rice field. LC-MS (Method E): m / z = 486.1 [M + H]⁺, 1.037 minutes.</p><p> Step 11: 1-Benzyl-4-fluoro-N-((1aR, 2R, 8bS) -4-trijuuteriomethyl-7- (methylsulfonyl) -3-oxo-1,1a, 2,3,4, 8b-Hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) -1H-pyrazole-3-carboxamide and 1-benzyl-4-fluoro-N-((1aS, 2S, 8bR) -4-trijuu Teriomethyl-7- (methylsulfonyl) -3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2-yl) -1H-pyrazole-3-carboxamide Preparation 1-Benzyl-4-fluoro-N- (cis-4-trijuuteriomethyl-7- (methylsulfonyl) -3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] ] Cyclopropa [d] azepine-2-yl) -1H-pyrazole-3-carboxamide racemic compound under the following conditions: Column: CHIRALPAK IA, 2.12 × 15 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 50% B to 50% B over 22 minutes; 254 &amp; 220 nm; Rt1: 10.61; Rt2: Separation by preparative chiral HPLC using 16.166; gave the title compound:</p><p> Example 183A (first elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.05 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 8.5, 2.3 Hz, 1H), 7.75 (d, J = 4.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H) ), 7.42-7.31 (m, 5H), 5.33 (s, 2H), 4.66 (s, 1H), 3.17 (s, 3H), 2.47-2.37 (m, 1H), 2.15-2.06 (m, 1H), 1.38-1.30 (m, 1H), 1.26-1.17 (m, 1H) .LC-MS (Method V): m / z = 486.1 [M + H]⁺, 3.132 minutes.</p><p> Example 183B (second elution isomer):¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.05 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 8.5, 2.3 Hz, 1H), 7.76 (d, J = 4.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H) ), 7.43-7.30 (m, 5H), 5.33 (s, 2H), 4.66 (s, 1H), 3.17 (s, 3H), 2.47-2.37 (m, 1H), 2.15-2.07 (m, 1H), 1.37-1.31 (m, 1H), 1.28-1.17 (m, 1H) .LC-MS (Method D): m / z = 486.1 [M + H]⁺, 1.390 minutes.</p><p> Example 184: (S) -4-Fluoro-1-((1-Methyl-1H-Pyrazole-4-yl) Methyl) -N- (5-Methyl-4-oxo-2,3,4,5- Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="304"><img file="JP6974331B2_D0338.tif" /></chemistry> Cesium carbonate (453 mg, 1.39 mmol), (S) -4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrazole [3,2-b] [1, 4] N, N-dimethyl of oxazepine-3-yl) -1H-pyrazole-3-carboxamide (100 mg, 0.33 mmol) and 4- (bromomethyl) -1-methyl-1H-pyrazole hydrochloride (208 mg, 0.82 mmol) It was added to the stirred mixture in formamide (7 mL). After stirring at room temperature for 3 hours, the reaction mixture was quenched by the addition of water (50 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Residues under the following conditions: Column; Xbridge Prep C18, 5 μm, 19 × 150 mm; Mobile Phase A; Water (0.1 mmol / L NH)₄HCO₃), Mobile phase B; MeCN; Flow rate: 20 mL / min; Gradient: Purified by preparative HPLC using 15% B ~ 36% B; UV254 &amp; 220 nm; over 10 minutes to give the title compound:¹1 H NMR (300 MHz, DMSO-d₆) δ 8.37 (dd, J = 4.8, 1.5 Hz, 1H), 8.22 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 4.2 Hz, 1H), 7.75 (s, 1H), 7.71 (dd) , J = 8.1, 1.5 Hz, 1H), 7.49 (s, 1H), 7.34 (dd, J = 8.1, 4.8 Hz, 1H), 5.19 (s, 2H), 4.91-4.81 (m, 1H), 4.69 ( dd, J = 11.1, 9.6 Hz, 1H), 4.53 (dd, J = 9.6, 7.5 Hz, 1H), 3.82 (s, 3H), 3.37 (s, 3H). LC-MS (Method D): m / z = 400.0 [M + H]⁺, 1.357 minutes.</p><p> Example 188: (S) -5-benzyl-N- (5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2,3-b] azepine-7-yl) iso Oxazole-3-carboxamide<chemistry num="305"><img file="JP6974331B2_D0339.tif" /></chemistry> The crude product was purified by preparative TLC (ethyl acetate / hexane, 3/1) to give a racemic compound. LC-MS (Method E): m / z = 378.2 [M + H]⁺, 0.998 minutes. 5-benzyl-N- (5-Methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2,3-b] azepine-7-yl) Isoxazole-3-carboxamide racemic compound The following conditions: Column: CHIRALPAK IA, 2 × 25 cm, 5 μm; Mobile phase A: Hexane: DCM = 5: 1, Mobile phase B: EtOH; Flow rate: 15 mL / min; Gradient: 50% at 20 minutes Separation by preparative chiral HPLC using B ~ 50% B; UV254 &amp; 220nm; Rt1: 11.1; Rt2: 15.01; gave the title compound as the first elution isomer:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.48-8.35 (m, 2H), 7.35-7.23 (m, 5H), 6.38 (s, 1H), 4.48 (dd, J = 8.0, 12.0 Hz, 1H), 4.16 (s, 2H), 3.47 ( s, 3H), 3.15-3.05 (m, 1H), 3.02-2.95 (m, 1H), 2.72-2.61 (m, 1H), 2.43-2.34 (m, 1H) .LC-MS (Method D): m / z = 378.0 [M + H]⁺, 1.645 minutes.</p><p> Example 190: (S) -5-benzyl-N- (5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2,3-b] azepine-7-yl)- 1,3,4-oxadiazole-2-carboxamide<chemistry num="306"><img file="JP6974331B2_D0340.tif" /></chemistry> The residue was purified by preparative TLC (ethyl acetate / hexane, 3/1) to give a racemic compound. LC-MS (Method C): m / z = 378.1 [M + H]⁺, 1.141 minutes. 5-benzyl-N- (5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino [2,3-b] azepine-7-yl) -1,3,4-oxadi Racemic compounds of azole-2-carboxamide under the following conditions: Column: CHIRALPAK IA, 2 × 25 cm, 5 μm; Mobile phase A: Hexane: DCM = 5: 1, Mobile phase B: EtOH; Flow rate: 15 mL / min; Gradient Separation by preparative chiral HPLC using 50% B ~ 50% B; UV254 &amp; 220nm; Rt1: 11.1; Rt2: 15.01; at 20 minutes to give the title compound as the first elution isomer:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.46 (d, J = 2.8 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 7.37-7.26 (m, 5H), 4.53 (dd, J = 12.0, 7.6 Hz, 1H), 4.32 (s, 2H), 3.48 (s, 3H), 3.18-3.06 (m, 1H), 3.03-2.97 (m, 1H), 2.73-2.62 (m, 1H), 2.49-2.39 (m, 1H) .LC -MS (Method J): m / z = 379.1 [M + H]⁺, 1.072 minutes.</p><p> Example 192: 5-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) Oxazole-2-carboxamide<chemistry num="307"><img file="JP6974331B2_D0341.tif" /></chemistry> The resulting crude product was subjected to the following conditions: Column: Xbridge Prep C18, 5 μm, 19 × 150 mm; Mobile Phase A: Water (0.1% NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 35% B to 66% B over 8 minutes; UV254 &amp; 220 nm; Rt: 6.98 min; Obtained.¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.34 (dd, J = 4.8, 1.6 Hz, 1H), 7.69 (dd, J = 8.0, 1.6 Hz, 1H), 7.38-7.22 (m, 6H), 7.04 (s, 1H), 5.07-4.96 ( m, 2H), 4.13 (s, 2H), 3.50 (s, 3H), 1.42 (d, J = 5.9 Hz, 3H). LC-MS (Method D): m / z = 393.1 [M + H]⁺, 1.524 minutes.</p><p> Example 193: 5-Benzyl-N-((3S, 4R) -1,4-dimethyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-b] [1,4] Oxazepine-3-yl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="308"><img file="JP6974331B2_D0342.tif" /></chemistry> The crude product was purified by preparative TLC (ethyl acetate / petroleum ether, 3/1) to give the title compound:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.22-8.19 (m, 1H), 7.94-7.90 (m, 1H), 7.43-7.39 (m, 1H), 7.35-7.26 (m, 5H), 5.14-5.07 (m, 2H), 4.31 (s) , 2H), 3.44 (s, 3H), 1.45 (d, J = 6.0 Hz, 3H) .LC-MS (Method T): m / z = 394.1 [M + H]⁺, 1.202 minutes.</p><p> Example 194: 5-Benzyl-N-((7S, 7aS, 8aR) -5-Methyl-6-oxo-5,6,7,7a,8,8a-Hexahydrocyclopropa [d] pyradino [2,, 3-b] Azepine-7-yl) Oxazole-2-carboxamide<chemistry num="309"><img file="JP6974331B2_D0343.tif" /></chemistry> The crude product was purified by preparative TLC (ethyl acetate / petroleum ether, 3/1) to give a racemic compound. LC-MS (Method E): m / z = 390.2 [M + H]⁺, 1.018 minutes. 5-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa [d] chirality [2,3-b] azepine-7-yl)- Racemic compound of oxazol-2-carboxamide (50 mg, 0.13 mmol) under the following conditions: Column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; Mobile phase A: MTBE, Mobile phase B: EtOH; Flow rate: 20 mL / Minutes; Gradient: 30 B to 30 B at 15 min; UV254 &amp; 220 nm; Rt1: 7.635; Rt2: 9.685; separated by preparative chiral HPLC to give the title compound as the first elution isomer. ::¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.45-8.40 (m, 2H), 7.39-7.23 (m, 5H), 7.04 (s, 1H), 4.77 (s, 1H), 4.14 (s, 2H), 3.42 (s, 3H), 2.67- 2.59 (m, 1H), 2.28-2.20 (m, 1H), 1.57-1.50 (m, 1H), 1.37-1.28 (m, 1H) .LC-MS (Method D): m / z = 390.1 [M + H]⁺, 1.361 minutes.</p><p> Examples 195: 1-benzyl-N-((7S, 7aS, 8aR) -5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa [d] pyrazino [2,, 3-b] Azepine-7-yl) -1H-1,2,3-triazole-4-carboxamide<chemistry num="310"><img file="JP6974331B2_D0344.tif" /></chemistry> The crude product was purified by preparative TLC (ethyl acetate / hexane, 3/1) to give a racemic compound. LC-MS (Method E): m / z = 390.2 [M + H]⁺, 0.932 minutes. 5-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydro-cyclopropa [d] pyrazino [2,3-b] azepine-7-yl) -1H The isomer compound of -1,2,3-triazole-2-carboxamide (50 mg, 0.129 mmol) was prepared under the following conditions: Column: CHIRALPAK IA, 2.12 × 15 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: IPA; Flow rate: 20 mL / min; Gradient: 50% B to 50% B over 20 minutes; UV254 &amp; 220 nm; Rt1: 11.273; Rt2: 15.609; Obtained as an elution isomer:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.42-8.38 (m, 3H), 7.41-7.32 (m, 5H), 5.65 (s, 2H), 4.79 (s, 1H), 3.40 (s, 3H), 2.64-2.57 (m, 1H), 2.26-2.20 (m, 1H), 1.54-1.49 (m, 1H), 1.33-1.26 (m, 1H) .LC-MS (Method J): m / z = 390.1 [M + H]⁺, 1.162 minutes.</p><p> Example 197: 5-Benzyl-N-((7S, 7aS, 8aR) -5-Methyl-6-oxo-5,6,7,7a,8,8a-Hexahydrocyclopropa [d] pyradino [2,, 3-b] Azepine-7-yl) Isoxazole-3-carboxamide<chemistry num="311"><img file="JP6974331B2_D0345.tif" /></chemistry> The crude product was purified by preparative TLC (ethyl acetate / hexane, 3/1) to give a racemic compound. LC-MS (Method E): m / z = 390.2 [M + H]⁺, 1.072 minutes. 5-benzyl-N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydro-cyclopropa [d] pyrazino [2,3-b] azepine-7-yl) -iso Racemic compounds of oxazole-2-carboxamide under the following conditions: Column: CHIRALPAK IA, 2 × 25 cm, 5 μm; Mobile phase A: Hexane: DCM = 5: 1, Mobile phase B: EtOH; Flow rate: 15 mL / min; Gradient Separation by preparative chiral HPLC using 50% B ~ 50% B; UV254 &amp; 220nm; Rt1: 15.4; Rt2: 19.4; at 24 minutes to give the title compound as the first elution isomer:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.42-8.38 (m, 2H), 7.36-7.24 (m, 5H), 6.44 (s, 1H), 4.76 (s, 1H), 4.18 (s, 2H), 3.57 (s, 3H), 2.64- 2.57 (m, 1H), 2.24-2.17 (m, 1H), 1.53-1.48 (m, 1H), 1.32-1.26 (m, 1H) .LC-MS (Method D): m / z = 390.0 [M + H]⁺, 1.747 minutes.</p><p> Example 198: 5-Benzyl-N-((7S, 7aS, 8aR) -5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa [d] pyradino [2,, 3-b] Azepine-7-yl) -1,3,4-thiadiazole-2-carboxamide<chemistry num="312"><img file="JP6974331B2_D0346.tif" /></chemistry> The crude product was purified by preparative TLC (ethyl acetate / hexane, 3/1) to give a racemic compound. LC-MS (Method E): m / z = 407.1 [M + H]⁺, 1.017 minutes.</p><p> 5-benzyl-N- (cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa [d] pyrazino [2,3-b] azepine-7-yl) The racemic compound of -1,3,4-thiadiazole-2-carboxamide was prepared under the following conditions: Column: Chilarpak ID-2, 2 × 25 cm, 5 μm; Mobile phase A: MTBE, Mobile phase B: EtOH; Flow rate: 20 mL / Minutes; Gradient: 30% B ~ 30% B over 26 minutes; UV254 &amp; 220nm; Rt1: 19.418; Rt2: 22.874; separated by preparative chiral HPLC with the title compound as the first elution isomer. Obtained:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.41-8.37 (m, 2H), 7.38-7.26 (m, 5H), 4.77 (s, 1H), 4.51 (s, 2H), 3.48 (s, 3H), 2.65-2.58 (m, 1H), 2.28-2.22 (m, 1H), 1.56-1.50 (m, 1H), 1.34-1.27 (m, 1H) .LC-MS (Method D): m / z = 407.1 [M + H]⁺, 1.680 minutes.</p><p> Example 200: (S) -5-benzyl-N- (2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo [4,5-b] azepine-6-yl ) -1,3,4-Oxadiazole-2-carboxamide<chemistry num="313"><img file="JP6974331B2_D0347.tif" /></chemistry> The crude product was purified by preparative TLC (ethyl acetate / petroleum ether, 3/1) to give a racemic compound. LC-MS (Method D): m / z = 398.10 [M + H]⁺, 1.284 minutes. 5-benzyl-N- (2,4-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-thiazolo [4,5-b] azepine-6-yl) -1,3,4- Racemic compounds of oxadiazole-2-carboxamide under the following conditions: Column: CHIRALPAK IA, 2.12 × 15 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 20 mL / min; Gradient: 13 minutes 50% B ~ 50% B; UV220 &amp; 254nm; Rt1: 7.88; Rt2: 10.109; was separated by preparative chiral HPLC to give the title compound as the first elution isomer:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 7.41-7.24 (m, 5H), 4.65 (dd, J = 11.5, 6.7 Hz, 1H), 4.33 (s, 2H), 3.36 (s, 3H), 3.06-2.84 (m, 2H), 2.72- 2.54 (m, 4H), 2.46-2.33 (m, 1H) .LC-MS (Method D): m / z = 398.10 [M + H]⁺, 1.283 minutes.</p><p> Example 201: (S) -1-benzyl-N- (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] oxazepine-3- Il) -1H-1,2,3-triazole-4-carboxamide<chemistry num="314"><img file="JP6974331B2_D0348.tif" /></chemistry> The crude product was purified by column chromatography (ethyl acetate / petroleum ether, 2/1) to give the title compound:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.41-8.33 (m, 2H), 7.68 (dd, J = 8.1, 1.6 Hz, 1H), 7.45-7.28 (m, 6H), 5.66 (s, 2H), 5.04 (dd, J = 11.6, 7.2) Hz, 1H), 4.69 (dd, J = 9.9, 7.2 Hz, 1H), 4.54 (dd, J = 11.6, 9.8 Hz, 1H), 3.49 (s, 3H). LC-MS (Method D): m / z = 379.1 [M + H]⁺, 1.239 minutes.</p><p> Example 203: 1-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -1H-1,2,3-triazole-4-carboxamide<chemistry num="315"><img file="JP6974331B2_D0349.tif" /></chemistry> The crude product should be as follows: Column: Xbridge Prep C18, 5 μm, 19 × 150 mm; Mobile phase A: Water (0.1% NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 25% B to 66% B over 8 minutes; UV254 &amp; 220 nm; Rt: 6.68 min; Obtained.¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.27 (s, 1H), 8.23-8.20 (m, 1H), 7.56 (dd, J = 8.0, 1.6 Hz, 1H), 7.29-7.17 (m, 6H), 5.54 (s, 2H), 4.97- 4.85 (m, 2H), 3.38 (s, 3H), 1.31 (d, J = 6.2 Hz, 3H). LC-MS (Method Q): m / z = 393.2 [M + H]⁺, 1.354 minutes.</p><p> Example 204: 2-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -2H-1,2,3-triazole-4-carboxamide<chemistry num="316"><img file="JP6974331B2_D0350.tif" /></chemistry> The crude product should be as follows: Column: Xbridge Prep C18, 5 μm, 19 × 150 mm; Mobile phase A: Water (0.1% NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 35% B ~ 72% B over 8 minutes; UV254 &amp; 220 nm; Rt: 5.95 min; Obtained.¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.32 (dd, J = 4.7, 1.5 Hz, 1H), 8.06 (s, 1H), 7.68 (dd, J = 8.0, 1.6 Hz, 1H), 7.40-7.27 (m, 6H), 5.70 (s, 2H), 5.09-4.97 (m, 2H), 3.49 (s, 3H), 1.41 (d, J = 6.1 Hz, 3H) .LC-MS (Method D): m / z = 393.10 [M + H]⁺, 1.479 minutes.</p><p> Example 205: 1-Benzyl-N-((3S, 4R) -1-trijuuteriomethyl-4-methyl-2-oxo-1,2,3,4-tetrahydropyrido [2,3-b]] [1,4] Oxazepine-3-yl) -4-fluoro-1H-pyrazole-3-carboxamide<chemistry num="317"><img file="JP6974331B2_D0351.tif" /></chemistry><chemistry num="318"><img file="JP6974331B2_D0352.tif" /></chemistry> The crude product was prepared under the following conditions: Column: Kinetex 5 μm EVO C18OBD column, 21.2 × 150 mm, 5 μm; Mobile phase A: Water (0.1% formic acid), Mobile phase B: MeCN; Flow rate: 25 mL / min; Gradient: 8 min Purification by preparative HPLC using 30% B-60% B; UV254 &amp; 220nm; Rt: 7.52 min; to give the title compound:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.23 (dd, J = 4.8, 1.6 Hz, 1H), 7.94 (dd, J = 8.0, 2.0 Hz, 1H), 7.77 (d, J = 4.4 Hz, 1H), 7.46-7.32 (m, 6H) , 5.35 (s, 2H), 5.18-5.07 (m, 2H), 1.45 (d, J = 6.0 Hz, 3H) .LC-MS (Method O): m / z = 413.2 [M + H]⁺, 1.472 minutes.</p><p> Example 206: 1-Benzyl-N-((1aS, 2S, 8bR) -7-cyano-4-trijuuteriomethyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [ b] Cyclopropa [d] Azepine-2-yl) -4-fluoro-1H-pyrazole-3-carboxamide<chemistry num="319"><img file="JP6974331B2_D0353.tif" /></chemistry><chemistry num="320"><img file="JP6974331B2_D0354.tif" /></chemistry> The crude product was purified by preparative TLC (ethyl acetate / hexane, 3/1) to give a racemic compound. LC-MS (Method C): m / z = 433.1 [M + H]⁺, 1.078 minutes. 1-benzyl-N- (cis-7-cyano-4-trijuuteriomethyl-3-oxo-1,1a,2,3,4,8b-hexahydrobenzo [b] cyclopropa [d] azepine-2- Il) -4-fluoro-1H-pyrazole-3-carboxamide racemic compound under the following conditions: Column: CHIRALPAK IA, 2.12 × 15 cm, 5 μm; Mobile phase A: Hexane, Mobile phase B: EtOH; Flow rate: 20 mL / Minutes; Gradient: 50% B ~ 50% B over 18 minutes; UV254 &amp; 220nm; Rt1: 8.283; Rt2: 14.011; separated by preparative chiral HPLC to give the title compound as the second elution isomer. ::¹1 H NMR (400 MHz, DMSO-d₆) δ 8.15 (d, J = 4.4 Hz, 1H), 8.09 (d, J = 6.8 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.77 (dd, J = 8.4, 2.0 Hz, 1H) ), 7.45 (d, J = 8.4 Hz, 1H), 7.41-7.28 (m, 5H), 5.35 (s, 2H), 4.46 (d, J = 6.8 Hz, 1H), 2.39-2.32 (m, 1H) , 2.03-1.96 (m, 1H), 1.19-1.14 (m, 1H), 1.12-1.08 (m, 1H) .LC-MS (Method D): m / z = 433.2 [M + H]⁺, 1.321 minutes.</p><p> Example 209: (S) -4-Fluoro-N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrazole [3,2-b] [1,4] Oxazepine-3- Il) -1- (oxazole-4-ylmethyl) -1H-pyrazole-3-carboxamide<chemistry num="321"><img file="JP6974331B2_D0355.tif" /></chemistry> The crude product is subjected to the following conditions: Column: Xbridge Prep C18; 19 × 150 mm; 5 μm; Mobile phase A: Water (0.1% NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: Purified by preparative HPLC using 21% B-25% B; UV254 &amp; 220 nm; over 10 minutes to give the title compound:¹1 H NMR (300 MHz, DMSO-d₆) δ 8.40 (d, J = 0.6 Hz, 1H), 8.36 (dd, J = 4.8,1.5 Hz, 1H), 8.23 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 0.9 Hz, 1H) ), 8.04 (d, J = 4.5 Hz, 1H), 7.70 (dd, J = 7.8, 1.5 Hz, 1H), 7.33 (dd, J = 8.1, 4.8 Hz, 1H), 5.28 (s, 2H), 4.89 -4.78 (m, 1H), 4.67 (dd, J = 11.4, 9.9 Hz, 1H), 4.50 (dd, J = 9.6, 7.5 Hz, 1H), 3.35 (s, 3H). LC-MS (Method T) : m / z = 387.2 [M + H]⁺, 0.973 minutes.</p><p> Example 213: (S) -N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyridine [3,2-b] [1,4] Oxazepine-3-yl) -5 -(Pyridine-2-ylmethyl) Thiazole-2-carboxamide<chemistry num="322"><img file="JP6974331B2_D0356.tif" /></chemistry> The title compound was prepared according to the method described herein using the appropriate starting material. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether, 3/1) to give the title compound:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.51-8.48 (m, 1H), 8.33 (dd, J = 4.8, 1.6 Hz, 1H), 7.84-7.77 (m, 2H), 7.66 (dd, J = 8.0, 1.6 Hz, 1H), 7.44- 7.38 (m, 1H), 7.34-7.27 (m, 2H), 4.97 (dd, J = 11.5, 7.2 Hz, 1H), 4.67 (dd, J = 9.9, 7.2 Hz, 1H), 4.52 (dd, J = 11.5, 9.9 Hz, 1H), 4.40 (s, 2H), 3.47 (s, 3H) .LC-MS (Method D): m / z = 396.0 [M + H]⁺, 1.786 minutes.</p><p> Example 214: (S) -4-fluoro-1-((5-fluoropyridin-2-yl) methyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [ b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="323"><img file="JP6974331B2_D0357.tif" /></chemistry> The crude product is subjected to the following conditions: Column: Gemini-NX / 5u, C18 150 × 21.2 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 45% B to 50% B over 8 minutes; UV254 &amp; 220 nm; Rt: 7.33; Purified by preparative HPLC using to obtain the title compound. rice field:¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.45 (d, J = 3.0 Hz, 1H), 7.84 (d, J = 4.5 Hz, 1H), 7.65-7.58 (m, 1H), 7.44-7.20 (m, 5H), 5.43 (s, 2H) , 4.97 (dd, J = 11.4, 7.5 Hz, 1H), 4.56 (dd, J = 9.9, 7.5 Hz, 1H), 4.37 (dd, J = 11.4, 9.9 Hz, 1H), 3.41 (s, 3H). LC-MS (Method D): m / z = 414.1 [M + H]⁺, 1.579 minutes.</p><p> Example 215: (S) -5-Benzyl-N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydropyrido [3,2-b] [1,4] Oxazepine-3- Il) -1,2,4-oxadiazole-3-carboxamide<chemistry num="324"><img file="JP6974331B2_D0358.tif" /></chemistry> Residues under the following conditions: Column: Xbridge Prep C18, 5 μm, 19 × 150 mm; Mobile Phase A: Water (0.1% NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 30% B-60% B over 8 minutes; UV254 &amp; 220 nm; Rt: 6.65 min; Obtained:¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.36-8.31 (m, 1H), 7.69-7.63 (m, 1H), 7.40-7.26 (m, 6H), 5.07-4.97 (m, 1H), 4.71-4.62 (m, 1H), 4.60-4.49 (s, 1H), 4.38 (s, 2H), 3.47 (s, 3H) .LC-MS (Method D): m / z = 380.1 [M + H]⁺, 1.322 minutes.</p><p> Example 216: (S) -1-((5-chloropyridin-2-yl) methyl) -4-fluoro-N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [ b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="325"><img file="JP6974331B2_D0359.tif" /></chemistry> Residues under the following conditions: Column: Gemini-NX / 5u, C18 150 × 21.2mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 40% B to 55% B over 8 minutes; UV254 &amp; 220 nm; Rt: 6.73 min; Obtained:¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.51 (d, J = 2.4 Hz, 1H), 7.82 (dd, J = 8.4, 3.6 Hz, 2H), 7.42-7.35 (m, 1H), 7.32-7.17 (m, 4H), 5.40 (s, 2H), 4.94 (dd, J = 11.4, 7.5 Hz, 1H), 4.54 (dd, J = 9.9, 7.5 Hz, 1H), 4.34 (dd, J = 11.7, 10.2 Hz, 1H), 3.37 (s, 3H) ). LC-MS (Method D): m / z = 430.1 [M + H]⁺, 1.673 minutes.</p><p> Example 217: 5-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -1,3,4-thiadiazole-2-carboxamide<chemistry num="326"><img file="JP6974331B2_D0360.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was subjected to the following conditions: Column: Gemini-NX / 5u, C18 150 × 21.2 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 55% B ~ 80% B over 6 minutes; UV254 &amp; 220 nm; Rt: 4.60 min; Obtained.¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.34-8.25 (m, 1H), 7.70-7.66 (m, 1H), 7.39-7.25 (m, 6H), 5.11-4.96 (m, 2H), 4.51 (s, 2H), 3.50 (s, 3H) ), 1.42 (d, J = 6.0 Hz, 3H). LC-MS (Method D): m / z = 410.0 [M + H]⁺, 1.725 minutes.</p><p> Example 218: 5-Benzyl-N-((1aS, 2S, 8bR) -7-cyano-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] Pyrido [2,3-b] azepine-2-yl) -4H-1,2,4-triazole-3-carboxamide<chemistry num="327"><img file="JP6974331B2_D0361.tif" /></chemistry> The crude product was purified by preparative TLC (ethyl acetate / hexane, 3/1) to give a racemic compound. LC-MS (Method D): m / z = 414.1 [M + H]⁺, 1.222 minutes. 5-benzyl-N- (cis-7-cyano-4-methyl-3-oxo-1,1a,2,3,4,8b-hexahydrocyclopropa [d] pyrido [2,3-b] azepine- 2-Il) -4H-1,2,4-triazole-3-carboxamide racemic compound under the following conditions: Column: CHIRAL ART Cellulose-SB, 2 × 25 cm, 5 μm; Mobile phase A: MTBE, Mobile phase B : EtOH; Flow rate: 20 mL / min; Gradient: 20% B ~ 20% B over 16 minutes; UV254 &amp; 220 nm; Rt1: 7.89; Rt2: 8.598; Was obtained as the second elution isomer:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.71 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.37-7.25 (m, 5H), 4.73 (s, 1H), 4.20 (s, 2H), 3.44 (s, 3H), 2.40-2.33 (m, 1H), 2.21-2.14 (m, 1H), 1.46-1.41 (m, 1H), 1.34-1.26 (m, 1H) .LC-MS (Method D): m / z = 414.1 [M + H]⁺, 1.221 minutes.</p><p> Example 219: (S) -5- (3-cyanobenzyl) -N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine- 7-il) Thiazole-2-carboxamide<chemistry num="328"><img file="JP6974331B2_D0362.tif" /></chemistry> The crude product obtained using the amide coupling procedure C was purified by preparative TLC (ethyl acetate / petroleum ether, 3/1) to give a racemic compound. LC-MS (Method S): m / z = 418.1 [M + H]⁺, 1.025 minutes. 5- (3-cyanobenzyl) -N- (9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido [2,3-b] azepine-7-yl) thiazole-2- The racemic compound of carboxamide was prepared under the following conditions: Column: (R, R) Whelk-O1, 21.1 × 250 mm, 5 μm; Mobile phase A: Hexane: dichloromethane = 4.5: 1, Mobile phase B: EtOH; Flow rate: 20 mL / min Gradient: 70% B ~ 70% B over 23 minutes; UV254 &amp; 220nm; Rt1: 12.88; Rt2: 18.81; separated by preparative chiral HPLC to give the title compound as the first elution isomer:¹1 H NMR (400 MHz, CD₃OD-d₄) δ 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 7.81 (dd, J = 7.6, 1.6 Hz, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.66-7.61 (m, 2H), 7.55-7.51 (m, 1H), 7.31-7.27 (m, 1H), 4.52-4.46 (m, 1H), 4.35 (s, 2H), 3.48 (s, 3H), 2.94-2.79 (m, 2H) 2.69-2.58 (m, 1H), 2.34-2.24 (m, 1H) .LC-MS (Method D): m / z = 418.0 [M + H]⁺, 1.716 minutes.</p><p> Example 220: (S) -4-fluoro-1-((6-methoxypyridin-2-yl) methyl) -N- (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [ b] [1,4] Oxazepine-3-yl) -1H-pyrazole-3-carboxamide<chemistry num="329"><img file="JP6974331B2_D0363.tif" /></chemistry> The crude product is subjected to the following conditions: Column: Gemini-NX / 5u, C18 150 × 21.2 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 40% B to 50% B over 8 minutes; UV254 &amp; 220 nm; Rt: 8.07 min; Obtained.¹1 H NMR (300 MHz, CD₃OD-d₄) δ 7.85 (d, J = 4.5 Hz, 1H), 7.63 (dd, J = 8.1, 7.2 Hz, 1H), 7.43-7.40 (m, 1H), 7.39-7.20 (m, 3H), 6.78 (d, J = 7.2, 1H), 6.71 (d, J = 8.4, 1H), 5.32 (s, 2H), 4.98 (dd, J = 11.4, 7.5 Hz, 1H), 4.58 (dd, J = 9.9, 7.5 Hz, 1H), 4.37 (dd, J = 11.4, 9.9 Hz, 1H), 3.86 (s, 3H), 3.40 (s, 3H) .LC-MS (Method D): m / z = 426.2 [M + H]⁺, 1.755 minutes.</p><p> Example 221: 5- (difluoro (phenyl) methyl) -N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] ] [1,4] Oxazepine-3-yl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="330"><img file="JP6974331B2_D0364.tif" /></chemistry> The crude product is subjected to the following conditions: Column: Gemini-NX / 5u, C18 150 × 21.2 mm; Mobile phase A: Water (10 mmol / L NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 47% B to 60% B over 10 minutes; UV254 &amp; 220 nm; Rt: 8.82 min; Obtained.¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.33 (dd, J = 4.8, 1.8 Hz, 1H), 7.69-7.66 (m, 3H), 7.62-7.53 (m, 3H), 7.32 (dd, J = 8.1, 4.8 Hz, 1H), 5.08- 4.93 (m, 2H), 3.50 (s, 3H), 1.44 (d, J = 6.3 Hz, 3H). LC-MS (Method O): m / z = 430.1 [M + H]⁺, 1.679 minutes.</p><p> Example 222: 5-Benzyl-N-((2R, 3S) -2,5-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-b] [1,4] Oxazepine-3-yl) -1,2,4-oxadiazole-3-carboxamide<chemistry num="331"><img file="JP6974331B2_D0365.tif" /></chemistry> The crude product should be as follows: Column: Xbridge Prep C18, 5 μm, 19 × 150 mm; Mobile phase A: Water (0.1% NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 40% B ~ 70% B over 8 minutes; UV254 &amp; 220 nm; Rt: 5.87 min; Obtained.¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.35-8.31 (m, 1H), 7.71-7.66 (m, 1H), 7.41-7.27 (m, 6H), 5.10-4.97 (m, 2H) 4.39 (s, 2H), 3.49 (s, 3H) , 1.40 (d, J = 6.2 Hz, 3H) .LC-MS (Method D): m / z = 394.1 [M + H]⁺, 2.709 minutes.</p><p> Example 223: 5- (4-fluorobenzyl) -N-((7S, 7aS, 8aR) -5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa [d] ] Pyrazino [2,3-b] Azepine-7-yl) -1,3,4-oxadiazole-2-carboxamide<chemistry num="332"><img file="JP6974331B2_D0366.tif" /></chemistry><chemistry num="333"><img file="JP6974331B2_D0367.tif" /></chemistry> The crude product was purified by preparative TLC (ethyl acetate / petroleum ether, 3/1) to give a racemic compound. LC-MS (Method D): m / z = 409.05 [M + H]⁺, 1.255 minutes. 5- (4-Fluorobenzyl) -N-cis-5-methyl-6-oxo-5,6,7,7a,8,8a-hexahydrocyclopropa [d] pyrazino [2,3-b] azepine- The racemic compound of 7-yl) -1,3,4-oxadiazole-2-carboxamide was prepared under the following conditions: Column: CHIRALPAK IE, 2 × 25 cm, 5 μm; Mobile phase A: MTBE, Mobile phase B: EtOH; Flow: 20 mL / min; Gradient: 30% B ~ 30% B at 16 min; UV254 &amp; 220 nm; Rt1: 10.514; Rt2: 13.482; Obtained as a body:¹1 H NMR (400 MHz, CDCl₃-d) δ 8.49-8.32 (m, 3H), 7.39-7.28 (m, 2H), 7.14-6.94 (m, 2H), 4.85 (d, J = 7.0 Hz, 1H), 4.25 (s, 2H), 3.45 (s, 3H), 2.71-2.62 (m, 1H), 2.30-2.21 (m, 1H), 1.57-1.50 (m, 1H), 1.30-1.22 (m, 1H) .LC-MS (Method V) : m / z = 409.05 [M + H]⁺, 2.450 minutes.</p><p> Example 224: (S) -4-Fluoro-N- (5-Methyl-4-oxo-2,3,4,5-Tetrahydrobenzo [b] [1,4] Oxazepine-3-yl) -1- (Pyrimidine-2-ylmethyl) -1H-pyrazole-3-carboxamide<chemistry num="334"><img file="JP6974331B2_D0368.tif" /></chemistry> The crude product should be as follows: Column: Xbridge Prep C18, 5 μm, 19 × 150 mm; Mobile phase A: Water (0.1% NH)₄HCO₃), Mobile phase B: MeCN; Flow rate: 20 mL / min; Gradient: 16% B ~ 43% B over 8 minutes; UV254 &amp; 220 nm; Rt: 7.47 min; Got¹1 H NMR (300 MHz, CD₃OD-d₄) δ 8.81-8.77 (m, 2H), 7.91-7.87 (m, 1H), 7.48-7.41 (m, 2H), 7.38-7.21 (m, 3H), 5.58 (s, 2H), 5.03-4.95 (m) , 1H), 4.62-4.56 (m, 1H), 4.43-4.34 (m, 1H), 3.42 (s, 3H) .LC-MS (Method D): m / z = 397.0 [M + H]⁺, 2.334 minutes.</p><p> Example 225: (S) -5-benzyl-N- (1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo [b] azepine-3-yl) -1,3, 4-Oxadiazole-2-carboxamide<chemistry num="335"><img file="JP6974331B2_D0369.tif" /></chemistry>¹1 H NMR (300 MHz, CD₃OD-d₄) δ 7.47-7.18 (m, 9H), 4.47 (dd, J = 11.7, 7.9 Hz, 1H), 4.31 (s, 2H), 3.40 (s, 3H), 2.93-2.82 (m, 1H), 2.73 ( dd, J = 13.6, 6.8 Hz, 1H), 2.52-2.43 (m, 1H), 2.33-2.21 (m, 1H) .LC-MS (Method D): m / z = 377.0 [M + H]⁺, 1.732 minutes.</p><p> Other compounds in Table 1 can be prepared or prepared according to the above-mentioned examples and / or general procedures described herein using appropriate starting materials.</p><p> Biological Assay Compounds were tested for binding and cell kinase activity according to the following protocol. The proGST-hRIPK1 (8-327) enzyme was produced by Proteros GmbH by the baculovirus expression system.</p><p> Cell Necroptosis Assay (Cell ICs in Tables 5-7)₅₀) To assess the ability of the compound to reverse human TNFα-induced necrosis. Test compounds at 10 concentrations were double evaluated at 2 test opportunities. FADD-deficient Jurkat cells were purchased from ATCC (ATCC-CRL-2572) and cultured in suspension in RPMI medium supplemented with 10% heat-inactivated FBS and 1% Pen-Strep. On the day of the experiment, cells were cultivated in culture medium 0.12 x 10⁵It was diluted to a cell / mL (5,000 cell / well) density and added to a 384-well plate containing 0.2 μL / well of test compound and reference compound (CRC) (200 ×) (40 μL). Then place the cell plate at 37 ° C-5% CO₂Incubated in. After 30 minutes, necrotic cell death was induced by human TNFα (10 ng / mL) and cell viability was measured by measuring cell ATP levels using the CellTiter-Glo® Kit (Promega) 48. Evaluated after hours. The luminescence was read using a Victor V (Perkin Elmer) multi-label plate reader. The data were expressed as% of maximum viability calculated in comparison to TNFα untreated control cells representing 100% cell viability. CRC analyzed by Dotmatics, IC₅₀The values were calculated by non-linear regression using a 4-parameter logistic equation.</p><p> The Fluorescent Polarized Binding (FP Binding) Assay (Berger SBet al. (2015) Cell Death Discovery, 1: 15009; Maki JLet al. (2012) Anal Biochem., 427 (2): 164-174) is made of polystyrene. In a 384-well black plate at room temperature (RT), at a final volume of 10.1 μl / well, 10 nM GST-hRIPK1 (8-327) enzyme and 5 nM fluorescently labeled ligand (14- (2-{[3-] ({2-{[4- (Cyanomethyl) Phenyl] Amino} -6-[(5-Cyclopropyl-1H-Pyrazole-3-yl) Amino] -4-pyrimidinyl} Amino) Propyl] Amino} -2-oxoethyl )-16,16,18,18-Tetramethyl-6,7,7a,8a,9,10,16,18-Octahydrobenzo [2 ", 3"] Indolidino [8 ", 7": 5', It was performed using 6'] pyrano [3', 2': 3,4] pyrido [1,2-a] indol-5-ium-2-sulfonate.</p><p> In the assay, test compounds were serially diluted in DMSO at a final concentration of 100-fold (final: 1% DMSO). In each well of the 384-well plate, 0.1 μL of compound solution (or DMSO in control) followed by 5 μL of GST-hRIPK1 (8-327) in assay buffer (50 mM HEPES pH 7.5, 10 mM NaCl, 50 mM MgCl).₂, 0.02% CHAPS, 0.5 mM DTT and 0.01% Pluronic F127) were dispensed at twice the final concentration. For negative controls, enzyme addition was replaced with assay buffer only.</p><p> After adding 5 μL of fluorescently labeled ligand at twice the final concentration in assay buffer, the plates were incubated for 30 minutes at room temperature. Finally, the coupling was measured as an FP value by an Envision (PerkinElmer) plate reader using a filter (S &amp; P-pol) for FP with excited λ = 531 nm and FP with emission λ = 595 nm.</p><p> The GST-hRIPK1 (8-327) enzyme was produced by Proteros GmbH by the baculovirus expression system.</p><p> The test compound was diluted in DMSO and 0.1 μL of solution was dispensed into each well of a 384-well white solid microplate. Assay buffers are 50 mM HEPES pH7.5, 50 mM NaCl, 30 mM MgCl₂Met. The buffer was supplemented with 0.02% CHAPS, 0.01% Pluronic F127, 0.1 mg / mL BSA and 1 mM DTT. MnCl₂(5 mM) was included in assay buffer on the day of the experiment. Enzymatic reactions included 1.5 μg / mL GST-hRIPK1 (8-327), 50 μM ATP for receptor-interacting protein kinase 1, and 15 μM ATP. 5 μL of enzyme and 5 μL of ATP were added to the plate at twice the final assay concentration and incubated for 3 hours at room temperature. After this reaction, 10 μL of ADP-Glo reagent (Promega) was added to each well and incubated for 40 minutes at room temperature. This stops the kinase reaction and depletes all residual ATP. 20 μL of ADP-Glo detection reagent was then added to each well and incubated for at least 15 minutes. The detection reagent converts ADP to ATP and introduces luciferase and luciferin to detect ATP. Luminescence is then measured with an Envision (PerkinElmer) plate reader. Test compound inhibition was expressed as percent inhibition of the internal assay control. For the concentration response curve, fit the normalized data and use XL-fit (IDBS) in Excel to IC₅₀Asked. I c₅₀Was averaged, and the average value was calculated for the minimum values of the two independent experiments.</p><p> Test compound inhibition was expressed as percent inhibition of the internal assay control. For the concentration response curve, fit the normalized data and use XL-fit (IDBS) in Excel to IC₅₀Asked. I c₅₀Was averaged, and the average value was calculated for the minimum values of the two independent experiments.</p><p> Cellular activity of receptor-interacting protein kinase 1 and binding of exemplary compounds were determined according to the above general procedure. The results are summarized in Table 5. In the table below, the activity is given as follows: +++ = 0.0001 μM &lt;IC₅₀&lt;1 μM; ++ = 1 μM &lt;IC₅₀&lt;10 μM; + = 10 μM &lt;IC₅₀;++^*= 3 μM &lt;IC₅₀。<tables num="5-1"><img file="JP6974331B2_D0370.tif" /></tables><tables num="5-2"><img file="JP6974331B2_D0371.tif" /></tables><tables num="5-3"><img file="JP6974331B2_D0372.tif" /></tables><tables num="6"><img file="JP6974331B2_D0373.tif" /></tables><tables num="7-1"><img file="JP6974331B2_D0374.tif" /></tables><tables num="7-2"><img file="JP6974331B2_D0375.tif" /></tables></p><p> The comparative compounds of Table 7 were prepared as described in Examples 12, 146, and 77 of WO2014 / 125444, respectively.</p><p> The in vivo efficacy of the compounds was described by Duprez et.al. (2011, Immunity 35 (6), 908-918) and Berger et.al. (2015, Cell Death). As described by Disc. 1,15009), a TNF-induced systemic inflammatory response syndrome model can be used to determine in mice. In this model system, TNF / zVAD (tumor necrosis factor / Z-Val-Ala-DL-Asp-fluoromethylketone, caspase inhibitor) treatment results in temperature loss and production of some inflammatory cytokines. .. The ability of the test compound to inhibit these inflammatory effects can be measured in this model by administering the test compound to mice for 15 minutes prior to administration of TNF / zVAD and measuring the inflammatory response. The dose required to inhibit the inflammatory response is a measure of the effectiveness of the compound at such doses. Using this model, compound 42 was pre-orally administered at 5 mg / kg for 15 minutes prior to intravenous administration of TNF / zVAD and temperature loss in mice was measured by an implantable temperature chip. Treatment of mice with 5 mg / kg of Compound 42 resulted in 96% inhibition of body temperature loss compared to TNF / zVAD vehicle-treated animals. By comparison, WO2014 / 125444 discloses in Table 2 that Example 12, which corresponds to Example A in Table 7 above, requires a dose of 30 mg / kg to achieve 93% inhibition. There is. Dose reduction has many important potential benefits, including less frequent doses to patients, improved patient compliance, and improved safety profiles, such as lower toxicity, while achieving similar efficacy. have.</p><p> Based on the known crystal structure of Comparative Example C and receptor-interacting protein kinase 1 (Harris et al. J. Med. Chem., 2016, 59 (5), pg. 2163-2178), the azepinone site (ie, book). X of the formula disclosed in the specification⁹The phenyl carbon atom adjacent to) interacts with the lipophilic pocket of the receptor-interacting protein kinase 1.</p><p> Certain compounds are X of the formula disclosed herein.⁹Was found to have significantly improved metabolic stability when compared to the carbon atom. For example, compound 42 has an average human hepatocyte clearance of 0.8 mL / min / kg compared to 6.8 mL / min / kg of Comparative Example A when tested according to the assay below compared to Comparative Example A. Was found to have. 6.8 mL / min / kg CL as described in the Metabolic Stability section below_hepEquivalent to approximately 32% hepatic blood flow clearance, while 0.8 mL / min / kg CL for compound 42_hepThe value corresponds to less than 4% hepatic blood flow clearance, X⁹Demonstrate a significant improvement in compound stability when is N atom. Lower CL from the data presented above_hepIt will be apparent to those skilled in the art that a compound having a value should allow lower human clinical doses, lower frequency of administration to patients, improved patient compliance, and improved safety profiles, eg, lower toxicity. be.</p><p> The blood-brain barrier (BBB) of MDCKII-MDR1 isolates circulating blood from the extracellular fluid of the central nervous system (CNS). Passive membrane permeability (Papp) and P-gp (P-glycoprotein) substrate efflux potential were determined using the MDCKII-MDR1 cell line as an in vitro model of effective permeability of compounds through the BBB. Bidirectional assays in the absence and presence of GF120918 (P-gp inhibitor) (apical to basal (A B) and basal to apical (B A)) were obtained from SOLVO Biotechnology. This was performed using pre-plated MDCKII-MDR1 cells (Corning HTS Transwell-96). Assay is HBSS + 12.5 mM HEPES Performed in triplicate at 3 μM for 90 minutes using transport buffer at pH 7.4. After incubating samples from donors and receivers, wells were removed and measured by LC-MS / MS. Samples were extracted by protein precipitation with acetonitrile containing an appropriate internal standard (IS) with known mass and molecular weight. The precipitate was centrifuged at 3000 rpm (revolutions per minute) for 10 minutes. The supernatant was then collected, diluted as needed and injected into the LC-MS / MS system. Test substances were selectively measured using the test substance and IS-specific parent / daughter ion pairs. The Papp (apparent permeability in nm / sec [nanometer / sec]) value was calculated according to the following equation:<chemistry num="336"><img file="JP6974331B2_D0376.tif" /></chemistry></p><p> In the equation, dQ / dt is the transmittance, C₀Is the initial concentration in the donor solution (expressed as the IS ratio), and A and B are the surface area of the filter (the surface area of the cell monolayer).</p><p> The single layer runoff ratio (ER) was derived using the following equation: runoff ratio = (B-APapp (nm / sec)) / (A-BPapp (nm / sec))</p><p> Compounds with MDCKII-MDR1 efflux ratios of 2.5 or less may demonstrate their ability to cross the blood-brain barrier.</p><p> Metabolic Stability (Hepatocytes) Metabolic stability of compounds was double evaluated in human cryopreserved hepatocytes (Bioreclamation IVT, NY, USA). Test substance (or control) in suspension 0.5 × 10⁶It was added to a 24-well incubation plate (Becton Dickinson Labware, USA) containing / mL hepatocytes. The plate was held at 37 ° C and stirred by constant orbital shaking (orbital speed of 350 rpm). At each time point (0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150 and 180 minutes), a Tecan Evo robot provided 50 μL of incubation mixture and 100 μL of acetonitrile containing an internal standard. It was aspirated and the reaction was quenched. The quenched mixture was dispensed into a 96-well plate with 120 μL of aqueous solution to equilibrate the solvent content at 37%. The sample was centrifuged (3000 rpm for 10 minutes), the plate was sealed and then injected into the LC-MS / MS system.</p><p> Appropriate parent / daughter ions were monitored for the test substance and IS by LC-MS / MS system. Unique clearance (Cl_int;10⁶ΜL / min per cell) is the primary excretion constant (k, min) of disintegration of the test substance.^-1), And the volume of the incubation. These values are set to a specific human scaling factor (hepatocyte 139 × 10).⁶Inherent organ clearance (CL) using / liver (g) and liver 25.7 g / body weight (kg))_int). Next, the unique organ CL is shown below in the well-stirred model: formula, Q._hIs human hepatic blood flow; using hepatic clearance (CL)_hep).<chemistry num="337"><img file="JP6974331B2_D0377.tif" /></chemistry></p><p> Liver clearance is expressed as mL / min / kg. Liver clearance is related to the flow of blood through the liver from which the compound has been completely removed. 20.9 mL / min / kg human CL_hepEquivalent to almost complete compound clearance by the liver, or 100% hepatic blood flow. Therefore, 6 mL / min / kg human CL_hepEquivalent to approximately 29% hepatic blood flow clearance. 2 mL / min / kg human CL_hepValues correspond to approximately 10% hepatic blood flow clearance. Human CL of 1 mL / min / kg or less_hepValues correspond to hepatic blood flow clearance of approximately 5% or less. 0 mL / min / kg human CL_hepThe value corresponds to undetectable compound clearance by the liver.</p><p> In certain embodiments, CL less than 5, 4, 3, 2, or 1 mL / min / kg when tested by the human liver stability assay described above._hepProvided are compounds having. In certain embodiments, such compounds do not easily cross the blood-brain barrier. In certain embodiments, such compounds have an efflux ratio of MDCKII-MDR1 greater than 2.5.</p><p> In certain embodiments, CL less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 mL / min / kg when tested by the human liver stability assay described above._hepProvided are compounds having. In certain embodiments, such compounds can cross the blood-brain barrier. In certain embodiments, such compounds have an MDCKII-MDR1 efflux ratio of 2.5 or less.</p><p> Protein Binding For protein binding in plasma, Rapid Equilibrium Dialysis Device (Thermo Scientific RED Device) or 96-well dialysis machine (HT Dialysis) Obtained using LLC). Plasma was mixed with the test / control compound to a final concentration of 0.5 μM (plasma). If necessary, plasma samples were pre-incubated with diisopropyl fluorophosphate (DFP) at a final concentration of 100 μM (2 hours at 37 ° C) to prevent compound degradation due to amide hydrolysis. A sample mixed with blank phosphate buffer was added to either device in the appropriate volume and incubated at 37 ° C for a total of 5 hours with stirring at 500 rpm. After incubation, an equal aliquot of dialysis matrix (plasma or buffer) is added to an equal volume of the opposite blank matrix, thereby ensuring that the volume of buffer is equal to plasma. The mixed matrix sample was extracted by protein precipitation using acetonitrile containing the appropriate IS. The sample was then centrifuged at 2800 rpm for 10 minutes. The supernatant was collected, diluted and then injected into an HPLC-MS / MS or UPLC-MS / MS system. Samples were analyzed for test and control compounds by monitoring appropriate parent / daughter ion transitions. The test item concentration was measured using the peak area ratio. The unbound fraction (Afu) was determined as the ratio of the peak area ratio of the buffer solution divided by the peak area ratio in plasma.</p><p> In Vivo Pharmacokinetics (PK) PK properties of study subjects were determined in male Sprague-Dawley Crl: CD (SD) rats, male beagle dogs and male cynomolgus monkeys. The study was conducted to the highest standards of animal welfare, in accordance with national legislation and with the approval of the Internal Animal Care and Use Committee.</p><p> The compound was administered by IV bolus to animals after an overnight fast. Compounds for IV administration in D5W (5% dextrose in water), 1% DMSO (dimethyl sulfoxide): 20% PEG400 (polyethylene glycol 400): 79% saline, or 5-50% NMP. Used to formulate as a solution. The pharmaceutical product was administered at a dose volume in the range of 0.5 to 2 mL / kg. The IV dose ranged from 0.5 to 1 mg / kg.</p><p> After administration, a series of 8-9 blood samples were collected over a 24-hour period. The sample was mixed with an anticoagulant and placed on wet ice before treatment. Plasma was collected after centrifugation and extracted using protein precipitates with acetonitrile containing IS. The treated supernatant was analyzed using UPLC or LC-MS / MS using the test substance and IS-specific parent / daughter ion pairs. Plasma concentrations were determined using calibration curves prepared using samples of known concentrations. Pharmacokinetic parameters using the measured concentrations were calculated using Phoenix WinNonlin. Unbound plasma clearance was calculated as the ratio of systemic clearance divided by the unbound fraction in plasma.</p><p> Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.</p><p> The invention exemplified herein can be suitably carried out without any element (s) or limitation (s) not specifically disclosed herein. Thus, for example, the terms "comprising", "including", and "containing" shall be read broadly and without limitation. In addition, the terms and expressions used herein are used as detailed descriptive terms rather than limited terms, and such terms and expressions are optional of the features or parts thereof shown and described. Although not intended to be used as an exclusion of the equivalent of, it is recognized that various modifications can be made within the scope of the invention described in the claims.</p><p> All publications, patent applications, patents and other references referred to herein are expressly incorporated by reference in their entirety, as if each were individually incorporated by reference. In case of conflict, this specification, including the definition, governs.</p><p> Although the present disclosure is described in conjunction with the above embodiments, it should be understood that the above detailed description and examples are intended to explain and not limit the scope of the present disclosure. Other aspects, benefits and modifications within the scope of this disclosure will be apparent to those skilled in the art to which this disclosure belongs.</p>