Aza fused ring compound as RIPK1 inhibitor and application of aza fused ring compound

Abstract

The present disclosure provides compounds of formula (I), pharmaceutical compositions thereof, and their use in the treatment and / or prevention of diseases or conditions associated with RIPK1 kinase activity. # imgabs0 #

Description

Aza-type fused ring compounds as RIPK1 inhibitors and their applications Technical Field

[0001] The present application relates to compounds that can be used to inhibit RIPK1 kinase activity, and / or the use of these compounds in treating and / or preventing diseases or disorders associated with RIPK1 kinase activity. Background Art

[0002] Protein kinases are enzymes found widely within and on the cell surface. Nearly 600 protein kinases have been discovered and characterized to date. They belong to a family of structurally related proteins whose known members are involved in virtually all cellular signaling activities. The catalytic function of protein kinases is to transfer the γ-phosphate group from an ATP molecule to a specific threonine, serine, or tyrosine residue on a target protein, causing a conformational change in the target protein, leading to a functional transition from a quiescent state to an activated state. Based on the specificity of their target amino acids, protein kinases are divided into two major categories: serine / threonine protein kinases and tyrosine protein kinases.

[0003] Protein kinases play a crucial role in the signal transduction and regulation of normal cell and organ functions, including cell growth, differentiation, proliferation, angiogenesis, apoptosis, cytoskeletal organization, regulation of metabolic reactions, membrane transport, and cell motility. Furthermore, non-catalytic functions of protein kinases also play an essential role, including allosteric effects, subcellular targeting, protein complex scaffolding, protein-protein competitive interactions, and DNA binding. However, dysregulated protein kinases, such as those caused by gene mutations or overexpression, can lead to a variety of pathological changes, including cancer, inflammation, autoimmune diseases, cardiovascular diseases, and neurological disorders. Consequently, protein kinases have become one of the most important targets in current drug development. The recent success of protein kinase inhibitors in clinical therapy has further demonstrated the feasibility of this strategy and revealed the promising prospects of using protein kinases as therapeutic targets.

[0004] Receptor-interacting protein kinase 1 (RIPK1) belongs to the TKL serine / threonine protein kinase family and consists of an N-terminal kinase domain, a receptor-interacting protein kinase homotypic interaction motif (RHIM) domain, and a C-terminal death domain. The C-terminal death domain of RIPK1 binds to other death domain-containing proteins (such as Fas, TNFR-1, TRAIL-R1, TRAIL-R2, and TRADD) and initiates downstream signaling. The RHIM domain primarily binds to other RHIM domain-containing proteins (such as TRIF and RIP3) to initiate downstream signaling. RIPK1 activation is primarily initiated by signals released by death receptors (such as TNFR-1, TRAILR, and FasR), Toll-like receptors (TLR3 / 4), interferon receptor 1 (IFNAR1), Z-DNA binding protein 1 (ZBP), Dectin-1, or RIPK3. Once activated by upstream signals, RIPK1 autophosphorylates and exerts kinase activity-dependent biological functions, such as Caspase 8 (CASP8)-dependent apoptosis, RIPK3 / MLKL-dependent necrosis, and inflammation. In addition, RIPK1 can also exert kinase-independent scaffolding functions, such as promoting cell survival and inflammatory gene expression. Other members of the RIP kinase family participate in diverse physiological activities. RIPK2 typically regulates innate and adaptive immune responses, RIPK3 interacts with RIPK1 to activate necrosis and apoptosis and regulates the activity of several metabolic enzymes, and RIPK4 participates in the development of stratified epithelial tissue and the NF-κB signaling pathway. The biological functions of other RIP kinase family members have yet to be clearly elucidated. Within the RIP kinase family, RIPK1 is crucial for the innate immune response and participates in downstream signaling initiated by TNF-α. After TNF-α stimulation induces the aggregation of TNF receptors, multiple proteins (such as linear K63-linked polyubiquitinated RIPl, TRAF2 / 5, TRADD, and cIAPs) are recruited to the cytoplasmic tail of the TNF receptor and form complex I, which participates in cell survival through the NF-κB and MAPK kinase signaling pathways. In addition, deubiquitination of RIP1 promotes the formation of complex II or DISC (death-inducing signaling complex) complex (RIPK1, TRADD, FADD, and caspase 8). After the DISC complex is formed, RIPK3 is expressed, inhibiting cell apoptosis. RIPK3 enters complex II, is phosphorylated by RIPK1, and initiates cell necroptosis after activation of MLKL and PGAM5.Necroptosis is a regulated, caspase-independent cell death pathway with morphological characteristics similar to necrosis. It can be induced by a variety of stimuli (such as TNF-α and Fas ligand) and occurs in various cell types, such as monocytes, fibroblasts, lymphocytes, macrophages, epithelial cells, and neurons. Under pathological conditions of excessive cellular stress, rapid energy loss, and the production of large amounts of oxidative species, necroptosis may be an important pathway of cell death and the predominant mode of cell death in certain conditions where highly energy-dependent processes fail. Studies have shown that RIPK1 is a key molecule in the necroptosis pathway. Activation of RIPK1 following dysregulation leads to necroptosis, which has become a significant pathogenic factor in a variety of diseases, including neuronal degeneration and inflammatory diseases, stroke, coronary heart disease and myocardial infarction, retinal degeneration, inflammatory bowel disease, kidney disease, liver disease, and lesions caused by COVID-19.

[0005] Potent, selective small molecule inhibitors of RIPK1 activity would block RIPK1-dependent pro-inflammatory signaling, thereby providing therapeutic benefits for inflammatory diseases characterized by dysregulated RIPK1 kinase activity. There is an urgent need in the art for such RIPK1 inhibitors.

[0006] Summary of the Invention

[0007] After long-term research, the present inventors unexpectedly discovered a class of compounds with significant RIPK1 activity inhibitory effects, which show efficient and highly selective RIPK1 kinase inhibition and can be used to treat or prevent diseases related to RIPK1 activity.

[0008] In particular, the present invention provides a compound of formula (I) or its mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which can be used as an inhibitor of RIPK1 kinase activity:

[0009] in,

[0010] X is selected from CH and N;

[0011] Y is selected from -CR a R b -、-O-、-NR a -and-S(O) m -;

[0012] Z is selected from -O and -S;

[0013] L is selected from a single bond, -(CR a R b ) n -、-(CR a R b )n O-、-(CR a R b ) n S-、-(CR a R b ) n NR a -、-O-、-NR a -and-S(O) m -;

[0014] Ring A is selected from C5-C 10 Aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally further substituted by one or more R 6 replace;

[0015] R 1 independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b and-NHS(O) m R a wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally further substituted by one or more groups selected from deuterium atoms, halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclic groups; preferably, R 1 an alkynyl, alkenyl, and allenyl group selected from the group consisting of:

[0016] R 2 and R 3 are each independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl;

[0017] or R 1 and R 2 Together with the atoms to which they are attached, they form C5-C 10aryl, heteroaryl, heterocyclyl or cycloalkyl, or R 2 and R 3 Together with the atoms to which they are attached, they form C5-C 10 aryl, heteroaryl, heterocyclic or cycloalkyl, wherein the C5-C 10 Aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally further substituted by one or more R 9 replace;

[0018] R 4 and R 5 are each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl and halocycloalkyl;

[0019] R 6 、R 7 、R 8 and R 9 are each independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b and-NHS(O) m R a wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally further substituted with one or more groups selected from deuterium atoms, halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, aryloxy, heteroaryl, cycloalkyl, and heterocyclic groups;

[0020] R a and R b are each independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl;

[0021] or R a and R btogether with the atoms to which they are attached, form a cycloalkyl or heterocyclic group, said cycloalkyl or heterocyclic group being optionally further substituted with one or more groups selected from deuterium atoms, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclic groups;

[0022] m is 0, 1, or 2;

[0023] n is 0, 1, 2 or 3.

[0024] In a preferred embodiment, the compound represented by general formula (I) according to the present invention, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (II) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0025] in,

[0026] R' is selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b and-NHS(O) m R a wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally further substituted with one or more groups selected from deuterium atoms, halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, aryloxy, heteroaryl, cycloalkyl and heterocyclic groups;

[0027] m is 0, 1, or 2;

[0028] L and ring A are as defined in the general formula (I).

[0029] In another preferred embodiment, the compound represented by general formula (I) according to the present invention, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (III), or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0030] in,

[0031] L and ring A are as defined in formula (I);

[0032] R' is as defined in the general formula (II).

[0033] Typical compounds of the present invention include, but are not limited to:

[0034] or its meso form, racemate, enantiomer, diastereomer, or mixture form, or its pharmaceutically acceptable salt.

[0035] The present invention further provides a method for preparing the compounds represented by general formula (I), (II) and (III) according to the present invention or their mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0036] The parent compound A is reacted with ethyl oxalyl chloride to obtain intermediate B, which is then ester-exchanged with compound C to obtain the compound shown in formula (I). 1 When it is bromine or iodine, a Sonogashira coupling reaction can be performed to obtain a compound represented by formula (II) or formula (III).

[0037] Among them, X, Y, Z, L, ring A, R 1 、R 2 、R 3 、R 4 and R 5 As defined in formula (I), R' is as defined in formula (II).

[0038] Description of terms of the invention

[0039] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0040] In the present invention, when referring to a "compound" having a specific structural formula, it generally also encompasses pharmaceutically acceptable salts, stereoisomers, diastereomers, enantiomers, racemic mixtures and isotopic derivatives thereof.

[0041] It is well known to those skilled in the art that, in addition to salts of compounds, solvates and hydrates are alternative forms of existence of compounds, and they can all be converted into the compounds under certain conditions. Therefore, when a compound is mentioned in the present invention, its solvates and hydrates are generally also included.

[0042] The "pharmaceutically acceptable salt" of the present invention refers to a salt of a compound of the present invention that is suitable for contact with human and mammalian tissues, without undue toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, and has the required biological activity, which can be regarded as a reasonable benefit / risk ratio. The salt can be prepared in situ during the final isolation and purification of the compound of the present invention, or separately by reacting a free base or free acid with a suitable reagent. For example, a free base can be reacted with a suitable acid. Examples of pharmaceutically acceptable acid addition salts are salts formed by an amino group (amine group) with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or an organic acid (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or by using other methods known in the art such as ion exchange. The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., methanol, ethanol, acetone and acetonitrile), adding an excess of an organic acid or an aqueous inorganic acid solution thereto to precipitate the salt from the resulting mixture, removing the solvent and the remaining free acid therefrom, and then isolating the precipitated salt. Other pharmaceutically acceptable salts include sodium alginate, ascorbate, benzenesulfonate, adipate, camphorsulfonate, aspartate, benzoate, bisulfate, borate, butyrate, camphorate, citrate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, heptanoate, hexanoate, hydroiodide, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0043] In the specification and claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates in which such isomers exist. Unless otherwise indicated, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Numerous geometric isomers of C=C double bonds, C=N double bonds, ring systems, etc. may also exist in the compounds, and all such stable isomers are encompassed by the present invention. The present invention describes cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, and they may be separated into mixtures of isomers or into separated isomeric forms.

[0044] The compounds of the present invention can be isolated in optically active or racemic forms. All methods for preparing the compounds of the present invention and the intermediates prepared therein are considered part of the present invention. When preparing enantiomeric or diastereomeric products, they can be separated by conventional methods (e.g., by chromatography or fractional crystallization). It should be understood that all tautomeric forms that may exist are included in the present invention. The compounds of the present invention are commercially available as known compounds in the prior art.

[0045] The term "alkyl" refers to a saturated aliphatic hydrocarbon group including branched and straight chain groups having a specified number of carbon atoms. 12 Alkyl, C1-C 10 C1-C8 alkyl, C1-C8 alkyl, more preferably C1-C6 alkyl, particularly preferably C1-C4 alkyl, especially C1-C3 alkyl.For example, "C1-C6 alkyl" means an alkyl having 1 to 6 carbon atoms. The example of alkyl includes but is not limited to methyl, ethyl, propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl) and pentyl (such as n-pentyl, isopentyl, neopentyl). Alkyl can be substituted or unsubstituted, and when substituted, substituent can be substituted on any usable point of attachment, and the substituent is preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate. For C1-C8 alkyl in the present invention, 12 In the case of an alkyl group, 1 to 4 -CH2- units are optionally replaced by O atoms, S atoms or -NH-.

[0046] The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl). For example, "C1-C6 alkoxy" refers to C1, C2, C3, C4, C5, C6 alkoxy. Preferred alkoxy groups are C1-C 10Alkoxy, C1-C8 alkoxy, more preferably C1-C6 alkoxy, particularly preferably C1-C4 alkoxy, especially C1-C3 alkoxy. The example of alkoxy includes but is not limited to methoxy, ethoxy, propoxy (such as n-propoxy and isopropoxy), tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate. Similarly, "alkylthio" means an alkyl as defined above connected through a sulphur bridge with a specified number of carbon atoms; for example methyl-S- and ethyl-S-. Similarly, preferred alkylthio is C1-C 10 Alkylthio, C1-C8 alkylthio, more preferably C1-C6 alkylthio, particularly preferably C1-C4 alkylthio, especially C1-C3 alkylthio.

[0047] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio. Preferred are C2-C6 alkenyl or C2-C4 alkenyl.

[0048] The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, etc. Alkynyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio. Preferred are C2-C6 alkynyl or C2-C4 alkynyl.

[0049] The term "halo" or "halogen" includes fluorine, chlorine, bromine and iodine. In the present invention, one or more halogens can be independently selected from fluorine, chlorine, bromine and iodine.

[0050] The term "haloalkyl" refers to a branched and straight-chain saturated aliphatic hydrocarbon group comprising a specified number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Preferred haloalkyl groups include halo (C1-C6 alkyl) or halo (C1-C4 alkyl).

[0051] The term "oxo" or "carbonyl" refers to an organic functional group composed of carbon and oxygen atoms connected by a double bond (C=O or C(O)).

[0052] The term "benzyl" refers to -CH2-phenyl or "Bn".

[0053] The term "hydroxy" refers to an -OH group.

[0054] The term "amino" refers to -NH2.

[0055] The term "cyano" refers to -CN.

[0056] The term "nitro" refers to -NO2.

[0057] The term "carboxy" refers to -C(O)OH.

[0058] The term "mercapto" refers to -SH.

[0059] The term "ester" or "carboxylate" refers to -C(O)O-(alkyl) or -C(O)O(cycloalkyl) where alkyl and cycloalkyl are as defined above.

[0060] The term "acyl" refers to a compound containing a -C(O)R group, where R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0061] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms. The cycloalkyl group of the present invention is preferably a C3-C8 cycloalkyl or a C3-C6 cycloalkyl group. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. Polycyclic cycloalkyl groups include, but are not limited to, spirocyclic, fused, and bridged cycloalkyl groups, such as norbornyl.

[0062] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include but are not limited to:

[0063] The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, aryloxy, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0064] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from N, O, and S (the N and S heteroatoms may be optionally oxidized), but excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; and most preferably, it contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Examples of monocyclic heterocyclyls include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and tetrahydropyranyl, and polycyclic heterocyclyls include, but are not limited to, spirocyclic, fused, and bridged heterocyclyls.

[0065] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include but are not limited to:

[0066] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, aryloxy, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0067] The term "aryl" refers to a monocyclic, bicyclic or tricyclic ring system having a conjugated π electron system with a total of 6 to 14 ring atoms, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring atoms. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes but is not limited to phenyl, naphthyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl and tetrahydronaphthyl. The aryl groups of the present invention are preferably C6-C 10Aryl. The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, aryloxy, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0068] The term "heteroaryl" refers to a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic ring or a 7-, 8-, 9-, or 10-membered aromatic bicyclic or aromatic polycyclic heterocyclic ring that is fully unsaturated or partially unsaturated and contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S (the N and S heteroatoms may be optionally oxidized). The nitrogen atom is substituted or unsubstituted (i.e., N or NR, where R is H or, if defined, another substituent). The heterocycle may be attached to its side group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic group of the present invention may be substituted on a carbon or nitrogen atom. The nitrogen in the heterocycle may be optionally quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than 1. When the term "heterocycle" is used, it is intended to include heteroaryl. Examples of heteroaryl groups include, but are not limited to, acridinyl, imidazolyl, furanyl, thienyl, oxazolyl, thiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, indolyl, indolizinyl, indazolyl, pyrimidinyl, phenazinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrrolyl, and quinolinyl. The term "heteroaryl" may also include biaryl structures formed by the above-defined "aryl", "heterocyclyl" or "cycloalkyl" and a monocyclic "heteroaryl", such as, but not limited to, "-phenylbipyridyl-", "-phenylbipyrimidyl-", "-pyridylbinaphthyl-", "-pyrimidylbinaphthyl-", and "-pyridylbipyrimidyl-", wherein the present invention also includes spirocyclic, fused ring, and bridged ring compounds containing, for example, the above-mentioned heterocycles.

[0069] As used herein, "optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes both instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0070] As used herein, "substituted" or "substituted" refers to one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group, being replaced independently of one another by a corresponding number of substituents, provided that normal valence is maintained and the substitution results in a stable compound. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0071] A "pharmaceutical composition" refers to a mixture containing one or more compounds of the present invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredients, and thereby exert their biological activity. DETAILED DESCRIPTION

[0072] To better illustrate the technical means and effects of the present invention, the present invention is further described below in conjunction with non-limiting examples. The examples of the present invention, including the descriptions provided in the examples, are intended to illustrate embodiments of the present invention and are not intended to limit the scope of any claims. According to the present invention, those skilled in the art will understand that many changes can be made to the disclosed specific embodiments without departing from the spirit and scope of the present invention and still achieve the same or similar results.

[0073] Unless otherwise stated, all materials / reagents were obtained from commercial suppliers and used without further purification. The structures of the compounds in the following examples were characterized and confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0074] 1 H NMR spectra were recorded at room temperature on a Bruker Avance 400 MHz spectrometer using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), or deuterated water (D2O). Chemical shifts (δ) are reported in ppm using tetramethylsilane (TMS) or the residual solvent peak as the internal standard. Coupling constants (J) are reported in Hertz (Hz). 1 The multiplicity of peaks in H NMR spectra is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), m (multiplet), and br (broad).

[0075] Liquid chromatography-mass spectrometry (LC-MS) was performed on a Shimadzu LCMS-2020 instrument, and preparative high-performance liquid chromatography (Prep-HPLC) on a Bonna-Agela FLEXA FL-H100G instrument. Thin-layer chromatography (TLC) used Yantai Huanghai HSGF254 thin-layer chromatography silica gel plates. The plates used for reaction monitoring were 2.5 × 8 cm with a coating thickness of 0.2 ± 0.03 mm, and the plates used for separation and purification were 20 × 20 cm with a coating thickness of 0.4–0.5 mm. Silica gel column chromatography used Qingdao Marine 100–200 mesh or 200–300 mesh silica gel as the carrier.

[0076] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention.

[0077] Example 1: (S)-N 1 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (1)

[0078] Synthesis route:

[0079] Step 1: Synthesis of O-(4-bromo-2-nitrophenyl)-N-(tert-butoxycarbonyl)-L-serine (1c)

[0080] To a suspension of sodium hydride (60% w / w dispersion in mineral oil, 1.74 g, 47.39 mmol) in DMF (N,N-dimethylformamide, 20 mL) was added a solution of (tert-butoxycarbonyl)-L-serine 1b (4.24 g, 20.66 mmol) in DMF (5 mL) at 0°C in an ice bath. The reaction mixture was stirred for 1 hour. A solution of 4-bromo-1-fluoro-2-nitrobenzene 1a (5 g, 22.73 mmol) in DMF (10 mL) was then slowly added dropwise to the reaction mixture at 0°C in an ice bath. The mixture was then warmed to room temperature and stirred for an additional 15 hours. TLC and LC-MS indicated the reaction was complete. The reaction mixture was poured into ice water (300 mL), and the aqueous phase was acidified to pH 4 with dilute hydrochloric acid (1 N) and extracted with ethyl acetate (100 mL x 5). The combined organic layers were washed sequentially with water (300 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (eluent: dichloromethane containing 1% methanol) to obtain compound 1c (3.5 g, yield 38%) as a yellow solid.

[0081] MS(ES + ):m / z 347.9[M- t Bu+H] + .

[0082] Step 2: Synthesis of O-(2-amino-4-bromophenyl)-N-(tert-butoxycarbonyl)-L-serine (1d)

[0083] To a solution of compound 1c (3.5 g, 8.6 mmol) in acetic acid (50 mL) was added zinc powder (2.8 g, 43.2 mmol) under a 0°C ice bath, and the resulting mixture was stirred at 30°C for 3 hours. TLC and LC-MS showed that the reaction was complete. The reaction mixture was filtered through celite, the filter cake was rinsed with dichloromethane (300 mL), and the filtrate was concentrated under reduced pressure. The residue after concentration was then dissolved in water (50 mL), neutralized with saturated sodium bicarbonate solution to pH = 7, and then extracted with dichloromethane (50 mL). The organic layer was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of compound 1d (3.4 g) as a black solid, which was used directly in the next step without further purification.

[0084] MS(ES + ):m / z 374.9[M+H] + .

[0085] Step 3: (S)-(7-Bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of tert-butyl butylcarbamate (1e)

[0086] To a solution of compound 1d (3.4 g, 9.1 mmol) in DMF (50 mL) at room temperature was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 1.74 g, 9.1 mmol), and the reaction mixture was stirred at room temperature for 2 hours. TLC and LC-MS indicated completion of the reaction. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (eluent: 15% ethyl acetate in petroleum ether) to afford compound 1e (880 mg, 28% yield over two steps) as a light yellow solid.

[0087] MS(ES + ):m / z 300.7[M- t Bu+H] + .

[0088] 1 H NMR (400MHz, DMSO-d6): δ10.03(s,1H),7.29–7.25(m,2H),7.14(d,J=7.6Hz,1H),7.07(d,J=8.4Hz,1H),4.35–4.26(m,3H),1.36(s,9H).

[0089] Step 4: (S)-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of tert-butyl butylcarbamate (1f)

[0090] To a mixture of compound 1e (2.1 g, 5.88 mmol) and cesium carbonate (2.5 g, 7.6 mmol) in DMF (30 mL) was added iodomethane (0.9 g, 6.5 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 15 hours. TLC and LC-MS showed that the reaction was complete. The reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed sequentially with water (50 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (eluent: 15% ethyl acetate in petroleum ether) to afford compound 1f (1.3 g, 60% yield) as a light yellow solid.

[0091] MS(ES + ):m / z 370.9[M+H] + .

[0092] 1H NMR (400MHz, DMSO-d6): δ7.74(d,J=2.0Hz,1H),7.43(dd,J=8.6,2.2Hz,1H),7.19(d ,J=8.4Hz,1H),7.15(d,J=8.8Hz,1H),4.40–4.25(m,3H),3.27(s,3H),1.34(s,9H).

[0093] Step 5: (S)-3-Amino-7-bromo-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine Synthesis of -4(5H)-ketone hydrochloride (1g)

[0094] To a solution of compound 1f (1.6 g, 4.3 mmol) in dichloromethane (20 mL) was added dropwise a solution of hydrogen chloride in 1,4-dioxane (4 N, 25 mL) at room temperature. The reaction was stirred at room temperature for 3 hours. TLC and LC-MS indicated the reaction was complete. The solvent and other volatiles were removed by concentration under reduced pressure to afford compound 1g (1.3 g, 98% yield) as a white solid.

[0095] MS(ES + ):m / z 272.2[M+H] + .

[0096] 1 H NMR (400MHz, DMSO-d6): δ8.66(s,3H),7.80(d,J=2.4Hz,1H),7.48(dd,J=8.6,2.2Hz,1H),7.23(d,J=8.8 Hz,1H),4.60(dd,J=10.0,7.3Hz,1H),4.46(t,J=10.6Hz,1H),4.34(dd,J=11.2,7.6Hz,1H),3.34(s,3H).

[0097] Step 6: (S)-2-(7-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of ethyl 2-oxo-3-yl)amino)ethyl 2-oxo-1-ylacetate (1h)

[0098] To a mixture of compound 1g (1.3 g, 4.2 mmol) and triethylamine (1.3 g, 12.8 mmol) in dichloromethane (30 mL) was slowly added dropwise a solution of ethyl oxalyl chloride (0.7 g, 5.1 mmol) in dichloromethane (5 mL) under an ice bath at 0°C. The reaction solution was slowly warmed to room temperature and stirred for 3 hours. TLC and LC-MS showed the reaction was complete. The reaction mixture was poured into water (200 mL) and extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (eluent: 20% ethyl acetate in petroleum ether) to afford compound 1h (1.4 g, 90% yield) as a white solid.

[0099] MS(ES + ):m / z 370.8[M+H] + .

[0100] 1 H NMR (400MHz, CDCl3): δ7.98(d,J=6.6Hz,1H),7.38–7.35(m,2H),7.09–7.07(m,1H),4.86(dt,J=11.1,7.2Hz,1H) ,4.67(dd,J=9.7,7.5Hz,1H),4.35(q,J=7.1Hz,2H),4.21(t,J=10.5Hz,1H),3.41(s,3H),1.37(t,J=7.1Hz,3H).

[0101] Step 7: (S)-N 1 -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (1)

[0102] To a solution of compound 1h (1.4 g, 3.8 mmol) in ethanol (20 mL) was added 2-phenylethylamine 1i (1.0 g, 8.3 mmol). The reaction mixture was heated to 80°C and stirred for an additional 4 hours. TLC and LC-MS indicated that the reaction was complete, with a large amount of white solid precipitated in the reaction mixture. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with petroleum ether containing 15% ethyl acetate (10 mL). The filter cake was drained to afford the title compound 1 (1.3 g, 77% yield) as a white solid.

[0103] MS(ES + ):m / z 446.0[M+H] + .

[0104] 1 H NMR (400MHz, CDCl3): δ8.22(d,J=7.5Hz,1H),7.35–7.28(m,5H),7.25–7.21(m,1H),7.18(d,J=7.3Hz,2H),7.06(d,J=8.9Hz,1H),4.8 1(dt,J=11.2,7.4Hz,1H),4.58(dd,J=9.6,7.5Hz,1H),4.23(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H).

[0105] Example 2: (S)-N 1 -(7-(cyclopropylethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (2)

[0106] Synthesis route:

[0107] Compound 1 (44.6 mg, 0.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (7.0 mg, 0.01 mmol), cuprous iodide (1.9 mg, 0.01 mmol), triethylamine (1 mL), DMF (2 mL), and cyclopropylacetylene 2a (13.2 mg, 0.2 mmol) were added sequentially to a sealed tube at room temperature. The air in the tube was quickly replaced with nitrogen three times, and the reaction solution was stirred at 80°C for 15 hours. TLC and LC-MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (eluent: 20% ethyl acetate in petroleum ether) to obtain the title compound 2 (38.8 mg, 90% yield) as a light yellow solid.

[0108] MS(ES + ):m / z 432.2[M+H] + .

[0109] 1H NMR (400MHz, CDCl3): δ8.26(d,J=7.2Hz,1H),7.37–7.27(m,4H),7.23–7.20(m,2 H),7.17(d,J=7.4Hz,2H),7.05(d,J=8.7Hz,1H),4.79(dt,J=11.1,7.4Hz,1H),4. 56(dd,J=9.5,7.5Hz,1H),4.22(t,J=10.5Hz,1H),3.57–3.52(m,2H),3.38(s,3H) ,2.83(t,J=7.0Hz,2H),1.48–4.41(m,1H),0.91–0.86(m,2H),0.83–0.80(m,2H).

[0110] Example 3: N 1 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (3)

[0111] Synthesis route:

[0112] The title compound 3 was prepared using the same synthetic route and method as in Example 1, except that the compound 4-bromo-1-fluoro-2-nitrobenzene 1a in step 1 was replaced by an equivalent amount of 4-bromo-2-fluoro-1-nitrobenzene 3a.

[0113] MS(ES + ):m / z 445.9[M+H] + .

[0114] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.1Hz,1H),7.39–7.34(m,2H),7.32–7.28(m,3H),7.25–7.21(m,1H),7.18(d,J=7.3Hz,2H),7.08(d,J=8.4Hz ,1H),4.81(dt,J=11.3,7.4Hz,1H),4.59(dd,J=9.7,7.4Hz,1H),4.24(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.39(s,3H),2.84(t,J=7.1Hz,2H).

[0115] Example 4: (S)-N 1-(8-(cyclopropylethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (4)

[0116] Synthesis route:

[0117] The title compound 4 was prepared by the same synthetic route and method as in Example 3, except that compound 1 was replaced by an equivalent amount of compound 3.

[0118] MS(ES + ):m / z 432.1[M+H] + .

[0119] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.4Hz,1H),7.34–7.28(m,3H),7.24–7.20(m,2 H),7.18–7.16(m,2H),7.09(d,J=8.3Hz,1H),4.79(dt,J=11.1,7.5Hz,1H),4.56 (dd,J=9.7,7.5Hz,1H),4.21(t,J=10.5Hz,1H),3.58–3.52(m,2H),3.38(s,3H), 2.83(t,J=7.1Hz,2H),1.47–4.42(m,1H),0.92–0.87(m,2H),0.83–0.79(m,2H).

[0120] Example 5: (S)-N 1 -(8-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (5)

[0121] Synthesis route:

[0122] Step 1: (S)-(8-Hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of tert-butyl butyl-3-yl)carbamate (5a)

[0123] To a mixture of compound 3e (1.0 g, 2.7 mmol), pinacol diboronate (863 mg, 3.4 mmol), and potassium acetate (540 mg, 5.4 mmol) in 1,4-dioxane (20 mL) was added Pd(dppf)Cl2 (102 mg, 0.14 mmol) at room temperature. The atmosphere in the flask was rapidly replaced with nitrogen three times, and the reaction solution was stirred at 110°C for 15 hours. TLC and LC-MS indicated the reaction was complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate (10 mL), filtered, and the filtrate concentrated under reduced pressure. The residue was dissolved in a mixture of THF / H2O (2:1, 30 mL), and sodium perborate tetrahydrate (831 mg, 5.4 mmol) was added. The reaction solution was stirred at 30°C for 2 hours. TLC and LC-MS indicated the reaction was complete. The product was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was then purified by silica gel column chromatography (eluent: petroleum ether containing 25% ethyl acetate) to give compound 5a (591 mg, yield 71%) as a gray solid.

[0124] MS(ES + ):m / z 309.0[M+H] + .

[0125] Step 2: (S)-3-Amino-8-hydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine Synthesis of -4(5H)-ketone (5b)

[0126] To a solution of compound 5a (339 mg, 1.1 mmol) in dichloromethane (5 mL) was added dropwise trifluoroacetic acid (2 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. TLC and LC-MS indicated the reaction was complete. The mixture was then neutralized with saturated sodium bicarbonate solution to pH 7, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 6% methanol in dichloromethane) to afford compound 5b (160 mg, 70% yield) as a light red solid.

[0127] MS(ES + ):m / z 209.2[M+H] + .

[0128] 1H NMR (400MHz, DMSO-d6): δ9.68(s,1H),7.18(d,J=8.8Hz,1H),6.63(dd,J=8.4,2.8Hz,1H),6.52(d,J=2.4Hz,1H),4. 20(dd,J=10.0,7.2Hz,1H),3.91(dd,J=11.6,10.0Hz,1H),3.58(dd,J=11.6,7.2Hz,1H),3.21(s,3H),1.75(br,2H).

[0129] Step 3: (S)-2-((8-((tert-Butyldimethylsilyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of ethyl 2-oxo-3-yl)amino)-2-oxoacetate (5c)

[0130] To a mixture of compound 5b (150 mg, 0.72 mmol), N,N-dimethylpyridin-4-amine (9 mg, 0.07 mmol), and triethylamine (219 mg, 2.16 mmol) in dichloromethane (3 mL) was slowly added dropwise a solution of tert-butyldimethylsilyl chloride (136 mg, 0.90 mmol) in dichloromethane (1 mL) at room temperature. The reaction was stirred at room temperature for 5 hours. TLC and LC-MS indicated the reaction was complete. The reaction was then placed in an ice bath at 0°C and a solution of ethyl oxalyl chloride (196 mg, 1.44 mmol) in dichloromethane (1 mL) was slowly added dropwise. The reaction was slowly warmed to room temperature and stirred for an additional 3 hours. TLC and LC-MS indicated the reaction was complete. The reaction was diluted with dichloromethane (30 mL) and then washed sequentially with water (15 mL), saturated ammonium chloride solution (20 mL), and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by silica gel column chromatography (eluent: 10-30% ethyl acetate in petroleum ether) to afford compound 5c (230 mg, yield 76%) as a white solid.

[0131] MS(ES + ):m / z 423.1[M+H] + .

[0132] Step 4: (S)-N 1 -(8-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (5)

[0133] To a solution of compound 5c (200 mg, 0.47 mmol) in ethanol (5 mL) was added 2-phenylethylamine (190 mg, 1.56 mmol). The reaction mixture was warmed to 80°C and stirred for 15 hours. TLC and LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: 10–50% ethyl acetate in petroleum ether) to afford the title compound 5 (150 mg, 83% yield) as a white solid.

[0134] MS(ES + ):m / z 384.0[M+H] + .

[0135] 1 H NMR (400MHz, CDCl3): δ8.27(d,J=7.6Hz,1H),7.32–7.28(m,3H),7.24–7.21(m,1H),7.18(d,J=7.6Hz,2H),7.06(d,J=8.6Hz,1H),6.71–6.66(m ,2H),4.83(dt,J=10.8,7.4Hz,1H),4.58(dd,J=9.7,7.4Hz,1H),4.20(t,J=10.5Hz,1H),3.60–3.54(m,2H),3.37(s,3H),2.84(t,J=6.9Hz,2H).

[0136] Example 6: (S)-N 1 -(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (6)

[0137] Synthesis route:

[0138] The title compound 6 was prepared by the same synthetic route and method as in Example 5, except that compound 3e was replaced by an equivalent amount of compound 1f.

[0139] MS(ES + ):m / z 384.1[M+H] + .

[0140] 1H NMR (400MHz, CDCl3): δ8.28 (d, J=7.5Hz, 1H), 7.32–7.28 (m, 3H), 7.24–7.2 1(m,1H),7.18(d,J=7.1Hz,2H),7.01(d,J=8.6Hz,1H),6.67–6.62(m,2H),5 .59(br,1H),4.82(dt,J=11.1,7.6Hz,1H),4.56(dd,J=9.7,7.6Hz,1H),4.1 6(t,J=10.1Hz,1H),3.60–3.54(m,2H),3.38(s,3H),2.84(t,J=7.1Hz,2H).

[0141] Example 7: (S)-N 1 -(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -methyl-N 2 -Synthesis of phenylacetamide (7)

[0142] Synthesis route:

[0143] The title compound 7 was prepared by the same synthetic route and method as in step 4 of Example 5, except that compound 1i was replaced by an equivalent amount of compound 7a.

[0144] MS(ES + ):m / z 398.1[M+H] + .

[0145] 1H NMR (400MHz, CDCl3): δ7.92 (minor), 7.80 (major) (d, J=7.5Hz, 1H), 7.32–7.27 (m, 1H), 7.24–7.17 (m, 2H), 7.13 (d, J= 7.1Hz,1H),7.03–6.99(m,1H),6.67–6.62(m,2H),5.97(s,1H),4.85(minor),4.74(major)(dt,J=11.0,7.4Hz,1H),4 .59(minor),4.53(major)(dd,J=9.6,7.7Hz,1H),4.17(minor),4.06(major)(t,J=10.4Hz,1H),3.96–3.82(major), 3.63–3.59(minor)(m,2H),3.37(minor),3.36(major)(s,3H),3.16(minor),2.99(major)(s,3H),2.91–2.86(m,2H).

[0146] Example 8: (S)-N 1 -(7-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (8)

[0147] Synthesis route:

[0148] To a mixture of compound 6 (35 mg, 0.09 mmol) and potassium carbonate (25 mg, 0.18 mmol) in DMF (0.5 mL) was added dropwise a solution of iodomethane 8a (17 mg, 0.12 mmol) in DMF (0.1 mL) at 0°C in an ice bath. The reaction was stirred at 0°C in an ice bath for 1.5 hours. TLC and LC-MS indicated the reaction was complete. The reaction solution was filtered, and the filtrate was purified by Prep-HPLC (water containing 30–95% acetonitrile as the mobile phase) to afford compound 8 (27 mg, 75% yield) as a white solid.

[0149] MS(ES + ):m / z 398.1[M+H] + .

[0150] 1H NMR (400MHz, CDCl3): δ: 8.24 (d, J = 7.4Hz, 1H), 7.31–7.28 (m, 3H), 7.24–7. 20(m,1H),7.17(d,J=7.2Hz,2H),7.09(d,J=8.6Hz,1H),6.76–6.72(m,2H), 4.82(dt,J=11.1,7.6Hz,1H),4.56(dd,J=9.6,7.7Hz,1H),4.16(t,J=10.4H z,1H),3.81(s,3H),3.59–3.53(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H).

[0151] Example 9: (S)-N 1 -(7-(allyloxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (9)

[0152] Synthesis route:

[0153] The title compound 9 was prepared by the same synthetic route and method as Example 8, except that iodomethane 8a was replaced by an equivalent amount of allyl bromide 9a.

[0154] MS(ES + ):m / z 424.0[M+H] + .

[0155] 1 H NMR (400MHz, CDCl3): δ: 8.25 (d, J = 7.2Hz, 1H), 7.31–7.28 (m, 3H), 7.25–7.22 (m, 1H), 7.17(d,J=7.1Hz,2H),7.09–7.06(m,1H),6.76–6.74(m,2H),6.09–5.99(m,1H),5.42 (d,J=17.3Hz,1H),5.32(d,J=10.5Hz,1H),4.82(dt,J=11.1,7.6Hz,1H),4.58–4.52( m,3H),4.16(t,J=10.4Hz,1H),3.58–3.53(m,2H),3.39(s,3H),2.83(t,J=7.0Hz,2H).

[0156] Example 10: (S)-N 1-(5-methyl-4-oxo-7-(prop-2-yn-1-oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (10)

[0157] Synthesis route:

[0158] The title compound 10 was prepared by the same synthetic route and method as in Example 8, except that iodomethane 8a was replaced by an equivalent amount of propargyl bromide 10a.

[0159] MS(ES + ):m / z 422.0[M+H] + .

[0160] 1 H NMR (400MHz, CDCl3): δ: 8.25 (d, J = 7.3Hz, 1H), 7.33–7.28 (m, 3H), 7.25–7.22 (m, 1H) ),7.17(d,J=7.2Hz,2H),7.10(d,J=8.5Hz,1H),6.85–6.82(m,2H),4.83(dt,J=11.0 ,7.6Hz,1H),4.69(d,J=2.2Hz,2H),4.56(dd,J=9.7,7.6Hz,1H),4.18(t,J=10.5Hz ,1H),3.58–3.53(m,2H),3.40(s,3H),2.83(t,J=7.0Hz,2H),2.56(t,J=2.2Hz,1H).

[0161] Example 11: (S)-N 1 -(5-methyl-4-oxo-7-(prop-2-yn-1-oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (11)

[0162] Synthesis route:

[0163] Compound 1 (44.6 mg, 0.1 mmol), palladium acetate (2.2 mg, 0.01 mmol), tri(o-methylphenyl)phosphine (6.1 mg, 0.02 mmol), triethylamine (28 mg, 0.28 mmol), DMF (1 mL), and 1-methyl-3-vinylbenzene 11a (13 mg, 0.11 mmol) were added sequentially to a sealed tube at room temperature. The air in the tube was quickly replaced with nitrogen three times, and the reaction solution was stirred at 80°C for 15 hours. TLC and LC-MS showed the reaction was complete. After cooling to room temperature, the reaction solution was directly concentrated under reduced pressure and purified by preparative TLC and then Prep-HPLC (water containing 30–95% acetonitrile as the mobile phase) to obtain compound 11 (4 mg, 8% yield) as a white solid.

[0164] MS(ES - ):m / z 482.1[MH] - .

[0165] 1 H NMR (400MHz, CDCl3): δ: 8.26 (d, J=7.6Hz, 1H), 7.38–7.28 (m, 7H), 7.24–6.93 (m, 8H), 4.86 (dt, J=11.4, 7.4Hz, 1H), 4. 60(dd,J=9.7,7.4Hz,1H),4.24(t,J=10.5Hz,1H),3.59–3.51(m,2H),3.46(s,3H),2.84(t,J=7.0Hz,2H),2.39(s,3H).

[0166] Example 12: (S)-N 1 -(5-methyl-4-oxo-7-(pyridin-4-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (12)

[0167] Synthesis route:

[0168] The title compound 12 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 4-ethynylpyridine 12a.

[0169] MS(ES + ):m / z 469.1[M+H] + .

[0170] 1H NMR (400MHz, CDCl3): δ8.63(s,2H),8.26(d,J=7.3Hz,1H),7.43–7.28(m,7H),7.24–7.15(m,4H),4.84(dt,J=11.2,7. 3Hz, 1H), 4.62 (dd, J = 9.5, 7.4Hz, 1H), 4.28 (t, J = 10.5Hz, 1H), 3.59–3.52 (m, 2H), 3.44 (s, 3H), 2.84 (t, J = 6.9Hz, 2H).

[0171] Example 13: (S)-N 1 -(5-methyl-4-oxo-7-(pyridin-3-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (13)

[0172] Synthesis route:

[0173] The title compound 13 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-ethynylpyridine 13a.

[0174] MS(ES + ):m / z 469.1[M+H] + .

[0175] 1 H NMR (400MHz, CDCl3): δ8.76(s,1H),8.56(s,1H),8.25(d,J=7.4Hz,1H),7.80(d,J=7.0Hz,1H),7.40–7.28(m,6H),7.22–7.13(m,4H),4. 83(dt,J=11.2,7.4Hz,1H),4.59(dd,J=9.6,7.4Hz,1H),4.26(t,J=10.5Hz,1H),3.57–3.52(m,2H),3.42(s,3H),2.82(t,J=6.9Hz,2H).

[0176] Example 14: (S)-N 1 -(5-methyl-4-oxo-7-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (14)

[0177] Synthesis route:

[0178] The title compound 14 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 2-ethynylpyridine 14a.

[0179] MS(ES + ):m / z 469.1[M+H] + .

[0180] 1 H NMR (400MHz, CDCl3): δ8.63(t,J=4.9Hz,1H),8.26(d,J=7.3Hz,1H),7.73–7.68(m,1H),7.55–7.45(m,2H),7.35–7.28(m,5H),7.22–7.15(m,4 H),4.84(dt,J=11.2,7.3Hz,1H),4.62(dd,J=9.6,7.4Hz,1H),4.27(t,J=10.5Hz,1H),3.59–3.52(m,2H),3.43(s,3H),2.83(t,J=7.0Hz,2H).

[0181] Example 15: (S)-N 1 -(5-methyl-4-oxo-7-(pyrimidin-5-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (15)

[0182] Synthesis route:

[0183] The title compound 15 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 5-ethynylpyrimidine 15a.

[0184] MS(ES + ):m / z 470.1[M+H] + .

[0185] 1H NMR (400MHz, CDCl3): δ9.16(d,J=8.8Hz,1H),8.86(d,J=9.1Hz,2H),8.25(d,J=7.6Hz,1H),7.41(s,1H),7.32–7.28(m,3H),7.23–7.15(m, 5H),4.85(dt,J=11.0,7.4Hz,1H),4.62(dd,J=9.7,7.2Hz,1H),4.28(t,J=10.5Hz,1H),3.59–3.48(m,2H),3.45(s,3H),2.86–2.80(m,2H).

[0186] Example 16: (S)-N 1 -(5-methyl-4-oxo-7-(thien-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (16)

[0187] Synthesis route:

[0188] The title compound 16 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 2-ethynylthiophene 16a.

[0189] MS(ES + ):m / z 474.0[M+H] + .

[0190] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.3Hz,1H),7.76–7.71(m,1H),7.37–7.28(m,6H),7.24–7.21(m,2H),7.18(d,J=7.1Hz,2H),7.06(d,J=8.6Hz ,1H),4.81(dt,J=11.2,7.4Hz,1H),4.57(dd,J=9.7,7.4Hz,1H),4.23(t,J=10.6Hz,1H),3.59–3.54(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H).

[0191] Example 17: (S)-N 1 -(5-methyl-4-oxo-7-(thien-3-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N2 -Synthesis of phenylacetamide (17)

[0192] Synthesis route:

[0193] The title compound 17 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-ethynylthiophene 17a.

[0194] MS(ES + ):m / z 474.0[M+H] + .

[0195] 1 H NMR (400MHz, CDCl3): δ8.27(d,J=6.8Hz,1H),7.55(d,J=2.2Hz,1H),7.37–7.35(m,2H),7.33–7.28(m,4H),7.24–7.13(m,5H),4.84( dt,J=11.2,7.4Hz,1H),4.61(dd,J=9.6,7.4Hz,1H),4.26(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.43(s,3H),2.84(t,J=7.1Hz,2H).

[0196] Example 18: (S)-N 1 -(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (18)

[0197] Synthesis route:

[0198] The title compound 18 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of (trimethylsilyl)acetylene 18a.

[0199] MS(ES + ):m / z 464.2[M+H] + .

[0200] 1H NMR (400MHz, CDCl3): δ8.24(d,J=7.5Hz,1H),7.33–7.28(m,5H),7.24–7.24(m,1H),7.18(d,J=6.8Hz,2H),7.10(d,J=8.8Hz,1H),4.79(dt,J =11.3,7.3Hz,1H),4.58(dd,J=9.7,7.3Hz,1H),4.23(t,J=10.6Hz,1H),3.59–3.52(m,2H),3.41(s,3H),2.84(t,J=7.0Hz,2H),0.26(s,9H).

[0201] Example 19: (S)-N 1 -(5-methyl-4-oxo-7-(prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (19)

[0202] Synthesis route:

[0203] The title compound 19 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of ethynyltrimethylsilane 19a (1 M solution in DMF).

[0204] MS(ES + ):m / z 406.1[M+H] + .

[0205] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.5Hz,1H),7.34–7.28(m,4H),7.24–7.20(m,2H),7.18(d,J=7.3Hz,2H),7.08(d,J=8.7Hz,1H),4.81(dt,J =11.2,7.4Hz,1H),4.58(dd,J=9.6,7.5Hz,1H),4.22(t,J=10.5Hz,1H),3.59–3.53(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H),2.05(s,3H).

[0206] Example 20: (S)-N 1 -(7-ethynyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N2 -Synthesis of phenylacetamide (20)

[0207] Synthesis route:

[0208] To a solution of compound 18 (18 mg, 0.04 mmol) in tetrahydrofuran (1.0 mL) was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.3 mL) at room temperature, and the reaction mixture was stirred at room temperature for 0.5 hours. TLC and LC-MS indicated the reaction was complete, and the mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (eluent: 25–40% ethyl acetate in petroleum ether) to afford the title compound 20 (8 mg, 51% yield) as a white solid.

[0209] MS(ES + ):m / z 392.0[M+H] + .

[0210] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.3Hz,1H),7.36–7.28(m,5H),7.24–7.20(m,1H),7.18(d,J=7.2Hz,2H),7.14–7.09(m,1H),4.81(dt,J= 11.3,7.4Hz,1H),4.60(dd,J=9.7,7.4Hz,1H),4.25(t,J=10.5Hz,1H),3.59–3.53(m,2H),3.41(s,3H),3.11(s,1H),2.84(t,J=7.0Hz,2H).

[0211] Example 21: (S)-N 1 -(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (21)

[0212] Synthesis route:

[0213] The title compound 21 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 4-ethynyl-2H-pyran 21a.

[0214] MS(ES + ):m / z 476.1[M+H] + .

[0215] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.3Hz,1H),7.32–7.28(m,4H),7.25–7.21(m,2 H),7.18(d,J=7.2Hz,2H),7.09(d,J=8.5Hz,1H),4.80(dt,J=11.1,7.4Hz,1H),4 .58(dd,J=9.6,7.4Hz,1H),4.23(t,J=10.5Hz,1H),3.97–3.92(m,2H),3.59–3.5 2(m,4H),3.41(s,3H),2.85–2.79(m,3H),1.93–1.89(m,2H),1.80–1.71(m,2H).

[0216] Example 22: (S)-N 1 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (22)

[0217] Synthesis route:

[0218] The title compound 22 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 4-ethynyl-1-methyl-1H-pyrazole 22a.

[0219] MS(ES + ):m / z 472.2[M+H] + .

[0220] 1H NMR (400MHz, CDCl3): δ8.26(d,J=7.4Hz,1H),7.65(s,1H),7.56(s,1H),7.34–7.28(m,5H),7.24–7 .20(m,1H),7.17(d,J=7.2Hz,2H),7.12(d,J=8.7Hz,1H),4.83(dt,J=11.2,7.4Hz,1H),4.60(dd,J =9.6,7.5Hz,1H),4.24(t,J=10.5Hz,1H),3.92(s,3H),3.58–3.54(m,2H),3.42(s,3H),2.84(t,J=7.1Hz,2H).

[0221] Example 23: (S)-N 1 -(5-methyl-4-oxo-7-(piperidin-4-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (23)

[0222] Synthesis route:

[0223] The title compound 23 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 4-ethynylpiperidine hydrochloride 23a.

[0224] MS(ES + ):m / z 475.5[M+H] + .

[0225] 1 H NMR (400MHz, DMSO-d6): δ8.81(t,J=5.9Hz,1H),8.77(d,J=7.4Hz,1H),7.54(s,1H),7.33–7.27(m,3H),7.22–7.18(m,4H),4.68–4.58(m,2H),4.40 –4.32(m,1H),3.40–3.35(m,2H),3.30(s,3H),3.22–3.19(m,2H),2.98–2 .93(m,3H),2.78(t,J=7.4Hz,2H),2.03–1.98(m,2H),1.79–1.69(m,2H).

[0226] Example 24: N 1-((3S)-5-methyl-4-oxo-7-(piperidin-3-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (24)

[0227] Synthesis route:

[0228] The title compound 24 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-ethynylpiperidine hydrochloride 24a.

[0229] MS(ES + ):m / z 475.5[M+H] + .

[0230] 1 H NMR (400MHz, DMSO-d6): δ8.82(t,J=6.1Hz,1H),8.76(d,J=7.1Hz,1H),7.52(s,1H),7.30–7. 27(m,3H),7.21–7.18(m,4H),4.68–4.57(m,2H),4.38–4.34(m,1H),3.40–3.36(m,2H),3.30 (s,3H),3.14–3.09(m,1H),2.90–2.85(m,1H),2.78(t,J=7.4Hz,2H),2.70–2.67(m,2H),2.6 4–2.58(m,1H),2.01–1.97(m,1H),1.69–1.63(m,1H),1.60–1.52(m,1H),1.48–1.42(m,1H).

[0231] Example 25: (S)-N 1 -(7-(imidazo[1,2-b]pyridazin-3-ylethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (25)

[0232] Synthesis route:

[0233] The title compound 25 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-ethynylimidazo[1,2-b]pyridazine 25a.

[0234] MS(ES+ ):m / z 509.1[M+H] + .

[0235] 1 H NMR (400MHz, CDCl3): δ8.53(d,J=3.8Hz,1H),8.26(d,J=7.2Hz,1H),8.15–8.10(m,2H),7.52–7.48(m,2H),7.32–7.28(m, 3H),7.24–7.17(m,5H),4.85(dt,J=11.2,7.3Hz,1H),4.63(dd,J=9.5,7.5Hz,1H ),4.28(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.45(s,3H),2.84(t,J=7.0Hz,2H).

[0236] Example 26: (S)-N 1 -(7-(cyclohex-1-en-1-ylethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (26)

[0237] Synthesis route:

[0238] The title compound 26 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 1-ethynyl-1-cyclohexene 26a.

[0239] MS(ES + ):m / z 472.1[M+H] + .

[0240] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.5Hz,1H),7.32–7.27(m,5H),7.24–7.21(m,1 H),7.18(d,J=7.2Hz,2H),7.09(d,J=8.8Hz,1H),6.25–6.22(m,1H),4.82(dt,J=1 1.2,7.4Hz,1H),4.59(dd,J=9.9,7.7Hz,1H),4.23(t,J=10.5Hz,1H),3.58–3.54( m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H),2.24–2.13(m,4H),1.71–1.61(m,4H).

[0241] Example 27: (S)-N 1 -(7-((3,5-difluorophenyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (27)

[0242] Synthesis route:

[0243] The title compound 27 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 1-ethynyl-3,5-difluorobenzene 27a.

[0244] MS(ES + ):m / z 504.1[M+H] + .

[0245] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.4Hz,1H),7.40–7.38(m,2H),7.32–7.28( m,3H),7.25–7.21(m,1H),7.19–7.16(m,3H),7.07–7.02(m,2H),6.83(tt,J= 8.9,2.3Hz,1H),4.84(dt,J=11.3,7.3Hz,1H),4.62(dd,J=9.7,7.3Hz,1H),4 .27(t,J=10.5Hz,1H),3.60–3.54(m,2H),3.44(s,3H),2.84(t,J=7.1Hz,2H).

[0246] Example 28: (S)-N 1 -(5-methyl-4-oxo-7-(3-phenoxyprop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (28)

[0247] Synthesis route:

[0248] The title compound 28 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of phenyl propargyl ether 28a.

[0249] MS(ES +):m / z 498.2[M+H] + .

[0250] 1 H NMR (400MHz, CDCl3): δ8.23 (d, J=7.0Hz, 1H), 7.35–7.28 (m, 7H), 7.24–7.2 1(m,1H),7.18(d,J=7.3Hz,2H),7.11(d,J=7.9Hz,1H),7.04–7.00(m,3H),4 .92(s,2H),4.80(dt,J=11.4,7.5Hz,1H),4.58(dd,J=9.9,7.3Hz,1H),4.2 4(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.39(s,3H),2.84(t,J=7.1Hz,2H).

[0251] Example 29: (S)-N 1 -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (29)

[0252] Synthesis route:

[0253] The title compound 29 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 2-methyl-3-butyn-2-ol 29a.

[0254] MS(ES + ):m / z 450.1[M+H] + .

[0255] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.3Hz,1H),7.32–7.27(m,5H),7.24–7.21(m,1H),7.18(d,J=7.0Hz,2H),7.10(d,J=8.7Hz,1H),4.80(dt,J=11.4, 7.3Hz,1H),4.59(dd,J=9.7,7.4Hz,1H),4.23(t,J=10.5Hz,1H),3.59–3. 54(m,2H),3.41(s,3H),2.84(t,J=7.1Hz,2H),1.86(br,1H),1.62(s,6H).

[0256] Example 30: (S)-N 1 -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (30)

[0257] Synthesis route:

[0258] The title compound 30 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of (S)-3-butyn-2-ol 30a.

[0259] MS(ES + ):m / z 436.0[M+H] + .

[0260] 1 H NMR (400MHz, CDCl3): δ8.24 (d, J=7.3Hz, 1H), 7.32–7.27 (m, 5H), 7.24–7.21 (m,1H),7.18(d,J=7.2Hz,2H),7.11(d,J=8.8Hz,1H),4.84–4.73(m,2H),4. 59(dd,J=9.7,7.4Hz,1H),4.24(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.41( s, 3H), 2.84 (t, J = 7.1Hz, 2H), 1.90 (d, J = 5.4Hz, 1H), 1.56 (d, J = 6.0Hz, 3H).

[0261] Example 31: (S)-N 1 -(7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (31)

[0262] Synthesis route:

[0263] The title compound 31 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-butyn-1-ol 31a.

[0264] MS(ES + ):m / z 436.0[M+H]+ .

[0265] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.4Hz,1H),7.32–7.27(m,5H),7.24–7.21(m,1H),7.18(d,J=7.3Hz,2H),7.09(d,J=8.8Hz, 1H),4.81(dt,J=11.1,7.3Hz,1H),4.59(dd,J=9.8,7.5Hz,1H),4.23(t,J=10.5Hz,1H),3.83( t,J=6.2Hz,2H),3.59–3.54(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H),2.70(t,J=6.3Hz,2H).

[0266] Example 32: (S)-N 1 -Benzyl-N 2 -(7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (32)

[0267] Synthesis route:

[0268] Step 1: (S)-N 1 -Benzyl-N 2 -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (32b)

[0269] To a solution of compound 1h (111 mg, 0.3 mmol) in ethanol (5 mL) was added benzylamine 32a (96 mg, 0.9 mmol). The reaction was warmed to 80°C and stirred for an additional 4 hours. TLC and LC-MS showed that the reaction was complete, with a large amount of white solid precipitated in the reaction solution. The reaction solution was cooled to room temperature and filtered. The filter cake was rinsed with petroleum ether containing 15% ethyl acetate (5 mL) and drained to afford compound 32b (118 mg, 91% yield) as a white solid.

[0270] MS(ES + ):m / z 432.0[M+H] + .

[0271] Step 2: (S)-N 1 -Benzyl-N 2-(7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (32)

[0272] Compound 32b (43.2 mg, 0.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (7.0 mg, 0.01 mmol), cuprous iodide (1.9 mg, 0.01 mmol), triethylamine (1 mL), DMF (2 mL), and 3-butyn-1-ol 31a (14.0 mg, 0.2 mmol) were added sequentially to a sealed tube at room temperature. The air in the tube was quickly replaced with nitrogen three times, and the reaction solution was stirred at 80°C for 15 hours. TLC and LC-MS showed the reaction was complete. After cooling to room temperature, the reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (eluent: 25–50% ethyl acetate in petroleum ether) to afford the title compound 32 (35.8 mg, 85% yield) as a white solid.

[0273] MS(ES + ):m / z 422.1[M+H] + .

[0274] 1 H NMR (400MHz, CDCl3): δ8.29(d,J=7.4Hz,1H),7.56(t,J=5.7Hz,1H),7.36–7.29(m,3H),7.28–7.25(m,4H),7.10(d,J=8.7Hz,1H),4.82(dt,J=11.2 ,7.4Hz,1H),4.60(dd,J=9.7,7.4Hz,1H),4.48(d,J=6.2Hz,2H),4.24(t, J=10.5Hz,1H),3.83(t,J=6.3Hz,2H),3.41(s,3H),2.70(t,J=6.3Hz,2H).

[0275] Example 33: (S)-N 1 -(2-Fluorophenethyl)-N 2 -(7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (33)

[0276] Synthesis route:

[0277] The title compound 33 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of 2-fluorophenethylamine 33a.

[0278] MS(ES + ):m / z 453.9[M+H] + .

[0279] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.4Hz,1H),7.34(t,J=6.0Hz,1H),7.28–7.26(m,2H),7.24–7.15(m,2H),7.10–7.00(m,3H),4.8 1(dt,J=11.4,7.4Hz,1H),4.59(dd,J=9.7,7.4Hz,1H),4.23(t,J=10.5Hz,1H),3.83(q,J=6.1Hz,2H),3.59–3.52(m,2H),3.40(s, 3H),2.89(t,J=6.9Hz,2H),2.70(t,J=6.2Hz,2H),1.82(t,J=6.2Hz,1H)..

[0280] Example 34: (S)-N 1 -(3-Fluorophenethyl)-N 2 -(7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (34)

[0281] Synthesis route:

[0282] The title compound 34 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of 3-fluorophenethylamine 34a.

[0283] MS(ES + ):m / z 454.2[M+H] + .

[0284] 1H NMR (400MHz, CDCl3): δ8.23(d,J=7.3Hz,1H),7.31–7.23(m,4H),7.10(d,J=8. 8Hz,1H),6.96–6.87(m,3H),4.80(dt,J=11.1,7.5Hz,1H),4.59(dd,J=9.6,7. 4Hz,1H),4.23(t,J=10.5Hz,1H),3.83(q,J=6.2Hz,2H),3.58–3.53(m,2H),3. 40(s,3H),2.84(t,J=7.1Hz,2H),2.70(t,J=6.2Hz,2H),1.85(t,J=6.2Hz,1H).

[0285] Example 35: (S)-N 1 -(4-Fluorophenethyl)-N 2 -(7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (35)

[0286] Synthesis route:

[0287] The title compound 35 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of 4-fluorophenethylamine 35a.

[0288] MS(ES + ):m / z 454.0[M+H] + .

[0289] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.4Hz,1H),7.30–7.26(m,3H),7.15–7.08(m ,3H),6.98(t,J=8.6Hz,2H),4.80(dt,J=11.2,7.4Hz,1H),4.58(dd,J=9.7,7. 4Hz,1H),4.23(t,J=10.5Hz,1H),3.83(q,J=6.0Hz,2H),3.58–3.49(m,2H),3. 40(s,3H),2.81(t,J=7.1Hz,2H),2.70(t,J=6.2Hz,2H),1.80(t,J=6.1Hz,1H).

[0290] Example 36: (S)-N 1-(3,5-difluorophenethyl)-N 2 -(7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (36)

[0291] Synthesis route:

[0292] The title compound 36 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of 3,5-difluorophenethylamine 36a.

[0293] MS(ES + ):m / z 472.0[M+H] + .

[0294] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.5Hz,1H),7.33–7.27(m,3H),7.10(d,J=8.7Hz,1H),6.72–6.66(m,3H),4.80(dt,J=11.1, 7.4Hz,1H),4.59(dd,J=9.6,7.5Hz,1H),4.23(t,J=10.6Hz,1H),3.83(q,J=6.2Hz,2H),3.58– 3.53(m,2H),3.41(s,3H),2.83(t,J=7.1Hz,2H),2.70(t,J=6.1Hz,2H),1.78(t,J=6.3Hz,1H).

[0295] Example 37: N 1 -((S)-7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -(1-phenylpropan-2-yl)oxalamide (37)

[0296] Synthesis route:

[0297] The title compound 37 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of 1-phenylpropane-2-amine 37a.

[0298] MS(ES + ):m / z 450.2[M+H]+ .

[0299] 1 H NMR (400MHz, CDCl3): δ8.26–8.20(m,1H),7.31–7.21(m,5H),7.17–7.13(m,3H),7.10(d,J=8.8Hz,1H),4.80(dt,J=11.1,7.5Hz,1H),4.60–4. 55(m,1H),4.25–4.19(m,2H),3.86–3.81(m,2H),3.40(s,3H),2.89–2. 82(m,1H),2.76–2.69(m,3H),1.81(t,J=6.0Hz,1H),1.17–1.14(m,3H).

[0300] Example 38: (S)-N 1 -(2-Fluorobenzyl)-N 2 -(7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (38)

[0301] Synthesis route:

[0302] The title compound 38 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of 2-fluorobenzylamine 38a.

[0303] MS(ES + ):m / z 440.0[M+H] + .

[0304] 1 H NMR (400MHz, CDCl3): δ8.26(d,J=7.3Hz,1H),7.58(t,J=6.0Hz,1H),7.33–7.27(m,4H),7.12–7.03(m,3H),4.81(dt,J=11.2,7.4Hz,1H),4.59(dd,J=9 .7,7.4Hz,1H),4.53(dd,J=6.1,2.8Hz,2H),4.23(t,J=10.5Hz,1H),3.83(q ,J=6.0Hz,2H),3.40(s,3H),2.70(t,J=6.2Hz,2H),1.77(t,J=6.0Hz,1H)..

[0305] Example 39: (S)-N1 -(3-Fluorobenzyl)-N 2 -(7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (39)

[0306] Synthesis route:

[0307] The title compound 39 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of 3-fluorobenzylamine 39a.

[0308] MS(ES + ):m / z 440.0[M+H] + .

[0309] 1 H NMR (400MHz, CDCl3): δ8.28(d,J=7.3Hz,1H),7.58(t,J=6.3Hz,1H),7.31–7.25(m,3H),7.12–6.96(m,4H),4.82(dt,J=11.3, 7.4Hz, 1H), 4.61 (dd, J = 9.7, 7.3Hz, 1H), 4.48 (dd, J = 6.2, 1.4Hz, 2H), 4.23 (dd, J = 11.1, 9. 9Hz, 1H), 3.83 (q, J = 6.1Hz, 2H), 3.41 (s, 3H), 2.70 (t, J = 6.3Hz, 2H), 1.78 (t, J = 6.2Hz, 1H).

[0310] Example 40: (S)-N 1 -(4-Fluorobenzyl)-N 2 -(7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (40)

[0311] Synthesis route:

[0312] The title compound 40 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of 4-fluorobenzylamine 40a.

[0313] MS(ES + ):m / z 440.0[M+H] +.

[0314] 1 H NMR (400MHz, CDCl3): δ8.28(d,J=7.4Hz,1H),7.55(t,J=5.8Hz,1H),7.28–7.22 (m,4H),7.10(d,J=8.8Hz,1H),7.01(t,J=8.6Hz,2H),4.81(dt,J=11.3,7.4Hz,1 H),4.59(dd,J=9.7,7.4Hz,1H),4.44(d,J=6.2Hz,2H),4.24(t,J=10.5Hz,1H),3 .83(q,J=6.2Hz,2H),3.41(s,3H),2.70(t,J=6.2Hz,2H),1.80(t,J=6.2Hz,1H).

[0315] Example 41: N 1 -((S)-7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -(1-phenylethyl)oxalamide (41)

[0316] Synthesis route:

[0317] The synthetic route and method were the same as those of Example 32, except that the benzylamine 32a in step 1 was replaced with an equivalent amount of 1-phenylethylamine 41a to obtain the title compound 41 (dr = 1:1).

[0318] MS(ES + ):m / z 436.0[M+H] + .

[0319] 1 H NMR (400MHz, CDCl3): δ8.28–8.25(m,1H),7.49(d,J=8.4Hz,1H),7.36–7.2 6(m,7H),7.12–7.09(m,1H),5.10–5.03(m,1H),4.84–4.76(m,1H),4.62–4 .54(m,1H),4.27–4.18(m,1H),3.83(t,J=5.9Hz,2H),3.40,3.39(1:1,s,3 H),2.70(t,J=6.2Hz,2H),1.82(br,1H),1.54,1.53(1:1,d,J=6.6Hz,3H).

[0320] Example 42: (S)-N 1 -(3-Fluorophenethyl)-N 2 -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (42)

[0321] Synthesis route:

[0322] The title compound 42 was prepared by the same synthetic route and method as in step 2 of Example 32, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 2-methyl-3-butyn-2-ol 29a.

[0323] MS(ES + ):m / z 468.0[M+H] + .

[0324] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=8.0Hz,1H),7.31–7.23(m,4H),7.11(d,J=8.8Hz,1H),6.96–6.8 8(m,3H),4.80(dt,J=11.4,7.4Hz,1H),4.59(dd,J=9.7,7.4Hz,1H),4.24(t,J=10.5Hz,1H),3.58 –3.53(m,2H),3.41(s,3H),2.84(t,J=7.0Hz,2H),2.00(s,1H),1.63(s,6H).

[0325] Example 43: (S)-N 1 -(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (43)

[0326] Synthesis route:

[0327] The title compound 43 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-alkynyloxetane-3-ol 43a.

[0328] MS(ES + ):m / z 464.1[M+H] +.

[0329] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.0Hz,1H),7.32–7.27(m,5H),7.25–7.21(m,1H),7.18(d,J=7.2Hz,2H),7.14(d,J=8.8Hz,1H),4.94(d,J=6.6Hz ,2H),4.85–4.78(m,3H),4.60(dd,J=9.7,7.2Hz,1H),4.26(t,J=10.5Hz, 1H),3.60–3.54(m,2H),3.42(s,3H),2.84(t,J=7.0Hz,2H),2.60(br,1H).

[0330] Example 44: (S)-N 1 -(7-((1-hydroxycyclohexyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (44)

[0331] Synthesis route:

[0332] The title compound 44 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 1-ethynyl-1-cyclohexanol 44a.

[0333] MS(ES - ):m / z 488.1[MH] - .

[0334] 1 H NMR (400MHz, CDCl3): δ8.23 (d, J=7.4Hz, 1H), 7.32–7.27 (m, 5H), 7.24–7.21 (m,1H),7.18(d,J=7.0Hz,2H),7.11(d,J=8.6Hz,1H),4.80(dt,J=11.3,7.4H z,1H),4.58(dd,J=9.7,7.3Hz,1H),4.24(t,J=10.5Hz,1H),3.59–3.54(m,2H ),3.41(s,3H),2.84(t,J=7.1Hz,2H),2.02–1.99(m,2H),1.77–1.55(m,8H).

[0335] Example 45: (S,Z)-N 1-(7-(5-hydroxy-3-methylpent-3-en-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (45)

[0336] Synthesis route:

[0337] The title compound 45 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of (Z)-3-methylpent-2-en-4-yn-1-ol 45a.

[0338] MS(ES - ):m / z 460.1[MH] - .

[0339] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.2Hz,1H),7.32–7.28(m,5H),7.24–7.21(m,1H) ,7.18(d,J=7.0Hz,2H),7.13(d,J=8.0Hz,1H),5.97(td,J=6.8,1.4Hz,1H),4.82(d t,J=11.2,7.4Hz,1H),4.59(dd,J=9.7,7.3Hz,1H),4.41(d,J=6.2Hz,2H),4.25(t, J=10.5Hz,1H),3.59–3.52(m,2H),3.42(s,3H),2.84(t,J=7.0Hz,2H),1.99(s,3H).

[0340] Example 46: N 1 -((3S)-7-(3-(3-hydroxypyrrolidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (46)

[0341] Synthesis route:

[0342] The title compound 46 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)pyrrolidin-3-ol 46a.

[0343] MS(ES+ ):m / z 491.3[M+H] + .

[0344] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.4Hz,1H),7.36–7.28(m,5H),7.24–7.20(m,1H),7.17(d,J=7. 1Hz,2H),7.10(d,J=8.8Hz,1H),4.80(dt,J=11.2,7.4Hz,1H),4.57(dd,J=9.6,7.4Hz,1H),4.47– 4.45(m,1H),4.24(t,J=10.5Hz,1H),3.76(s,2H),3.58–3.53(m,2H),3.40(s,3H),3.17–3.11(m, 1H), 2.94 (s, 2H), 2.84 (t, J = 7.1Hz, 2H), 2.78–2.72 (m, 1H), 2.32–2.24 (m, 1H), 1.93–1.86 (m, 1H).

[0345] Example 47: (S)-N 1 -(5-methyl-4-oxo-7-(3-(4-carbonylpiperidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (47)

[0346] Synthesis route:

[0347] The title compound 47 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)piperidin-4-one 47a.

[0348] MS(ES + ):m / z 503.1[M+H] + .

[0349] 1H NMR (400MHz, CDCl3): δ8.23(d,J=7.4Hz,1H),7.32–7.28(m,5H),7.24–7.21(m,1H) ),7.17(d,J=7.1Hz,2H),7.10(d,J=8.9Hz,1H),4.81(dt,J=11.3,7.4Hz,1H),4.5 8(dd,J=9.7,7.3Hz,1H),4.24(t,J=10.5Hz,1H),3.70(s,2H),3.59–3.53(m,2H), 3.41(s,3H),2.99(t,J=5.4Hz,4H),2.84(t,J=7.1Hz,2H),2.58(t,J=5.5Hz,4H).

[0350] Example 48: (S)-N 1 -(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (48)

[0351] Synthesis route:

[0352] The title compound 48 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 4-(prop-2-yn-1-yl)morpholine 48a.

[0353] MS(ES + ):m / z 491.0[M+H] + .

[0354] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.4Hz,1H),7.32–7.28(m,5H),7.24–7.20(m,1H) ),7.17(d,J=7.1Hz,2H),7.11(d,J=8.8Hz,1H),4.81(dt,J=11.2,7.4Hz,1H),4.5 8(dd,J=9.7,7.3Hz,1H),4.24(t,J=10.5Hz,1H),3.85(t,J=4.6Hz,4H),3.62(s,2 H),3.59–3.53(m,2H),3.41(s,3H),2.84(t,J=7.1Hz,2H),2.77(t,J=4.4Hz,4H).

[0355] Example 49: (S)-N1 -(5-methyl-4-oxo-7-(3-(piperazin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (49)

[0356] Synthesis route:

[0357] The title compound 49 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)piperazine 49a.

[0358] MS(ES + ):m / z 490.1[M+H] + .

[0359] 1 H NMR (400MHz, CDCl3): δ8.26(d,J=6.8Hz,1H),7.39–7.35(m,2H),7.31–7.27(m,3 H),7.23–7.19(m,1H),7.17(d,J=7.2Hz,2H),7.11(d,J=8.3Hz,1H),4.79(dt,J=1 1.2,6.8Hz,1H),4.57(dd,J=9.6,7.4Hz,1H),4.24(t,J=10.5Hz,1H),3.59–3.52( m,4H),3.40(s,3H),3.30–3.23(m,4H),2.95–2.87(m,4H),2.83(t,J=7.1Hz,2H).

[0360] Example 50: (S)-N 1 -(7-(4-aminobut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (50)

[0361] Synthesis route:

[0362] The title compound 50 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of but-3-yn-1-amine 50a.

[0363] MS(ES + ):m / z 435.0[M+H]+ .

[0364] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.3Hz,1H),7.32–7.28(m,5H),7.24–7.21(m,1H),7.18(d,J=7.0Hz,2H),7.10(d,J=8.8Hz,1H),4.81(dt,J=11. 5,7.4Hz,1H),4.58(dd,J=9.8,7.2Hz,1H),4.24(t,J=10.5Hz,1H),3.60–3.53(m,4H),3.40(s,3H),2.84(t,J=7.0Hz,2H),2.67(t,J=6.6Hz,2H).

[0365] Example 51: (S)-N 1 -(5-methyl-7-(4-(methylsulfonylamino)but-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (51)

[0366] Synthesis route:

[0367] The title compound 51 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of N-(but-3-yn-1-yl)methanesulfonamide 51a.

[0368] MS(ES + ):m / z 513.0[M+H] + .

[0369] 1 H NMR (400MHz, CDCl3): δ8.24 (d, J=7.4Hz, 1H), 7.32–7.27 (m, 5H), 7.24–7.2 1(m,1H),7.18(d,J=7.2Hz,2H),7.11(d,J=8.8Hz,1H),4.81(dt,J=11.1,7. 4Hz,1H),4.63–4.57(m,2H),4.24(t,J=10.6Hz,1H),3.59–3.51(m,2H),3. 41–3.35(m,5H),3.02(s,3H),2.84(t,J=7.0Hz,2H),2.73(t,J=6.4Hz,2H).

[0370] Example 52: (S)-N1 -(7-(3-methoxyprop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (52)

[0371] Synthesis route:

[0372] The title compound 52 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of methyl propargyl ether 52a.

[0373] MS(ES + ):m / z 436.1[M+H] + .

[0374] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.0Hz,1H),7.32–7.28(m,5H),7.24–7.20(m,1H),7.18(d,J=7.2Hz,2H),7.11(d,J=8.7Hz,1H),4.81(dt,J=11.4 ,7.1Hz,1H),4.59(dd,J=9.6,7.4Hz,1H),4.32(s,2H),4.24(t,J=10.5Hz ,1H),3.59–3.53(m,2H),3.46(s,3H),3.40(s,3H),2.84(t,J=7.1Hz,2H).

[0375] Example 53: (S)-2-(2-(2-(4-((5-methyl-4-oxo-3-(2-oxo-2-(phenylethylamino)acetamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of tert-butyl ester (53)

[0376] Synthesis route:

[0377] A mixture of compound 23 (60 mg, 0.13 mmol), potassium carbonate (54 mg, 0.39 mmol), and tert-butyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate 53a (57 mg, 0.15 mmol) was dissolved in DMF (1.0 mL) at room temperature. The reaction solution was heated to 80°C and stirred for 2 hours. TLC and LC-MS showed the reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was then separated and purified by preparative TLC (eluent: 5% methanol in dichloromethane) to afford the title compound 53 (55 mg, 65% yield) as a colorless oil.

[0378] MS(ES + ):m / z 677.1[M+H] + .

[0379] Example 54: (S)-1-(2-(2-(carboxymethoxy)ethoxy)ethyl)-4-((5-methyl-4-oxo-3-(2-oxo-2-(phenylethylamino)acetamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of 2,2,2-trifluoroacetate (54) of 1-(7-yl)ethynyl)piperidin-1-cation

[0380] Synthesis route:

[0381] To a solution of compound 53 (34 mg, 0.05 mmol) in dichloromethane (0.6 mL) was added trifluoroacetic acid (0.6 mL), and the reaction was stirred at room temperature for 2 hours. TLC and LC-MS indicated the reaction was complete. The reaction solution was concentrated under reduced pressure and dried in vacuo to afford the title compound 54 (36 mg, 98% yield) as a light yellow oil.

[0382] MS(ES + ):m / z 621.2[M+H] + .

[0383] Example 55: N 1-((S)-7-((1-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-carbonylbutan-2-yl)amino)-2-carbonylethoxy)ethoxy)ethyl)piperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (55)

[0384] Synthesis route:

[0385] Compound 54 (35 mg, 0.05 mmol), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride 55a (25 mg, 0.05 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 19 mg, 0.1 mmol), 1-hydroxybenzotriazole (HOBt, 14 mg, 0.1 mmol) and N,N-diisopropylethylamine (DIPEA, 39 mg, 0.3 mmol) were dissolved in dichloromethane (1.0 mL) at room temperature, and the reaction solution was stirred at room temperature for 15 h. TLC and LC-MS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure and purified by Prep-HPLC (water containing 30–80% acetonitrile as the mobile phase) to obtain compound 55 (11 mg, 23% yield) as a white solid.

[0386] MS(ES + ):m / z 1033.2[M+H] +

[0387] 1H NMR (400MHz, CDCl3): δ8.67(s,1H),8.24(d,J=7.5Hz,1H),7.80(s,1H),7.39–7.28(m,9H),7.24–7.21(m,2H),7.17(d,J=6 .9Hz,2H),7.09(d,J=8.2Hz,1H),4.83–4.77(m,2H),4.63(d,J=8.9Hz,1H),4.59–4.52(m,3H),4.42–4.38(m,1H),4.24(t,J =10.5Hz,1H),4.13–4.09(m,1H),3.97(d,J=11.0Hz,1H),3.93–3.85(m,3H),3.76–3.62(m,6H),3.58–3.48(m,3H),3.39(s ,3H),3.33–3.12(m,6H),2.85–2.78(m,3H),2.51(s,3H),2.35–2.29(m,2H),2.05–2.01(m,2H),1.83(br,1H),0.99(s,9H).

[0388] Example 56: N 1 -((3S)-7-((1-(2-(2-(2-((2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-4-yl)amino)-2-carbonylethoxy)ethoxy)ethyl)piperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (56)

[0389] Synthesis route:

[0390] The synthetic route and method were the same as those of Example 55, except that (2R,4S)-1-((R)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride 55a was replaced by an equivalent amount of 3-(4-amino-1-carbonylisoindolin-2-yl)piperidine-2,6-dione 56a (Lenalidomide) to obtain the title compound 56.

[0391] MS(ES + ):m / z 862.2[M+H] +

[0392] 1H NMR (400MHz, DMSO-d6): δ11.01(s,1H),9.68(s,1H),8.81(t,J=5.9Hz,1H),8.74(d,J=7.3Hz,1H),7.74(d,J=7.7Hz,1H),7.57–7.47 (m,3H),7.29–7.25(m,3H),7.20–7.17(m,4H),5.14(dd,J=13.2,4.8Hz,1H),4.67–4.55(m,2H),4.44–4.32(m,3H),4.14(s,2H),3.70 –3.68(m,2H),3.61–3.59(m,2H),3.54(t,J=5.4Hz,2H),3.43–3.35(m,2H),3.29(s,3H),2.90–2.86(m,1H),2.77(t,J=7.5Hz,2H),2 .73–2.67(m,2H),2.61–2.57(m,2H),2.39–2.33(m,2H),2.18–2.09(m,2H),2.03–1.97(m,2H),1.81–1.75(m,2H),1.56–1.48(m,2H).

[0393] Example 57: (S)-N 1 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (57)

[0394] Synthesis route:

[0395] The title compound 57 was prepared by the same synthetic route and method as in Example 1, except that 4-bromo-1-fluoro-2-nitrobenzene 1a in step 1 was replaced with an equivalent amount of 1-fluoro-2-nitrobenzene 57a.

[0396] MS(ES + ):m / z 368.1[M+H] + .

[0397] 1H NMR (400MHz, CDCl3): δ8.26(d,J=7.2Hz,1H),7.32–7.28(m,3H),7.25–7.21(m,4H),7.19–7.17(m,3H),4.83(dt,J=11.2 ,7.5Hz,1H),4.61(dd,J=9.6,7.6Hz,1H),4.23(t,J=10.4Hz,1H),3.58–3.55(m,2H),3.42(s,3H),2.84(t,J=7.2Hz,2H).

[0398] Example 58: (S)-N 1 -Benzyl--N 2 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (58)

[0399] Synthesis route:

[0400] The title compound 58 was prepared by the same synthetic route and method as in step 7 of Example 57, except that 2-phenylethylamine 1i was replaced by an equivalent amount of benzylamine 32a.

[0401] MS(ES + ):m / z 354.1[M+H] + .

[0402] 1 H NMR (400MHz, CDCl3): δ8.31(d,J=7.6Hz,1H),7.55(t,J=4.8Hz,1H),7.35–7.27(m,4H),7.24–7.17(m,5H),4.84( dt,J=11.1,7.6Hz,1H),4.62(dd,J=9.8,7.6Hz,1H),4.48(d,J=6.0Hz,2H),4.24(t,J=10.0Hz,1H),3.43(s,3H).

[0403] Example 59: (S)-N 1 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -(3-phenylpropyl)oxamide (59)

[0404] Synthesis route:

[0405] The title compound 59 was prepared by the same synthetic route and method as in step 7 of Example 57, except that 2-phenylethylamine 1i was replaced by an equivalent amount of 3-phenyl-1-propylamine 59a.

[0406] MS(ES + ):m / z 382.1[M+H] + .

[0407] 1 H NMR (400MHz, CDCl3): δ8.27(d,J=4.4Hz,1H),7.30–7.28(m,2H),7.25–7.15(m,8H),4.83(dt,J=10.9,6.8Hz,1H),4.62(dd,J=9 .8,7.4Hz,1H),4.24(dd,J=11.1,9.8Hz,1H),3.42(s,3H),3.33(q,J=6.9Hz,2H),2.65(t,J=7.6Hz,2H),1.88(qn,J=7.4Hz,2H).

[0408] Example 60: (S)-N 1 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of Benzoxamide (60)

[0409] Synthesis route:

[0410] Step 1: (S)-2-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of 2-oxoacetic acid (60a)

[0411] To a solution of compound 57g (60 mg, 0.2 mmol) in tetrahydrofuran:methanol:water (1:1:1, 6 mL) was added lithium hydroxide monohydrate (26 mg, 0.6 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. TLC and LC-MS showed that the reaction was complete. The reaction mixture was poured into water (10 mL), acidified with dilute hydrochloric acid (1 N) to a pH of approximately 6, and then extracted with ethyl acetate (20 mL x 5). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of compound 60a (46 mg), which was used directly in the next step without further purification.

[0412] MS(ES +):m / z 263.1[M+H] + .

[0413] Step 2: (S)-N 1 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of Benzoxamide (60)

[0414] To a solution of compound 60a (46 mg, 0.17 mmol) and aniline (20 mg, 0.2 mmol) in pyridine (0.5 mL) was slowly added dropwise with phosphorus oxychloride (72 mg, 0.47 mmol) under a 0°C ice bath. The resulting mixture was stirred at 0°C for 0.5 h. TLC and LC-MS indicated the reaction was complete. The reaction mixture was poured into ice water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was then separated and purified by Prep-HPLC (water containing 30–90% acetonitrile as the mobile phase) to afford compound 60 (5 mg, 7% yield over two steps) as a white solid.

[0415] MS(ES + ):m / z 340.1[M+H] + .

[0416] 1 H NMR (400MHz, CDCl3): δ9.01 (s, 1H), 8.42 (d, J = 7.1Hz, 1H), 7.69–7.60 (m, 3H), 7.43–7.35 (m, 3H), 7.24–7.16 ( m,3H),4.88(dt,J=11.1,7.4Hz,1H),4.68(dd,J=9.7,7.5Hz,1H),4.27(dd,J=11.0,9.9Hz,1H),3.44(s,3H).

[0417] Example 61: N 1 -(8-Bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -3-yl)-N 2 -Synthesis of phenylacetamide (61)

[0418] Synthesis route:

[0419] Step 1: Synthesis of (E)-7-bromo-3,4-dihydronaphthalen-1(2H)-one oxime (61b)

[0420] To a solution of 7-bromo-3,4-dihydronaphthalen-1(2H)-one 61a (5.0 g, 22 mmol) in ethanol (50 mL) were added hydroxylamine hydrochloride (3.1 g, 44 mmol) and sodium acetate (3.6 g, 44 mmol). The reaction was stirred at 70°C for 2 hours. TLC and LC-MS indicated the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove most of the solvent. The residue was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product of compound 61b (5.3 g) as a yellow solid, which was used directly in the next step without further purification.

[0421] MS(ES + ):m / z 283.0[M+CH3CN+H] + .

[0422] 1 H NMR (400MHz, CDCl3): δ8.24(br,1H),8.03(d,J=2.0Hz,1H),7.37(dd,J=8.2,2.4Hz,1H),7 .03(d,J=8.0Hz,1H),2.80(t,J=6.8Hz,2H),2.71(t,J=6.4Hz,2H),1.86(qn,J=6.4Hz,2H).

[0423] Step 2: 8-Bromo-1,3,4,5-tetrahydro-2H-benzo[b]azepine Synthesis of -2-ketone (61c)

[0424] A mixture of phosphorus pentoxide (5.4 g, 38 mmol) and methanesulfonic acid (54 mL) was stirred at 90°C for 1 hour. After cooling to 50°C, compound 61b was added in five portions. The resulting mixture was then stirred at 80°C for 16 hours. TLC and LC-MS showed the reaction was complete. The reaction mixture was slowly poured into ice water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting product was then purified by silica gel column chromatography (eluent: 30% ethyl acetate in petroleum ether) to afford compound 61c (3.8 g, 70% yield) as a light yellow solid.

[0425] MS(ES + ):m / z 282.9[M+CH3CN+H] + .

[0426] 1H NMR (400MHz, DMSO-d6): δ9.61 (s, 1H), 7.27–7.24 (m, 1H), 7.22–7.19 (m, 1H), 7.13 (d, J = 2.0Hz, 1H), 2.65 (t, J = 7.2Hz, 2H), 2.16–2.06 (m, 4H).

[0427] Step 3: 8-Bromo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepine Synthesis of -2-ketone (61d)

[0428] To a mixture of compound 61c (3.8 g, 16 mmol) and potassium carbonate (6.6 g, 47 mmol) in DMF (30 mL) was added iodomethane (4.5 g, 32 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 15 hours. TLC and LC-MS showed that the reaction was complete. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (eluent: 20% ethyl acetate in petroleum ether) to afford compound 61d (3.4 g, 84% yield) as a white solid.

[0429] MS(ES + ):m / z 255.9[M+H] + .

[0430] 1 H NMR (400MHz, CDCl3): δ7.31 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.0, 2.0 Hz, 1H), 7.06 (d, J = 8. 0Hz,1H),3.33(s,3H),2.67(t,J=6.8Hz,2H),2.30(t,J=6.8Hz,2H),2.17–2.14(m,2H).

[0431] Step 4: 8-Bromo-3-iodo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepine Synthesis of -2-ketone (61e)

[0432] To a solution of compound 61d (1.5 g, 5.9 mmol) and N,N,N',N'-tetramethylethylenediamine (2.1 g, 17.8 mmol) in dichloromethane (15 mL) was added dropwise iodotrimethylsilane (3.6 g, 17.8 mmol) under an ice bath at 0°C. The reaction mixture was stirred at 0°C for 1 hour, followed by the addition of iodine (2.3 g, 8.9 mmol), and the reaction mixture was stirred at 0°C for an additional 2 hours. TLC and LC-MS indicated the reaction was complete. The reaction was quenched with 5% aqueous sodium thiosulfate (40 mL), and the aqueous phase was extracted with dichloromethane (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting mixture was then purified by silica gel column chromatography (eluent: 5% ethyl acetate in petroleum ether) to afford compound 61e (1.5 g, 66% yield) as a light yellow solid.

[0433] MS(ES + ):m / z 381.7[M+H] + .

[0434] 1 H NMR (400MHz, DMSO-d6): δ7.61(d,J=2.0Hz,1H),7.41(dd,J=8.0,2.0Hz,1H),7 .24(d,J=8.0Hz,1H),4.61(t,J=8.4Hz,1H),3.28(s,3H),2.72–2.54(m,4H),.

[0435] Step 5: 3-Azido-8-bromo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepine Synthesis of -2-ketone (61f)

[0436] To a solution of compound 61e (1.5 g, 3.9 mmol) in DMF (15 mL) was added sodium azide (309 mg, 4.7 mmol) in an ice bath at 0°C. The reaction mixture was warmed to room temperature and stirred for 3 hours. TLC and LC-MS indicated the reaction was complete. The reaction was quenched with ice water (20 mL) and filtered. The filter cake was rinsed with ice water (5 mL) and drained to afford compound 61f (1.1 g, 96% yield) as a white solid, which was used directly in the next step without further purification.

[0437] MS(ES + ):m / z 296.8[M+H] + .

[0438] Step 6: 3-Amino-8-bromo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepine Synthesis of -2-ketone (61 g)

[0439] To a solution of compound 61e (1.1 g, 3.7 mmol) and triphenylphosphine (1.1 g, 4.0 mmol) in tetrahydrofuran (20 mL) was added water (132 mg, 7.3 mmol), and the reaction mixture was stirred at room temperature for 15 hours. TLC and LC-MS showed the reaction was complete. The reaction solution was directly concentrated under reduced pressure and purified by silica gel column chromatography (eluent: 1–5% methanol in dichloromethane) to afford compound 61g (790 mg, 79% yield) as a white solid.

[0440] MS(ES + ):m / z 270.9[M+H] + .

[0441] 1 H NMR (400MHz, CDCl3): δ7.30–7.27(m,2H),7.08(d,J=7.6Hz,1H),3.37(s,3H),3.35–3. 33(m,1H),2.77–2.68(m,1H),2.59–2.53(m,1H),2.42–2.32(m,1H),1.91–1.83(m,1H).

[0442] Step 7: 2-(8-Bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine Synthesis of ethyl 2-oxo-3-yl)amino)-2-oxoacetate (61h)

[0443] To a mixture of compound 61g (790 mg, 2.9 mmol) and triethylamine (587 mg, 5.8 mmol) in dichloromethane (15 mL) was slowly added dropwise a solution of ethyl oxalyl chloride (478 mg, 3.5 mmol) in dichloromethane (2 mL) under an ice bath at 0°C. The reaction solution was slowly warmed to room temperature and stirred for 3 hours. TLC and LC-MS showed the reaction was complete. The reaction mixture was poured into water (100 mL) and extracted with dichloromethane (60 mL x 3). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (eluent: 20% ethyl acetate in petroleum ether) to afford compound 61h (985 mg, 92% yield) as a white solid.

[0444] MS(ES + ):m / z 368.9[M+H] + .

[0445] 1H NMR (400MHz, CDCl3): δ8.02(d,J=6.7Hz,1H),7.37–7.33(m,2H),7.13(d,J=8.0Hz,1H),4.43(dt,J=11.0,7 .4Hz,1H),4.34(q,J=7.1Hz,2H),3.41(s,3H),2.85–2.60(m,3H),2.00–1.92(m,1H),1.37(t,J=7.1Hz,3H).

[0446] Step 8: N 1 -(8-Bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -3-yl)-N 2 -Synthesis of phenylacetamide (61)

[0447] To a solution of compound 61h (985 mg, 2.7 mmol) in ethanol (20 mL) was added 2-phenylethylamine 1i (787 mg, 6.0 mmol). The reaction mixture was warmed to 80°C and stirred for an additional 4 hours. TLC and LC-MS showed that the reaction was complete, with a large amount of white solid precipitated in the reaction mixture. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with petroleum ether containing 15% ethyl acetate (10 mL). The filter cake was drained to afford the title compound 61 (971 mg, 81% yield) as a white solid.

[0448] MS(ES + ):m / z 446.0[M+H] + .

[0449] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.5Hz,1H),7.35–7.28(m,5H),7.24–7.20(m,1H),7.18(d,J=7.0Hz,2H),7.11(d,J=8.6Hz, 1H),4.39(dt,J=11.2,7.5Hz,1H),3.62–3.49(m,2H),3.40(s,3H),2.87–2.76(m,3H),2.64–2.53(m,2H),2.05–1.97(m,1H).

[0450] Example 62: N 1 -(8-(cyclopropylethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -3-yl)-N 2 -Synthesis of phenylacetamide (62)

[0451] Synthesis route:

[0452] Compound 61 (44.4 mg, 0.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (7.0 mg, 0.01 mmol), cuprous iodide (1.9 mg, 0.01 mmol), triethylamine (1 mL), DMF (2 mL), and cyclopropylacetylene 2a (13.2 mg, 0.2 mmol) were added sequentially to a sealed tube at room temperature. The air in the tube was quickly replaced with nitrogen three times, and the reaction solution was stirred at 80°C for 15 hours. TLC and LC-MS showed that the reaction was complete. After cooling to room temperature, the reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (eluent: 20% ethyl acetate in petroleum ether) to obtain the title compound 62 (37.4 mg, 87% yield) as a white solid.

[0453] MS(ES + ):m / z 430.2[M+H] + .

[0454] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.6Hz,1H),7.35–7.28(m,3H),7.24–7.17(m,5H),7.12(d,J=7.7Hz,1H),4.37(dt,J=11.3,7.5Hz,1H),3.61 –3.50(m,2H),3.38(s,3H),2.89–2.79(m,3H),2.63–2.52(m,2H),2.05 –1.95(m,1H),1.51–1.42(m,1H),0.91–0.85(m,2H),0.83–0.79(m,2H).

[0455] Example 63: N 1 -(7-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -3-yl)-N 2 -Synthesis of phenylacetamide (63)

[0456] Synthesis route:

[0457] The synthetic route and method are the same as those of Example 61, except that the compound 7-bromo-3,4-dihydronaphthalene-1(2H)-one 61a in step 1 is replaced by an equivalent amount of 6-bromo-3,4-dihydronaphthalene-1(2H)-one 63a to obtain the title compound 63.

[0458] MS(ES + ):m / z 446.0[M+H] + .

[0459] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.5Hz,1H),7.45(dd,J=8.5,2.1Hz,1H),7.38(d,J=2.1Hz,1H),7.34–7.28(m,3H),7.24–7.20(m,1H),7.18(d,J=7.2 Hz,2H),7.05(d,J=8.5Hz,1H),4.38(dt,J=11.2,7.5Hz,1H),3.62–3.49(m, 2H),3.38(s,3H),2.89–2.80(m,3H),2.64–2.54(m,2H),2.05–1.97(m,1H).

[0460] Example 64: N 1 -(7-(cyclopropylethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -3-yl)-N 2 -Synthesis of phenylacetamide (64)

[0461] Synthesis route:

[0462] The title compound 64 was prepared by the same synthetic route and method as Example 62, except that compound 61 was replaced by an equivalent amount of compound 63.

[0463] MS(ES + ):m / z 430.2[M+H] + .

[0464] 1H NMR (400MHz, CDCl3): δ8.24(d,J=7.6Hz,1H),7.36–7.27(m,4H),7.25–7.20( m,2H),7.17(d,J=7.3Hz,2H),7.07(d,J=8.2Hz,1H),4.37(dt,J=11.2,7.4Hz ,1H),3.61–3.48(m,2H),3.38(s,3H),2.88–2.77(m,3H),2.62–2.52(m,2H), 2.04–1.95(m,1H),1.49–1.42(m,1H),0.91–0.85(m,2H),0.83–0.79(m,2H).

[0465] Example 65: N 1 -(8-(4-hydroxybut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -3-yl)-N 2 -Synthesis of phenylacetamide (65)

[0466] Synthesis route:

[0467] The title compound 65 was prepared by the same synthetic route and method as Example 62, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-butyn-1-ol 31a.

[0468] MS(ES + ):m / z 434.0[M+H] + .

[0469] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.4Hz,1H),7.35–7.28(m,3H),7.23–7.15(m,6H),4.38(dt,J=11.2,7.6Hz,1H),3.83(t,J=6.2Hz,2H) ,3.60–3.50(m,2H),3.39(s,3H),2.89–2.80(m,3H),2.70(t,J=6.2Hz,2H),2.65–2.53(m,2H),2.04–1.96(m,1H),1.42(t,J=7.2Hz,1H).

[0470] Example 66: N 1 -(1-methyl-2-oxo-8-(piperidin-4-ylethynyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine -3-yl)-N2 -Synthesis of phenylacetamide (66)

[0471] Synthesis route:

[0472] The title compound 66 was prepared by the same synthetic route and method as Example 62, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 4-ethynylpiperidine hydrochloride 23a.

[0473] MS(ES + ):m / z 473.3[M+H] + .

[0474] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.3Hz,1H),7.34–7.28(m,3H),7.23–7.16(m,6H),4.38(dt,J=11.2,7.6Hz,1H),3.58–3.52(m,2H), 3.45–3.40(m,5H),3.29–3.23(m,2H),3.10–3.06(m,1H),2.88–2.81(m,3H),2.66–2.54(m,2H),2.32–2.24(m,2H),2.11–1.96(m,3H).

[0475] Example 67: N 1 -(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -3-yl)-N 2 Synthesis of -phenylacetamide (67)

[0476] Synthesis route:

[0477] The synthetic route and method are the same as those of Example 61, except that the compound 7-bromo-3,4-dihydronaphthalen-1(2H)-one 61a in step 1 is replaced by an equivalent amount of 3,4-dihydronaphthalen-1(2H)-one 67a to obtain the title compound 67.

[0478] MS(ES + ):m / z 366.1[M+H] + .

[0479] 1H NMR (400MHz, CDCl3): δ8.27(d,J=7.7Hz,1H),7.34–7.27(m,4H),7.24–7.16(m,6H),4.41(dt,J=11.3, 7.6Hz,1H),3.62–3.49(m,2H),3.41(s,3H),2.93–2.81(m,3H),2.66–2.56(m,2H),2.04–1.97(m,1H).

[0480] Example 68: N 1 -Benzyl-N 2 -(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine Synthesis of oxalamide (68)

[0481] Synthesis route:

[0482] The title compound 68 was prepared by the same synthetic route and method as in step 8 of embodiment 67, except that 2-phenylethylamine 1i was replaced by an equivalent amount of benzylamine 32a.

[0483] MS(ES + ):m / z 352.1[M+H] + .

[0484] 1 H NMR (400MHz, CDCl3): δ8.33(d,J=7.1Hz,1H),7.57(t,J=5.4Hz,1H),7.35–7.27(m,6H),7.23–7.17(m,3H),4.48(d, J=6.2Hz,2H),4.43(dt,J=11.3,7.5Hz,1H),3.42(s,3H),2.93–2.84(m,1H),2.68–2.58(m,2H),2.06–1.98(m,1H).

[0485] Example 69: N 1 -(9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine -7-yl)-N 2 Synthesis of -phenylacetamide (69)

[0486] Synthesis route:

[0487] The synthetic route and method are the same as those of Example 61, except that the compound 7-bromo-3,4-dihydronaphthalen-1(2H)-one 61a in step 1 is replaced by an equivalent amount of 6,7-dihydroquinolin-8(5H)-one 69a to obtain the title compound 69.

[0488] MS(ES + ):m / z 367.1[M+H] + .

[0489] 1 H NMR (400MHz, CDCl3): δ8.41 (dd, J=4.8, 1.5Hz, 1H), 8.34 (d, J=7.2Hz, 1H), 7.5 8(dd,J=7.5,1.4Hz,1H),7.32–7.28(m,3H),7.24–7.20(m,1H),7.18(d,J=7.2 Hz,2H),7.13(dd,J=7.5,4.8Hz,1H),4.40(dt,J=11.3,7.4Hz,1H),3.61–3.52 (m,2H),3.51(s,3H),2.87–2.82(m,3H),2.74–2.62(m,2H),2.10–2.00(m,1H).

[0490] Example 70: N 1 -(8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine -7-yl)-N 2 -Synthesis of phenylacetamide (70)

[0491] Synthesis route:

[0492] The title compound 70 was prepared by the same synthetic route and method as steps 4-8 of Example 69, except that compound 69d in step 4 was replaced by an equivalent amount of compound 69c.

[0493] MS(ES + ):m / z 353.1[M+H] + .

[0494] 1H NMR (400MHz, DMSO-d6): δ10.42(s,1H),8.81(t,J=6.0Hz,1H),8.66(d,J=7.8Hz,1H),8.30(dd,J=4.8,1.2Hz,1H),7.76(d ,J=7.4Hz,1H),7.30–7.26(m,2H),7.21–7.16(m,4H),4.13(dt,J=11.3,8.1Hz,1H),2.79–2.64(m,5H),2.43–2.31(m,3H).

[0495] Example 71: (R)-N 1 -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (71)

[0496] Synthesis route:

[0497] The title compound 2 was prepared by the same synthetic route and method as in Example 1, except that (tert-butoxycarbonyl)-L-serine 1b was replaced by an equivalent amount of (tert-butoxycarbonyl)-D-serine 71a.

[0498] MS(ES + ):m / z 422.0[M+H] + .

[0499] 1 H NMR (400MHz, CDCl3): δ8.22(d,J=7.5Hz,1H),7.35–7.28(m,5H),7.25–7.21(m,1H),7.18(d,J=7.3Hz,2H),7.06(d,J=8.7Hz,1H),4.8 1(dt,J=11.3,7.4Hz,1H),4.58(dd,J=9.7,7.4Hz,1H),4.23(t,J=10.5Hz,1H),3.59–3.54(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H).

[0500] Example 72: (S)-N 1 -(7-(3-(1H-imidazol-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (72)

[0501] Synthesis route:

[0502] The title compound 72 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)-1H-imidazole 72a.

[0503] MS(ES + ):m / z 472.2[M+H] + .

[0504] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.3Hz,1H),7.77(br,1H),7.32–7.28(m,6H),7.24–7.21(m,2H),7.17(d,J=7.2Hz,2H),7.13(d,J=8.4Hz,1H),4.9 6(s,2H),4.81(dt,J=11.3,7.4Hz,1H),4.59(dd,J=9.7,7.3Hz,1H),4.25 (t,J=10.6Hz,1H),3.59–3.53(m,2H),3.41(s,3H),2.84(t,J=7.1Hz,2H).

[0505] Example 73: (S)-N 1 -(5-methyl-7-((1-methylpiperidin-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (73)

[0506] Synthesis route:

[0507] To a solution of compound 23 (47 mg, 0.1 mmol) in methanol (3.0 mL) was added paraformaldehyde (18 mg, 0.2 mmol) at room temperature. The reaction mixture was stirred for 2 minutes, followed by the addition of sodium cyanoborohydride (13 mg, 0.2 mmol) and acetic acid (12 mg, 0.2 mmol), and the mixture was stirred at room temperature for 15 hours. TLC and LC-MS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was then purified by silica gel column chromatography (eluent: 5–10% methanol in dichloromethane) to afford the title compound 73 (20 mg, 41% yield) as a white solid.

[0508] MS(ES +):m / z 489.3[M+H] + .

[0509] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.4Hz,1H),7.35–7.28(m,3H),7.25–7.21(m,3H),7.17 (d,J=7.2Hz,2H),7.11(d,J=8.8Hz,1H),4.81(dt,J=11.1,7.4Hz,1H),4.57(dd,J=9.6,7. 5Hz,1H),4.24(t,J=10.6Hz,1H),3.59–3.54(m,2H),3.41(s,3H),3.18–3.12(m,2H),3.0 0–2.95(m,2H),2.84(t,J=7.0Hz,2H),2.69(s,3H),2.33–2.28(m,2H),2.07–2.02(m,3H).

[0510] Example 74: (S)-N 1 -(7-((1-(cyanomethyl)piperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (74)

[0511] Synthesis route:

[0512] The title compound 74 can be prepared by the same synthetic route and method as Example 73 through the same reaction.

[0513] MS(ES + ):m / z 514.2[M+H] + .

[0514] 1H NMR (400MHz, CDCl3): δ8.24 (d, J=7.2Hz, 1H), 7.32–7.28 (m, 4H), 7.25–7.21 (m, 2H), 7.17(d,J=7.2Hz,2H),7.09(d,J=8.2Hz,1H),4.80(dt,J=11.1,7.4Hz,1H),4.58(dd, J=9.4,7.6Hz,1H),4.23(t,J=10.5Hz,1H),3.58–3.54(m,4H),3.40(s,3H),2.85–2.8 2(m,4H),2.66(br,1H),2.49(t,J=8.6Hz,2H),2.00–1.97(m,2H),1.84–1.77(m,2H).

[0515] Example 75: (S)-N 1 -(7-((4-(dimethylamino)phenyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (75)

[0516] Synthesis route:

[0517] The title compound 75 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 4-ethynyl-N,N-dimethylaniline 75a.

[0518] MS(ES + ):m / z 511.3[M+H] + .

[0519] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.6Hz,1H),7.40(d,J=8.7Hz,2H),7.35–7.28(m ,5H),7.24–7.21(m,1H),7.18(d,J=7.2Hz,2H),7.12(d,J=8.8Hz,1H),6.66(d,J= 8.8Hz, 2H), 4.84 (dt, J=11.2, 7.3Hz, 1H), 4.61 (dd, J=9.7, 7.4Hz, 1H), 4.23 (t, J= 10.5Hz,1H),3.59–3.54(m,2H),3.43(s,3H),3.00(s,6H),2.84(t,J=7.1Hz,2H).

[0520] Example 76: (S)-N 1 -(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (76)

[0521] Synthesis route:

[0522] The title compound 76 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-ethynyloxetane 76a.

[0523] MS(ES + ):m / z 448.2[M+H] + .

[0524] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.3Hz,1H),7.31–7.28(m,5H),7.24–7.21(m,1H),7.16(d,J=6.9Hz,2H),7.11(d,J=8.8Hz,1H),4.91–4.86(m,2H) ,4.82–4.78(m,3H),4.59(dd,J=9.7,7.4Hz,1H),4.24(t,J=10.5Hz,1H), 4.10–4.02(m,1H),3.59–3.52(m,2H),3.41(s,3H),2.84(t,J=7.1Hz,2H).

[0525] Example 77: (R)-N 1 -(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (77)

[0526] Synthesis route:

[0527] The title compound 77 was prepared by the same synthetic route and method as Example 43, except that compound 1 was replaced by an equivalent amount of compound 71.

[0528] MS(ES + ):m / z 464.1[M+H] + .

[0529] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.4Hz,1H),7.32–7.28(m,5H),7.24–7.21(m,1H),7.18(d,J=7.3Hz,2H),7.14(d,J=8.8Hz,1H),4.94(d,J=6.6Hz ,2H),4.85–4.78(m,3H),4.60(dd,J=9.6,7.4Hz,1H),4.26(t,J=10.6Hz, 1H),3.59–3.54(m,2H),3.42(s,3H),2.84(t,J=7.1Hz,2H),2.69(br,1H).

[0530] Example 78: (S)-N 1 -(7-((3-methoxyoxetane-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (78)

[0531] Synthesis route:

[0532] The title compound 78 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-ethynyl-3-methoxyoxetane 78a.

[0533] MS(ES + ):m / z 478.3[M+H] + .

[0534] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.2Hz,1H),7.34–7.28(m,5H),7.24–7.21(m ,1H),7.18(d,J=7.3Hz,2H),7.14(d,J=8.8Hz,1H),4.85(d,J=6.6Hz,2H),4.83 –4.80(m,1H),4.77(d,J=6.5Hz,2H),4.59(dd,J=9.7,7.3Hz,1H),4.26(t,J=10 .6Hz,1H),3.59–3.52(m,2H),3.42(s,3H),3.41(s,3H),2.84(t,J=7.1Hz,2H).

[0535] Example 79: (S)-N 1-(7-(3-(3-hydroxyoxetane-3-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (79)

[0536] Synthesis route:

[0537] The title compound 79 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-(prop-2-yn-1-yl)oxetane-3-ol 79a.

[0538] MS(ES + ):m / z 478.2[M+H] + .

[0539] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.3Hz,1H),7.32–7.27(m,5H),7.24–7.21(m,1H),7.18(d,J=6.9Hz,2H),7.11(d,J=8.8Hz, 1H),4.80(dt,J=11.3,7.4Hz,1H),4.69(d,J=7.0Hz,2H),4.60–4.56(m,3H),4.24(t,J=10. 5Hz,1H),3.59–3.52(m,2H),3.41(s,3H),3.01(s,2H),2.84(t,J=7.2Hz,2H),3.54(s,1H).

[0540] Example 80: N 1 -((3S)-7-((3-Hydroxytetrahydrofuran-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (80)

[0541] Synthesis route:

[0542] The title compound 80 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-ethynyltetrahydrofuran-3-ol 80a.

[0543] MS(ES + ):m / z 476.2[MH]- .

[0544] 1 H NMR (400MHz, CDCl3): δ8.24 (d, J=7.3Hz, 1H), 7.32–7.28 (m, 5H), 7.24–7.21 (m, 1H),7.18(d,J=6.8Hz,2H),7.12(d,J=8.7Hz,1H),4.80(dt,J=11.3,7.3Hz,1H), 4.59(dd,J=9.7,7.3Hz,1H),4.25(t,J=10.5Hz,1H),4.11–3.92(m,4H),3.61–3 .52(m,2H),3.41(s,3H),2.84(t,J=7.0Hz,2H),2.46–2.30(m,2H),2.24(s,1H).

[0545] Example 81: (S)-N 1 -(7-(3-(4-hydroxypiperidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (81)

[0546] Synthesis route:

[0547] The title compound 81 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)piperidin-4-ol 81a.

[0548] MS(ES + ):m / z 505.3[M+H] + .

[0549] 1H NMR (400MHz, CDCl3): δ8.23(d,J=7.5Hz,1H),7.32–7.28(m,5H),7.24–7.21(m,1H),7.17(d,J=7.1 Hz,2H),7.10(d,J=8.9Hz,1H),4.81(dt,J=11.2,7.4Hz,1H),4.58(dd,J=9.7,7.4Hz,1H),4.23(dd ,J=11.0,10.0Hz,1H),3.75(br,1H),3.59–3.54(m,2H),3.51(s,2H),3.40(s,3H),2.90–2.86(m,2 H),2.84(t,J=7.2Hz,2H),2.44–2.39(m,2H),1.99–1.95(m,2H),1.71–1.63(m,2H),1.41(br,1H).

[0550] Example 82: N 1 -((3S)-5-methyl-7-(3-(1-methyl-2-carbonylpyrrolidin-3-yl)prop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (82)

[0551] Synthesis route:

[0552] The title compound 82 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 1-methyl-3-(prop-2-yn-1-yl)pyrrolidin-2-one 82a.

[0553] MS(ES + ):m / z 503.2[M+H] + .

[0554] 1H NMR (400MHz, CDCl3): δ8.23(d,J=7.4Hz,1H),7.32–7.28(m,3H),7.24–7.21(m,3H),7 .18(d,J=7.0Hz,2H),7.08(d,J=8.7Hz,1H),4.80(dt,J=11.3,7.4Hz,1H),4.57(dd,J =9.7,7.4Hz,1H),4.22(t,J=10.5Hz,1H),3.59–3.53(m,2H),3.42–3.35(m,5H),2.89 (s,3H),2.88–2.79(m,3H),2.74–2.61(m,2H),2.38–2.30(m,1H),2.07–1.98(m,1H).

[0555] Example 83: (S)-N 1 -(7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (83)

[0556] Synthesis route:

[0557] To a mixture of compound 49 (39 mg, 0.08 mmol) and potassium carbonate (22 mg, 0.16 mmol) in acetonitrile (1.0 mL) was added dropwise a solution of 2-bromoethanol 83a (15 mg, 0.12 mmol) in acetonitrile (0.2 mL) at room temperature. The reaction was stirred at room temperature for 1.5 hours. TLC and LC-MS showed the reaction was complete. The reaction solution was filtered, the filter cake was washed with a small amount of acetonitrile, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (eluent: 5–10% methanol in dichloromethane) to afford the title compound 83 (36 mg, 84% yield) as a white solid.

[0558] MS(ES + ):m / z 534.3[M+H] + .

[0559] 1H NMR (400MHz, CDCl3): δ8.24(d,J=7.5Hz,1H),7.32–7.28(m,5H),7.24–7.21(m,1H),7.18(d,J=7.4Hz,2H),7.10(d,J=8.8Hz,1H),4 .81(dt,J=11.6,7.5Hz,1H),4.58(dd,J=9.3,7.7Hz,2H),4.23(t,J=10.5Hz,1H),3.63(t,J=5.2Hz,2H),3.59–3.54(m,2H),3.52(s, 2H),3.41(s,3H),2.84(t,J=7.0Hz,2H),2.72–2.59(m,8H),2.58(t,J=5.2Hz,2H).

[0560] Example 84: (S)-N 1 -(7-(3-(2,5-dicarbonylpyrrolidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (84)

[0561] Synthesis route:

[0562] The title compound 84 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)pyrrolidine-2,5-dione 84a.

[0563] MS(ES + ):m / z 503.2[M+H] + .

[0564] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.3Hz,1H),7.32–7.27(m,5H),7.24–7.21(m,1H),7.17(d,J=7.1Hz,2H),7.09(d,J=8.8Hz,1H),4.78(dt,J=11.2 ,7.4Hz,1H),4.58(dd,J=9.7,7.3Hz,1H),4.49(s,2H),4.23(t,J=10.5Hz ,1H),3.60–3.52(m,2H),3.39(s,3H),2.84(t,J=7.1Hz,2H),2.80(s,4H).

[0565] Example 85: (S)-N 1 -(5-methyl-4-oxo-7-(3-(3-carbonylpiperazin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (85)

[0566] Synthesis route:

[0567] The title compound 85 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 4-(prop-2-yn-1-yl)piperazin-2-one 85a.

[0568] MS(ES + ):m / z 504.2[M+H] + .

[0569] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.5Hz,1H),7.32–7.28(m,5H),7.24–7.21(m,1 H),7.17(d,J=7.2Hz,2H),7.11(d,J=8.8Hz,1H),5.96(s,1H),4.81(dt,J=11.3, 7.4Hz,1H),4.58(dd,J=9.7,7.3Hz,1H),4.24(t,J=10.5Hz,1H),3.63(s,2H),3. 59–3.53(m,2H),3.46–3.43(m,2H),3.41(s,3H),3.36(s,2H),2.86–2.82(m,4H).

[0570] Example 86: (S)-(3-(5-methyl-4-oxo-3-(2-oxo-2-(phenylethylamino)acetamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of tert-butyl (7-yl)prop-2-yn-1-yl)carbamate (86)

[0571] Synthesis route:

[0572] The synthetic route and method were the same as those in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of tert-butyl prop-2-yn-1-ylcarbamate 86a to prepare compound 86.

[0573] MS(ES +):m / z 521.2[M+H] + .

[0574] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.5Hz,1H),7.32–7.27(m,5H),7.24–7.21(m,1H),7.17(d,J=7.1Hz,2H),7.10(d,J=8.7Hz,1H),4.84–4.77(m,2H ),4.59(dd,J=9.7,7.3Hz,1H),4.23(t,J=10.5Hz,1H),4.15(d,J=4.8Hz, 2H),3.61–3.52(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H),1.47(s,9H).

[0575] Example 87: (S)-N 1 -(7-(3-aminoprop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of phenylacetamide hydrochloride (87)

[0576] Synthesis route:

[0577] To a solution of compound 86 (26 mg, 0.05 mmol) in dichloromethane (1 mL) was added dropwise a solution of hydrogen chloride in 1,4-dioxane (4 N, 0.2 mL) at room temperature. The reaction was stirred at room temperature for 3 hours. TLC and LC-MS indicated the reaction was complete. The solvent and other volatiles were removed by concentration under reduced pressure to afford the title compound 87 (22 mg, 96% yield) as a white solid.

[0578] MS(ES + ):m / z 421.2[M+H] + .

[0579] 1H NMR (400MHz, DMSO-d6): δ8.81–8.77(m,2H),8.44(br,3H),7.56(d,J=1.5Hz,1H),7.37(dd,J=8.3,1.6Hz,1H),7.30–7.26(m,3H ),7.21–7.18(m,3H),4.69–4.60(m,2H),4.42–4.35(m,1H),4.00(s,2H),3.39–3.36(m,2H),3.30(s,3H),2.77(t,J=7.4Hz,2H).

[0580] Example 88: (S)-N 1 -(7-(3-(2-hydroxyacetylamino)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (88)

[0581] Synthesis route:

[0582] To a solution of compound 87 (23 mg, 0.05 mmol) in DMF (2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 12 mg, 0.06 mmol), N,N-diisopropylethylamine (DIPEA, 16 mg, 0.12 mmol), and glycolic acid (5 mg, 0.06 mmol) at room temperature. The reaction was stirred at room temperature for 6 hours. TLC and LC-MS indicated the reaction was complete. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. This was then purified by silica gel column chromatography (eluent: 5–10% methanol in dichloromethane) to afford the title compound 88 (15 mg, 63% yield) as a white solid.

[0583] MS(ES + ):m / z 479.2[M+H] + .

[0584] 1H NMR (400MHz, DMSO-d6): δ8.82(t,J=5.9Hz,1H),8.75(d,J=7.4Hz,1H),8.26(t, J=5.7Hz,1H),7.53(d,J=1.2Hz,1H),7.32–7.26(m,3H),7.21–7.18(m,4H),5.5 4(t,J=5.8Hz,1H),4.69–4.55(m,2H),4.41–4.32(m,1H),4.15(d,J=4.2Hz,2H) ,3.85(d,J=5.8Hz,2H),3.39–3.35(m,2H),3.29(s,3H),2.77(t,J=7.4Hz,2H).

[0585] Example 89: (S)-N 1 -(7-(3-acrylamidoprop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (89)

[0586] Synthesis route:

[0587] Acryloyl chloride (6 mg, 0.06 mmol) was added to a solution of compound 87 (23 mg, 0.05 mmol) and triethylamine (15 mg, 0.15 mmol) in dichloromethane (2 mL) at 0°C in an ice bath. The reaction solution was slowly warmed to room temperature and stirred for an additional 3 hours. TLC and LC-MS indicated the reaction was complete. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (eluent: 5–10% methanol in dichloromethane) to afford the title compound 89 (20 mg, 84% yield) as a white solid.

[0588] MS(ES + ):m / z 475.2[M+H] + .

[0589] 1H NMR (400MHz, DMSO-d6): δ8.82(t,J=5.9Hz,1H),8.76(d,J=7.4Hz,1H),8.66(t,J=5.2Hz,1 H),7.55(d,J=1.5Hz,1H),7.33–7.26(m,3H),7.22–7.17(m,4H),6.25(dd,J=17.1,10.0Hz, 1H),6.14(dd,J=17.1,2.1Hz,1H),5.65(dd,J=10.0,2.2Hz,1H),4.68–4.57(m,2H),4.41– 4.33(m,1H),4.22(d,J=5.5Hz,2H),3.39–3.35(m,2H),3.29(s,3H),2.77(t,J=7.4Hz,2H).

[0590] Example 90: (S)-N 1 -(7-(azetidin-3-ylethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (90)

[0591] Synthesis route:

[0592] The synthetic route and method were the same as those in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-ethynylazetidine hydrochloride 90a to prepare compound 90.

[0593] MS(ES + ):m / z 447.2[M+H] + .

[0594] 1 H NMR (400MHz, CDCl3): δ8.26(d,J=5.3Hz,1H),7.34–7.28(m,5H),7.24–7.20(m,1H),7.17(d,J=7.3Hz,2H),7.12(d,J=8.3Hz,1H),4.84–4. 78(m,1H),4.61–4.56(m,1H),4.30–4.19(m,5H),4.01–3.93(m,1H),3.59–3.53(m,2H),3.41(s,3H),2.84(t,J=7.0Hz,2H),2.41(br,1H).

[0595] Example 91: (S)-N 1-(7-((1-formylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (91)

[0596] Synthesis route:

[0597] The title compound 91 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-ethynylazetidine-1-carbaldehyde 91a.

[0598] MS(ES + ):m / z 475.2[M+H] + .

[0599] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.3Hz,1H),8.02(s,1H),7.32–7.28(m,5H),7.25–7.21( m,1H),7.18(d,J=7.1Hz,2H),7.12(d,J=8.7Hz,1H),4.81(dt,J=11.3,7.4Hz,1H),4.59(d d,J=9.7,7.3Hz,1H),4.48(t,J=8.5Hz,1H),4.36(t,J=9.3Hz,1H),4.27–4.22(m,2H),4.1 4–4.10(m,1H),3.77–3.70(m,1H),3.61–3.52(m,2H),3.41(s,3H),2.84(t,J=7.1Hz,2H).

[0600] Example 92: (S)-N 1 -(7-((1-formyl-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 -Synthesis of phenylacetamide (92)

[0601] Synthesis route:

[0602] The title compound 92 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 3-ethynyl-3-hydroxyazetidine-1-carbaldehyde 92a.

[0603] MS(ES + ):m / z 491.1[M+H] + .

[0604] 1 H NMR (400MHz, CDCl3): δ8.24 (d, J = 7.3Hz, 1H), 8.11 (s, 1H), 7.34–7.28 (m, 5H), 7.25–7. 21(m,1H),7.19–7.14(m,3H),4.81(dt,J=11.3,7.2Hz,1H),4.59(dd,J=9.5,7.5Hz,1H) ,4.53(d,J=8.7Hz,1H),4.42(d,J=10.5Hz,1H),4.35(d,J=8.5Hz,1H),4.25(t,J=10.6 Hz,1H),4.21(d,J=10.2Hz,1H),3.59–3.52(m,2H),3.42(s,3H),2.84(t,J=7.0Hz,2H).

[0605] Example 93: (S)-N 1 -(7-((1-acetyl-3-hydroxyazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -phenylacetamide (93)

[0606] Synthesis route:

[0607] The title compound 93 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 1-(3-ethynyl-3-hydroxyazetidin-1-yl)ethane-1-one 93a.

[0608] MS(ES + ):m / z 505.1[M+H] + .

[0609] 1H NMR (400MHz, CD3OD): δ7.54(d,J=1.6Hz,1H),7.39(dd,J=8.3,1.9Hz,1H),7.29–7.25(m,3H),7.22–7.18(m,5H),4.84–4.78(m,1H),4.60–4.50(m ,3H),4.41(t,J=10.7Hz,1H),4.29(d,J=10.0Hz,1H),4.05(d,J=10.3Hz, 1H),3.48–3.44(m,2H),3.39(s,3H),2.82(t,J=7.6Hz,2H),1.92(s,3H).

[0610] Example 94: (S)-5-(5-methyl-4-oxo-3-(2-oxo-2-(phenylethylamino)acetamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of ethyl 4-pentynoate (94)

[0611] Synthesis route:

[0612] The title compound 94 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of ethyl 4-pentynoate 94a.

[0613] MS(ES + ):m / z 492.2[M+H] + .

[0614] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.4Hz,1H),7.32–7.28(m,3H),7.24–7.21(m,3H) ,7.17(d,J=7.1Hz,2H),7.08(d,J=8.8Hz,1H),4.80(dt,J=11.3,7.4Hz,1H),4.58( dd,J=9.7,7.4Hz,1H),4.25–4.16(m,3H),3.59–3.53(m,2H),3.39(s,3H),2.84(t, J=7.1Hz,2H),2.73(t,J=7.0Hz,2H),2.62(t,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H).

[0615] Example 95: (S)-5-(5-methyl-4-oxo-3-(2-oxo-2-(phenylethylamino)acetamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of 4-(7-yl)pent-4-ynoic acid (95)

[0616] Synthesis route:

[0617] To a solution of compound 94 (59 mg, 0.12 mmol) in tetrahydrofuran:methanol:water (1:1:1, 6 mL) was added lithium hydroxide monohydrate (15 mg, 0.36 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. TLC and LC-MS indicated the reaction was complete. The reaction mixture was poured into water (10 mL), acidified with dilute hydrochloric acid (1 N) to a pH of approximately 5, and then extracted with ethyl acetate (20 mL x 5). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (eluent: 5–10% methanol in dichloromethane) to afford the title compound 95 (26 mg, 47% yield) as a white solid.

[0618] MS(ES + ):m / z 464.1[M+H] + .

[0619] 1 H NMR (400MHz, DMSO-d6): δ12.31(br,1H),8.82(t,J=5.9Hz,1H),8.74(d,J=7.4Hz,1H),7.49(s,1H),7.30–7.26(m,3H),7 .21–7.16(m,4H),4.67–4.56(m,2H),4.35(t,J=7.2Hz,1H),3.33–3.27(m,5H),2.77(t,J=7.7Hz,2H),2.67–2.59(m,4H).

[0620] Example 96: (S)-1-((5-methyl-4-oxo-3-(2-oxo-2-(phenylethylamino)acetamido)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of methyl cyclopropane-1-carboxylate (96)

[0621] Synthesis route:

[0622] The title compound 96 was prepared by the same synthetic route and method as in Example 2, except that cyclopropylacetylene 2a was replaced by an equivalent amount of 1-ethynylcyclopropane-1-carboxylic acid methyl ester 96a.

[0623] MS(ES+ ):m / z 490.2[M+H] + .

[0624] 1 H NMR (400MHz, CDCl3): δ8.23 (d, J=7.3Hz, 1H), 7.32–7.28 (m, 5H), 7.24–7.21 (m, 1H),7.18(d,J=7.2Hz,2H),7.09(d,J=8.7Hz,1H),4.79(dt,J=11.1,7.3Hz,1H), 4.58(dd,J=9.5,7.5Hz,1H),4.23(t,J=10.5Hz,1H),3.78(s,3H),3.59–3.54(m ,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H),1.68–1.63(m,2H),1.45–1.42(m,2H).

[0625] Example 97: (S)-N 1 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -(2-(thiophen-2-yl)ethyl)oxalamide (97)

[0626] Synthesis route:

[0627] The title compound 97 was prepared by the same synthetic route and method as in step 7 of Example 57, except that 2-phenylethylamine 1i was replaced by an equivalent amount of 2-(2-thienyl)ethylamine 97a.

[0628] MS(ES + ):m / z 374.1[M+H] + .

[0629] 1 H NMR (400MHz, CDCl3): δ8.26(d,J=7.4Hz,1H),7.39(t,J=6.4Hz,1H),7.25–7.14(m,5H),6.93(dd,J=5.1,3.4Hz,1H),6.83–6.82(m,1H),4.8 3(dt,J=11.2,7.5Hz,1H),4.62(dd,J=9.7,7.4Hz,1H),4.23(dd,J=11.1,9.8Hz,1H),3.63–3.54(m,2H),3.42(s,3H),3.06(t,J=6.8Hz,2H).

[0630] Example 98: (S)-N 1 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -(2-(thiophen-3-yl)ethyl)oxalamide (98)

[0631] Synthesis route:

[0632] The title compound 98 was prepared by the same synthetic route and method as in step 7 of Example 57, except that 2-phenylethylamine 1i was replaced by an equivalent amount of 2-(3-thienyl)ethylamine 98a.

[0633] MS(ES + ):m / z 374.1[M+H] + .

[0634] 1 H NMR (400MHz, CDCl3): δ8.26(d,J=7.7Hz,1H),7.32–7.17(m,6H),7.01–6.99(m,1H),6.93(dd,J=4.9,1.2Hz,1H),4.83(dt,J=11. 2,7.4Hz,1H),4.61(dd,J=9.8,7.4Hz,1H),4.23(dd,J=11.1,9.8Hz,1H),3.59–3.53(m,2H),3.42(s,3H),2.88(t,J=7.0Hz,2H).

[0635] Example 99: (S)-N 1 -(2-Fluorophenethyl)-N 2 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (99)

[0636] Synthesis route:

[0637] The title compound 99 was prepared by the same synthetic route and method as in step 7 of Example 57, except that 2-phenylethylamine 1i was replaced by an equivalent amount of 2-(2-fluorophenyl)ethylamine 99a.

[0638] MS(ES + ):m / z 386.0[M+H] + .

[0639] 1H NMR (400MHz, CDCl3): δ8.25(d,J=6.9Hz,1H),7.34–7.14(m,7H),7.08–7.00(m,2H),4.83(dt,J=11.2,7.5Hz,1H), 4.61(dd,J=9.7,7.5Hz,1H),4.23(dd,J=11.0,10.0Hz,1H),3.59–3.54(m,2H),3.42(s,3H),2.89(t,J=7.0Hz,2H).

[0640] Example 100: (S)-N 1 -(3-Fluorophenethyl)-N 2 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (100)

[0641] Synthesis route:

[0642] The title compound 100 was prepared by the same synthetic route and method as in step 7 of Example 57, except that 2-phenylethylamine 1i was replaced by an equivalent amount of 2-(3-fluorophenyl)ethylamine 100a.

[0643] MS(ES + ):m / z 386.0[M+H] + .

[0644] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.4Hz,1H),7.31–7.16(m,6H),6.96–6.87(m,3H),4.83(dt,J=11.2,7.5Hz,1 H),4.61(dd,J=9.7,7.5Hz,1H),4.23(t,J=10.5Hz,1H),3.59–3.53(m,2H),3.42(s,3H),2.84(t,J=7.1Hz,2H).

[0645] Example 101: (S)-N 1 -(3-Chlorophenethyl)-N 2 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (101)

[0646] Synthesis route:

[0647] The title compound 101 was prepared by the same synthetic route and method as in step 7 of Example 57, except that 2-phenylethylamine 1i was replaced by an equivalent amount of 2-(3-chlorophenyl)ethylamine 101a.

[0648] MS(ES + ):m / z 402.0[M+H] + .

[0649] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.7Hz,1H),7.30–7.18(m,8H),7.06(d,J=6.3Hz,1H),4.83(dt,J=11.1,7.5Hz, 1H), 4.62 (dd, J = 9.7, 7.4Hz, 1H), 4.23 (t, J = 10.5Hz, 1H), 3.58–3.52 (m, 2H), 3.42 (s, 3H), 2.82 (t, J = 7.2Hz, 2H).

[0650] Example 102: (S)-N 1 -(3,5-difluorobenzyl)-N 2 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (102)

[0651] Synthesis route:

[0652] The title compound 102 was prepared by the same synthetic route and method as in step 7 of Example 57, except that 2-phenylethylamine 1i was replaced by an equivalent amount of 3,5-difluorobenzylamine 102a.

[0653] MS(ES + ):m / z 390.0[M+H] + .

[0654] 1 H NMR (400MHz, DMSO-d6): δ9.39(t,J=6.4Hz,1H),8.80(d,J=7.7Hz,1H),7.49(dd,J=7.5,1.9Hz,1H),7.34 –7.22(m,3H),7.13–7.07(m,1H),6.98–6.93(m,2H),4.69–4.56(m,2H),4.39–4.32(m,3H),3.30(s,3H).

[0655] Example 103: (S)-N1 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -(2-phenoxyethyl)oxalamide (103)

[0656] Synthesis route:

[0657] The title compound 103 was prepared by the same synthetic route and method as in step 7 of Example 57, except that 2-phenylethylamine 1i was replaced by an equivalent amount of 2-phenoxyethylamine 103a.

[0658] MS(ES + ):m / z 384.0[M+H] + .

[0659] 1 H NMR (400MHz, CDCl3): δ8.27(d,J=7.2Hz,1H),7.66(t,J=6.3Hz,1H),7.30–7.17(m,6H),6.96(t,J=7.3Hz,1H),6.87(d,J=8.2Hz,2H),4. 84(dt,J=11.2,7.4Hz,1H),4.63(dd,J=9.7,7.4Hz,1H),4.23(t,J=10.5Hz,1H),4.06(t,J=5.2Hz,2H),3.77–3.67(m,2H),3.42(s,3H).

[0660] Example 104: (S)-N 1 -(7-(3-(1H-imidazol-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -benzyloxamide (104)

[0661] Synthesis route:

[0662] The title compound 104 was prepared using the same synthetic route and method as in step 2 of Example 32, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)-1H-imidazole 72a.

[0663] MS(ES + ):m / z 458.2[M+H] + .

[0664] 1 H NMR (400MHz, CDCl3): δ8.29(d,J=7.4Hz,1H),7.72(s,1H),7.55(t,J=5.8Hz,1H),7.35–7.26(m,8H),7.14(d,J=8.3Hz,2H),4.9 7(s,2H),4.82(dt,J=11.4,7.5Hz,1H),4.60(dd,J=9.6,7.5Hz,1H),4.48(d,J=6.2Hz,2H),4.26(t,J=10.5Hz,1H),3.41(s,3H).

[0665] Example 105: (S)-N 1 -Benzyl-N 2 -(7-(3-(4-hydroxypiperidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (105)

[0666] Synthesis route:

[0667] The title compound 105 was prepared using the same synthetic route and method as in step 2 of Example 32, except that 3-butyn-1-ol 31a was replaced with an equivalent amount of 1-(prop-2-yn-1-yl)piperidin-4-ol 81a.

[0668] MS(ES + ):m / z 491.3[M+H] + .

[0669] 1 H NMR (400MHz, CDCl3): δ8.28(d,J=7.5Hz,1H),7.54(t,J=5.8Hz,1H),7.36–7.25(m,7H),7.11(d,J=8.9Hz,1H),4.82(dt,J=11.3,7. 4Hz,1H),4.60(dd,J=9.7,7.3Hz,1H),4.48(d,J=6.3Hz,2H),4.25(dd,J=11.1,9.9Hz,1H),3.76(br,1H),3.52(s,2H),3.41(s,3H), 2.92–2.87(m,2H),2.47–2.40(m,2H),2.00–1.95(m,2H),1.72–1.63(m,2H),1.42(br,1H).

[0670] Example 106: (S)-N 1 -Benzyl-N 2 -(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (106)

[0671] Synthesis route:

[0672] The title compound 106 was prepared using the same synthetic route and method as in step 2 of Example 32, except that 3-butyn-1-ol 31a was replaced with an equivalent amount of 4-(prop-2-yn-1-yl)morpholine 48a.

[0673] MS(ES + ):m / z 477.2[M+H] + .

[0674] 1 H NMR (400MHz, CDCl3): δ8.29(d,J=7.4Hz,1H),7.55(t,J=5.9Hz,1H),7.36–7.25(m,7H),7.11(d,J=8.9Hz,1H),4.82(dt,J=11.4,7.3Hz,1H),4.60(d d,J=9.7,7.4Hz,1H),4.48(d,J=6.2Hz,2H),4.25(dd,J=11.0,10.0Hz,1H ),3.78(t,J=4.6Hz,4H),3.50(s,2H),3.41(s,3H),2.64(t,J=4.5Hz,4H).

[0675] Example 107: (S)-N 1 -Benzyl-N 2 -(5-methyl-4-oxo-7-(3-(3-carbonylpiperazin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (107)

[0676] Synthesis route:

[0677] The title compound 107 was prepared by the same synthetic route and method as in step 2 of Example 32, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 4-(prop-2-yn-1-yl)piperazin-2-one 85a.

[0678] MS(ES+ ):m / z 490.3[M+H] + .

[0679] 1 H NMR (400MHz, CDCl3): δ8.29 (d, J=7.5Hz, 1H), 7.55 (t, J=6.0Hz, 1H), 7.36–7. 25(m,7H),7.12(d,J=8.9Hz,1H),5.88(s,1H),4.83(dt,J=11.2,7.4Hz,1H),4 .60(dd,J=9.7,7.4Hz,1H),4.48(d,J=6.2Hz,2H),4.26(t,J=10.5Hz,1H),3.6 3(s,2H),3.46–3.43(m,2H),3.42(s,3H),3.36(s,2H),2.83(t,J=5.4Hz,2H).

[0680] Example 108: (S)-N 1 -(5-methyl-4-oxo-7-(3-(3-carbonylpiperazin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -(2-methylbenzyl)oxalamide (108)

[0681] Synthesis route:

[0682] The title compound 108 was prepared by the same synthetic route and method as in Example 32, except that the benzylamine 32a in step 1 and the 3-butyn-1-ol 31a in step 2 were replaced by equivalent amounts of 2-methylbenzylamine 108a and 4-(prop-2-yn-1-yl)piperazin-2-one 85a, respectively.

[0683] MS(ES + ):m / z 504.3[M+H] + .

[0684] 1H NMR (400MHz, CDCl3): δ8.29(d,J=7.5Hz,1H),7.38(t,J=5.7Hz,1H),7.30–7.28(m,2H ),7.22–7.17(m,4H),7.12(d,J=8.9Hz,1H),5.89(s,1H),4.82(dt,J=11.2,7.4Hz,1H) ,4.60(dd,J=9.7,7.3Hz,1H),4.48(d,J=5.9Hz,2H),4.26(t,J=10.5Hz,1H),3.63(s, 2H),3.45–3.43(m,2H),3.42(s,3H),3.36(s,2H),2.83(t,J=5.4Hz,2H),2.31(s,3H).

[0685] Example 109: (R)-N 1 -(3-Fluorophenethyl)-N 2 -(7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (109)

[0686] Synthesis route:

[0687] The title compound 109 was prepared by the same synthetic route and method as Example 34, except that compound 1h in step 1 was replaced by an equivalent amount of compound 71g.

[0688] MS(ES + ):m / z 454.2[M+H] + .

[0689] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.4Hz,1H),7.33–7.23(m,4H),7.09(d,J=8.7 Hz,1H),6.96–6.87(m,3H),4.80(dt,J=11.2,7.4Hz,1H),4.58(dd,J=9.7,7.4Hz ,1H),4.23(dd,J=11.0,10.0Hz,1H),3.83(q,J=6.2Hz,2H),3.58–3.53(m,2H),3 .40(s,3H),2.84(t,J=7.1Hz,2H),2.70(t,J=6.3Hz,2H),1.85(t,J=6.2Hz,1H).

[0690] Example 110: (S)-N 1 -(3-Fluorophenethyl)-N 2 -(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (110)

[0691] Synthesis route:

[0692] The title compound 110 was prepared by the same synthetic route and method as in step 2 of Example 34, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 3-alkynoxetane-3-ol 43a.

[0693] MS(ES + ):m / z 480.0[MH] - .

[0694] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.3Hz,1H),7.33–7.24(m,4H),7.15(d,J=8.8Hz,1H),6.94–6.87(m,3H),4.95–4.92(m,2H),4.83–4 .79(m,3H),4.60(dd,J=9.8,7.3Hz,1H),4.26(t,J=10.6Hz,1H),3.59–3.51(m,2H),3.42(s,3H),2.84(t,J=6.9Hz,2H),2.58(s,1H).

[0695] Example 111: (S)-N 1 -(5-(cyclopropylmethyl)-7-((3-hydroxyoxetan-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -(3-fluorophenethyl)oxalamide (111)

[0696] Synthesis route:

[0697] Steps 1–3 were the same as the synthetic route and method of steps 4–6 of Example 1, except that iodomethane in step 4 of Example 1 was replaced with an equivalent amount of (iodomethyl)cyclopropane 111a; steps 4–5 were the same as the synthetic route and method of Example 34, except that compound 1h in step 1 of Example 34 and 3-butyn-1-ol 31a in step 2 were replaced with equivalent amounts of compound 111d and 3-alkynoxetane-3-ol 43a, respectively, to give the title compound 111.

[0698] MS(ES + ):m / z 520.2[MH] - .

[0699] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.4Hz,1H),7.36–7.23(m,4H),7.16(d,J=8.2Hz,1H),6.96 –6.87(m,3H),4.94(d,J=6.6Hz,2H),4.83–4.76(m,3H),4.58(dd,J=9.6,7.4Hz,1H),4.26(t, J=10.5Hz,1H),4.11–4.05(m,1H),3.59–3.51(m,2H),3.48–3.43(m,1H),2.84(t,J=7.1Hz,2 H),2.73(s,1H),1.07–0.99(m,1H),0.49–0.41(m,2H),0.31–0.26(m,1H),0.18–0.12(m,1H).

[0700] Example 112: (S)-N 1 -(3-Fluorophenethyl)-N 2 -(7-((1-hydroxycyclohexyl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (112)

[0701] Synthesis route:

[0702] The title compound 112 was prepared by the same synthetic route and method as in step 2 of Example 34, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 1-ethynyl-1-cyclohexanol 44a.

[0703] MS(ES + ):m / z 508.2[M+H] + .

[0704] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.5Hz,1H),7.30–7.23(m,4H),7.11(d,J=8.0Hz,1H),6.96–6.87(m,3H),4.80(dt,J=11.3,7.4Hz,1H),4.59 (dd,J=9.6,7.5Hz,1H),4.24(t,J=10.5Hz,1H),3.59–3.52(m,2H),3.41(s,3H),2.84(t,J=7.1Hz,2H),2.04–2.00(m,3H),1.79–1.59(m,8H).

[0705] Example 113: N 1 -(3-Fluorophenethyl)-N 2 -((3S)-7-(3-(3-hydroxypyrrolidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (113)

[0706] Synthesis route:

[0707] The title compound 113 was prepared by the same synthetic route and method as in step 2 of Example 34, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)pyrrolidin-3-ol 46a.

[0708] MS(ES + ):m / z 509.2[M+H] + .

[0709] 1H NMR (400MHz, CDCl3): δ8.23(d,J=7.4Hz,1H),7.31–7.23(m,4H),7.10(d,J=8.8Hz,1H),6.96– 6.87(m,3H),4.80(dt,J=11.2,7.4Hz,1H),4.58(dd,J=9.7,7.4Hz,1H),4.43–4.39(m,1H),4.2 4(t,J=10.5Hz,1H),3.65(s,2H),3.58–3.53(m,2H),3.40(s,3H),3.03–2.97(m,1H),2.84(t, J=7.1Hz,2H),2.79(d,J=3.6Hz,2H),2.60–2.54(m,1H),2.32–2.20(m,1H),1.85–1.77(m,1H).

[0710] Example 114: N 1 -(3-Fluorophenethyl)-N 2 -((S)-7-(3-((R)-3-hydroxypyrrolidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (114)

[0711] Synthesis route:

[0712] The title compound 114 was prepared by the same synthetic route and method as in step 2 of Example 34, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of (R)-1-(prop-2-yn-1-yl)pyrrolidin-3-ol 114a.

[0713] MS(ES + ):m / z 509.2[M+H] + .

[0714] 1H NMR (400MHz, CDCl3): δ8.23(d,J=7.4Hz,1H),7.31–7.23(m,4H),7.10(d,J=8.9Hz,1H),6.96– 6.87(m,3H),4.80(dt,J=11.3,7.4Hz,1H),4.58(dd,J=9.7,7.4Hz,1H),4.43–4.39(m,1H),4.2 4(t,J=10.5Hz,1H),3.65(s,2H),3.59–3.53(m,2H),3.40(s,3H),3.03–2.97(m,1H),2.84(t, J=7.1Hz,2H),2.80(d,J=3.7Hz,2H),2.61–2.55(m,1H),2.31–2.20(m,1H),1.85–1.77(m,1H).

[0715] Example 115: N 1 -(3-Fluorophenethyl)-N 2 -((S)-7-(3-((S)-3-hydroxypyrrolidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (115)

[0716] Synthesis route:

[0717] The title compound 115 was prepared by the same synthetic route and method as in step 2 of Example 34, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of (S)-1-(prop-2-yn-1-yl)pyrrolidin-3-ol 115a.

[0718] MS(ES + ):m / z 509.2[M+H] + .

[0719] 1H NMR (400MHz, CDCl3): δ8.23(d,J=7.5Hz,1H),7.31–7.23(m,4H),7.10(d,J=8.9Hz,1H),6.96– 6.87(m,3H),4.81(dt,J=11.3,7.4Hz,1H),4.58(dd,J=9.7,7.4Hz,1H),4.43–4.39(m,1H),4.2 4(t,J=10.5Hz,1H),3.65(s,2H),3.59–3.53(m,2H),3.40(s,3H),3.02–2.97(m,1H),2.84(t, J=7.1Hz,2H),2.79(d,J=3.7Hz,2H),2.61–2.55(m,1H),2.30–2.20(m,1H),1.85–1.77(m,1H).

[0720] Example 116: N 1 -(3-Fluorophenethyl)-N 2 -((3S)-5-methyl-4-oxo-7-(piperidin-3-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (116)

[0721] Synthesis route:

[0722] The title compound 116 was prepared by the same synthetic route and method as in step 2 of Example 34, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 3-ethynylpiperidine hydrochloride 24a.

[0723] MS(ES + ):m / z 493.4[M+H] + .

[0724] 1H NMR (400MHz, CDCl3): δ8.24(d,J=7.2Hz,1H),7.39–7.34(m,2H),7.29–7.22(m,2H),7.09(d,J= 8.2Hz,1H),6.96–6.87(m,3H),4.79(dt,J=11.0,7.3Hz,1H),4.58(dd,J=9.5,7.5Hz,1H),4.24( t,J=10.5Hz,1H),3.58–3.53(m,3H),3.41(s,3H),3.36–3.33(m,1H),3.28–3.22(m,1H),3.04(t ,J=9.9Hz,2H),2.84(t,J=7.0Hz,2H),2.15–2.10(m,1H),2.05–1.96(m,2H),1.79–1.70(m,1H).

[0725] Example 117: (S)-N 1 -(3-Fluorophenethyl)-N 2 -(5-methyl-4-oxo-7-(pyridin-3-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (117)

[0726] Synthesis route:

[0727] The title compound 117 was prepared by the same synthetic route and method as in step 2 of Example 34, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 3-ethynylpyridine 13a.

[0728] MS(ES + ):m / z 487.2[M+H] + .

[0729] 1H NMR (400MHz, CDCl3): δ8.80(br,1H),8.60(br,1H),8.25(d,J=7.3Hz,1H),7.82(d, J=7.3Hz,1H),7.42–7.40(m,2H),7.33–7.29(m,2H),7.27–7.25(m,1H),7.18(d,J=8 .8Hz,1H),6.96–6.87(m,3H),4.84(dt,J=11.2,7.4Hz,1H),4.62(dd,J=9.7,7.4Hz, 1H), 4.27 (t, J = 10.5Hz, 1H), 3.59–3.54 (m, 2H), 3.45 (s, 3H), 2.84 (t, J = 7.1Hz, 2H).

[0730] Example 118: (S)-N 1 -(3-Fluorophenethyl)-N 2 -(5-methyl-4-oxo-7-(3-(4-carbonylpiperidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (118)

[0731] Synthesis route:

[0732] The title compound 118 was prepared by the same synthetic route and method as in step 2 of Example 34, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)piperidin-4-one 47a.

[0733] MS(ES + ):m / z 521.1[M+H] + .

[0734] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.5Hz,1H),7.32–7.23(m,4H),7.11(d,J=8 .9Hz,1H),6.96–6.87(m,3H),4.81(dt,J=11.3,7.4Hz,1H),4.58(dd,J=9.8,7 .3Hz,1H),4.24(dd,J=11.2,9.9Hz,1H),3.65(s,2H),3.59–3.53(m,2H),3.4 1(s,3H),2.94(t,J=6.1Hz,4H),2.84(t,J=7.1Hz,2H),2.54(t,J=6.1Hz,4H).

[0735] Example 119: (S)-N 1 -(3-Fluorophenethyl)-N 2 -(5-methyl-4-oxo-7-(3-(3-carbonylpyrrolidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (119)

[0736] Synthesis route:

[0737] The title compound 119 was prepared by the same synthetic route and method as in step 2 of Example 34, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)pyrrolidin-3-one 119a.

[0738] MS(ES + ):m / z 507.1[M+H] + .

[0739] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.4Hz,1H),7.30–7.23(m,4H),7.12(d,J=8.4 Hz,1H),6.96–6.87(m,3H),4.81(dt,J=11.3,7.4Hz,1H),4.59(dd,J=9.7,7.4H z,1H),4.24(t,J=10.5Hz,1H),3.76(s,2H),3.59–3.53(m,2H),3.41(s,3H),3. 16(s,2H),3.10(t,J=7.0Hz,2H),2.84(t,J=7.1Hz,2H),2.48(t,J=7.0Hz,2H).

[0740] Example 120: (S)-N 1 -(3-Fluorophenethyl)-N 2 -(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (120)

[0741] Synthesis route:

[0742] The title compound 120 was prepared by the same synthetic route and method as in step 2 of Example 34, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 4-(prop-2-yn-1-yl)morpholine 48a.

[0743] MS(ES + ):m / z 509.0[M+H] + .

[0744] 1 H NMR (400MHz, CDCl3): δ8.23(d,J=7.4Hz,1H),7.31–7.23(m,4H),7.11(d,J=8 .8Hz,1H),6.96–6.87(m,3H),4.81(dt,J=11.3,7.4Hz,1H),4.59(dd,J=9.7,7 .4Hz,1H),4.24(dd,J=11.0,10.0Hz,1H),3.78(t,J=4.6Hz,4H),3.59–3.53(m ,2H),3.50(s,2H),3.41(s,3H),2.84(t,J=7.1Hz,2H),2.64(t,J=4.5Hz,4H).

[0745] Example 121: (S)-N 1 -(3-Fluorophenethyl)-N 2 -(7-(3-(4-(2-hydroxyethyl)piperazin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (121)

[0746] Synthesis route:

[0747] The title compound 121 was prepared using the same synthetic route and method as in step 2 of Example 34, except that 3-butyn-1-ol 31a was replaced with an equivalent amount of 2-(4-(prop-2-yn-1-yl)piperazin-1-yl)ethane-1-ol 121a.

[0748] MS(ES + ):m / z 552.3[M+H] + .

[0749] 1H NMR (400MHz, CDCl3): δ8.23(d,J=7.3Hz,1H),7.32–7.23(m,4H),7.11(d,J=8.8H z,1H),6.96–6.87(m,3H),4.81(dt,J=11.1,7.4Hz,1H),4.59(dd,J=9.6,7.5Hz, 1H),4.24(t,J=10.5Hz,1H),3.62(t,J=5.3Hz,2H),3.58–3.53(m,2H),3.52(s,2 H),3.41(s,3H),2.84(t,J=7.1Hz,2H),2.68–2.59(m,8H),2.57(t,J=5.3Hz,2H).

[0750] Example 122: (S)-N 1 -(7-(3-(2,5-dicarbonylpyrrolidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -(3-fluorophenethyl)oxalamide (122)

[0751] Synthesis route:

[0752] The title compound 122 was prepared by the same synthetic route and method as in step 2 of Example 34, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)pyrrolidine-2,5-dione 84a.

[0753] MS(ES + ):m / z 521.2[M+H] + .

[0754] 1 H NMR (400MHz, CDCl3): δ8.22(d,J=7.2Hz,1H),7.31–7.23(m,4H),7.09(d,J=9.0Hz,1H),6.96–6.87(m,3H),4.78(dt,J=11.3,7.4Hz,1H) ,4.58(dd,J=9.6,7.4Hz,1H),4.49(s,2H),4.23(t,J=10.5Hz,1H),3.58–3.53(m,2H),3.39(s,3H),2.84(t,J=7.1Hz,2H),2.79(s,4H).

[0755] Example 123: (S)-N 1-(3-Fluorophenethyl)-N 2 -(5-methyl-4-oxo-7-(3-(3-carbonylpiperazin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of oxalamide (123)

[0756] Synthesis route:

[0757] The title compound 123 was prepared by the same synthetic route and method as in step 2 of Example 34, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 4-(prop-2-yn-1-yl)piperazin-2-one 85a.

[0758] MS(ES + ):m / z 522.3[M+H] + .

[0759] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.5Hz,1H),7.32–7.23(m,4H),7.12(d,J =8.9Hz,1H),6.96–6.87(m,3H),5.94(s,1H),4.81(dt,J=11.3,7.4Hz,1H), 4.59(dd,J=9.7,7.4Hz,1H),4.25(t,J=10.5Hz,1H),3.63(s,2H),3.59–3. 53(m,2H),3.46–3.43(m,2H),3.41(s,3H),3.36(s,2H),2.86–2.82(m,4H).

[0760] Example 124: N 1 -((S)-7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((S)-1-phenylethyl)oxalamide (124)

[0761] Synthesis route:

[0762] The title compound 124 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of (S)-1-phenylethylamine 124a.

[0763] MS(ES +):m / z 434.2[MH] - .

[0764] 1 H NMR (400MHz, CDCl3): δ8.29(d,J=7.4Hz,1H),7.55(d,J=8.3Hz,1H),7.35–7.2 6(m,7H),7.11(d,J=8.0Hz,1H),5.08(qn,J=7.3Hz,1H),4.80(dt,J=11.2,7.4 Hz,1H),4.60(dd,J=9.7,7.4Hz,1H),4.25(t,J=10.5Hz,1H),3.83(t,J=6.2Hz ,2H),3.39(s,3H),2.70(t,J=6.3Hz,2H),1.96(br,1H),1.54(d,J=6.9Hz,3H).

[0765] Example 125: N 1 -((S)-7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (125)

[0766] Synthesis route:

[0767] The title compound 125 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of (R)-1-phenylethylamine 125a.

[0768] MS(ES + ):m / z 434.2[MH] - .

[0769] 1H NMR (400MHz, CDCl3): δ8.25(d,J=7.4Hz,1H),7.48(d,J=8.3Hz,1H),7.36–7.26(m,7H),7.10(d,J=8.7Hz,1H),5.07(qn,J= 7.3Hz,1H),4.80(dt,J=11.2,7.4Hz,1H),4.56(dd,J=9.7,7.3Hz,1H),4.21(t,J=10.5Hz,1H),3.83 (q,J=6.2Hz,2H),3.40(s,3H),2.70(t,J=6.3Hz,2H),1.80(t,J=6.2Hz,1H),1.53(d,J=6.9Hz,3H).

[0770] Example 126: N 1 -((3S)-7-(3-(3-hydroxypyrrolidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (126)

[0771] Synthesis route:

[0772] The title compound 126 was prepared by the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)pyrrolidin-3-ol 46a.

[0773] MS(ES + ):m / z 491.3[M+H] + .

[0774] 1H NMR (400MHz, CDCl3): δ8.25(d,J=7.4Hz,1H),7.49(d,J=8.3Hz,1H),7.36–7.28(m,7H),7.10(d, J=8.7Hz,1H),5.07(qn,J=7.3Hz,1H),4.81(dt,J=11.2,7.4Hz,1H),4.56(dd,J=9.7,7.4Hz,1H) ,4.43–4.39(m,1H),4.21(t,J=10.6Hz,1H),3.66(s,2H),3.40(s,3H),3.03–2.97(m,1H),2.80( d,J=3.6Hz,2H),2.61–2.55(m,1H),2.30–2.21(m,1H),1.85–1.78(m,1H),1.53(d,J=6.9Hz,3H).

[0775] Example 127: N 1 -((S)-7-(3-((R)-3-hydroxypyrrolidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((S)-1-phenylethyl)oxalamide (127)

[0776] Synthesis route:

[0777] The title compound 127 was prepared by the same synthetic route and method as in step 2 of Example 124, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of (R)-1-(prop-2-yn-1-yl)pyrrolidin-3-ol 114a.

[0778] MS(ES + ):m / z 491.3[M+H] + .

[0779] 1H NMR (400MHz, CDCl3): δ8.26(d,J=7.4Hz,1H),7.48(d,J=8.4Hz,1H),7.35–7.27(m,7H),7.11(d, J=8.2Hz,1H),5.07(qn,J=7.3Hz,1H),4.80(dt,J=11.2,7.4Hz,1H),4.60(dd,J=9.7,7.4Hz,1H) ,4.44–4.40(m,1H),4.25(t,J=10.5Hz,1H),3.67(s,2H),3.39(s,3H),3.05–3.00(m,1H),2.82( d,J=3.6Hz,2H),2.64–2.58(m,1H),2.30–2.20(m,1H),1.86–1.79(m,1H),1.54(d,J=6.9Hz,3H).

[0780] Example 128: N 1 -((S)-7-(3-((R)-3-hydroxypyrrolidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (128)

[0781] Synthesis route:

[0782] The title compound 128 was prepared by the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of (R)-1-(prop-2-yn-1-yl)pyrrolidin-3-ol 114a.

[0783] MS(ES + ):m / z 491.3[M+H] + .

[0784] 1H NMR (400MHz, CDCl3): δ8.25(d,J=7.3Hz,1H),7.49(d,J=8.2Hz,1H),7.36–7.28(m,7H),7.10(d, J=8.8Hz,1H),5.07(qn,J=7.3Hz,1H),4.81(dt,J=11.2,7.4Hz,1H),4.56(dd,J=9.7,7.4Hz,1H) ,4.44–4.39(m,1H),4.21(t,J=10.5Hz,1H),3.66(s,2H),3.40(s,3H),3.04–2.98(m,1H),2.81( d,J=3.6Hz,2H),2.62–2.56(m,1H),2.30–2.20(m,1H),1.85–1.78(m,1H),1.53(d,J=6.9Hz,3H).

[0785] Example 129: N 1 -((S)-7-(3-((S)-3-hydroxypyrrolidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((S)-1-phenylethyl)oxalamide (129)

[0786] Synthesis route:

[0787] The title compound 129 was prepared by the same synthetic route and method as in step 2 of Example 124, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of (S)-1-(prop-2-yn-1-yl)pyrrolidin-3-ol 115a.

[0788] MS(ES + ):m / z 491.3[M+H] + .

[0789] 1H NMR (400MHz, CDCl3): δ8.26(d,J=7.4Hz,1H),7.48(d,J=8.4Hz,1H),7.35–7.27(m,7H),7.12(d, J=8.2Hz,1H),5.07(qn,J=7.3Hz,1H),4.80(dt,J=11.2,7.4Hz,1H),4.60(dd,J=9.7,7.4Hz,1H) ,4.44–4.40(m,1H),4.25(t,J=10.5Hz,1H),3.68(s,2H),3.39(s,3H),3.07–3.02(m,1H),2.84( d,J=3.4Hz,2H),2.66–2.60(m,1H),2.30–2.21(m,1H),1.87–1.80(m,1H),1.54(d,J=6.9Hz,3H).

[0790] Example 130: N 1 -((S)-7-(3-((S)-3-hydroxypyrrolidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (130)

[0791] Synthesis route:

[0792] The title compound 130 was prepared by the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of (S)-1-(prop-2-yn-1-yl)pyrrolidin-3-ol 115a.

[0793] MS(ES + ):m / z 491.3[M+H] + .

[0794] 1H NMR (400MHz, CDCl3): δ8.25(d,J=7.4Hz,1H),7.49(d,J=8.3Hz,1H),7.36–7.27(m,7H),7.10(d,J=8.8Hz,1H),5.07(qn,J= 7.3Hz,1H),4.80(dt,J=11.3,7.5Hz,1H),4.56(dd,J=9.8,7.4Hz,1H),4.44–4.40(m,1H),4.21(t,J=10.5Hz,1H),3.67(s,2H),3.4 0(s,3H),3.06–3.00(m,1H),2.83(d,J=3.2Hz,2H),2.65–2.59(m,1H),2.30–2.21(m,1H),1.87–1.79(m,1H),1.53(d,J=6.9Hz,3H).

[0795] Example 131: (S)-N 1 -(5-methyl-7-(oxetan-3-ylethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (131)

[0796] Synthesis route:

[0797] The title compound 131 was prepared by the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 3-ethynyloxetane 76a.

[0798] MS(ES + ):m / z 448.2[M+H] + .

[0799] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.4Hz,1H),7.47(d,J=8.3Hz,1H),7.35–7.27(m,7H),7.12(d,J=8.8Hz,1H),5.01(qn,J=7.2Hz,1H),4.92– 4.86(m,2H),4.83–4.76(m,3H),4.57(dd,J=9.8,7.4Hz,1H),4.22(t,J=10.5Hz,1H),4.09–4.01(m,1H),3.42(s,3H),1.53(d,J=6.9Hz,3H).

[0800] Example 132: N 1 -((S)-7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (132)

[0801] Synthesis route:

[0802] The title compound 132 was prepared by the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 3-alkynoxetane-3-ol 43a.

[0803] MS(ES + ):m / z 464.2[M+H] + .

[0804] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.3Hz,1H),7.47(d,J=8.4Hz,1H),7.37–7.28(m,7H),7.15(d,J=8.7Hz,1H),5.07(qn,J=7.5Hz,1H),4 .94(d,J=7.0Hz,2H),4.85–4.78(m,3H),4.58(dd,J=9.8,7.3Hz,1H),4.23(dd,J=11.2,9.9Hz,1H),3.42(s,3H),1.53(d,J=6.9Hz,3H).

[0805] Example 133: N 1 -((S)-7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((S)-1-phenylethyl)oxalamide (133)

[0806] Synthesis route:

[0807] The title compound 133 was prepared by the same synthetic route and method as in step 2 of Example 124, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 3-alkynoxetane-3-ol 43a.

[0808] MS(ES+ ):m / z 464.1[M+H] + .

[0809] 1 H NMR (400MHz, CDCl3): δ8.26(d,J=7.3Hz,1H),7.47(d,J=8.4Hz,1H),7.37–7.28(m,7H),7.15(d,J=8.7Hz,1H),5.08(qn,J=7.5Hz,1H),4 .93(d,J=6.9Hz,2H),4.84–4.77(m,3H),4.62(dd,J=9.5,7.4Hz,1H),4.27(dd,J=11.2,9.8Hz,1H),3.41(s,3H),1.53(d,J=6.9Hz,3H).

[0810] Example 134: (S)-N 1 -(7-(3-(1H-imidazol-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (134)

[0811] Synthesis route:

[0812] The title compound 134 was prepared by the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)-1H-imidazole 72a.

[0813] MS(ES + ):m / z 472.2[M+H] + .

[0814] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.5Hz,1H),7.77(s,1H),7.47(d,J=8.3Hz,1H),7.36–7.28(m, 7H),7.17–7.13(m,3H),5.07(qn,J=7.3Hz,1H),4.98(s,2H),4.81(dt,J=11.2,7.4Hz,1H),4.57 (dd,J=9.8,7.3Hz,1H),4.23(t,J=10.6Hz,1H),3.41(s,3H),1.53(d,J=6.9Hz,3H).

[0815] Example 135: N 1 -((S)-5-methyl-4-oxo-7-(piperidin-4-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (135)

[0816] Synthesis route:

[0817] The title compound 135 was prepared by the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 4-ethynylpiperidine hydrochloride 23a.

[0818] MS(ES + ):m / z 475.3[M+H] + .

[0819] 1 H NMR (400MHz, CDCl3): δ8.27(d,J=7.4Hz,1H),7.49(d,J=8.3Hz,1H),7.36–7.25(m,7H) ,7.11(d,J=8.7Hz,1H),5.07(qn,J=7.2Hz,1H),4.80(dt,J=11.2,7.4Hz,1H),4.56(dd, J=9.8,7.4Hz,1H),4.22(t,J=10.7Hz,1H),3.42(s,3H),3.38–3.32(m,2H),3.17–3.09( m,2H),3.02–2.97(m,1H),2.24–2.16(m,2H),2.05–1.97(m,2H),1.53(d,J=6.9Hz,3H).

[0820] Example 136: N 1 -((S)-5-methyl-7-((1-methylpiperidin-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (136)

[0821] Synthesis route:

[0822] The title compound 136 was prepared by the same synthetic route and method as Example 73, except that compound 23 was replaced by an equivalent amount of compound 135.

[0823] MS(ES + ):m / z 489.3[M+H] + .

[0824] 1 H NMR (400MHz, DMSO-d6): δ9.19(d,J=8.6Hz,1H),8.75(t,J=6.4Hz,1H),7.53 (s,1H),7.35–7.28(m,5H),7.24–7.18(m,2H),5.00–4.93(m,1H),4.67–4.55 (m,2H),4.38–4.32(m,1H),3.29(s,3H),3.07–2.93(m,3H),2.83–2.72(m,2H ),2.67(s,3H),2.02–1.94(m,2H),1.84–1.72(m,2H),1.43(d,J=6.9Hz,3H).

[0825] Example 137: N 1 -((S)-7-((1-(cyanomethyl)piperidin-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (137)

[0826] Synthesis route:

[0827] The title compound 137 can be prepared by the same synthetic route and method as Example 136 through the same reaction.

[0828] MS(ES + ):m / z 514.3[M+H] + .

[0829] 1H NMR (400MHz, CDCl3): δ8.25(d,J=7.5Hz,1H),7.49(d,J=8.4Hz,1H),7.36–7.25(m,7H),7.10 (d,J=8.5Hz,1H),5.07(qn,J=7.3Hz,1H),4.80(dt,J=11.3,7.5Hz,1H),4.56(dd,J=9.8,7.4 Hz,1H),4.20(dd,J=11.1,10.0Hz,1H),3.54(s,2H),3.40(s,3H),2.86–2.81(m,2H),2.70–2 .63(m,1H),2.52–2.46(m,2H),2.01–1.96(m,2H),1.85–1.77(m,2H),1.53(d,J=6.9Hz,3H).

[0830] Example 138: N 1 -((S)-7-(3-(4-hydroxypiperidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (138)

[0831] Synthesis route:

[0832] The title compound 138 was prepared by the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)piperidin-4-ol 81a.

[0833] MS(ES + ):m / z 505.3[M+H] + .

[0834] 1H NMR (400MHz, CDCl3): δ8.25(d,J=7.4Hz,1H),7.47(d,J=8.4Hz,1H),7.36–7.28(m,7H),7.10(d,J=8.8Hz,1H),5.07(qn,J= 7.2Hz,1H),4.81(dt,J=11.2,7.4Hz,1H),4.56(dd,J=9.7,7.4Hz,1H),4.21(t,J=10.5Hz,1H),3.78–3.72(m,1H),3.50(s,2H),3.4 0(s,3H),2.91–2.86(m,2H),2.44–2.39(m,2H),1.99–1.95(m,2H),1.71–1.62(m,2H),1.53(d,J=6.9Hz,3H),1.41(d,J=4.1Hz,1H).

[0835] Example 139: N 1 -((S)-5-methyl-4-oxo-7-(3-(4-carbonylpiperidin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (139)

[0836] Synthesis route:

[0837] The title compound 139 was prepared by the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)piperidin-4-one 47a.

[0838] MS(ES + ):m / z 503.2[M+H] + .

[0839] 1H NMR (400MHz, CDCl3): δ8.25(d,J=7.5Hz,1H),7.48(d,J=8.5Hz,1H),7.36–7.2 8(m,7H),7.11(d,J=8.9Hz,1H),5.07(qn,J=7.3Hz,1H),4.81(dt,J=11.2,7.5 Hz,1H),4.56(dd,J=9.7,7.4Hz,1H),4.22(t,J=10.5Hz,1H),3.66(s,2H),3.4 1(s,3H),2.94(t,J=5.9Hz,4H),2.54(t,J=6.1Hz,4H),1.53(d,J=6.9Hz,3H).

[0840] Example 140: N 1 -((S)-5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (140)

[0841] Synthesis route:

[0842] The title compound 140 was prepared by the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 4-(prop-2-yn-1-yl)morpholine 48a.

[0843] MS(ES + ):m / z 491.2[M+H] + .

[0844] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.5Hz,1H),7.49(d,J=8.2Hz,1H),7.36–7.2 8(m,7H),7.11(d,J=8.8Hz,1H),5.07(qn,J=7.3Hz,1H),4.81(dt,J=11.2,7.4 Hz,1H),4.56(dd,J=9.7,7.4Hz,1H),4.21(t,J=10.5Hz,1H),3.78(t,J=4.4Hz ,4H),3.51(s,2H),3.40(s,3H),2.64(t,J=4.2Hz,4H),1.53(d,J=6.9Hz,3H).

[0845] Example 141: N 1-((S)-5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((S)-1-phenylethyl)oxalamide (141)

[0846] Synthesis route:

[0847] The title compound 141 was prepared by the same synthetic route and method as in step 2 of Example 124, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 4-(prop-2-yn-1-yl)morpholine 48a.

[0848] MS(ES + ):m / z 491.2[M+H] + .

[0849] 1 H NMR (400MHz, CDCl3): δ8.26(d,J=7.3Hz,1H),7.47(d,J=8.3Hz,1H),7.35–7.2 8(m,7H),7.12(d,J=8.2Hz,1H),5.08(qn,J=7.3Hz,1H),4.80(dt,J=11.2,7.4 Hz,1H),4.60(dd,J=9.7,7.4Hz,1H),4.25(t,J=10.5Hz,1H),3.78(t,J=4.6Hz ,4H),3.50(s,2H),3.39(s,3H),2.64(t,J=4.4Hz,4H),1.54(d,J=6.9Hz,3H).

[0850] Example 142: N 1 -((S)-5-methyl-4-oxo-7-(3-(piperazin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (142)

[0851] Synthesis route:

[0852] The title compound 142 was prepared by the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 1-(prop-2-yn-1-yl)piperazine 49a.

[0853] MS(ES + ):m / z 490.3[M+H] + .

[0854] 1 H NMR (400MHz, DMSO-d6): δ9.17(d,J=8.7Hz,1H),8.82–8.80(m,1H),7.69(s,1H),7.40(dd,J=8.3,1.8Hz,1H),7.35–7.20(m,6H),4.97(qn,J =7.4Hz,1H),4.68–4.58(m,2H),4.40–4.34(m,1H),3.98(s,2H),3.31(s,3H),3.30–3.26(m,4H),3.16–3.08(m,4H),1.44(d,J=7.1Hz,3H).

[0855] Example 143: N 1 -((S)-7-(3-(4-acetylpiperazin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (143)

[0856] Synthesis route:

[0857] The title compound 143 was prepared using the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced with an equivalent amount of 1-(4-(prop-2-yn-1-yl)piperazin-1-yl)ethan-1-one 143a.

[0858] MS(ES + ):m / z 532.3[M+H] + .

[0859] 1H NMR (400MHz, CDCl3): δ8.25(d,J=7.5Hz,1H),7.47(d,J=8.4Hz,1H),7.36–7.27(m,7H ),7.11(d,J=8.8Hz,1H),5.07(qn,J=7.2Hz,1H),4.81(dt,J=11.2,7.4Hz,1H),4.56(d d,J=9.8,7.4Hz,1H),4.22(dd,J=11.1,9.9Hz,1H),3.71–3.65(m,2H),3.56(s,2H),3 .55–3.49(m,2H),3.41(s,3H),2.64–2.52(m,4H),2.11(s,3H),1.53(d,J=6.9Hz,3H).

[0860] Example 144: N 1 -((S)-7-(3-(2,5-dicarbonylpyrrolidin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (144)

[0861] Synthesis route:

[0862] The title compound 144 was prepared using the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced with an equivalent amount of 1-(prop-2-yn-1-yl)pyrrolidine-2,5-dione 84a.

[0863] MS(ES + ):m / z 525.2[M+Na] + .

[0864] 1 H NMR (400MHz, CDCl3): δ8.25(br,1H),7.49(d,J=8.2Hz,1H),7.36–7.27(m,7H),7.09(d,J=8.7Hz,1H),5.06(qn,J=7.3Hz,1H),4.8 1–4.75(m,1H),4.55(dd,J=9.6,7.4Hz,1H),4.49(s,2H),4.21(t,J=10.6Hz,1H),3.39(s,3H),2.79(s,4H),1.53(d,J=6.9Hz,3H).

[0865] Example 145: N1 -((S)-5-methyl-4-oxo-7-(3-(3-carbonylpiperazin-1-yl)prop-1-yn-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (145)

[0866] Synthesis route:

[0867] The title compound 145 was prepared by the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 4-(prop-2-yn-1-yl)piperazin-2-one 85a.

[0868] MS(ES + ):m / z 526.2[M+Na] + .

[0869] 1 H NMR (400MHz, CDCl3): δ8.26(d,J=7.2Hz,1H),7.51(d,J=8.4Hz,1H),7.36–7.27(m, 7H),7.11(d,J=8.8Hz,1H),6.11(s,1H),5.06(qn,J=7.3Hz,1H),4.81(dt,J=11.2,7 .2Hz,1H),4.56(dd,J=9.7,7.4Hz,1H),4.22(t,J=10.5Hz,1H),3.63(s,2H),3.45–3 .42(m,2H),3.41(s,3H),3.36(s,2H),2.83(t,J=5.4Hz,2H),1.53(d,J=6.9Hz,3H).

[0870] Example 146: N 1 -((S)-7-(3-(dimethylamino)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (146)

[0871] Synthesis route:

[0872] The title compound 146 was prepared by the same synthetic route and method as in step 2 of Example 125, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of N,N-dimethylpropargylamine 146a.

[0873] MS(ES + ):m / z 449.2[M+H] + .

[0874] 1 H NMR (400MHz, CD3OD): δ7.64(br,1H),7.48(d,J=8.2Hz,1H),7.37–7.32(m,5H),7.31–7.24(m,3H),5.04(qn,J=7 .0Hz,1H),4.86–4.82(m,1H),4.59–4.43(m,2H),4.34(s,2H),3.42(s,3H),3.04(s,6H),1.52(d,J=6.9Hz,3H).

[0875] Example 147: N 1 -((S)-5-methyl-7-((1-methylazetidin-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (147)

[0876] Synthesis route:

[0877] Step 1 is the same as the synthetic route and method of Example 90, except that compound 1 is replaced by an equivalent amount of compound 125b; Step 2 is the same as the synthetic route and method of Example 73, except that compound 23 is replaced by an equivalent amount of compound 147a, to obtain the title compound 147.

[0878] MS(ES + ):m / z 461.1[M+H] + .

[0879] 1H NMR (400MHz, DMSO-d6): δ9.19(d,J=9.0Hz,1H),8.75(d,J=7.3Hz,1H),7.54(d, J=1.7Hz,1H),7.35–7.28(m,5H),7.23–7.17(m,2H),4.97(qn,J=7.7Hz,1H),4. 68–4.55(m,2H),4.35(dd,J=8.9,7.9Hz,1H),3.55(t,J=7.0Hz,2H),3.39–3.36 (m,1H),3.29(s,3H),3.01(t,J=6.9Hz,2H),2.54(s,3H),1.44(d,J=7.1Hz,3H).

[0880] Example 148: N 1 -((S)-7-((1-(cyanomethyl)azetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (148)

[0881] Synthesis route:

[0882] The title compound 148 can be prepared by the same synthetic route and method as in Step 2 of Example 147 through the same reaction.

[0883] MS(ES + ):m / z 486.2[M+H] + .

[0884] 1 H NMR (400MHz, DMSO-d6): δ9.19(d,J=8.6Hz,1H),8.75(d,J=7.6Hz,1H),7.55(d, J=1.7Hz,1H),7.35–7.28(m,5H),7.23–7.18(m,2H),4.97(qn,J=7.3Hz,1H),4. 68–4.55(m,2H),4.35(dd,J=9.0,7.0Hz,1H),3.67(s,2H),3.62(t,J=7.1Hz,2H ),3.54–3.47(m,1H),3.30(s,3H),3.26(t,J=6.8Hz,2H),1.44(d,J=7.0Hz,3H).

[0885] Example 149: N 1-((S)-7-((1-acryloylazetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (149)

[0886] Synthesis route:

[0887] The title compound 149 was prepared by the same synthetic route and method as Example 89, except that compound 87 was replaced by an equivalent amount of compound 147a.

[0888] MS(ES + ):m / z 501.2[M+H] + .

[0889] 1 H NMR (400MHz, DMSO-d6): δ9.19(d,J=8.7Hz,1H),8.77(d,J=7.5Hz,1H),7.61(s,1H),7.35–7. 28(m,5H),7.23–7.19(m,2H),3.32(dd,J=17.0,10.3Hz,1H),6.12(dd,J=17.0,1.8Hz,1H),5. 70(dd,J=10.3,1.8Hz,1H),4.97(qn,J=7.4Hz,1H),4.68–4.54(m,2H),4.35(t,J=7.7Hz,1H), 4.30–4.23(m,2H),4.13–4.09(m,2H),3.81–3.74(m,1H),3.29(s,3H),1.43(d,J=7.0Hz,3H).

[0890] Example 150: N 1 -((S)-7-((1-(2-hydroxyethyl)azetidin-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (150)

[0891] Synthesis route:

[0892] The title compound 150 was prepared by the same synthetic route and method as Example 83, except that compound 49 was replaced by an equivalent amount of compound 147a.

[0893] MS(ES + ):m / z 491.2[M+H] + .

[0894] 1 H NMR (400MHz, CDCl3): δ8.25(d,J=7.7Hz,1H),7.47(d,J=8.2Hz,1H),7.37–7.27(m,7H), 7.10(d,J=8.6Hz,1H),5.07(qn,J=7.5Hz,1H),4.84–4.77(m,1H),4.58(dd,J=9.7,7.4Hz ,1H),4.21(t,J=10.7Hz,1H),3.78(t,J=7.5Hz,2H),3.58(t,J=5.1Hz,2H),3.52–3.48( m,1H),3.40(s,3H),3.27(t,J=7.2Hz,2H),2.69(t,J=5.1Hz,2H),1.53(d,J=7.0Hz,3H).

[0895] Example 151: N 1 -((S)-5-methyl-7-((1-nitrosoazetidin-3-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (151)

[0896] Synthesis route:

[0897] To a mixture of compound 147a (22 mg, 0.05 mmol) in acetic acid (0.75 mL) and water (0.25 mL) was added sodium nitrite (7 mg, 0.1 mmol) at room temperature, and the reaction was stirred at room temperature for 6 hours. TLC and LC-MS indicated the reaction was complete. The mixture was then neutralized with saturated sodium bicarbonate solution to pH 7, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 5–10% methanol in dichloromethane) to afford the title compound 151 (16 mg, 67% yield) as a light yellow solid.

[0898] MS(ES + ):m / z 476.2[M+H] + .

[0899] 1H NMR (400MHz, DMSO-d6): δ9.19(d,J=8.6Hz,1H),8.77(d,J=7.4Hz,1H),7.62(s,1H),7.36–7.27(m,5H),7.23–7.19(m,2H),5.23 (t,J=9.7Hz,1H),4.96(qn,J=7.3Hz,1H),4.90–4.86(m,1H),4.68–4.56(m,2H),4.48(t,J=10.4Hz,1H),4.35(t,J=7.4Hz,1H), 4.13–4.08(m,1H),3.97–3.90(m,1H),3.29(s,3H),1.43(d,J=7.0Hz,3H).

[0900] Example 152: N 1 -((S)-7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((S)-1-phenylpropan-2-yl)oxalamide (152)

[0901] Synthesis route:

[0902] The title compound 152 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of (S)-1-phenylpropane-2-amine 152a.

[0903] MS(ES + ):m / z 450.2[M+H] + .

[0904] 1 H NMR (400MHz, CDCl3): δ8.24(d,J=7.4Hz,1H),7.30–7.19(m,5H),7.15–7.13(m,3H),7.10(d,J=8.9Hz,1H),4.80(dt,J=11.2,7.4Hz,1H),4.58(dd,J =9.7,7.3Hz,1H),4.24–4.17(m,2H),3.84(t,J=6.2Hz,2H),3.40(s,3H),2 .87–2.82(m,1H),2.76–2.69(m,3H),1.77(br,1H),1.16(d,J=6.7Hz,3H).

[0905] Example 153: N1 -((S)-7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylpropan-2-yl)oxalamide (153)

[0906] Synthesis route:

[0907] The title compound 153 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of (R)-1-phenylpropane-2-amine 153a.

[0908] MS(ES + ):m / z 450.2[M+H] + .

[0909] 1 H NMR (400MHz, CDCl3): δ8.21(d,J=7.5Hz,1H),7.31–7.20(m,5H),7.17–7.13(m,3H),7.10(d,J=8.8Hz,1H),4.80(dt,J=11.3,7.4Hz,1H),4.58(dd,J =9.8,7.8Hz,1H),4.25–4.15(m,2H),3.83(t,J=6.0Hz,2H),3.40(s,3H),2 .89–2.82(m,1H),2.76–2.68(m,3H),1.78(br,1H),1.15(d,J=6.6Hz,3H).

[0910] Example 154: N 1 -((S)-7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -(2-phenylpropyl)oxamide (154)

[0911] Synthesis route:

[0912] The synthetic route and method were the same as those of Example 32, except that the benzylamine 32a in step 1 was replaced with an equivalent amount of 2-phenylpropan-1-amine 154a to obtain the title compound 154 (dr = 1:1).

[0913] MS(ES +):m / z 450.2[M+H] + .

[0914] 1 H NMR (400MHz, CDCl3): δ8.21(d,J=7.7Hz,1H),7.33–7.15(m,8H),7.08(d,J=8. 7Hz,1H),4.81–4.75(m,1H),4.60–4.53(m,1H),4.25–4.18(m,1H),3.85–3.81( m,2H),3.62–3.53(m,1H),3.40,3.39(1:1,s,3H),3.37–3.31(m,1H),2.99–2. 92(m,1H),2.70(t,J=6.2Hz,2H),1.78(t,J=6.1Hz,1H),1.29(d,J=7.0Hz,3H).

[0915] Example 155: N 1 -((S)-7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-2-phenylpropyl)oxamide (155)

[0916] Synthesis route:

[0917] The title compound 155 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of (R)-2-phenylpropan-1-amine 155a.

[0918] MS(ES + ):m / z 450.2[M+H] + .

[0919] 1H NMR (400MHz, CDCl3): δ8.21 (d, J=7.4Hz, 1H), 7.33–7.15 (m, 8H), 7.08 (d, J= 8.9Hz,1H),4.82–4.75(m,1H),4.60–4.54(m,1H),4.25–4.18(m,1H),3.85– 3.81(m,2H),3.62–3.52(m,1H),3.39(s,3H),3.37–3.31(m,1H),2.99–2.92 (m,1H),2.70(t,J=6.2Hz,2H),1.77(t,J=5.9Hz,1H),1.29(d,J=6.9Hz,3H).

[0920] Example 156: N 1 -((S)-7-(4-hydroxybut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((S)-2-phenylpropyl)oxamide (156)

[0921] Synthesis route:

[0922] The title compound 156 was prepared by the same synthetic route and method as Example 32, except that the benzylamine 32a in step 1 was replaced by an equivalent amount of (S)-2-phenylpropan-1-amine 156a.

[0923] MS(ES + ):m / z 450.2[M+H] + .

[0924] 1 H NMR (400MHz, CDCl3): δ8.21 (d, J=7.1Hz, 1H), 7.33–7.15 (m, 8H), 7.08 (d, J= 8.7Hz,1H),4.82–4.75(m,1H),4.60–4.54(m,1H),4.25–4.18(m,1H),3.85– 3.81(m,2H),3.62–3.53(m,1H),3.40(s,3H),3.37–3.31(m,1H),2.99–2.92 (m,1H),2.70(t,J=6.2Hz,2H),1.77(t,J=6.2Hz,1H),1.29(d,J=7.0Hz,3H).

[0925] Example 157: N 1-((S)-7-(4-hydroxybut-1-yn-1-yl)-5-isopropyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -(2-phenylpropyl)oxamide (157)

[0926] Synthesis route:

[0927] Steps 1–3 were the same as the synthetic route and method of steps 4–6 of Example 1, except that iodomethane in step 4 of Example 1 was replaced by an equivalent amount of 2-iodopropane 157a; steps 4–5 were the same as the synthetic route and method of Example 154, except that compound 1h was replaced by an equivalent amount of compound 157d, to obtain the title compound 157.

[0928] MS(ES + ):m / z 478.2[M+H] + .

[0929] 1 H NMR (400MHz, CDCl3): δ8.22(d,J=7.7Hz,1H),7.33–7.15(m,8H),7.09(d,J=8.5Hz,1 H),4.75–4.63(m,2H),4.49–4.43(m,1H),4.17–4.10(m,1H),3.84(t,J=6.1Hz,2H), 3.62–3.53(m,1H),3.40–3.29(m,1H),2.98–2.90(m,1H),2.70(t,J=6.3Hz,2H),1.7 7(br,1H),1.46(dd,J=6.8,2.0Hz,3H),1.28(d,J=7.0Hz,3H),1.17(d,J=6.8Hz,3H).

[0930] Example 158: N 1 -((S)-7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-2-phenylpropyl)oxalamide (158)

[0931] Synthesis route:

[0932] The title compound 158 was prepared by the same synthetic route and method as in step 2 of Example 155, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 3-alkynoxetane-3-ol 43a.

[0933] MS(ES + ):m / z 478.2[M+H] + .

[0934] 1 H NMR (400MHz, CDCl3): δ8.22(d,J=7.3Hz,1H),7.33–7.29(m,4H),7.24–7.17( m,4H),7.13(d,J=8.9Hz,1H),4.93(d,J=6.7Hz,2H),4.82–4.76(m,3H),4.59( dd,J=9.7,7.4Hz,1H),4.25(t,J=10.6Hz,1H),3.60–3.54(m,1H),3.41(s,3H ),3.39–3.34(m,1H),2.99–2.92(m,1H),2.70(br,1H),1.29(d,J=6.9Hz,3H).

[0935] Example 159: N 1 -((S)-5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-2-phenylpropyl)oxamide (159)

[0936] Synthesis route:

[0937] The title compound 159 was prepared by the same synthetic route and method as in step 2 of Example 155, except that 3-butyn-1-ol 31a was replaced by an equivalent amount of 4-(prop-2-yn-1-yl)morpholine 48a.

[0938] MS(ES + ):m / z 505.2[M+H] + .

[0939] 1H NMR (400MHz, DMSO-d6): δ8.75(d,J=7.6Hz,1H),8.69(t,J=6.1Hz,1H),7.56(d,J=1.8Hz,1H),7.33(dd,J=8.3,1.9Hz,1H),7.30–7.26(m,2H),7.22– 7.17(m,4H),4.67–4.57(m,2H),4.40–4.32(m,1H),3.61(t,J=4.5Hz,4H), 3.51(s,2H),3.38–3.22(m,9H),3.08–2.97(m,1H),1.14(d,J=7.0Hz,3H).

[0940] Example 160: (S)-N 1 -(5-methyl-7-(3-morpholinoprop-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -(2-phenylpropan-2-yl)oxalamide (160)

[0941] Synthesis route:

[0942] The title compound 160 was prepared by the same synthetic route and method as in Example 32, except that the benzylamine 32a in step 1 and the 3-butyn-1-ol 31a in step 2 were replaced by equivalent amounts of 2-phenylpropane-2-amine 160a and 4-(prop-2-yn-1-yl)morpholine 48a, respectively.

[0943] MS(ES + ):m / z 505.3[M+H] + .

[0944] 1 H NMR (400MHz, DMSO-d6): δ8.22(d,J=7.5Hz,1H),8.22(s,1H),7.38–7.23(m,7H),7.12(d,J=8.1Hz,1H),4.79(dt,J=11.3,7.4Hz,1H),4.58 (dd,J=9.7,7.4Hz,1H),4.22(dd,J=11.1,9.9Hz,1H),3.79(t,J=4.5Hz,4H),3.52(s,2H),3.39(s,3H),2.66(t,J=4.6Hz,4H),1.73(s,6H).

[0945] Example 161: 4-(3-((S)-5-methyl-4-oxo-3-(2-oxo-2-(((R)-1-phenylethyl)amino)acetylamino)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Synthesis of morpholine 4-oxide (161)

[0946] Synthesis route:

[0947] To a solution of compound 140 (25 mg, 0.05 mmol) in dichloromethane (2 mL) was added m-chloroperbenzoic acid (mCPBA, 17 mg, 0.1 mmol) at room temperature, and the reaction was stirred at room temperature for 2 hours. TLC and LC-MS showed the reaction was complete, and the product was concentrated under reduced pressure and purified by silica gel column chromatography (5–10% methanol in dichloromethane as eluent) to afford the title compound 161 (21 mg, 83% yield) as a white solid.

[0948] MS(ES + ):m / z 507.2[M+H] + .

[0949] 1 H NMR (400MHz, CDCl3): δ8.27(d,J=7.5Hz,1H),7.48(d,J=8.4Hz,1H),7.39–7.27(m,7H),7.17 (d,J=8.8Hz,1H),5.07(qn,J=7.3Hz,1H),4.81(dt,J=11.2,7.4Hz,1H),4.68(s,1H),4.57(d d,J=9.7,7.3Hz,1H),4.43(t,J=14.7Hz,1H),4.26(t,J=10.7Hz,1H),3.92(dd,J=12.6,3.2H z,1H),3.82(td,J=11.5,3.3Hz,1H),3.49–3.39(m,4H),1.96(br,5H),1.53(d,J=6.9Hz,3H).

[0950] Example 162: N 1-((S)-7-(3-(4-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-carbonylbutan-2-yl)amino)-2-carbonylethoxy)ethoxy)ethyl)piperazin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (162)

[0951] Synthesis route:

[0952] Steps 1, 2 and 3 were the same as the synthetic routes and methods of Examples 53, 54 and 55, respectively, except that compound 23 was replaced by an equivalent amount of compound 142 to obtain the title compound 162.

[0953] MS(ES + ):m / z 1046.5[MH] - .

[0954] 1 H NMR (400MHz, CDCl3): δ8.68(s,1H),8.25(d,J=7.4Hz,1H),7.67–7.51(m,2H),7.38–7.27(m,11H),7.09(d, J=8.1Hz,1H),5.38–5.31(m,3H),5.06(qn,J=7.3Hz,1H),4.83–4.71(m,2H),4.61–4.51(m,3H),4.35(dd,J =14.9,5.2Hz,1H),4.21(t,J=10.6Hz,1H),4.07–3.94(m,3H),3.70–3.59(m,7H),3.49(s,2H),3.39(s,3H) ,2.69(br,8H),2.52(s,3H),2.22(t,J=7.6Hz,2H),2.04–1.98(m,2H),1.53(d,J=6.9Hz,3H),0.95(s,9H).

[0955] Example 163: N 1-((S)-7-(3-(4-((S)-14-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-15,15-dimethyl-12-oxo-3,6,9-trioxa-13-azahexadecyl)piperazin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (163)

[0956] Synthesis route:

[0957] Steps 1, 2 and 3 were the same as the synthetic routes and methods of Examples 53, 54 and 55, respectively, except that compound 23 and tert-butyl 2-(2-(2-(tosylcarbonyl)ethoxy)ethoxy)acetate 53a were replaced by equivalent amounts of compound 142 and tert-butyl 3-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propionate 163a, respectively, to produce the title compound 163.

[0958] MS(ES + ):m / z 1104.5[MH] - .

[0959] 1 H NMR (400MHz, CDCl3): δ8.67(s,1H),8.27(d,J=7.3Hz,1H),7.68–7.41(m,2H),7.37–7.27(m,11H),7.1 1–7.02(m,2H),5.06(qn,J=7.2Hz,1H),4.83–4.70(m,2H),4.61–4.48(m,4H),4.33(dd,J=15.0,5.2Hz, 1H),4.22(t,J=10.6Hz,1H),4.10(d,J=11.3Hz,1H),3.75–3.56(m,14H),3.50(s,2H),3.39(s,3H),2.7 1–2.61(m,8H),2.51(s,3H),2.49–2.44(m,2H),2.23–2.10(m,4H),1.52(d,J=6.9Hz,3H),0.93(s,9H).

[0960] Example 164: N 1-((3S)-7-(3-(4-(2-(2-(2-(3-((2-(2,6-dicarbonylpiperidin-3-yl)-1-carbonylisoindolin-4-yl)amino)-3-carbonylpropoxy)ethoxy)ethoxy)ethyl)piperazin-1-yl)prop-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (164)

[0961] Synthesis route:

[0962] The title compound 164 was prepared using the same synthetic route and method as in step 3 of Example 163, except that (2R,4S)-1-((R)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride 55a was replaced by an equivalent amount of 3-(4-amino-1-carbonylisoindolin-2-yl)piperidine-2,6-dione 56a (Lenalidomide).

[0963] MS(ES + ):m / z 935.3[M+H] + .

[0964] 1 H NMR (400MHz, CDCl3): δ9.66(br,1H),9.24(s,1H),8.25(d,J=7.5Hz,1H),7.92(d,J=7.9Hz,1H),7.66(d,J=7.4Hz,1H),7.60–7.54( m,1H),7.45(t,J=7.7Hz,1H),7.38(s,1H),7.35–7.28(m,5H),7.09(d,J=8.2Hz,1H),5.20–5.12(m,1H),5.09–5.00(m,1H),4.82–4 .76(m,1H),4.57–4.43(m,3H),4.21(t,J=10.6Hz,1H),3.83(t,J=5.4Hz,2H),3.68–3.61(m,6H),3.60–3.55(m,2H),3.51–3.48(m, 3H),3.47(s,2H),3.40(s,3H),2.89–2.68(m,10H),2.41–2.28(m,2H),2.23–2.15(m,2H),2.04–1.97(m,2H),1.51(d,J=6.9Hz,3H).

[0965] Example 165: N 1 -((S)-1-methyl-8-(3-morpholinoprop-1-yn-1-yl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (165)

[0966] Synthesis route:

[0967] Step 1: Synthesis of (S)-3-((4-bromo-2-nitrophenyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (165b)

[0968] To a suspension of sodium hydride (60% w / w dispersion in mineral oil, 1.8 g, 45 mmol) in DMF (N,N-dimethylformamide, 50 mL) was added a solution of (S)-3-amino-2-((tert-butoxycarbonyl)amino)propanoic acid 165a (4.4 g, 21.54 mmol) in DMF (10 mL) at 0°C in an ice bath. The reaction was stirred for 1 hour. A solution of 4-bromo-1-fluoro-2-nitrobenzene 1a (5 g, 22.73 mmol) in DMF (20 mL) was then slowly added dropwise to the reaction mixture at 0°C in an ice bath. The mixture was then warmed to room temperature and stirred for an additional 15 hours. TLC and LC-MS indicated the reaction was complete. The reaction mixture was poured into ice water (200 mL), and the aqueous phase was acidified to pH 4 with dilute hydrochloric acid (1 N) and extracted with ethyl acetate (100 mL x 5). The combined organic layers were washed sequentially with water (100 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (eluent: dichloromethane containing 1% methanol) to give compound 165b (6 g, yield 69%) as a yellow solid.

[0969] MS(ES + ):m / z 403.9[M+H] + .

[0970] Step 2: Synthesis of (S)-3-((2-amino-4-bromophenyl)amino)-2-((tert-butoxycarbonyl)amino)propanoic acid (165c)

[0971] Zinc powder (5.7 g, 87 mmol) was added to a solution of compound 165b (6 g, 14.84 mmol) in acetic acid (60 mL) under an ice bath at 0°C, and the resulting mixture was stirred at 30°C for 48 hours. TLC and LC-MS showed that the reaction was complete. The reaction mixture was filtered through celite, the filter cake was rinsed with dichloromethane (300 mL), and the filtrate was concentrated under reduced pressure. The residue after concentration was then dissolved in water (50 mL), neutralized with saturated sodium bicarbonate solution to pH = 7, and then extracted with dichloromethane (100 mL x 3). The organic layer was collected, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of compound 165c (6.6 g) as a black solid, which was used directly in the next step without further purification.

[0972] MS(ES + ):m / z 373.9[M+H] + .

[0973] Step 3: (S)-(8-Bromo-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine Synthesis of tert-butyl butylcarbamate (165d)

[0974] To a solution of compound 165c (6.6 g, 17.64 mmol) in pyridine (200 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 3.38 g, 17.63 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 15 hours. TLC and LC-MS indicated completion of the reaction. After concentration under reduced pressure to remove most of the pyridine solvent, the reaction mixture was poured into saturated aqueous citric acid (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting mixture was then purified by silica gel column chromatography (eluent: 30% ethyl acetate in petroleum ether) to afford compound 165d (3 g, 57% yield over two steps) as a white solid.

[0975] MS(ES + ):m / z 355.9[M+H] + .

[0976] 1H NMR (400MHz, DMSO-d6): δ9.79 (s, 1H), 7.07–7.05 (m, 2H), 6.91 (d, J = 8.0Hz, 1H), 6.77 (d, J = 8.4Hz, 1H), 5.90 (d, J = 5.6Hz, 1H), 4.17–4.11 (m, 1H), 3.46–3.43 (m, 1H), 3.31–3.26 (m, 1H), 1.37 (s, 9H).

[0977] Step 4: (S)-7-Bromo-3-((tert-butoxycarbonyl)amino)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine Synthesis of tert-butyl 1-carboxylate (165e)

[0978] Compound 165d (1.0 g, 2.8 mmol), di-tert-butyl dicarbonate (808 mg, 3.7 mmol), 4-dimethylaminopyridine (37 mg, 0.3 mmol), triethylamine (708 mg, 7.0 mmol), and tetrahydrofuran (10 mL) were added sequentially to a reaction flask at room temperature. The reaction mixture was warmed to 70°C and stirred for 15 hours. TLC and LC-MS showed the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (eluent: 50% dichloromethane in petroleum ether) to afford compound 165e (640 mg, 50% yield) as a white solid.

[0979] MS(ES + ):m / z 456.0[M+H] + .

[0980] 1 H NMR (400MHz, DMSO-d6): δ9.16(s,1H),7.94(s,1H),6.67(d,J=8.4Hz,1H),7.32–7.79(m,1H),7.22(d, J=8.4Hz,1H),4.80–4.76(m,1H),3.93(t,J=5.6Hz,1H),3.69–3.67(m,1H),1.46(s,9H),1.40(s,9H).

[0981] Step 5: (S)-7-Bromo-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine Synthesis of tert-butyl 1-carboxylate (165f)

[0982] To a mixture of compound 165e (640 mg, 1.4 mmol) and cesium carbonate (593 mg, 1.8 mmol) in DMF (10 mL) was added iodomethane (213 mg, 1.5 mmol) at room temperature under nitrogen, and the reaction mixture was stirred at room temperature for 6 hours. TLC and LC-MS showed that the reaction was complete. The reaction mixture was poured into ice water (40 mL), and a solid precipitated. After stirring for 10 minutes, the mixture was filtered and the filter cake was collected and slurried with petroleum ether (50 mL) containing 15% ethyl acetate to afford compound 165f (320 mg, 38% yield) as a white solid.

[0983] MS(ES + ):m / z 469.9[M+H] + .

[0984] Step 6: (S)-3-Amino-8-bromo-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepine Synthesis of -2-keto hydrochloride (165 g)

[0985] To a solution of compound 165f (282 mg, 0.6 mmol) in dichloromethane (5 mL) was added dropwise a solution of hydrogen chloride in 1,4-dioxane (4 N, 5 mL) at room temperature. The reaction was stirred at room temperature for 4 hours. TLC and LC-MS showed the reaction was complete. The solvent and other volatiles were removed by concentration under reduced pressure, and the mixture was then slurried with ethyl acetate containing 7% methanol (30 mL) to afford compound 165g (152 mg, 74% yield) as a white solid.

[0986] MS(ES + ):m / z 269.8[M+H] + .

[0987] 1 H NMR (400MHz, DMSO-d6): δ9.17(s,3H),7.05(d,J=8.0Hz,1H),6.76–6.72(m,2H),5 .09(br,2H),4.59(s,1H),3.84(t,J=5.6Hz,1H),3.79–3.77(m,1H),2.71(s,3H).

[0988] Step 7: (S)-2-(8-Bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine Synthesis of ethyl 2-oxo-3-yl)amino)-2-oxoacetate (165h)

[0989] To a mixture of compound 165g (152 mg, 0.44 mmol) and triethylamine (178 mg, 1.76 mmol) in dichloromethane (8 mL) was slowly added dropwise a solution of ethyl oxalyl chloride (72 mg, 0.53 mmol) in dichloromethane (1 mL) under an ice bath at 0°C. The reaction solution was slowly warmed to room temperature and stirred for 3 hours. TLC and LC-MS showed the reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then purified by silica gel column chromatography (eluent: 30% ethyl acetate in petroleum ether) to afford compound 165h (117 mg, 72% yield) as a white solid.

[0990] MS(ES + ):m / z 370.0[M+H] + .

[0991] Step 8: N 1 -((S)-8-Bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (165i)

[0992] To a solution of compound 165h (100 mg, 0.27 mmol) in ethanol (10 mL) was added (R)-1-phenylethylamine 125a (75 mg, 0.62 mmol). The reaction was warmed to 80°C and stirred for 4 hours. TLC and LC-MS showed the reaction was complete. The reaction was cooled to room temperature, concentrated under reduced pressure, and then slurried with 15% ethyl acetate in petroleum ether (30 mL) to afford compound 165i (96 mg, 80% yield) as a white solid.

[0993] MS(ES + ):m / z 445.1[M+H] + .

[0994] Step 9: N 1 -((S)-1-methyl-8-(3-morpholinoprop-1-yn-1-yl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (165)

[0995] Compound 165i (44.5 mg, 0.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (7.0 mg, 0.01 mmol), cuprous iodide (1.9 mg, 0.01 mmol), triethylamine (1 mL), DMF (2 mL), and 4-(prop-2-yn-1-yl)morpholine 48a (25.0 mg, 0.2 mmol) were added sequentially to a sealed tube at room temperature. The air in the tube was quickly replaced with nitrogen three times, and the reaction solution was stirred at 80°C for 15 hours. TLC and LC-MS showed the reaction was complete. After cooling to room temperature, the reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was then purified by silica gel column chromatography (eluent: dichloromethane containing 0.5% methanol) to give the title compound 165 (30.3 mg, yield 62%) as a white solid.

[0996] MS(ES + ):m / z 490.2[M+H] + .

[0997] 1 H NMR (400MHz, CDCl3): δ8.09(d,J=8.0Hz,1H),7.60(d,J=8.4Hz,1H),7.37–7.29(m,5H),6.75–6.73(m,3H),5.74(br,1H),5.06(qn,J=7.2Hz,1H),4.9 9–4.92(m,1H),3.95–3.91(m,1H),3.87–3.83(m,1H),3.78(t,J=4.4Hz,4H ),3.50(s,2H),2.85(s,3H),2.65(t,J=4.4Hz,4H),1.55(d,J=6.9Hz,3H).

[0998] Example 166: N 1 -((S)-1,5-dimethyl-8-(3-morpholinoprop-1-yn-1-yl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine -3-yl)-N 2 Synthesis of -((R)-1-phenylethyl)oxalamide (166)

[0999] Synthesis route:

[1000] Steps 1-5 were the same as the synthetic routes and methods of steps 5-9 of Example 165, respectively, except that the reaction temperature of step 5 of Example 165 was changed from room temperature to 50°C and compound 165e was replaced with an equivalent amount of compound 165d to obtain the title compound 166.

[1001] MS(ES + ):m / z 504.3[M+H] + .

[1002] 1 H NMR (400MHz, CDCl3): δ8.30(d,J=7.6Hz,1H),7.50(d,J=8.4Hz,1H),7.36–7.27(m,6H), 7.23(d,J=1.8Hz,1H),6.99(d,J=8.4Hz,1H),5.07(qn,J=7.3Hz,1H),4.54(dt,J=11.5,7 .2Hz,1H),3.78(t,J=4.6Hz,4H),3.50(s,2H),3.44(dd,J=9.4,6.8Hz,1H),3.37(s,3H), 3.32(dd,J=11.4,9.6Hz,1H),2.75(s,3H),2.64(t,J=4.4Hz,4H),1.53(d,J=6.9Hz,3H).

[1003] Example 167: N 1 -(3-Fluorophenethyl)-N 2 -(8-(4-hydroxybut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine Synthesis of oxalamide (167)

[1004] Synthesis route:

[1005] The title compound 167 was prepared by the same synthetic route and method as Example 34, except that compound 1h in step 1 was replaced by an equivalent amount of compound 61h.

[1006] MS(ES + ):m / z 452.2[M+H] + .

[1007] 1H NMR (400MHz, CDCl3): δ8.25(d,J=7.5Hz,1H),7.33(t,J=6.0Hz,1H),7.28–7.23 (m,3H),7.16(d,J=7.7Hz,1H),7.00–6.87(m,3H),4.38(dt,J=11.0,7.6Hz,1H) ,3.83(q,J=6.3Hz,2H),3.58–3.52(m,2H),3.40(s,3H),2.89–2.80(m,3H),2.7 0(t,J=6.3Hz,2H),2.65–2.53(m,2H),2.05–1.96(m,1H),1.78(t,J=6.3Hz,1H).

[1008] Example 168: N 1 -(8-(4-hydroxybutyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine -3-yl)-N 2 Synthesis of -phenylacetamide (168)

[1009] Synthesis route:

[1010] Compound 167 (13 mg, 0.03 mmol), Lindlar's catalyst (3 mg), and methanol (1 mL) were added sequentially to a sealed tube at room temperature. The air in the tube was rapidly replaced with hydrogen three times, and a hydrogen balloon was added under a hydrogen atmosphere. The reaction solution was stirred at room temperature for 15 hours. The reaction solution was quenched with water (5 mL) and extracted with dichloromethane (5 mL x 3). The combined organic layers were concentrated under reduced pressure to obtain the crude product, which was separated and purified by Prep-HPLC (water containing 30–80% acetonitrile as the mobile phase) to obtain compound 168 (3 mg, 22% yield) as a white solid.

[1011] MS(ES + ):m / z 456.2[M+H] + .

[1012] 1H NMR (400MHz, CDCl3): δ8.27(d,J=6.3Hz,1H),7.34–7.27(m,3H),7.23–7.17(m,3H),7.12(d,J=7.6Hz,1H),7.02–6.98(m,2H),4.41(dt,J=11.1, 7.6Hz,1H),3.68(q,J=5.4Hz,2H),3.62–3.49(m,2H),3.40(s,3H),2.86 –2.78(m,3H),2.66–2.53(m,4H),2.05–1.94(m,1H),1.75–1.60(m,4H).

[1013] In vitro kinase activity assay

[1014] RIPK1 kinase activity was detected using the ADP-Glo ​​assay and the RIPK1 kinase reaction system (Promega, catalog number: VA7593). The RIPK1 kinase activity assay was performed according to the Promega kit instructions.

[1015] Inhibition rate of compound (1 μM) on RIPK1 kinase activity

[1016] The experimental method is briefly described as follows: The RIPK1 kinase concentration in the RIPK1 kinase reaction system was determined by kinase titration and S / B10. Compounds were diluted in 1× Kinase Buffer D (1% DMSO), and 1 μL of a 100 μM compound stock in DMSO was added to 19 μL of 1× Kinase Buffer D. RIPK1 kinase was diluted in 1× Kinase Buffer D. 2.5× ATP / substrate was diluted in 1× Kinase Buffer D. The final concentration of ATP in the kinase reaction system was 10 μM, and the final concentration of MBP substrate was 100 μg / mL. 1 μL of the diluted compound was mixed with 2 μL of diluted RIPK1 kinase and incubated at room temperature for 15 minutes. 2 μL of 2.5× ATP / substrate was added, mixed, and incubated at room temperature for 1 hour. 5 μL of ADP-Glo ​​reagent was added to each well and incubated at room temperature for 1 hour. 10 μL of ADP detection reagent was added to each well and incubated at room temperature for 0.5-1 hour. The chemiluminescent signal was read on a microplate reader, and the percentage of kinase activity inhibition was calculated.

[1017] Table 1 below provides the inhibition rate ranges of some compounds on RIPK1 kinase activity at 1 μM: A: ≥75%; B: 50-74%; C: 25-49%.

[1018] Table 1 Inhibition rate range of compounds (1 μM) on RIPK1 kinase activity

[1019] In vitro kinase activity IC50 assay

[1020] The experimental method is briefly described as follows: The RIPK1 kinase concentration in the RIPK1 kinase reaction system was determined by kinase titration and S / B10. Compounds were diluted in 1× Kinase Buffer D (1% DMSO). 1 μL of a 1 mM compound stock in DMSO was added to 19 μL of 1× Kinase Buffer D. A 1:5 serial dilution of the compound was performed in 1× Kinase Buffer D for a total of eight concentration points, with a control containing the same DMSO volume. RIPK1 kinase was diluted in 1× Kinase Buffer D. 2.5× ATP / substrate was diluted in 1× Kinase Buffer D. The final ATP concentration in the kinase reaction system was 10 μM, and the final MBP substrate concentration was 100 μg / mL. 1 μL of the diluted compound was mixed with 2 μL of the diluted RIPK1 kinase and incubated at room temperature for 15 minutes. 2 μL of 2.5× ATP / substrate was added, mixed, and incubated at room temperature for 1 hour. 5 μL of ADP-Glo ​​reagent was added to each well and incubated at room temperature for 1 hour. Add 10 μL of ADP detection reagent to each well and incubate at room temperature for 0.5-1 hour. Read the chemiluminescent signal using a microplate reader and calculate the kinase inhibition rate. The IC50 value is calculated by fitting the nonlinear regression curve log[inhibitor] vs. response—Variable slope (four parameters) in GraphPad Prism.

[1021] Table 2 below provides the IC50 range of some compounds for RIPK1 kinase activity: A<100 nM.

[1022] Table 2 IC50 range of compounds for RIPK1 kinase activity

[1023] Determination of the inhibitory activity on cell necrosis and apoptosis in U937

[1024] The biological activity of RIPK1 inhibitors was determined by inhibiting necroptosis in U937 cells. U937 cells were purchased from Huatuo Biotechnology and stored in liquid nitrogen and revived before the experiment. U937 cells were cultured in RPMI-1640 medium (supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin) at 37°C and 5% CO2. The activity of the compounds was assessed by measuring cellular ATP levels using the Promega CellTiter-Glo 2.0 Assay Cell Viability Kit (Catalog No. G9242).

[1025] Inhibitory effect of compound (1 μM) on necroptosis in U937 cells

[1026] The experimental method is briefly described as follows: U937 cells in the logarithmic growth phase were collected by centrifugation and diluted to 5×10 cells / mL using RPMI1640 medium (supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin). 5 A cell suspension at a concentration of 100 μL / mL was plated into a sterile white 384-well cell culture plate at 15 μL / well. Test compounds were dissolved in DMSO to a 10 mM stock solution and diluted to 10 μM with culture medium. A control containing the same volume of DMSO was also set up, with duplicate wells for each concentration. The diluted compounds were added to the 384-well cell culture plate containing cells at 2.5 μL / well and incubated at 37°C, 5% CO₂ for 15 minutes. Z-VAD-FMK (Biyuntian, catalog number: C1202-5mg) was dissolved in DMSO to a 20 mM stock solution. SM-164 (Biyuntian, catalog number: SC0114-10mM) was dissolved in DMSO to a 10 mM stock solution and diluted to 0.1 mM. hTNF-α (Sino Biological, catalog number: 10602-HNAE) was dissolved in sterile water to 10 μg / mL. A TSZ mixture was prepared in RPMI1640 medium (supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin). The mixture contained 133.3 μM Z-VAD-FMK, 33.3 ng / mL hTNF-α, and 0.3 μM SM-164. After incubation with the compound and cells for 15 minutes, 7.5 μL of the TSZ mixture was added to each well, mixed thoroughly, and incubated at 37°C, 5% CO₂ for 20 hours. After 20 hours, the plate was removed and allowed to equilibrate at room temperature for 30 minutes. Then, 10 μL of pre-equilibrated CellTiter-Glo reagent was added to each well and mixed thoroughly by vortexing. After incubation in the dark for 10 minutes, chemiluminescence was measured in each well using a microplate reader. % inhibition was calculated as (1 - (no TSZ, TSZ & compound) / (no TSZ, TSZ)) × 100.

[1027] Table 3 below provides the inhibition rate ranges of some compounds on necroptosis of U937 cells at 1 μM: A: ≥90%; B: 50-89%.

[1028] Table 3 Inhibitory rate interval of compounds (1 μM) on necroptosis in U937 cells

[1029] EC50 of the compounds inhibiting necroptosis in U937 cells

[1030] The experimental method is briefly described as follows: U937 cells in the logarithmic growth phase were collected by centrifugation and diluted to 5×10 cells / mL using RPMI1640 medium (supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin). 5A cell suspension at a concentration of 100 cells / mL was added to a sterile white 384-well cell culture plate at 15 μL / well. Test compounds were dissolved in DMSO to a 10 mM stock solution and serially diluted in culture medium at a 1:3 ratio for a total of 10 concentration points. A control containing the same DMSO volume was also established, with duplicate wells for each concentration. The diluted compounds were added to the 384-well cell culture plate containing cells at 2.5 μL / well and incubated at 37°C, 5% CO₂ for 15 minutes. Z-VAD-FMK (Biyuntian, catalog number: C1202-5mg) was dissolved in DMSO to a 20 mM stock solution. SM-164 (Biyuntian, catalog number: SC0114-10mM) was dissolved in DMSO to a 10 mM stock solution and diluted to 0.1 mM. hTNF-α (Sino Biological, catalog number: 10602-HNAE) was dissolved in sterile water to 10 μg / mL. A TSZ mixture was prepared in RPMI1640 medium (supplemented with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin) containing 133.3 μM Z-VAD-FMK, 33.3 ng / mL hTNF-α, and 0.3 μM SM-164. After incubation with the compounds and cells for 15 minutes, 7.5 μL of the TSZ mixture was added to each well, mixed thoroughly, and incubated at 37°C, 5% CO₂ for 20 hours. After 20 hours, the plate was removed and allowed to equilibrate at room temperature for 30 minutes. Then, 10 μL of pre-equilibrated CellTiter-Glo reagent was added to each well and mixed thoroughly by vortexing. After 10 min of storage in the dark, the chemiluminescence reading of each well was measured using a microplate reader, and the inhibition rate (%) was calculated as (1-(no TSZ-TSZ & compound) / (no TSZ-TSZ))×100. The EC50 was obtained by fitting the nonlinear regression curve log[inhibitor] vs. response—Variable slope (four parameters) in GraphPad Prism.

[1031] Table 4 below provides the EC50 intervals of some compounds for inhibiting necroptosis in U937 cells: A<100 nM; B: 100-500 nM; C: 500-2000 nM.

[1032] Table 4 EC50 intervals of compounds for inhibiting necroptosis in U937 cells

Claims

1. Compound of formula (I): or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, in, X is selected from CH and N; Y is selected from -CR a R b -、-O-、-NR a -and-S(O) m -; Z is selected from -O and -S; L is selected from a single bond, -(CR a R b ) n -、-(CR a R b ) n O-、-(CR a R b ) n S-、-(CR a R b ) n NR a -、-O-、-NR a -and-S(O) m -; Ring A is selected from C5-C 10 Aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally further substituted by one or more R 6 replace; R 1 independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b and-NHS(O) m R a wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally further substituted by one or more groups selected from deuterium atoms, halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group, and R7; preferably, R 1 an alkynyl, alkenyl, and allenyl group selected from the group consisting of: R 2 and R 3 are each independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl; or R 1 and R 2 Together with the atoms to which they are attached, they form C5-C 10 aryl, heteroaryl, heterocyclyl or cycloalkyl, or R 2 and R 3 Together with the atoms to which they are attached, they form C5-C 10 aryl, heteroaryl, heterocyclic or cycloalkyl, wherein the C5-C 10 Aryl, heteroaryl, heterocyclyl or cycloalkyl is optionally further substituted by one or more R 9 replace; R 4 and R 5 are each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl and halocycloalkyl; R 6 、R 7 、R 8 and R 9 are each independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxy, thiol, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b and-NHS(O) m R a wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally further substituted with one or more groups selected from deuterium atoms, halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, aryloxy, heteroaryl, cycloalkyl, and heterocyclic groups; R a and R b are each independently selected from hydrogen, a deuterium atom, a halogen, an amino group, a cyano group, an oxo group, a hydroxyl group, a mercapto group, an alkyl group, an alkoxy group, an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocyclic group; or R a and R b together with the atoms to which they are attached, form a cycloalkyl or heterocyclic group, said cycloalkyl or heterocyclic group being optionally further substituted with one or more groups selected from deuterium atoms, halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclic groups; m is 0, 1, or 2; n is 0, 1, 2 or 3.

2. The compound of formula I according to claim 1, or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the following formula (II): in, R' is selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxy, mercapto, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -NR a R b 、-C(O)R a 、-O(O)CR a 、-C(O)OR a 、-C(O)NR a R b 、-NHC(O)R a 、-S(O) m R a 、-S(O) m NR a R b and-NHS(O) m R a wherein the alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclic group is optionally further substituted with one or more groups selected from deuterium atoms, halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, alkoxy, hydroxyalkyl, alkenyl, alkynyl, aryl, aryloxy, heteroaryl, cycloalkyl, and heterocyclic groups; m is 0, 1, or 2; L and ring A are as defined in claim 1.

3. The compound of formula I according to claim 1, or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the following formula (III): in, L and ring A are as defined in claim 1; R' is as defined in claim 2.

4. The compound according to any one of claims 1 to 3, or its mesoform, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

6. Use of the compound according to any one of claims 1 to 4, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt in the preparation of a medicament for treating or preventing a disease or disorder associated with RIPK1 kinase activity.

7. The use according to claim 6, wherein the disease or condition associated with RIPK1 kinase activity is selected from neurodegenerative diseases and inflammatory diseases, stroke, coronary heart disease and myocardial infarction, retinal degenerative diseases, inflammatory bowel disease, kidney disease, liver disease and lesions caused by COVID-19.

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