Ripk1 inhibitors

Abstract

The present application provides a class of novel compounds with RIPK1 inhibitory activity shown in formula (I), a pharmaceutical composition containing the compounds, useful intermediates for preparing the compounds and a method for treating related diseases mediated by RIPK1 using the compounds of the present application.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and relates to novel compounds having RIPK1 inhibitory activity, pharmaceutical compositions containing said compounds, useful intermediates for the preparation of said compounds, and methods of treatment of related diseases mediated by RIPK1 using the compounds of the present application. BACKGROUND

[0002] Necroptosis is a signal pathway regulating cell necrosis, which is regulated by RIPK1 kinase and its downstream regulatory factors. RIPK1 (Receptor-interacting serine / threonine-protein kinase 1), as an important regulatory molecule in cell survival, inflammation and disease, is involved in innate immune signals and can mediate necroptosis of cells. RIPK1 protein contains three domains: N-terminal kinase domain, intermediate domain RHIM (homology interaction motif), and C-terminal death domain. More and more studies have confirmed that the kinase activity of RIPK1 is involved in necroptosis of cells. When cell casepase 8 is inhibited, the presence of TNF-α can activate the TNF-R1-RIPK1 / RIPK3-MIKL related signal transduction pathway. In this process, TNF-α mediates the activation of RIPK1 kinase, and the activated RIPK1 combines with the RHIM domain of downstream RIPK3 through its RHIM domain, and then recruits mixed-lineage kinase domain-like protein (MLKL), leading to necroptosis of cells and mediation of release of cytoplasmic inflammatory cytokines.

[0003] The RIPK1-mediated necroptosis signal pathway is closely related to many chronic diseases in humans. It includes neurodegenerative diseases, inflammation, blood and solid organ malignancies, bacterial and viral infections, and lysosomal storage diseases, etc. The use of RIP3 gene knockout mice (RIP1-mediated programmed necrosis is completely blocked) and Necrostatin-1 (a tool inhibitor of RIP1 kinase activity with poor oral bioavailability) has proved that abnormal regulation of RIP1 kinase-mediated necroptosis is related to inflammation. RIP3 gene knockout mice have shown protective effects on inflammatory bowel diseases (including ulcerative colitis and Crohn's disease), photoreceptor cell necrosis induced by retinal detachment, retinitis pigmentosa, frog skin peptide-induced acute pancreatitis, and sepsis / systemic inflammatory response syndrome. The use of Necrostatin-1 can effectively alleviate ischemic brain injury, retinal ischemia / reperfusion injury, Huntington's disease, renal ischemia / reperfusion injury, cisplatin-induced renal injury, and traumatic brain injury.

[0004] An effective, selective, small molecule inhibitor of RIP1 kinase activity that is capable of blocking RIP1-dependent necroptosis, thereby providing therapeutic effects for diseases or events associated with DAMPs, cell death, and / or inflammation. SUMMARY

[0005] The present application provides a compound represented by formula (I) or its isomers and pharmaceutically acceptable salts:

[0006]

[0007] wherein X is CH2 or O; Y is CH or N; Z is CR'R", R' and R" are each independently hydrogen or C 1-4 alkyl; W is N or CR aa alkyl; R aa is hydrogen, C 1-4 alkyl or halogen;

[0008] R a is H, 7-9 membered spiro heterocycloalkyl, 6-11 membered fused heterocyclyl, 7-9 membered bridged heterocycloalkyl, R b is H, C 1-4 alkyl or halogen, 6-11 membered fused heterocyclyl;

[0009] wherein said 7-9 membered spiro heterocycloalkyl, 6-11 membered fused heterocyclyl, 7-9 membered bridged heterocycloalkyl is optionally substituted with 1-2 R d , R d is halogen, C 1-4 alkyl, hydroxyl, C 3-6 cycloalkyl, C 1-4 haloalkyl;

[0010] R c is 5-6 membered heteroaryl, C 3-6 cycloalkyl, C 1-4 alkyl, C 1-4 unsaturated hydrocarbon, said 5-6 membered heteroaryl, C 3-6 cycloalkyl, C 1-4 alkyl, C 1-4 unsaturated hydrocarbon can be further substituted with 1-2 hydroxyl or C 1-4 alkyl;

[0011] R is H, C 1-4 alkyl; or R and ring A form a structural unit m is 1, 2, or 3;

[0012] ring A is 5-10 membered heteroaryl or is 8-9 membered fused heterocyclyl, wherein said 5-10 membered heteroaryl or 8-9 membered fused heterocyclyl is optionally substituted with 1-2 R esubstituted, R e is halogen, C 1-4 alkyl;

[0013] R f is hydrogen, halogen or C 1-4 alkyl;

[0014] L1is selected from a bond, or -(CH2) n -, n is selected from 1 or 2;

[0015] ring B is C 5-7 cycloalkyl or phenyl, and said phenyl can be further substituted with halogen or C 1-4 alkyl;

[0016] provided that when R a is 7-9 membered spiro heterocycloalkyl or ring A is not 5-6 membered heteroaryl containing a nitrogen atom.

[0017] The present application provides a compound represented by formula (I) or its isomers and pharmaceutically acceptable salts:

[0018]

[0019] wherein X is CH2or O; Y is CH or N; Z is CR'R", R' and R" are each independently hydrogen or C 1-4 alkyl; W is N or CR aa is hydrogen, C aa alkyl or halogen; 1-4 alkyl or halogen;

[0020] R a is H, 7-9 membered spiro heterocycloalkyl, 6-11 membered fused heterocyclyl, 7-9 membered bridged heterocycloalkyl, R b is H, C 1-4 alkyl or halogen, 6-11 membered fused heterocyclyl;

[0021] wherein said 7-9 membered spiro heterocycloalkyl, 6-11 membered fused heterocyclyl, 7-9 membered bridged heterocycloalkyl is optionally substituted with 1-2 R d substituted, R d is halogen, C 1-4 alkyl, hydroxyl, C 3-6 cycloalkyl, C 1-4 haloalkyl;

[0022] R c is 5-6 membered heteroaryl, C 3-6 cycloalkyl, C 1-4 alkyl, C 1-4 unsaturated hydrocarbon, said 5-6 membered heteroaryl, C 3-6 cycloalkyl, C1-4 alkyl, C 1-4 Unsaturated hydrocarbon groups can be further substituted with 1-2 hydroxyl or C 1-4 alkyl groups;

[0023] Ring A is a 5-10 membered heteroaryl or is an 8-9 membered fused heterocyclyl, wherein said 5-10 membered heteroaryl or 8-9 membered fused heterocyclyl is optionally substituted with 1-2 R e substituents, R e is halogen, C 1-4 alkyl;

[0024] R f is hydrogen, halogen or C 1-4 alkyl;

[0025] L1is selected from a bond, or -(CH2) n -, n is selected from 1 or 2;

[0026] Ring B is C 5-7 cycloalkyl or phenyl, and said phenyl can be further substituted with halogen or C 1-4 alkyl;

[0027] provided that when R a is a 7-9 membered spiroheterocycloalkyl or , Ring A is not a 5-6 membered heteroaryl containing a nitrogen atom.

[0028] In some embodiments of the present application, in the above-mentioned compounds of formula (I) and formula (I-1), W is CH, CF.

[0029] The present application provides a compound represented by formula (I’), or an isomer thereof and a pharmaceutically acceptable salt thereof:

[0030]

[0031] wherein, X is CH2or O; Y is CH or N; Z is CR’R”, R’ and R” are each independently hydrogen or C 1-4 alkyl;

[0032] R a is H, 7-9 membered spiroheterocycloalkyl, 6-11 membered fused heterocyclyl or wherein said 7-9 membered spiroheterocycloalkyl, 6-11 membered fused heterocyclyl is optionally substituted with 1-2 R d substituents, R d is halogen, C 1-4 alkyl, hydroxyl;

[0033] R b is H, halogen or 6-11 membered fused heterocyclyl;

[0034] R cC5-6heteroaryl, C 3-6 C3-6cycloalkyl, C 1-4 C1-6alkyl, C 1-4 C1-6alkyl, C 3-6 C3-6cycloalkyl, C 1-4 C1-6alkyl, C 1-4 C1-6alkyl, C 1-4 C1-6alkyl, C

[0035] R is halo, C e C1-6alkyl, C e C1-6alkyl, C 1-4 C1-6alkyl, C

[0036] R is halo, C f C1-6alkyl, C 1-4 C1-6alkyl, C

[0037] L1is selected from a bond, or -(CH2) n -, n is selected from 1 or 2;

[0038] R is C 5-7 C3-6cycloalkyl or phenyl, and said phenyl can be further substituted with halo or C 1-4 C1-6alkyl;

[0039] provided that when R a is 7-9 membered spiro heterocycloalkyl or ring A is not a 5-6 membered heteroaryl containing a nitrogen atom.

[0040] In some embodiments of the present application, in the above-mentioned compounds of formula (I), (I-1) or (I'), X is O, CH2.

[0041] In some embodiments of the present application, in the above-mentioned compounds of formula (I), (I-1) or (I'), Y is CH, N.

[0042] In some embodiments of the present application, in the above-mentioned compounds of formula (I), (I-1) or (I'), Z is CR'R", each of R' and R" is independently hydrogen, C 1-4 alkyl.

[0043] In some embodiments of the present application, in the above-mentioned compounds of formula (I), (I-1) or (I'), Z is CH2, -CH(CH3)-.

[0044] In some embodiments of the present application, in the above-mentioned compounds of formula (I), (I-1) or (I'), R a is H, 7-9 membered spiro heterocycloalkyl, 6-11 membered fused heterocyclyl or

[0045] In some embodiments of the application, the above-mentioned compounds of formula (I), (I-l) or (I') are those wherein R a is a 7-9 membered bridged heterocycloalkyl group.

[0046] In some embodiments of the application, the above-mentioned compounds of formula (I), (I-l) or (I') are those wherein R d is halogen, C 1-4 alkyl, hydroxy.

[0047] In some embodiments of the application, the above-mentioned compounds of formula (I), (I-l) or (I') are those wherein R d is C 3-6 cycloalkyl, C 1-4 haloalkyl.

[0048] In some embodiments of the application, the above-mentioned compounds of formula (I), (I-l) or (I') are those wherein R d is -F, -CH3, -CH(CH3)2, -C2H5.

[0049] In some embodiments of the application, the above-mentioned compounds of formula (I), (I-l) or (I') are those wherein R d is -CF3.

[0050] In some embodiments of the application, the above-mentioned compounds of formula (I), (I-l) or (I') are those wherein R a is a 7-9 membered spiro heterocycloalkyl group, wherein said 7-9 membered spiro heterocycloalkyl group is optionally substituted by 1-2 R d ; preferably R a is selected from

[0051] In some embodiments of the application, the above-mentioned compounds of formula (I), (I-l) or (I') are those wherein R a is a 6-11 membered fused heterocyclyl group, and said 6-11 membered fused heterocyclyl group is optionally substituted by 1-2 R d ; preferably R a

[0052]

[0053] In some embodiments of the application, the above-mentioned compounds of formula (I), (I-l) or (I') are those wherein R a is a 6-11 membered fused heterocyclyl group, and said 6-11 membered fused heterocyclyl group is optionally substituted by 1-2 R d ; preferably R a is selected from

[0054] In some embodiments of the application, the compound of formula (I), (I-l) or (I') is one wherein R a is a 7-9 membered bridged heterocyclyl, and said 7-9 membered bridged heterocyclyl is optionally substituted with 1-2 R d ; preferably, R a is selected from

[0055] In some embodiments of the application, the compound of formula (I), (I-l) or (I') is one wherein R a is R c is a 5-6 membered heteroaryl, C 3-6 cycloalkyl, C 1-4 alkyl, said C 1-4 alkyl can be further substituted with 1 or 2 hydroxy groups.

[0056] In some embodiments of the application, the compound of formula (I), (I-l) or (I') is one wherein R a is selected from

[0057] In some embodiments of the application, the compound of formula (I), (I-l) or (I') is one wherein R b is H, halogen or a 6-11 membered fused heterocyclyl, and said 6-11 membered fused heterocyclyl is optionally substituted with 1-2 R d ; preferably, R b is selected from -H, -F or

[0058]

[0059] In some embodiments of the application, the compound of formula (I), (I-l) or (I') is one wherein R b is halogen or a 6-11 membered fused heterocyclyl, and said 6-11 membered fused heterocyclyl is optionally substituted with 1-2 R d ; preferably, R b is selected from -Cl,

[0060] In some embodiments of the application, the compound of formula (I), (I-l) or (I') is one wherein ring A is a 5-10 membered heteroaryl or is an 8-9 membered fused heterocyclyl, wherein said 5-10 membered heteroaryl or 8-9 membered fused heterocyclyl is optionally substituted with 1-2 R e , any carbon atom is optionally replaced with N, O, R e is halogen, C 1-4 alkyl.

[0061] In some embodiments of the application, in the above-mentioned compounds of formula (I), (I-l) or (I'), R e is -F or -CH3.

[0062] In some embodiments of the application, in the above-mentioned compounds of formula (I), (I-l) or (I'), R e is -Cl.

[0063] In some embodiments of the application, in the above-mentioned compounds of formula (I), (I-l) or (I'), ring A is a 5-10 membered heteroaryl, and said 5-10 membered heteroaryl is optionally substituted with 1-2 R e ; preferably, ring A is selected from

[0064]

[0065] In some embodiments of the application, in the above-mentioned compounds of formula (I), (I-l) or (I'), ring A is a 5-10 membered heteroaryl, and said 5-10 membered heteroaryl is optionally substituted with 1-2 R e ; preferably, ring A is selected from

[0066] In some embodiments of the application, in the above-mentioned compounds of formula (I), (I-l) or (I'), ring A is a 8-9 membered fused heterocyclyl, and said 8-9 membered fused heterocyclyl is optionally substituted with 1-2 R e ; preferably, ring A is selected from

[0067]

[0068] In some embodiments of the application, in the above-mentioned compounds of formula (I), (I-l) or (I'), ring A is a 8-9 membered fused heterocyclyl, and said 8-9 membered fused heterocyclyl is optionally substituted with 1-2 R e ; preferably, ring A is selected from

[0069] In some embodiments of the application, in the above-mentioned compounds of formula (I), (I-l) or (I'), L1 is selected from a chemical bond, or -(CH2) n ; n is selected from 1 or 2;

[0070] In some embodiments of the application, in the above-mentioned compounds of formula (I), (I-l) or (I'), ring B is a C 5-7 cycloalkyl; preferably, ring B is selected from

[0071] In some embodiments of the present application, the above-mentioned compounds of formula (I), (I-1) or (I') are those wherein ring B is phenyl, and said phenyl is further substituted by halogen or C 1-4 In some embodiments of the present application, the above-mentioned compounds of formula (I), (I-1) or (I') are those wherein ring B is phenyl, and said phenyl is further substituted by halogen or C

[0072] In some embodiments of the present application, the above-mentioned compounds of formula (I), (I-1) or (I') are those wherein ring B is phenyl, and said phenyl is further substituted by halogen or C

[0073]

[0074] R a , R b , L1, ring B, X, Y, Z, R f T1, T2, T3, T4 are each independently C, CR g , N, O; said R g is hydrogen, halogen or C 1-4 alkyl.

[0075] In some embodiments of the present application, the above-mentioned compounds of formula (I), (I-1) or (I') are those wherein ring B is phenyl, and said phenyl is further substituted by halogen or C

[0076]

[0077] R a , T1, T2, T3, T4 are as defined above.

[0078] The present application also provides the following compounds, isomers and pharmaceutically acceptable salts thereof,

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or excipient.

[0088] The present application also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating a RIPK1-mediated disease, wherein the RIPK1-mediated disease is a cell inflammatory disease, a neurodegenerative disease, a cancer.

[0089] Technical effects

[0090] The compound of the present application has obvious enzymatic inhibitory activity and can be used for the treatment of cell inflammatory diseases, neurodegenerative diseases and cancers.

[0091] Explanation and definition

[0092] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as undefined or unclear without a specific definition, but should be understood according to the ordinary meaning.

[0093] The term "pharmaceutically acceptable" means those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0094] The term "pharmaceutically acceptable salt" refers to derivatives of the compounds of the present application produced by reaction with relatively nontoxic inorganic or organic acids or bases. These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting a purified compound in its free form with a suitable inorganic or organic acid or base. When the compound contains relatively acidic functionalities, base addition salts can be prepared by treatment with inorganic or organic bases, including alkali and alkaline earth metal hydroxides, and organic amines. When the compound contains relatively basic functionalities, acid addition salts can be prepared by treatment with inorganic or organic acids, including alkali and alkaline earth metal salts, and organic amines.

[0095] The compounds of the present application can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are included in the scope of the present application.

[0096] The compounds of the present application can exist in geometric and stereoisomeric forms, such as cis and trans isomers, enantiomers, diastereomers, and mixtures thereof, as well as racemic mixtures and other mixtures.

[0097] The term "enantiomer" refers to a stereoisomer whose mirror image is not superimposable.

[0098] The term "diastereomer" refers to a stereoisomer whose molecules have two or more chiral centers and whose molecules are not mirror images of one another.

[0099] The term "cis-trans isomer" refers to a configuration that exists in a molecule where a double bond or a ring-forming carbon atom single bond cannot freely rotate.

[0100] Unless otherwise indicated, the use of a dashed wedge bond and a dashed wedge bond represents the absolute configuration of a stereogenic center, and the use of a straight dashed bond and a straight dashed bond represents the relative configuration of a stereogenic center. For example represents that the methyl and amino groups are on the same side of the cyclopentane ring. Stereoisomers of the compounds of the application can be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, one enantiomer of a compound of the application can be prepared by asymmetric catalysis techniques or chiral auxiliary derivatization techniques. Alternatively, a single stereoisomer can be obtained from a mixture by chiral resolution techniques. Or, a single stereoisomer can be prepared directly using a chiral starting material. Separation of optically pure compounds of the application is typically accomplished using preparative chromatography on a chiral column to achieve separation of the chiral compounds.

[0101] The absolute stereochemistry of the compounds of the application can be determined by conventional techniques. For example, single crystal X-ray diffraction studies can be used to determine absolute stereochemistry. Alternatively, the absolute stereochemistry of the compound of the application can be determined by asymmetric synthesis using a chiral starting material. Compounds designated herein as "absolute configuration not determined" are typically resolved from racemic material by chiral preparative SFC to provide a single isomer, which is then characterized and tested.

[0102] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow conditioners, disintegrants, wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, and dispersing agents, depending upon the nature of the dosage form and the means of administration. Pharmaceutically acceptable carriers are formulated in accordance with routine procedures, such as those described in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, incorporated herein by reference. They include, but are not limited to: the type and nature of the active pharmaceutical agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the therapeutic indication for which the agent is being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as a variety of solid and semi-solid dosage forms. Such carriers include a number of different ingredients and additives, which are included in the formulation for a variety of reasons (e.g., to stabilize the active pharmaceutical agent, to bind the agents, etc.), and such additional ingredients are well known to those of ordinary skill in the art.

[0103] The term "excipient" generally refers to a carrier, diluent, and / or vehicle necessary for formulating an effective pharmaceutical composition.

[0104] The term "effective prophylactic or therapeutic amount" refers to the amount of a compound of the present application or a pharmaceutically acceptable salt thereof that is sufficient to treat a disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prophylaxis. It will be appreciated, however, that optimal dosages will vary depending on the particular compound of Formula I or a pharmaceutically acceptable salt thereof and composition employed, and the condition to be treated. For any particular patient, specific therapeutic effective dose levels will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or coincidental with the particular compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

[0105] The term "halogen" means a fluorine, chlorine, bromine, or iodine atom, unless otherwise specified.

[0106] The term "C 1-4 The term "C 1-4 A straight-chain or branched saturated hydrocarbon radical. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, i-butyl, and the like.

[0107] The term "C 1-4"Unsaturated hydrocarbyl" is used to indicate a straight-chain or branched-chain hydrocarbyl group containing one or more unsaturated bonds, such as a double bond, a triple bond, or both. Examples include, but are not limited to, vinyl, propenyl, allyl, and the like. 1-4 "Unsaturated hydrocarbyl" is used to indicate a straight-chain or branched-chain hydrocarbyl group containing one or more unsaturated bonds, such as a double bond, a triple bond, or both. Examples include, but are not limited to, vinyl, propenyl, allyl, and the like.

[0108] Unless otherwise specified, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbyl group. The polycyclic hydrocarbyl group includes bridged, fused, and spirocyclic rings. The bridged ring refers to a ring formed by two rings sharing two non-adjacent ring atoms. The fused ring refers to a ring formed by two rings sharing two adjacent ring atoms. The spirocyclic ring refers to a ring formed by two rings sharing one ring atom. Cycloalkyl is preferably a C3-20cycloalkyl, more preferably a C3-10cycloalkyl, and even more preferably a C3-6cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. 3-12 Cycloalkyl, more preferably C 3-8 Cycloalkyl, more preferably C 3-6 Cycloalkyl, more preferably C

[0109] Unless otherwise specified, "spiroheterocycloalkyl" refers to a spirocyclic group in which one or more carbon atoms in the spirocyclic ring skeleton is replaced by a heteroatom or a heteroatom group selected from N, NR, O, S, N(O), S(O), S(O)2, R being H or a reasonably existing substituent, preferably 1-2 N, NR and / or O. Spiroheterocycloalkyl is preferably a 5-13 membered spiroheterocycloalkyl, a 6-12 membered spiroheterocycloalkyl, or a 7-11 membered spiroheterocycloalkyl. Examples of spiroheterocycloalkyl groups include, but are not limited to

[0110] Unless otherwise specified, "heterocyclyl" refers to a monocyclic, saturated or unsaturated, non-aromatic ring containing one or more heteroatoms in the ring atoms. The heteroatom is selected from N, NR, O, S, N(O), S(O), S(O)2, R being H or a reasonably existing substituent; the ring C atom can be further oxidized to form C(O). Preferably, the heteroatom is 1-3 heteroatoms selected from N, O, or S; preferably a 5-6 membered heterocyclyl. Specific examples of heterocyclyl groups include, but are not limited to: Unless otherwise specified, "fused heterocyclyl" refers to a non-aromatic ring structure composed of two or more rings sharing two adjacent ring atoms between adjacent rings, and at least one of the rings is a heterocyclyl, and the heterocycle can be oxidized; the fused heterocyclyl includes a monocyclic heterocyclyl fused with a monocyclic heterocyclyl or a cycloalkyl or an aryl or a heteroaryl, and also includes a heteroaryl fused with a cycloalkyl or a monocyclic heterocyclyl. Examples of fused heterocyclyl groups include, but are not limited to

[0111] Unless otherwise specified, "bridged heterocyclyl" refers to a polycyclic heterocyclic radical formed by any two rings sharing two non-adjacent atoms, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably, 7 to 9 members. Depending on the number of rings, it can be a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, preferably bicyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0112] Unless otherwise specified, "heteroaryl" means the term "heteroaryl" means, unless otherwise specified, a stable monocyclic or polycyclic aromatic hydrocarbon radical, preferably containing carbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S. The heteroaryl group can be oxidized. The polycyclic heteroaryl groups include heteroaromatic ring and heteroaromatic ring, heteroaromatic ring and benzene ring, etc. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyrimidinyl, pyridyl, isoquinolyl, cinnolinyl, phthalazinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, and the like.

[0113] Unless otherwise specified, the term "optionally substituted with 1-2 R d "substituted" means that it can be substituted with one or 2 R d , or can not be substituted with R d .

[0114] Unless otherwise specified, the term "5-6 membered heteroaromatic ring containing nitrogen atom" means that at least one of the ring atoms in the 5-membered or 6-membered heteroaromatic ring is N or NH, examples include but are not limited to

[0115] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by the combination of the embodiments listed below with other chemical synthetic methods well known to those skilled in the art, and equivalent alternatives thereof well known to those skilled in the art, preferred embodiments include but are not limited to the examples of the present application.

[0116] The solvents used in the present application can be commercially available.

[0117] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The NMR measurements are determined using a Bruker Neo 400M or a Bruker Ascend 400 NMR instrument, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and / or deuterated chloroform (CDCl3) as the determination solvent, and tetramethylsilane (TMS) as the internal standard.

[0118] The determination of liquid chromatography-mass spectrometry (LC-MS) is performed using an Agilent 1260-6125B single quadrupole mass spectrometer or a Waters H-Class SQD2 mass spectrometer (ion source is electrospray ionization). The determination of HPLC is performed using a Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.

[0119] The preparation of high performance liquid chromatography is performed using a Waters 2555-2489 (10 μm, ODS 250 cm x 5 cm) or a GILSON Trilution LC, and the chromatographic column is a Welch XB-C18 column (5 um, 21.2*150 mm).

[0120] The thin layer chromatography silica gel plate is a Yantai Jiangyou Silica Gel Development Co., Ltd. GF254 silica gel plate or a Rushan City Shangbang New Material Co., Ltd. GF254 silica gel plate, and the TLC uses a specification of 0.15 mm-0.20 mm, and the preparation type is 20 x 20 cm. The column chromatography generally uses silica gel with a mesh size of 200-300 as the carrier.

[0121] The compounds are named according to the conventional naming principles in the art or using software naming, and the commercially available compounds use the supplier catalog name. DETAILED DESCRIPTION

[0122] The present application is described in detail below by way of examples, but it does not mean any unfavorable limitation of the present application. The compounds of the present application can be prepared by various synthesis methods known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of other chemical synthesis methods, and the equivalent replacement methods known to those skilled in the art, and the preferred embodiments include but are not limited to the examples of the present application. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0123] I. Preparation method

[0124] Example 1 : 5-benzyl-N-((2R,3S)-2,5-dimethyl-7-(3-methylbut-3-en-1 - yne-1 -yl)-4-oxo-2,3,4,5-tetrahydrobenzo[6][1,4]oxazepin-3-yl)-1 H-1,2,4- triazole-3-carboxamide

[0125] Scheme:

[0126]

[0127] Procedure:

[0128] Step A: Sodium hydride (726 mg, 18.2 mmol, 60%) was slowly added to a solution of (tert-butoxycarbonyl)-L-threonine (1993 mg, 9.09 mmol) in N,N- dimethylformamide (30 mL) under ice-bath. The mixture was stirred at 0 °C for half an hour. Then 4-bromo-1 -fluoro-2-nitrobenzene (2.0 g, 9.1 mmol) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 2 hours.

[0129] After LCMS monitoring showed the disappearance of the starting material, 3 moles of hydrochloric acid was added dropwise to the reaction system, and the pH of the reaction solution was adjusted to pH = 3-4. Water (100 mL) was added to the mixture, and extracted with ethyl acetate (50 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to obtain 1600 mg of O-(4-bromo-2-nitrophenyl)-N-(tert- butoxycarbonyl)-L-threonine.

[0130] MS (ESI) M / Z: 441.1 [M+Na] + , 443.0 [M+2+Na] + .

[0131] Step B: O-(4-bromo-2-nitrophenyl)-N-(tert-butoxycarbonyl)-L-threonine (1600 mg, 3.8 mmol) was dissolved in N,N-dimethylformamide (25 mL), and potassium carbonate (1053 mg, 7.6 mmol) and iodomethane (812 mg, 5.7 mmol) were added. The mixture was stirred at 25 °C for 2 hours.

[0132]

[0133] ​After LCMS monitoring showed the starting material was consumed, water (40 mL) was added to the reaction system. The mixture was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1000 mg of crude product O-(2-amino-4-bromophenyl)-N-(tert-butoxycarbonyl)-L- threonine methyl ester.

[0134] MS (ESI) M / Z: 425.0 [M + Na] + , 427.0 [M + 2 + Na] + .

[0135] Step C: (O-(4-bromo-2-nitrophenyl)-N-(tert-butoxycarbonyl)-L-threonine methyl ester (1200 mg, 2.8 mmol) was dissolved in tetrahydrofuran / water (5:1, 30 mL), and iron powder (773 mg, 13.9 mmol) and ammonium chloride (740 mg, 13.9 mmol) were added. The mixture was stirred at 60 degrees Celsius for 4 hours.

[0136] After LCMS monitoring showed the starting material was consumed, water (40 mL) was added to the reaction system. The mixture was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1000 mg of crude product O-(2-amino-4-bromophenyl)-N-(tert-butoxycarbonyl)-L- threonine methyl ester.

[0137] MS (ESI) M / Z: 425.0 [M + Na] + , 427.0 [M + 2 + Na] + .

[0138] Step D: (O-(2-amino-4-bromophenyl)-N-(tert-butoxycarbonyl)-L-threonine methyl ester (1000 mg, 2.5 mmol) was dissolved in tetrahydrofuran (15 mL), and sodium hydroxide solution (1 M, 6 mL) was added. The mixture was stirred at room temperature for 3 hours.

[0139] After LCMS monitoring showed the starting material was consumed, water (40 mL) was added to the reaction system, and the pH was adjusted to 5-6 with 1 molar dilute hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 800 mg of crude product O-(2-amino-4-bromophenyl)-N-(tert-butoxycarbonyl)-L-threonine.

[0140] MS (ESI) M / Z: 389.1 [M+H] + ,391.0[M+2+H] + .

[0141] Step E: O-(2-amino-4-bromophenyl)-N-(tert-butoxycarbonyl)-L-threonine (800 mg, 2.1 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (531 mg, 4.1 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1172 mg, 3.1 mmol) were added. The mixture was stirred at room temperature for 1 hour.

[0142] After LCMS monitoring showed the disappearance of the starting material, water (80 mL) was added to the reaction system. The mixed solution was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined. The organic phases were first washed with saturated brine (20 mL × 2), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 400 mg of tert-butyl ((2R, 3S)-7-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine -3-yl)carbamate.

[0143] MS (ESI) M / Z: 393.0 [M+Na] + .

[0144] Step F: tert-butyl ((2R,3S)-7-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine 1-3-yl)carbamate (400 mg, 1.07 mmol) was dissolved in N,N-dimethylformamide (10 mL), cesium carbonate (526 mg, 1.62 mmol) was added, and iodomethane (230 mg, 1.62 mmol) was added dropwise, and the mixture was stirred at room temperature for 5 hours.

[0145] After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction system. The mixed solution was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined. The organic phases were first washed with saturated brine (20 mL × 2), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 380 mg of tert-butyl ((2R, 3S)-7-bromo-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepine -3-yl)carbamate.

[0146] MS (ESI) M / Z: 407.1 [M+Na] +,409.1[M+2+Na] + .

[0147] Step G: tert-butyl ((2R, 3S)-7-bromo-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl) carbamate (380 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (861 mg, 6.2 mmol) and cuprous iodide (40 mg, 0.2 mmol) were added. After degassing by bubbling nitrogen for 5 minutes, tetrakis(triphenylphosphine)palladium (239 mg, 0.2 mmol) and trimethyl[(2-methylbut-3-yn-2-yl)oxy]silane (973 mg, 6.22 mmol) were added and reacted in a microwave reactor at 120 degrees Celsius for 2 hours.

[0148] After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction system. The mixed solution was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined. The organic phases were first washed with saturated brine (20 mL × 2), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 160 mg of tert-butyl ((2R, 3S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)carbamate.

[0149] MS (ESI) M / Z: 411.1 [M+Na] + .

[0150] Step H: tert-butyl ((2R, 3S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-2,5-dimethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)carbamate (60 mg, 0.2 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 2 hours.

[0151] After LCMS monitoring showed that the starting material disappeared, the solvent was removed under reduced pressure to give 40 mg of crude product (2R,3S)-3-amino-2,5-dimethyl-7-(3-methylbut-3-en-1-yn-1-yl)-2,3-dihydrobenzo[b][1,4]oxazepine -4(5H)-one).

[0152] MS (ESI) M / Z: 271.1 [M+H] + .

[0153] Step I: (2R, 3S)-3-amino-2, 5-dimethyl-7-(3-methylbut-3-en-1-yn-1-yl)-2, 3- dihydrobenzo [b] [1, 4] oxazepin-4(5H)-one (30 mg, 0.10 mmol) was dissolved in N, N- dimethylformamide (3 mL), 5-benzyl-lH-l, 2, 4-triazole-3-carboxylic acid (34 mg, 0.2 mmol), N, N-diisopropyl ethylamine (108 mg, 0.3 mmol) and 1-propylphosphonic anhydride (57 mg, 0.44 mmol, 50% in ethyl acetate) were added. The mixture was stirred at room temperature for 2 hours. LCMS monitoring showed the disappearance of the starting material, and then the mixture was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. 10 mg of the final product 5-benzyl-N-((2R, 3S)-2, 5-dimethyl-7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2, 3, 4, 5-tetrahydrobenzo[b][l, 4]oxazepin-3-yl)-lH-l, 2, 4-triazole-3-carboxamide (Compound 1) was obtained.

[0154] LCMS monitoring showed the disappearance of the starting material, and then the mixture was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. 10 mg of the final product 5-benzyl-N-((2R, 3S)-2, 5-dimethyl-7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2, 3, 4, 5-tetrahydrobenzo[b][l, 4]oxazepin-3-yl)-lH-l, 2, 4-triazole-3-carboxamide (Compound 1) was obtained.

[0155] MS (ESI) M / Z: 456.1 [M+H] + .

[0156] 1 H NMR (400 MHz, CDC13) δ 8.13 (d, J = 7.0 Hz, 1H), 7.32 - 7.27 (m, 5H), 7.26 - 7.24 (m, 3H), 7.13 (d, J = 8.2 Hz, 1H), 5.44 - 5.40 (m, 1H), 5.35 - 5.31 (m, 1H), 5.11 - 5.04 (m, 1H), 4.99 - 4.91 (m, 1H), 4.17 (s, 2H), 3.42 (s, 3H), 1.99 (s, 3H), 1.41 (d, J = 6.3 Hz, 3H).

[0157] Example 2: 5-benzyl-N-((2R, 3S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-2, 5-dimethyl-4-oxo- 2, 3, 4, 5-tetrahydrobenzo [b] [1, 4] oxazepin-3-yl)-lH-l, 2, 4-triazole-3-carboxamide

[0158]

[0159] Scheme:

[0160] ​​

[0161] Procedure:

[0162] Step A: tert-Butyl ((2R,3S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-2,5-dimethyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (60 mg, 0.15 mmol) was dissolved in 1,4-dioxane (1 mL), hydrochloric acid in dioxane (0.2 mL, 0.8 mmol, 4 M) was added, and the reaction solution was stirred at room temperature for 2 hours.

[0163] After LCMS monitoring showed the disappearance of the starting material, the solvent was removed under reduced pressure to give 30 mg of (2R,3S)-3-amino-7-(3-hydroxy-3- methylbut-1-yn-1-yl)-2,5-dimethyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one.

[0164] MS (ESI) M / Z: 289.1 [M+H] + .

[0165] Step B: (2R,3S)-3-amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-2,5-dimethyl-2,3- dihydrobenzo[b][1,4]oxazepin-4(5H)-one (30 mg, 0.1 mmol) and 5-benzyl-1H-1,2,4- triazole-3-carboxylic acid (30 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (54 mg, 0.41 mmol) and 1-propylphosphonic anhydride (66 mg, 0.2 mmol, 50% in ethyl acetate) were added, and stirring was performed at room temperature for 1 hour.

[0166] After LCMS monitoring showed the disappearance of the starting material, the solvent was concentrated under reduced pressure, and the resulting residue was purified by preparative high-performance liquid chromatography. This gave 6.0 mg of 5-benzyl-N-((2R,3S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-2,5-dimethyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (Compound 2).

[0167] MS (ESI) M / Z: 456.1 [M+H-H2O] + .

[0168] 1 ​​​​H NMR (400 MHz, DMSO-d6) δ 7.93 - 7.85 (m, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.37 - 7.17 (m, 8H), 4.88 - 4.82 (m, 2H), 4.13 (s, 2H), 3.34 (s, 3H), 1.47 (s, 6H), 1.28 - 1.26 (m, 3H).

[0169] Example 3: (5S,7S)-7-fluoro-N-((S)-5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2- yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2- b][1,2,4]triazole-2-carboxamide -3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

[0170]

[0171] (5R,7R)-7-fluoro-N-((S)-5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole- 2-carboxamide -3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

[0172]

[0173] Reaction Scheme:

[0174]

[0175]

[0176] Procedure:

[0177] Step A: (tert-Butoxycarbonyl)-L-serine (27 g, 0.1 mol) was dissolved in N,N- dimethylformamide (150 mL) solution at 0 degree Celsius, sodium hydride (11 g, 0.5 mol) was added. The reaction system was stirred at 0 degree Celsius for half an hour. 4-bromo-1-fluoro-2- nitrobenzene (27 g, 0.1 mmol) was dissolved in N,N-dimethylformamide (50 mL) solution and added to the reaction system. The reaction system was stirred at 0 degree Celsius for two hours.

[0178] LCMS showed the reaction was complete. The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with saturated brine (100 mL × 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 13 g of O-(4-bromo-2-nitrophenyl)-N-(tert-butyloxycarbonyl)-L-serine.

[0179] MS (ESI) M / Z: 427.0 [M+Na] + .

[0180] Step B: Dissolve O-(4-bromo-2-nitrophenyl)-N-(tert-butyloxycarbonyl)-L-serine (13 g, 0.03 mol) in a mixture of tetrahydrofuran (60 mL), ethanol (60 mL), and water (30 mL) at room temperature. Add iron powder (12 g, 0.2 mol) and ammonium chloride (12 g, 0.2 mmol). Stir the reaction at 80°C for 12 hours.

[0181] LCMS showed the reaction was complete. The mixed solution was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with saturated brine (100 mL × 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 10 g of O-(2-amino-4-bromophenyl)-N-(tert-butyloxycarbonyl)-L-serine.

[0182] MS (ESI) M / Z: 375.1 [M+H] + .

[0183] Step C: Dissolve O-(2-amino-4-bromophenyl)-N-(tert-butoxycarbonyl)-L-serine (10 g, 26.7 mmol) in N,N-dimethylformamide (100 mL) at room temperature, add N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (15 g, 40 mmol) and N,N-diisopropylethylamine (10 g, 80.1 mmol). The reaction system is stirred at room temperature for 2 hours.

[0184] LCMS showed that the reaction was complete. The mixed solution was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined. The organic phase was first washed with saturated brine (100 mL × 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5 g of tert-butyl (S)-(7-bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)carbamate.

[0185] MS (ESI) M / Z: 379.0 [M+Na] + .

[0186] Step D: tert-Butyl (S)-(7-bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin- 3-yl)carbamate (5 g, 14 mmol) was dissolved in N,N-dimethylformamide (50 mL) solution, iodomethane (4 g, 28 mmol) and cesium carbonate (13 g, 42 mmol) were added. The reaction was stirred at room temperature for 2 hours. Step D: tert-Butyl (S)-(7-bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin- 3-yl)carbamate (5 g, 14 mmol) was dissolved in N,N-dimethylformamide (50 mL) solution, iodomethane (4 g, 28 mmol) and cesium carbonate (13 g, 42 mmol) were added. The reaction was stirred at room temperature for 2 hours.

[0187] LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (100 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 3 g of tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin- 3-yl)carbamate.

[0188] MS (ESI) M / Z: 393.0 [M+Na] + .

[0189] Step D: tert-Butyl (S)-(7-bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin- 3-yl)carbamate (5 g, 14 mmol) was dissolved in N,N-dimethylformamide (50 mL) solution, iodomethane (4 g, 28 mmol) and cesium carbonate (13 g, 42 mmol) were added. The reaction was stirred at room temperature for 2 hours. Step D: tert-Butyl (S)-(7-bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin- 3-yl)carbamate (5 g, 14 mmol) was dissolved in N,N-dimethylformamide (50 mL) solution, iodomethane (4 g, 28 mmol) and cesium carbonate (13 g, 42 mmol) were added. The reaction was stirred at room temperature for 2 hours.

[0190] LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (100 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 3 g of tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin- 3-yl)carbamate.

[0191] MS (ESI) M / Z: 393.0 [M+Na] + .

[0192] ​​Step F: tert-Butyl (S)-(5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)- 2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine-3-yl)carbamate (200 mg, 0.47 mmol) was dissolved in a solution of hydrochloric acid / 1,4-dioxane (10 mL, 4 N). The reaction was stirred at room temperature for 1 h. Step F: tert-Butyl (S)-(5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)- 2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine-3-yl)carbamate (200 mg, 0.47 mmol) was dissolved in a solution of hydrochloric acid / 1,4-dioxane (10 mL, 4 N). The reaction was stirred at room temperature for 1 h.

[0193] LCMS showed the reaction was complete. Concentration under reduced pressure gave 150 mg of (S)-3-amino-5-methyl-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)- 2,3-dihydrobenzo[b][l,4]oxazepine-4(5H)-one.

[0194] MS (ESI) M / Z: 318.2 [M+H] + .

[0195] Step G: Benzaldehyde (10.0 g, 0.09 mol) was dissolved in ethanol (100 mL), and hydroxylamine hydrochloride (13.09 g, 0.18 mol) was added. The reaction was stirred at room temperature for 10 h and filtered. The filtrate was concentrated under reduced pressure, water (100 mL) was added to the mixture, and it was extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated to give the crude product benzaldehyde oxime (11 g), which was used in the next step without further purification.

[0196] MS (ESI) M / Z: 122.1 [M+H] + .

[0197] Step H: Benzaldehyde oxime (10.0 g) was dissolved in 1,4-dioxane (180 mL), then methyl acrylate (7.1 g, 0.1 mol), sodium iodide (12.4 g, 0.1 mmol), and 2,6- dimethylpyridine (8.8 g, 0.1 mmol) were added, respectively. Then tert-butyl hypochlorite (17.9 g, 0.2 mmol) was slowly added dropwise into the stirred mixture. The reaction mixture was stirred at room temperature for 12 h.

[0198] LCMS monitoring showed the disappearance of the starting material. Concentration under reduced pressure, water (100 mL) was added to the mixture, and it was extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography to give 8.0 g of 3-phenyl-4,5-dihydroisoxazole-5-carboxylic acid methyl ester.

[0199] MS (ESI) M / Z: 206.2 [M+H] + .​

[0200] Step I: 3-Phenyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid methyl ester (8.0 g, 34.1 mmol) was dissolved in ethanol (300 mL), wet palladium on carbon (4356 mg) was added and the reaction was stirred under hydrogen (4 megaPascal) at 50 degrees Celsius for 12 hours.

[0201] LCMS monitoring showed the disappearance of starting material. Palladium on carbon was filtered off and the filtrate was concentrated under reduced pressure to give 6.0 g of 3-hydroxy-5-phenylpyrrolidin-2-one.

[0202] MS (ESI) M / Z: 178.1 [M+H] + .

[0203] Step J: 3-Hydroxy-5-phenylpyrrolidin-2-one (6.0 g, 33.9 mmol) was dissolved in dichloromethane (150 mL), imidazole (4610 mg, 67.7 mmol) was added. Then tert-butyldimethylsilyl chloride (7655 mg, 50.79 mmol) was added dropwise slowly. The reaction mixture was stirred at 25 degrees Celsius for 16 hours.

[0204] LCMS monitoring showed the disappearance of starting material. Concentrated under reduced pressure, water (100 mL) was added and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give 4 g of (3R,5S)-3-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one.

[0205] MS (ESI) M / Z: 292.2 [M+H] + .

[0206] 1 H NMR (400 MHz, CDC13) δ 7.41 - 7.37 (m, 2 H), 7.34 - 7.26 (m, 3 H), 6.15 (s, 1 H), 4.86 (dd, J = 7.2, 5.2 Hz, 1 H), 4.40 (dd, J = 7.0, 5.1 Hz, 1 H), 2.54 - 2.43 (m, 1 H), 2.28 - 2.18 (m, 1 H), 0.93 (s, 9 H), 0.17 (d, J = 6.4 Hz, 6 H).

[0207] Step K: (3R, 5S)-3-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (2 g, 6.9 mmol) was dissolved in N,N-dimethylformamide (60 mL), sodium hydride (60%, 4.1 g, 10.3 mmol) was added slowly under ice bath, the mixture was stirred under ice bath for 20 minutes, then diphenylphosphoryl azide (2235 mg, 10.3 mmol) was added. The reaction was stirred at room temperature for 16 hours.

[0208] LCMS monitoring showed the disappearance of starting material. Filtration, concentration under reduced pressure to give 2 g of crude product (3R, 5S)-1-amino-3-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one. The crude product was used directly in the next step without further purification.

[0209] MS (ESI) M / Z: 307.2 [M+H] + .

[0210] Step L: (3R, 5S)-1-amino-3-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (2000 mg, 6.52 mmol) was dissolved in ethanol (250 mL), 2-ethoxy-2-iminoacetic acid ethyl ester (1421 mg, 9.78 mmol) was added to the solution. The reaction mixture was stirred at 60 degrees Celsius for 12 hours.

[0211] LCMS monitoring showed the disappearance of starting material, concentration under reduced pressure to give 2100 mg of crude product 2-((3R, 5S)-3-((tert-butyldimethylsilyl)oxy)-2-oxo-5-phenylpyrrolidin-1-yl)amino)-2-iminoacetic acid ethyl ester. The crude product was used directly in the next step without further purification.

[0212] MS (ESI) M / Z: 406.1 [M+H] + .

[0213] Step M: 2-((3R, 5S)-3-((tert-butyldimethylsilyl)oxy)-2-oxo-5-phenylpyrrolidin-1-yl)amino)-2-iminoacetic acid ethyl ester (2000 mg, 4.9 mmol) was dissolved in toluene (50 mL), p-toluenesulfonic acid (938 mg, 4.9 mmol) was added. The reaction mixture was stirred at 120 degrees Celsius for 24 hours.

[0214] LCMS monitoring showed the disappearance of starting material, concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 400 mg of (5S, 7R)-7-hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylic acid ethyl ester.

[0215] MS (ESI) M / Z: 274.1 [M+H] + .

[0216] Step N: (5S,7R)-7-Hydroxy-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2- carboxylic acid ethyl ester (400 mg, 0.4 mmol) was dissolved in dichloromethane (15 mL) and diethylamine sulfide trifluoride (707 mg, 4.4 mmol) was added dropwise under ice bath. The reaction mixture was stirred for 1 hour under ice bath.

[0217] LCMS monitoring showed the starting material was consumed. The reaction was quenched with water (20 mL). The resulting mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography to give 170 mg of (5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid ethyl ester.

[0218] MS (ESI) M / Z: 274.1 [M+H] + .

[0219] 1 H NMR (400 MHz, CDC13) δ 7.45 - 7.34 (m, 3H), 7.28 - 7.23 (m, 2H), 6.16 - 5.90 (m, 1H), 5.56 - 5.49 (m, 1H), 4.54 - 4.44 (m, 2H), 3.67 - 3.59 (m, 1H), 3.02 - 2.92 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H).

[0220] Step O: (5S,7S)-7-Fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2- carboxylic acid ethyl ester (170 mg, 0.62 mmol) was dissolved in tetrahydrofuran / water (4: 1, 10 mL) and lithium hydroxide (44 mg, 1.85 mmol) was added. The mixture was stirred at room temperature for 1 hour.

[0221] LCMS monitoring showed the starting material was consumed. The reaction was quenched with water (20 mL). The resulting mixture was extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography to give 170 mg of (5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxylic acid ethyl ester.

[0222] MS (ESI) M / Z: 274.1 [M+H]+ .

[0223] Step P: (5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2- carboxylic acid (25 mg, 0.1 mmol) was dissolved in dichloromethane (5 mL), added (S)-3-amino-5-methyl-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][l,4]oxazepine-4(5H)-one (32 mg, 0.1 mmol), N,N-diisopropyl ethylamine (52 mg, 0.4 mmol) and 1-propylphosphonic anhydride (128 mg, 0.25 mmol, 50% in ethyl acetate). The mixture was stirred at room temperature for 0.5 h.

[0224] LCMS monitoring showed the disappearance of the starting material, and then concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography. 5 mg of compound 3-P1 and 4 mg of compound 3-P2 (compound 3-P1, retention time 11.2 min; compound 3-P2, retention time 11.8 min) were obtained. Both compound 3-P1 and compound 3-P2 were single configuration, and they were enantiomers of each other.

[0225] Compound 3-P1:

[0226] MS (ESI) M / Z: 547.3 [M+H] + .

[0227] 1 H NMR (400 MHz, DMSO-d6) d 8.63 (d, J = 8.4 Hz, 1H), 7.46 - 7.37 (m, 3H), 7.24 (d, J = 6.8 Hz, 2H), 7.02 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 6.32 - 6.12 (m, 2H), 5.73 - 5.62 (m, 1H), 4.89 - 4.75 (m, 1H), 4.54 - 4.44 (m, 1H), 4.32 - 4.19 (m, 1H), 3.74 - 3.64 (m, 9H), 3.27 (s, 3H), 2.76 - 2.62 (m, 1H), 1.79 - 1.70 (m, 4H).

[0228] Compound 3-P2:

[0229] MS (ESI) M / Z: 547.3 [M+H] + .

[0230] 1 ​H NMR(400MHz, DMSO-d6))δ8.61(d,J=8.3Hz,1H),7.49–7.33(m,3H),7.28–7.19(m,2 H),7.03(d,J=8.6Hz,1H),6.47(d,J=2.4Hz,1H),6.36–6.12(m,2H),5.73–5.64(m, 1H),4.87–4.75(m,1H),4.55–4.45(m,1H),4.33–4.20(m,1H),3.81–3.68(m,1H),3 .61(s,4H),3.58–3.52(m,4H),3.27(s,3H),2.78–2.61(m,1H),1.82–1.66(m,4H).

[0231] Example 4: (5S,7S)-7-Fluoro-N-((S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

[0232]

[0233] (5S,7S)-7-Fluoro-N-((S)-5-methyl-7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

[0234]

[0235] Reaction route:

[0236]

[0237] Steps:

[0238] Step A: At room temperature, tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)carbamate (1 g, 2.7 mmol) was dissolved in N,N-dimethylformamide (20 mL), and [(1,1-dimethyl-2-propynyl)oxy]trimethylsilane (0.84 g, 5.4 mmol), dichlorobis(triphenylphosphine)palladium (0.38 g, 0.5 mmol), cuprous iodide (0.1 g, 0.3 mmol) and triethylamine (1 g, 10.8 mmol) were added. The reaction system was stirred at 90 degrees Celsius for 12 hours.

[0239] LCMS showed that the reaction was completed. The mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 0.5 g of tert-butyl (S)-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate. -3-yl)carbamate.

[0240] MS (ESI) M / Z: 397.1 [M+Na] + .

[0241] Step B: tert-Butyl (S)-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (300 mg, 0.8 mmol) was dissolved in hydrochloric acid / 1,4-dioxane (10 mL) solution. The reaction system was stirred at room temperature for 1 hour. -3-yl)carbamate (300 mg, 0.8 mmol) was dissolved in hydrochloric acid / 1,4-dioxane (10 mL) solution. The reaction system was stirred at room temperature for 1 hour.

[0242] LCMS showed that the reaction was completed. Concentration under reduced pressure gave 160 mg of (S)-3-amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one. -4(5H)-one.

[0243] MS (ESI) M / Z: 275.2 [M+H] + .

[0244] Step C: (S)-3-amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (160 mg, 0.6 mmol) was dissolved in methanol (10 mL), and sodium borohydride (0.1 g, 2.4 mmol) was added. The reaction system was stirred at room temperature for 1 hour. -4(5H)-ketone (60 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (5 mL), (5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2- carboxylic acid (67 mg, 0.24 mmol), N,N-diisopropylethylamine (125 mg, 0.97 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (184 mg, 0.48 mmol) were added. The mixture was stirred at 25 °C for 2 hours.

[0245] LCMS monitoring showed the disappearance of starting material, and the mixture was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography. The purification conditions were as follows, column: Xbridge 5u C18 150 x 19 mm; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile. The product was collected to give 5 mg (5S,7S)-7-fluoro-N-((S)-7-(3-hydroxy-3-methylbut-l-yn-l-yl)-5-methyl-4-oxo- 2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine-5-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2- b][l,2,4]triazole-2-carboxamide (Compound 4-P1, retention time 6.43 min) and 10 mg (5S,7S)-7-fluoro-N-((S)-5-methyl-7-(3-methylbut-3-en-l-yn-l-yl)-4-oxo-2,3,4,5- tetrahydrobenzo[b][l,4]oxazepine-5-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole- 2-carboxamide (Compound 4-P2, retention time 6.72 min). -3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide (Compound 4-P2, retention time 6.72 min). -3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide (Compound 4-P2, retention time 6.72 min).

[0246] Compound 4-P1:

[0247] MS (ESI) M / Z: 504.2 [M+H] + .

[0248] 1H NMR (400 MHz, DMSO-d6) δ 8.70 - 8.59 (m, 1H), 7.53 - 7.49 (m, 1H), 7.46 - 7.35 (m, 3H), 7.30 - 7.16 (m, 4H), 6.34-6.09 (m, 1H), 5.75-5.62 (m, 1H), 5.55-5.42 (m, 1H), 4.89-4.75 (m, 1H), 4.70-4.59 (m, 1H), 4.45-4.35 (m, 1H), 3.78-3.67 (m, 1H), 3.30 (s, 3H), 2.75-2.63 (m, 1H), 1.47 (s, 6H).

[0249] Compound 4-P2:

[0250] MS (ESI) M / Z: 486.1 [M+H] + .

[0251] 1 H NMR (400 MHz, DMSO-d6) δ 8.72 - 8.61 (m, 1H), 7.66 - 7.60 (m, 1H), 7.45 - 7.38 (m, 3H), 7.36 (dd, J = 8.4, 1.9 Hz, 1H), 7.26 - 7.19 (m, 3H), 6.33 - 6.11 (m, 1H), 5.72 - 5.63 (m, 1H), 5.46 - 5.40 (m, 2H), 4.88 - 4.79 (m, 1H), 4.69 - 4.60 (m, 1H), 4.45 - 4.37 (m, 1H), 3.82 - 3.66 (m, 1H), 3.33 (s, 3H), 2.76 - 2.63 (m, 1H), 1.96 (s, 3H).

[0252] Example 5: (S)-N-((S)-5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine- 2-carboxamide -3-yl)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide

[0253]

[0254] (R)-N-((S)-5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide -3-yl)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide

[0255]

[0256] Reaction Scheme:

[0257]

[0258] Procedure:

[0259] Step A: 3-Bromo-lH-pyrazole (7.0 g, 47.6 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (10.4 g, 49.9 mmol) were dissolved in acetonitrile (100 mL) and cesium carbonate (23.3 g, 71.4 mmol) was added. The reaction mixture was stirred at room temperature for 6 h.

[0260] After LCMS monitoring showed the disappearance of starting material, the reaction mixture was concentrated and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate and purified by column chromatography on silica gel to give 10.0 g of 3-bromo-l-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-lH-pyrazole.

[0261] MS (ESI) M / Z: 297.0 [M+Na] + .

[0262] Step B: n-Butyllithium in n-hexane (2.5 M, 15 mL) was dissolved in tetrahydrofuran (50 mL) and diisopropylamine (5 mL) was added dropwise slowly under nitrogen protection. The mixture was stirred in an ice-water bath for 30 min. Meanwhile, 3-bromo-l-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-lH-pyrazole (5.0 g, 18.2 mmol) was dissolved in tetrahydrofuran (100 mL). When the temperature of the system dropped to -78 °C, the above mixture was added in small portions. The mixture was stirred at -78 °C for another 40 min. Benzaldehyde (5.8 g, 54.6 mmol) was added and the mixture was stirred for another 1.5 h.

[0263] After LCMS monitoring showed the disappearance of starting material, the reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography on silica gel to give 3.0 g of (3-bromo-l-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-lH-pyrazol-5-yl)(phenyl)methanol.

[0264] MS (ESI) M / Z: 403.1 [M+Na] + , 405.1 [M+2+Na] + .

[0265] Step C: (3-Bromo-l-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-lH-pyrazol-5-yl)(phenyl)methanol (1.5 g, 3.9 mmol) and 4-toluenesulfonic acid (0.4 g, 2.1 mmol) were mixed at room temperature, after the temperature rose to 120 Celsius, the reaction was refluxed for 15 minutes.

[0266] LCMS monitoring showed the starting material disappeared, the reaction was directly concentrated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1) to give 1.0 g of 2-bromo-4-phenyl-6,7-dihydro-4H-pyrazolo[5,l- c] [l,4] oxazine.

[0267] MS (ESI) M / Z: 279.1 [M+H] + .

[0268] Step D: 2-Bromo-4-phenyl-6,7-dihydro-4H-pyrazolo[5,l-c] [l,4] oxazine (500.0 mg, 1.8 mmol), palladium acetate (40.2 mg, 0.2 mmol), diphenyl-l-pyrenylphosphine (73.9 mg, 0.2 mmol), triethylamine (1.8 g, 17.9 mmol) were dissolved in 1-butanol (10 mL), the reaction system was stirred under carbon monoxide at 105 Celsius for 16 hours.

[0269] LCMS monitoring showed the starting material disappeared, the reaction was extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 300 mg of 4-phenyl-6,7-dihydro-4H-pyrazolo[5,l-c] [l,4] oxazine-2-carboxylic acid butyl ester.

[0270] MS (ESI) M / Z: 301.2 [M+H] + .

[0271] Step E: 4-Phenyl-6,7-dihydro-4H-pyrazolo[5,l-c] [l,4] oxazine-2-carboxylic acid butyl ester (150.0 mg, 0.5 mmol) was dissolved in tetrahydrofuran: water = 2: 1 (6 mL), the reaction system was stirred at room temperature for 16 hours.

[0272] LCMS monitoring showed the starting material disappeared, the reaction was adjusted to pH = 5 with dilute hydrochloric acid, and then extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give 80 mg of 4-phenyl-6,7-dihydro-4H-pyrazolo[5,l-c] [l,4] oxazine-2-carboxylic acid.

[0273] MS (ESI) M / Z: 245.1 [M+H] + .

[0274] Step F: 4-phenyl-6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazine-2-carboxylic acid (80.0 mg, 0.3 mmol) and (S)-3-amino-5-methyl-7-(7-oxo-2-azaspiro[3.5]non-2-yl)-2,3- dihydrobenzo[b][l,4]oxazepine-4(5H)-one (124.7 mg, 0.4 mmol) were dissolved in dichloromethane (10 mL) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (136.9 mg, 0.4 mmol) and triethylamine (99.4 mg, 1.0 mmol) were added. The reaction was stirred at room temperature for 1 hour. LCMS monitoring showed the disappearance of the starting material, the reaction solution was directly concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. 1.91 mg of compound 5-P1 (retention time 7.8 min) and 1.19 mg of compound 5-P2 (retention time 8.17 min) were obtained, both compound 5-P1 and compound 5-P2 were single configuration, and they were enantiomers of each other.

[0275] LCMS monitoring showed the disappearance of the starting material, the reaction solution was directly concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. 1.91 mg of compound 5-P1 (retention time 7.8 min) and 1.19 mg of compound 5-P2 (retention time 8.17 min) were obtained, both compound 5-P1 and compound 5-P2 were single configuration, and they were enantiomers of each other.

[0276] Compound 5-P1:

[0277] MS (ESI) M / Z: 544.3 [M+H] + .

[0278] 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 8.4 Hz, 1H), 7.40-7.36 (m, 5H), 7.01 (d, J = 8.4 Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 6.29 (dd, J = 8.4, 2.8 Hz, 1H), 6.10 (s, 1H), 5.87 (s, 1H), 4.83-4.76 (m, 1H), 4.40-4.29 (m, 4H), 4.25-4.21 (m, 1H), 4.16-4.10 (m, 1H), 3.62-3.59 (m, 4H), 3.55-3.53 (m, 4H), 3.27 (s, 3H), 1.75-1.72 (m, 4H).

[0279] Compound 5-P2:

[0280] MS (ESI) M / Z: 544.3 [M+H] + .

[0281] 1H NMR(400MHz,DMSO-d6)δ8.11(d,J=8.4Hz,1H),7.40-7.36(m,5H),7.01(d,J=8 .4Hz,1H),6.46(d,J=2.4Hz,1H),6.29(dd,J=8.4,2.8Hz,1H),6.09(s,1H),5.8 7(s,1H),4.82-4.75(m,1H),4.41-4.34(m,2H),4.32-4.22(m,3H),4.15-4.09 (m,1H),3.62-3.58(m,4H),3.55-3.53(m,4H),3.27(s,3H),1.75-1.72(m,4H).

[0282] Example 6: N-((S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide

[0283]

[0284] Reaction route:

[0285]

[0286] Steps:

[0287] Step A: 4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylic acid (70.0 mg, 0.3 mmol) and (S)-3-amino-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine were reacted at room temperature. -4(5H)-one (78.6 mg, 0.3 mmol) was dissolved in dichloromethane (10 mL), and 1-propylphosphonic anhydride (455.9 mg, 1.4 mmol) and triethylamine (116.0 mg, 1.1 mmol) were added thereto. The reaction system was stirred at room temperature for 1 hour.

[0288] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was directly concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 3.08 mg of N-((S)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxamide (Compound 6).

[0289] MS (ESI) M / Z: 501.2 [M+H] + .

[0290] 1 H NMR (400 MHz, DMSO-d6) δ 8.19 - 8.14 (m, 1H), 7.49 (t, J=1.6 Hz, 1H), 7.40 - 7.36 (m, 5H), 7.28 - 7.26 (m, 1H), 7.20 - 7.18 (m, 1H), 6.10 - 6.09 (m, 1H), 5.88 (s, 1H), 5.49 (s, 1H), 4.85 - 4.77 (m, 1H), 4.60 - 4.50 (m, 1H), 4.39 - 4.26 (m, 4H), 4.17 - 4.10 (m, 1H), 3.30 - 3.29 (m, 3H), 1.46 (s, 6H).

[0291] Example 7: (S)-4-(2-fluorophenyl)-N-(5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide -3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0292]

[0293] Scheme:

[0294]

[0295] Procedure:

[0296] Step A: 4-bromopyrazolo[1,5-a]pyridine-2-carboxylate (250 mg, 0.92 mmol) was dissolved in a solution of 1,4-dioxane (8 mL) and water (2 mL) at room temperature, (2-fluorophenyl)boronic acid (136 mg, 0.97 mmol) and 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium (68 mg, 0.09 mmol) and potassium carbonate (256 mg, 1.86 mmol) were added. The reaction was stirred at 90 degrees Celsius for 12 hours.

[0297] LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 220 mg of ethyl 4-(2-fluorophenyl)pyrazolo[l,5-a]pyridine-2-carboxylate.

[0298] MS (ESI) M / Z: 285.1 [M+H] + .

[0299] Step B: Ethyl 4-(2-fluorophenyl)pyrazolo[l,5-a]pyridine-2-carboxylate (220 mg, 0.77 mmol) was dissolved in a solution of tetrahydrofuran (10 mL), water (2 mL) and methanol (1 mL) at room temperature, and lithium hydroxide (200 mg, 0.63 mmol) was added. The reaction system was stirred at room temperature for 12 hours.

[0300] LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 220 mg of ethyl 4-(2-fluorophenyl)pyrazolo[l,5-a]pyridine-2-carboxylate.

[0301] MS (ESI) M / Z: 285.1 [M+H] + .

[0302] Step C: 4-(2-Fluorophenyl)pyrazolo[l,5-a]pyridine-2-carboxylic acid (30 mg, 0.11 mmol) was dissolved in a solution of DMF (8 mL) at room temperature, and (S)-3-amino-5-methyl-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (37 mg, 0.11 mmol), HATU (133 mg, 0.35 mmol) and DIEA (45 mg, 0.35 mmol) were added. The reaction system was stirred at room temperature for 1 hour.

[0303] LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography to give 4 mg of (S)-4-(2-fluorophenyl)-N-(5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-7-yl)pyrazole-l-carboxamide. ​-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (Compound 7)

[0304] MS (ESI) M / Z: 556.2 [M+H] + .

[0305] 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 7.2 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 7.67 - 7.62 (m, 1H), 7.60 - 7.54 (m, 1H), 7.44 - 7.36 (m, 3H), 7.22 - 7.17 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 1.2 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 6.31 (dd, J = 8.4, 2.8 Hz, 1H), 4.93 - 4.85 (m, 1H), 4.49 - 4.42 (m, 1H), 4.32 (dd, J = 9.6, 8.0 Hz, 1H), 3.62 (s, 4H), 3.58 - 3.51 (m, 4H), 3.29 (s, 3H), 1.79 - 1.71 (m, 4H).

[0306] Example 8: N-((3S)-5-methyl-4-oxo-7-(tetrahydro-1H-furan[3,4-c]pyrrol-5(3H)-yl)- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-[1,2,4]triazolyl[1,5-a]pyridine- 2-carboxamide -3-yl)-5-phenyl-[1,2,4]triazolyl[1,5-a]pyridine-2-carboxamide

[0307]

[0308] Reaction Scheme:

[0309]

[0310] Procedure:

[0311] Step A: 2,4,6-trimethylbenzenesulfonyl chloride (20.0 g, 91.4 mmol), tert-butyl hydroxy aminoformate (12.2 g, 91.4 mmol) were dissolved in methyl tert-butyl ether (100 mL), triethylamine (11.1 g, 0.232 mol) was added slowly dropwise after cooling to 0 degree Celsius, the reaction system was stirred at room temperature for 2 hours.

[0312] After LCMS monitoring showed that the raw material disappeared, the reaction liquid was filtered to remove triethylamine hydrochloride, the filtrate was concentrated and then slurried with n-hexane, then filtered, and the filter cake was dried under vacuum to obtain 18.0 g of tert-butyl ((methylsulfonyl)oxy)carbamate.

[0313] MS (ESI) M / Z: 338.1 [M+Na] + .

[0314] Step B: To trifluoroacetic acid (50 mL) was slowly added tert-butyl ((hydrazinecarbonyl)oxy)carbamate (18 g, 57.1 mmol) under ice water bath, the mixture was stirred for 1 hour under ice water bath.

[0315] After LCMS monitoring showed the starting material was consumed, the reaction was poured into ice water, a white precipitate was formed, the mixture was filtered to give 13 g of O- (hydrazinecarbonyl)hydroxylamine.

[0316] MS (ESI) M / Z: 216.1 [M+H] + .

[0317] Step C: To a solution of O- (hydrazinecarbonyl)hydroxylamine (13.0 g, 28.9 mmol) and 6-bromopyridin-2-amine (11.5 g, 66.4 mmol) in dichloromethane (100 mL) was stirred at room temperature for 16 hours.

[0318] After LCMS monitoring showed the starting material was consumed, the reaction was filtered, the filter cake was dried under vacuum to give 6.0 g of 1,2-diamino-6-bromopyridin-1-ium salt.

[0319] MS (ESI) M / Z: 188.0 [M] + .

[0320] Step D: To a solution of 1,2-diamino-6-bromopyridin-1-ium salt (6.0 g) in ethanol (100 mL) was added potassium hydroxide (2.5 g, 18.6 mmol), the mixture was stirred at room temperature for 10 minutes, then turned to brown black, diethyl oxalate (6.8 g, 46.5 mmol) was added, the stirring was continued at room temperature for 16 hours.

[0321] After LCMS monitoring showed the starting material was consumed, the reaction was extracted with ethyl acetate (2 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to give 1.3 g of 5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester.

[0322] MS (ESI) M / Z: 270.0 [M+H] + .

[0323] Step E: Ethyl 5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (700 mg, 1.8 mmol), phenylboronic acid (632.0 mg, 5.2 mmol), potassium carbonate (1.0 g, 7.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (379.2 mg, 0.5 mmol) were dissolved in 1,4-dioxane / water = 10 / 3 (26 mL) at room temperature, and the reaction system was stirred at 110 °C under nitrogen protection for 4 hours.

[0324] After LCMS monitoring showed the disappearance of the starting material, the mixture was extracted with ethyl acetate (2×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 400.0 mg of ethyl 5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate.

[0325] MS (ESI) M / Z: 268.1 [M+H] + .

[0326] Step F: Ethyl 5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (400.0 mg, 1.5 mmol) was dissolved in tetrahydrofuran / water = 10 / 3 (13 mL) at room temperature, potassium hydroxide (251.9 mg, 4.5 mmol) was added, and the reaction system was stirred at room temperature for 1 hour.

[0327] After LCMS monitoring showed the disappearance of the starting material, the pH was adjusted to 5 with dilute hydrochloric acid, and then extracted with ethyl acetate (2×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 300.0 mg of 5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid.

[0328] MS (ESI) M / Z: 240.1 [M+H] + .

[0329] Step G: 5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (60.0 mg, 0.2 mmol) and (3S)-3-amino-5-methyl-7-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxazepine were reacted at room temperature. -4(5H)-ketone (47.3 mg, 0.2 mmol) (prepared as Intermediate 3-8) was dissolved in dichloromethane (10 mL), and 1-propylphosphonic anhydride (314.6 mg, 0.9 mmol) and triethylamine (80.0 mg, 0.8 mmol) were added. The reaction system was stirred at room temperature for 1 hour.

[0330] LCMS monitoring showed that after the disappearance of the raw materials, the reaction solution was directly concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. 31.36 mg of N-((3S)-5-methyl-4-oxo-7-(tetrahydro-1H-furan[3,4-c]pyrrol-5(3H)-yl)- 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2- carboxamide (compound 8) was obtained. N-((3S)-5-methyl-4-oxo-7-(tetrahydro-1H-furan[3,4-c]pyrrol-5(3H)-yl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (compound 8) was prepared according to the above method.

[0331] MS (ESI) M / Z: 525.0 [M+H] + .

[0332] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 8.0 Hz, 1H), 7.98-7.94 (m, 3H), 7.89-7.85 (m, 1H), 7.60-7.58 (m, 3H), 7.48-7.46 (m, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 8.8, 2.4 Hz, 1H), 4.91-4.84 (m, 1H), 4.50 (t, J = 10.4 Hz, 1H), 4.38-4.33 (m, 1H), 3.88-3.84 (m, 2H), 3.54-3.52 (m, 2H), 3.37 (s, 2H), 3.32 (s, 3H), 3.22-3.19 (m, 2H), 3.00-2.99 (m, 2H).

[0333] Example 9: (S)-N-(5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide -3-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0334]

[0335] Reaction Scheme:

[0336]

[0337] Procedure:

[0338] Step A: 5-phenyl-[l,2,4]triazole[l,5-a]pyridine-2-carboxylic acid (53 mg, 0.22 mmol) was dissolved in DMF (8 mL) solution at room temperature, (S)-3-amino-5-methyl-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3- dihydrobenzo[b][l,4]oxazepine-4(5H)-one (70 mg, 0.22 mmol), T3P (140 mg, 0.44 mmol) and N,N-diisopropylethylamine (86 mg, 0.66 mmol) were added. The reaction was stirred at room temperature for 1 h. Step A: 5-phenyl-[l,2,4]triazole[l,5-a]pyridine-2-carboxylic acid (53 mg, 0.22 mmol) was dissolved in DMF (8 mL) solution at room temperature, (S)-3-amino-5-methyl-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3- dihydrobenzo[b][l,4]oxazepine-4(5H)-one (70 mg, 0.22 mmol), T3P (140 mg, 0.44 mmol) and N,N-diisopropylethylamine (86 mg, 0.66 mmol) were added. The reaction was stirred at room temperature for 1 h.

[0339] LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2) first, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 22 mg of (S)-N-(5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5- tetrahydrobenzo[b][l,4]oxazepine-3-yl)-5-phenyl-[l,2,4]triazole[l,5-a]pyridine-2- carboxamide (Compound 9).

[0340] MS (ESI) M / Z: 539.2 [M+H] + .

[0341] 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 8.0 Hz, 1H), 8.03 - 7.92 (m, 3H), 7.88 (dd, J = 8.8, 7.2 Hz, 1H), 7.64 - 7.54 (m, 3H), 7.48 (dd, J = 7.2, 1.2 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 2.8 Hz, 1H), 6.31 (dd, J = 8.8, 2.4 Hz, 1H), 4.94 - 4.77 (m, 1H), 4.54 - 4.43 (m, 1H), 4.36 (dd, J = 9.6, 8.0 Hz, 1H), 3.72 - 3.47 (m, 8H), 3.30 (s, 3H), 1.83 - 1.64 (m, 4H).

[0342] Example 10: (S)-N-(5-methyl-4-oxo-7-(2-oxo-6-azaspiro[3.3]heptan-6-yl)-2,3,4,5- tetrahydrobenzo[b][l,4]oxazepine-3-yl)-5-phenyl-[l,2,4]triazole[l,5-a]pyridine-2- carboxamide ​-3-yl)-5-phenyl-[1,2,4]triazolyl[1,5-a]pyridine-2-carboxamide

[0343]

[0344] Scheme:

[0345]

[0346] Procedure:

[0347] Step A: tert-Butyl [(S)-7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl]carbamate (150 mg, 0.40 mmol) and 2-oxo-6-azaspiro[3.3]heptane (44 mg, 0.44 mmol) were dissolved in 1,4-dioxane (3 mL), and tris(dibenzylideneacetone)dipalladium) (37 mg, 0.04 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (47 mg, 0.08 mmol) and cesium carbonate (263 mg, 0.81 mmol) were added. The mixture was stirred at 100 °C for 12 hours under the protection of a nitrogen balloon.

[0348] After LCMS monitoring showed the disappearance of the starting material, water (50 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (30 mL x 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 90 mg of tert-butyl (S)-(5-methyl-4-oxo-7-(2-oxo-6-azaspiro[3.3]heptan-6-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)carbamate.

[0349] MS (ESI) M / Z: 334.1 [M-55] + .

[0350] Step B: tert-Butyl (S)-(5-methyl-4-oxo-7-(2-oxo-6-azaspiro[3.3]heptan-6-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)carbamate (45 mg, 0.11 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (132 mg, 1.1 mmol) was added. The reaction solution was stirred at room temperature for 3 hours.

[0351] After LCMS monitoring showed that the starting material disappeared, the mixture was concentrated under reduced pressure to give 30 mg of (S)-3-amino-5-methyl-7-(2-oxa-6-azaspiro[3.3]heptane-6-yl)-2,3-dihydrobenzo[b][1,4]oxazepine -4(5H)-one.

[0352] MS (ESI) M / Z: 290.1 ​​[M+H] + .

[0353] Step C: (S)-3-amino-5-methyl-7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2,3-dihydrobenzo[b][1,4]oxazepine -4(5H)-one (25 mg, 0.08 mmol) and 5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (21 mg, 0.08 mmol) were dissolved in dichloromethane (5 mL), and 1-propylphosphonic anhydride (34 mg, 0.26 mmol) and ethyldiisopropylamine (34 mg, 0.26 mmol) were added. The mixture was stirred at room temperature for 1 hour.

[0354] After LCMS monitoring showed the disappearance of the starting material, the product was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 7 mg of (S)-N-(5-methyl-4-oxo-7-(2-oxo-6-azaspiro[3.3]heptane-6-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-5-phenyl-[1,2,4]triazolyl[1,5-a]pyridine-2-carboxamide (Compound 10).

[0355] MS (ESI) M / Z: 511.2 [M+H] + .

[0356] 1 H NMR(400MHz,DMSO-d6)δ8.79(d,J=8.0Hz,1H),8.00–7.94(m,3H),7.91–7.8 4(m,1H),7.64–7.57(m,3H),7.48(d,J=7.2Hz,1H),7.06(d,J=8.4Hz,1H),6 .51(d,J=2.4Hz,1H),6.33(dd,J=8.4,2.4Hz,1H),4.92–4.80(m,J=11.2,8. 0Hz,1H),4.71(s,4H),4.50(s,1H),4.35(s,1H),4.00(s,4H),3.30(s,3H).

[0357] Example 11: (S)-N-(5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5- tetrahydrobenzo[b][l,4]oxazepine-3-yl)-4-phenyl-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrimidine-2-carboxamide -3-yl)-4-phenyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-2-carboxamide

[0358]

[0359] Scheme:

[0360]

[0361] Procedure:

[0362] Step A: Pyrazolo[l,5-a]pyrimidine-2-carboxylic acid (2.0 g, 12.3 mmol) was dissolved in methanol (50 mL), concentrated sulfuric acid (1.2 mL) was added, and the reaction was stirred at 65 °C for 16 h.

[0363] After LCMS monitoring showed the disappearance of the starting material, methanol was distilled off, water (50 mL) and dichloromethane (50 mL) were added to the reaction solution, and it was washed with a IN NaHC03solution (50 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1) to give 1.8 g of pyrazolo[l,5-a]pyrimidine-2-carboxylic acid methyl ester.

[0364] MS (ESI) M / Z: 178.1 [M+H] + .

[0365] Step B: Pyrazolo[l,5-a]pyrimidine-2-carboxylic acid methyl ester (1.8 g, 10.1 mmol) was dissolved in methanol (50 mL), Pd / C (0.24 g) was added, and the resulting solution was stirred in a hydrogenation reactor at 25 °C for 16 h under 15 psi of hydrogen.

[0366] After LCMS monitoring showed the disappearance of the starting material, Pd / C was filtered off, and the resulting filtrate was concentrated to give 1.5 g of 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-2-carboxylic acid methyl ester.

[0367] MS (ESI) M / Z: 182.2 [M+H] + .

[0368] Step C: 4,5,6,7-Tetrahydropyrazolo[l,5-a]pyrimidine-2-carboxylic acid methyl ester (200 mg, 1.1 mmol) was dissolved in dioxane (5 mL), iodobenzene (450 mg, 204 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) (64 mg, 0.11 mmol), tris(dibenzylideneacetone)dipalladium (101 mg, 0.11 mmol) and cesium carbonate (720 mg, 2.2 mmol) were added, the reaction was stirred at 100 degree Celsius for 16 hours under nitrogen protection.

[0369] After LCMS monitoring showed the disappearance of the starting material, the reaction was concentrated, dichloromethane (150 mL) was added to the reaction, and it was washed with water. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to obtain 140 mg of 4-phenyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-2-carboxylic acid methyl ester.

[0370] MS (ESI) M / Z: 258.0 [M+H] + .

[0371] Step D: 4-phenyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-2-carboxylic acid methyl ester (140 mg, 0.54 mmol) was dissolved in methanol (5 mL), lithium hydroxide (78 mg, 3.26 mmol) was added, and the reaction was stirred at 25 degree Celsius for 4 hours.

[0372] After LCMS monitoring showed the disappearance of the starting material, dilute hydrochloric acid was added to neutralize the system to pH = 7, and it was concentrated to obtain 80 mg of 4-phenyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-2-carboxylic acid.

[0373] MS (ESI) M / Z: 244.1 [M+H] + .

[0374] Step E: (S)-3-amino-5-methyl-7-(7-oxo-2-azaspiro[3.5]non-2-yl)-2,3-dihydrobenzo[b][l,4]oxazepine -4(5H)-one (52.0 mg, 0.164 mmol) and 4-phenyl-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-2-carboxylic acid (40 mg, 0.164 mmol) were dissolved in acetonitrile (5 mL), and N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate TCTH (92 mg, 0.33 mmol) and methylimidazole (27 mg, 0.33 mmol) and triethylamine (33 mg, 0.33 mmol) were added thereto. The reaction system was stirred at 25 degree Celsius for 4 hours.

[0375] LCMS monitoring showed that after the disappearance of the raw material, the reaction solution was directly concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. 18 mg of (S)-N-(5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-4-yl)-4-phenyl-4,5,6,7-tetrahydropyrrolo[1,5-a]pyrimidine-2-carboxamide (compound 11) was obtained. -3-yl)-4-(spiro[3.3]heptan-2-yl)-4,5,6,7-tetrahydropyrrolo[1,5-a]pyrimidine-2-carboxamide

[0376] MS (ESI) M / Z: 543.0 [M+H] + .

[0377] 1 H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.4 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.24 (s, 1H), 7.10 (t, J = 7.6 Hz, 2H), 6.65-6.47 (m, 2H), 6.05 (s, 1H), 5.09-4.97 (m, 1H), 4.68-4.56 (m, 1H), 4.30-4.12 (m, 3H), 3.84 (s, 4H), 3.74-3.61 (m, 6H), 3.40 (s, 3H), 2.45-2.25 (m, 2H), 1.99-1.85 (m, 4H).

[0378] Example 12: (S)-N-(5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-4-yl)-4-(spiro[3.3]heptan-2-yl)-4,5,6,7-tetrahydropyrrolo[1,5-a]pyrimidine-2-carboxamide -3-yl)-4-(spiro[3.3]heptan-2-yl)-4,5,6,7-tetrahydropyrrolo[1,5-a]pyrimidine-2-carboxamide

[0379]

[0380] Reaction Scheme:

[0381]

[0382] Operation Steps:

[0383] Step A: 4,5,6,7-Tetrahydropyrrolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester (200 mg, 1.1 mmol) was dissolved in methanol (5 mL), and spiro[3.3]heptan-2-one (182 mg, 1.66 mmol) and sodium cyanoborohydride (138 mg, 2.2 mmol) were added. The reaction was stirred at 25 degrees Celsius for 16 hours.

[0384] LCMS monitoring showed the disappearance of starting material, methanol was evaporated, concentrated and purified by silica gel column chromatography to give 140 mg of methyl 4-(spiro[3.3]heptan-2-yl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-2-carboxylate.

[0385] MS (ESI) M / Z: 276.3 [M+H] + .

[0386] 1 H NMR (400 MHz, MeOD) δ 5.86 (s, 1H), 4.07 (t, J = 6.3 Hz, 2H), 3.85 (s, 3H), 3.74 - 3.53 (m, 1H), 3.18 - 2.95 (m, 2H), 2.44 - 2.32 (m, 2H), 2.27 - 2.16 (m, 2H), 2.11-2.10 (m, 4H), 2.01 - 1.96 (m, 2H), 1.95 - 1.87 (m, 2H).

[0387] Step B: Methyl 4-(spiro[3.3]heptan-2-yl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-2-carboxylate (100 mg, 0.36 mmol) was dissolved in tetrahydrofuran (10 mL), lithium hydroxide (43 mg, 1.8 mmol) was added, the resulting solution was added with 2 mL of water, stirred at 25 degrees Celsius for 4 hours.

[0388] LCMS monitoring showed the disappearance of starting material, the reaction was neutralized to pH = 7 with dilute hydrochloric acid (1 N), the filtrate was concentrated to give 80 mg of 4-(spiro[3.3]heptan-2-yl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-2-carboxylic acid.

[0389] MS (ESI) M / Z: 262.2 [M+H] + .

[0390] Step C: (S)-3-amino-5-methyl-7-(7-oxo-2-azaspiro[3.5]non-2-yl)-2,3-dihydrobenzo[b][l,4]oxazepine -4(5H)-one (50.0 mg, 0.19 mmol) and 4-(spiro[3.3]heptan-2-yl)-4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine-2-carboxylic acid (60 mg, 0.19 mmol) were dissolved in acetonitrile (5 mL), and N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate TCTH (107 mg, 0.38 mmol) and methylimidazole (31 mg, 0.38 mmol) and triethylamine (38 mg, 0.38 mmol) were added thereto. The reaction system was stirred at 25 degrees Celsius for 2 hours.

[0391] LCMS monitoring showed that the starting material disappeared, the reaction solution was directly concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. 8 mg of (S)-N-(5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-4-yl)-4-(spiro[3.3]heptan-2-yl)-4,5,6,7-tetrahydropyrrolo[1,5-a]pyrimidine-2-carboxamide (compound 12) was obtained. -3-yl)-4-(spiro[3.3]heptan-2-yl)-4,5,6,7-tetrahydropyrrolo[1,5-a]pyrimidine-2-carboxamide (compound 12).

[0392] MS (ESI) M / Z: 561.3 [M+H] + .

[0393] 1 H NMR (400 MHz, CDCl3) δ 7.80-7.65 (m, 1H), 7.16-7.08 (m, 1H), 6.80-6.52 (m, 2H), 5.82 (s, 1H), 5.15-4.87 (m, 1H), 4.65-4.54 (m, 1H), 4.28-4.16 (m, 1H), 4.14-4.03 (m, 2H), 4.00-3.78 (m, 4H), 3.73-3.78 (m, 4H), 3.64-3.56 (m, 1H), 3.39 (s, 3H), 3.07-3.00 (m, 2H), 2.35-2.25 (m, 2H), 2.23-2.12 (m, 2H), 2.05-2.02 (m, 4H), 2.00-1.89 (m, 6H), 1.85-1.83 (m, 2H).

[0394] Example 13: 4-methyl-N-((S)-5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-4-yl)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazepine-2-carboxamide -3-yl)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazepine-2-carboxamide

[0395]

[0396] The preparation method is referred to Example 5, and the target product 4-methyl-N-((S)-5-methyl-4-oxo-7-(7-oxo-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-4-yl)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazepine-2-carboxamide (compound 13) is obtained. -3-yl)-4-phenyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazepine-2-carboxamide (compound 13).

[0397] MS (ESI) M / Z: 558.3 [M+H] + .

[0398] 1 H NMR (400 MHz, DMSO-d6) δ 8.19 - 8.10 (m, 1H), 7.41 - 7.30 (m, 5H), 7.04 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.31 (dd, J = 8.4, 2.4 Hz, 1H), 4.88 - 4.81 (m, 1H), 4.48 - 4.35 (m, 1H), 4.34 - 4.26 (m, 1H), 4.25 - 4.04 (m, 3H), 3.76 - 3.67 (m, 1H), 3.66 - 3.60 (m, 4H), 3.59 - 3.48 (m, 4H), 3.30 - 3.26 (m, 3H), 1.80 - 1.69 (m, 7H).

[0399] Example 14: N-((3S)-5-methyl-4-oxo-8-(tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)- 2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2- carboxamide -3-yl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide

[0400]

[0401] Scheme:

[0402]

[0403] Procedure:

[0404] Step A: Sodium hydride (1.9 g, 47.7 mol, 60%) was added to N,N-dimethylformamide (80 mL) under ice bath. A solution of (tert-butoxycarbonyl)-L-serine (5000 mg, 22.7 mmol) in N,N-dimethylformamide (20 mL) was added dropwise to the suspension of sodium hydride. The mixture was stirred at 0 °C for 0.5 h. Then, 4-bromo-2-fluoro-l-nitrobenzene (4663 mg, 22.7 mol) in N,N-dimethylformamide (10 mL) was added dropwise to the reaction mixture. The mixture was stirred at 0 °C for 2 h.

[0405] LCMS monitoring showed disappearance of starting material, dilute hydrochloric acid (3N HCI) was added to adjust the pH of the solution to 3-4, water (100 mL) was added to the mixture, which was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography to give 4000 mg of O-(5-bromo-2-nitrophenyl)-N-(tert-butoxycarbonyl)-L-serine.

[0406] MS (ESI) M / Z: 427.0 [M+Na] + .

[0407] Step B: O-(5-bromo-2-nitrophenyl)-N-(tert-butoxycarbonyl)-L-serine (4000 mg, 9.87 mmol) was dissolved in ethanol (80 mL) and water (20 mL), iron powder (2205 mg, 39.49 mmol) and ammonium chloride (2112 mg, 39.48 mmol) were added. The mixture was stirred at 60 degrees Celsius for 6 hours.

[0408] LCMS monitoring showed disappearance of starting material, water (100 mL) was added to the mixture, which was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give 2500 mg of crude product O-(2-amino-5-bromophenyl)-N-(tert-butoxycarbonyl)-L-serine.

[0409] MS (ESI) M / Z: 397.1 [M+Na] + .

[0410] Step C: O-(2-amino-5-bromophenyl)-N-(tert-butoxycarbonyl)-L-serine (2000 mg, 5.3 mmol) was dissolved in dimethyl sulfoxide (40 mL), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2000 mg, 5.3 mmol) and N,N-diisopropylethylamine (1343 mg, 10.6 mmol) were added. The mixture was stirred at 25 degrees Celsius for 1 hour.

[0411] LCMS monitoring showed disappearance of starting material, water (80 mL) was added and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography to give 1000 mg of (S)-(8-bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)carbamic acid tert-butyl ester.

[0412] MS (ESI) M / Z: 379.0 [M+Na] + .​

[0413] Step D: (S)-(8-Bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine-3- yl)carbamic acid tert-butyl ester (600 mg, 1.7 mmol) was dissolved in N,N- dimethylformamide (8 mL), cesium carbonate (310 mg, 2.21 mmol) and iodomethane (310 mg, 2.0 mmol) were added. The mixture was stirred at 25 °C for 3 h.

[0414] After LCMS monitoring showed the disappearance of starting material, water (30 mL) was added and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by column chromatography on silica gel to give 400 mg of (S)-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine-3- yl)carbamic acid tert-butyl ester.

[0415] MS (ESI) M / Z: 393.1 [M+Na] + .

[0416] Step E: (S)-(8-Bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine-3- yl)carbamic acid tert-butyl ester (323 mg, 0.9 mmol) was dissolved in 1,4- dioxane (8 mL), tris(dibenzylideneacetone)dipalladium (80 mg, 0.1 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (100 mg, 0.2 mmol), hexahydro-lH- furo[3,4-c]pyrrole (102 mg, 0.9 mmol) and cesium carbonate (849 mg, 2.6 mmol) were added, and the mixture was replaced with nitrogen three times. The mixture was stirred at 110 °C for 12 h. After LCMS monitoring showed the disappearance of starting material, water (30 mL) was added and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by column chromatography on silica gel to give 160 mg of ((3S)-5-methyl-4-oxo-8-(tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)- 2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine-3-yl)carbamic acid tert-butyl ester.

[0417]

[0418] MS (ESI) M / Z: 404.1 [M+H] + .

[0419] ​​​​Step F: tert-Butyl ((3S)-5-methyl-4-oxo-8-(tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)- yl)-2,3,4,5-tetrahydrobenzo[6][l,4]oxazepin-3-yl)carbamate (150 mg, 0.3 mmol) was dissolved in hydrochloric acid 1,4-dioxane (5 mL, 4 M). The reaction mixture was stirred at 25 °C for 2 hours. LCMS monitoring showed the disappearance of starting material after which the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. This resulted in 110 mg of (3S)-3-amino-5-methyl-8-(tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)-2,3- dihydrobenzo[6][l,4]oxazepin-4(5H)-one.

[0420] LCMS monitoring showed the disappearance of starting material after which the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. This resulted in 110 mg of (3S)-3-amino-5-methyl-8-(tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)-2,3- dihydrobenzo[6][l,4]oxazepin-4(5H)-one.

[0421] MS (ESI) M / Z: 304.1 [M+H] + .

[0422] Step G: (3S)-3-amino-5-methyl-8-(tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)-2,3- dihydrobenzo[6][l,4]oxazepin-4(5H)-one (50 mg, 0.2 mmol), and 5-phenyl- [l,2,4]triazolo[l,5-a]pyridine-2-carboxylic acid (39 mg, 0.2 mmol) were dissolved in dichloromethane (6 mL). Triethylamine (67 mg, 0.7 mmol) and 1- propylphosphonic anhydride (79 mg, 0.3 mmol) were added. The reaction was stirred at 25 °C for 1 hour. LCMS monitoring showed the disappearance of starting material after which the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. This resulted in 110 mg of (3S)-3-amino-5-methyl-8-(tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)-2,3- dihydrobenzo[6][l,4]oxazepin-4(5H)-one.

[0423] LCMS monitoring showed the disappearance of starting material after which the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. This resulted in 110 mg of (3S)-3-amino-5-methyl-8-(tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)-2,3- dihydrobenzo[6][l,4]oxazepin-4(5H)-one. LCMS monitoring showed the disappearance of starting material after which the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography. This resulted in 110 mg of (3S)-3-amino-5-methyl-8-(tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)-2,3- dihydrobenzo[6][l,4]oxazepin-4(5H)-one.

[0424] MS (ESI) M / Z: 525.2 [M+H] + .

[0425] 1 ​H NMR(400MHz,DMSO-d6)δ8.82–8.59(m,1H),8.06–7.81(m,4H),7.71–7.42(m,4H),7.37–7.22(m,1H),6.60–6.30(m,2H ),5.00–4.77(m,1H),4.60–4.36(m,2H),3.94–3.78(m,2H),3.58–3.51(m,2H),3.30–3.13(m,7H),3.06–2.92(m,2H).

[0426] Example 15: N-((S)-7-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-5-phenyl-[1,2,4]triazolyl[1,5-a]pyridine-2-carboxamide

[0427]

[0428] Reaction route:

[0429]

[0430] Steps:

[0431] Step A: (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine) Tert-butyl 3-(4-(2-methyl-3-yl)carbamate (301 mg, 0.81 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the addition of benzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (200 mg, 0.81 mmol), Pd2(dba)3 (75 mg, 0.08 mmol), xantphos (94 mg, 0.16 mmol), and cesium carbonate (794 mg, 2.43 mmol). The reaction was stirred at 100°C for 12 hours. LCMS indicated the reaction was complete. The mixed solution was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The organic phase was first washed with saturated brine (50 mL × 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 220 mg of 5-((S)-3-((tert-butyloxycarbonyl)amino)-5-methyl-4-oxy-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -7-yl)benzyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.

[0432] MS (ESI) M / Z: 559.2 [M+Na] + .

[0433] Step B: 5-((S)-3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-7- yl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylic acid benzyl ester (220 mg, 0.38 mmol) was dissolved in a solution of hydrochloric acid / 1,4-dioxane (10 mL). The reaction was stirred at room temperature for 1 hour.

[0434] LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 180 mg of 5-((S)-3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-7- yl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylic acid benzyl ester.

[0435] MS (ESI) M / Z: 437.2 [M+H] + .

[0436] Step C: 5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxylic acid (33 mg, 0.13 mmol) was dissolved in acetonitrile (8 mL) at room temperature, and 5-((S)-3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-7- yl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylic acid benzyl ester (60 mg, 0.13 mmol), T3P (88 mg, 0.27 mmol), and N,N-diisopropylethylamine (53 mg, 0.41 mmol) were added. The reaction was stirred at room temperature for 1 hour.

[0437] LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 60 mg of 5-((S)-5-methyl-4-oxo-3-(5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carbonyl)-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-7- yl)hexahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylic acid benzyl ester.

[0438] MS (ESI) M / Z: 658.3 [M+H] + .​​​​

[0439] Step D: To a solution of benzyl 7-((S)-5-methyl-4-oxo-3-(5-phenyl-[l,2,4]triazolo[l,5- a]pyridine-2-carboxamido)-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-7-yl)hexahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxylate (60 mg, 0.09 mmol) in dichloromethane (5 mL) was added palladium chloride (2 mg, 0.009 mmol), triethylamine (28 mg, 0.27 mmol) and triethylsilane (22 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 9 h. LCMS showed the reaction was completed. The mixture was extracted with dichloromethane (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 10 mg of N-((S)-7-(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][l,4]oxazepin-3-yl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide (Compound 15).

[0440] LCMS showed the reaction was completed. The mixture was extracted with dichloromethane (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 10 mg of N-((S)-7-(hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][l,4]oxazepin-3-yl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide (Compound 15).

[0441] MS (ESI) M / Z: 524.3 [M+H] + .

[0442] 1 H NMR (400 MHz, DMSO-d6) d 8.84 (d, J = 7.6 Hz, 1H), 8.11 - 7.98 (m, 3H), 7.97 - 7.90 (m, 1H), 7.71 - 7.60 (m, 3H), 7.54 (dd, J = 7.2, 1.2 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 8.8, 2.4 Hz, 1H), 5.00 - 4.88 (m, 1H), 4.61 - 4.51 (m, 1H), 4.44 - 4.38 (m, 1H), 3.46 - 3.40 (m, 2H), 3.39 (s, 3H), 3.32 - 3.18 (m, 4H), 3.08 - 2.97 (m, 2H), 2.95 - 2.84 (m, 2H).​ N-((S)-7-((3aR,6aR)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(lH)-yl)-5-methyl- 4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine-3-yl)-5-phenyl-[l,2,4]triazolo[l,5- a]pyridine-2-carboxamide N-((S)-7-((3aR,6aR)-5,5-difluorohexahydrocyclopenta[c]pyrrol-2(lH)-yl)-5-methyl- 4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepine-3-yl)-5-phenyl-[l,2,4]triazolo[l,5- a]pyridine-2-carboxamide

[0443]

[0444]

[0445] Preparation method refers to example 8, purification conditions as follows, column: Xbridge 5u C18 150*19mm; mobile phase: water (containing 0.1% trifluoroacetic acid) and acetonitrile, to get compound 16-P1 (retention time 9.3 min) and compound 16-P2 (retention time 10.00 min).

[0446] Compound 16-P1:

[0447] MS (ESI) M / Z: 559.2 [M+H] + .

[0448] 1 H NMR (400 MHz, DMSO-d6) d 8.77 (d, J = 8.0 Hz, 1H), 8.00 - 7.94 (m, 3H), 7.91 - 7.84 (m, 1H), 7.63 - 7.57 (m, 3H), 7.48 (d, J = 7.2 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 2.4 Hz, 1H), 6.53 (dd, J = 8.8, 2.6 Hz, 1H), 4.96 - 4.78 (m, 1H), 4.54 - 4.45 (m, 1H), 4.40 - 4.26 (m, 1H), 3.42 - 3.38 (m, 2H), 3.33 (s, 3H), 3.27 - 3.21 (m, 2H), 3.00 - 2.88 (m, 2H), 2.45 - 2.35 (m, 2H), 2.09 - 1.97 (m, 2H).

[0449] Compound 16-P2:

[0450] MS (ESI) M / Z: 559.2 [M+H] + .

[0451] 1H NMR (400 MHz, DMSO-d6) δ 8.76 (d, J = 8.0 Hz, 1H), 8.00 - 7.94 (m, 3H), 7.92 - 7.84 (m, 1H), 7.64 - 7.57 (m, 3H), 7.48 (d, J = 6.4 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 6.39 (dd, J = 8.8, 2.4 Hz, 1H), 4.99 - 4.82 (m, 1H), 4.51 - 4.42 (m, 1H), 4.41 - 4.24 (m, 1H), 3.48 - 3.42 (m, 2H), 3.33 (s, 3H), 3.06 - 2.97 (m, 2H), 2.45 - 2.34 (m, 2H), 2.24 - 2.13 (m, 2H), 2.10 - 1.96 (m, 2H).

[0452] The following target compounds were prepared according to the synthetic procedure described above for Example 8:

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460] The following target compounds were prepared according to the synthetic procedure described above for Example 12:

[0461]

[0462]

[0463] Example 29: 5-benzyl-N-((S)-7-((3aS,6aS)-5,5-difluorooctahydrocyclopenta[c]pyrrol-2(lH)-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-lH-l,2,4-triazole-3-carboxamide

[0464]

[0465] ​5-benzyl-N-((S)-7-((3aR,6aS)-5,5-difluorooctahydrocyclopenta[c]pyrrol-2(lH)-yl)-5- methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-lH-indole-6-carboxamide -3-yl)-lH-indole-6-carboxamide

[0466]

[0467] Referring to the synthetic route of Example 8, the purification conditions are as follows, column: Xbridge 5u C18 150*30mm; mobile phase: water (containing 10 mmol / l formic acid) and acetonitrile, to obtain 12 mg of compound 29-P1 (retention time 2.037 min) and 7 mg of compound 29-P2 (retention time 2.078 min). Compound 29-P1:

[0468] MS (ESI) M / Z: 523.2 [M+H] + .

[0469] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.37 - 7.19 (m, 6H), 7.05 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 2.6 Hz, 1H), 6.55 - 6.49 (m, 1H), 4.91 - 4.72 (m, 2H), 4.51 - 4.42 (m, 1H), 4.33 - 4.24 (m, 1H), 4.11 (s, 2H), 3.42 - 3.34 (m, 2H), 3.30 (s, 3H), 3.26 - 3.20 (m, 2H), 2.94 (s, 2H), 2.44 - 2.32 (m, 2H), 2.09 - 1.98 (m, 2H).

[0470] Compound 29-P2:

[0471] MS (ESI) M / Z: 523.2 [M+H] + .

[0472] 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.36 - 7.16 (m, 6H), 7.02 (d, J = 8.6 Hz, 1H), 6.51 (d, J = 2.6 Hz, 1H), 6.37 (dd, J = 8.8, 2.6 Hz, 1H), 4.86 - 4.78 (m, 1H), 4.46 - 4.41 (m, 1H), 4.30-4.24 (s, 1H), 4.11 (s, 2H), 3.47 - 3.42 (m, 2H), 3.29 (s, 3H), 3.05 - 2.99 (m, 2H), 2.43 - 2.35 (m, 2H), 2.20-2.14 (s, 2H), 2.06 - 1.97 (m, 2H).

[0473] Example 34: (S)-5-benzyl-N-(7-(2-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5- methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide Example 34: (S)-5-benzyl-N-(7-(2-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5- methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

[0474]

[0475] Example 34: (S)-5-benzyl-N-(7-(2-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5- methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide Example 34: (S)-5-benzyl-N-(7-(2-isopropyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5- methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

[0476]

[0477] The synthesis of Reference Example 8 was followed, and the purification conditions were as follows, column: Xbridge 5u C18 150 x 19 mm; mobile phase: water (containing 0.1% TFA) and acetonitrile, to give 28.35 mg of compound 34-P1 (retention time 6.05 min) and 16.22 mg of compound 34-P2 (retention time 6.97 min).

[0478] Compound 34-P1:

[0479] MS (ESI) M / Z: 527.3 [M+H] + .

[0480] 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 9.6 Hz, 1H), 7.64 (s, 1H), 7.34 - 7.22 (m, 6H), 7.10 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.53 (dd, J = 8.8, 2.4 Hz, 1H), 4.89 - 4.82 (m, 1H), 4.53 - 4.44 (m, 2H), 4.37 (s, 4H), 4.33 - 4.29 (m, 1H), 4.12 (s, 2H), 3.35 (s, 3H), 1.44 (d, J = 6.4 Hz, 6H).

[0481] Compound 34-P2:

[0482] MS (ESI) M / Z: 527.3 [M+H] + .

[0483] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 9.6 Hz, 1H), 7.64 (s, 1H), 7.34 - 7.22 (m, 6H), 7.10 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.53 (dd, J = 8.8, 2.4 Hz, 1H), 4.89 - 4.82 (m, 1H), 4.53 - 4.44 (m, 2H), 4.37 (s, 4H), 4.33 - 4.29 (m, 1H), 4.12 (s, 2H), 3.35 (s, 3H), 1.44 (d, J = 6.4 Hz, 6H).

[0484] Example 35: N-((3S)-5-methyl-7-(2-oxotetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)-4- oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine- 2-carboxamide -3-yl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2-carboxamide

[0485]

[0486] Scheme:

[0487]

[0488] Procedure:

[0489] Step A: tert-Butyl ((3S)-5-methyl-4-oxo-7-(tetrahydro-lH-thieno[3,4-c]pyrrol-5(3H)-yl)- 2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)carbamate A solution of tert-butyl (3S)-3-amino-5-methyl-7-(2-oxotetrahydro-lH-thieno[3,4- c]pyrrol-5(3H)-yl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (50 mg, 0.14 mmol) in dichloromethane (5 mL) was added triethylamine (22 mg, 0.22 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour.

[0490] LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the product (3S)-3-amino-5-methyl-7-(2-oxotetrahydro-lH-thieno[3,4- c]pyrrol-5(3H)-yl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (50 mg). -3-yl)carbamate (80 mg).

[0491] MS (ESI) M / Z: 436.2 [M+H] + .

[0492] A solution of tert-butyl (3S)-3-amino-5-methyl-7-(2-oxotetrahydro-lH-thieno[3,4- c]pyrrol-5(3H)-yl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (50 mg, 0.14 mmol) in dichloromethane (5 mL) was added triethylamine (22 mg, 0.22 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. -3-yl)carbamate (80 mg).

[0493] LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the product (3S)-3-amino-5-methyl-7-(2-oxotetrahydro-lH-thieno[3,4- c]pyrrol-5(3H)-yl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (50 mg).

[0494] MS (ESI) M / Z: 436.2 [M+H] + .

[0495] Step C: Dissolve 5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (38 mg, 0.16 mmol) in acetonitrile (6 mL) at room temperature, add (3S)-3-amino-5-methyl-7-(2-oxidotetrahydro-1H-thiophene[3,4-c]pyrrol-5(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (50 mg, 0.15 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (63 mg, 0.22 mmol), and N-methylimidazole (31 mg, 0.37 mmol). The reaction mixture was stirred at room temperature for 1 hour.

[0496] LCMS showed that the reaction was complete. The mixed solution was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL × 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography. The final product was 1 mg N-((3S)-5-methyl-7-(2-oxidotetrahydro-1H-thiophene[3,4-c]pyrrol-5(3H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (Compound 35).

[0497] MS (ESI) M / Z: 557.2 [M+H] + .

[0498] 1 H NMR(400MHz,DMSO-d6)δ8.77(d,J=8.0Hz,1H),8.40(s,2H),7.99–7.95(m,2H),7.91– 7.84(m,1H),7.63–7.57(m,2H),7.48(d,J=6.0Hz,1H),7.06(d,J=8.8Hz,1H),6.64(d, J=2.8Hz,1H),6.49(dd,J=8.8,2.8Hz,1H),4.93–4.84(m,1H),4.53–4.46(m,1H),4.4 0–4.33(m,1H),3.33(s,3H),3.30–3.24(m,6H),2.98–2.92(m,2H),1.26–1.20(m,2H).

[0499] Example 41: (S)-5-Benzyl-N-(7-(2-cyclopropyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-1H-1,2,4-triazole-3-carboxamide

[0500]

[0501] (S)-5-Benzyl-N-(7-(1-cyclopropyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-1H-1,2,4-triazole-3-carboxamide

[0502]

[0503] Referring to the synthesis method of Example 8, the purification conditions were as follows: chromatographic column: Xbridge 5u C18 150 x 19 mm; mobile phase: water (containing 0.1% TFA) and acetonitrile, to obtain 16.51 mg of compound 44-P1 (retention time 6.93 min) and 6.67 mg of compound 44-P2 (retention time 7.08 min). Compound 41-P1:

[0504] MS (ESI) M / Z: 525.3 [M+H] + .

[0505] 1 H NMR (400MHz, DMSO-d6) δ8.46(d,J=8.0Hz,1H),7.66(s,1H),7.30-7.24(m,6H),7.09(d,J=8.8Hz,1H),6.67(d,J=2.4Hz,1H),6.53(dd,J=8.8,2.8Hz ,1H),4.88-4.81(m,1H),4.49-4.44(m,2H),4.37–4.33(m,4H),4.12(s,2 H),3.71-3.68(m,1H),3.34(s,3H),1.07-1.04(m,2H),0.98-0.93(m,2H).

[0506] Compound 41-P2:

[0507] MS (ESI) M / Z: 525.3 [M+H] + .

[0508] 1H NMR (400 MHz, MeOD) δ 7.90 (s, 1H), 7.37-7.31 (m, 7H), 7.17 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.66 (dd, J = 8.8, 2.8 Hz, 1H), 4.74 (s, 2H), 4.56-4.54 (m, 1H), 4.51 (s, 2H), 4.41-4.33 (m, 2H), 3.85-3.79 (m, 1H), 3.47 (s, 2H), 2.68 (s, 3H), 1.32-1.30 (m, 2H), 1.29-1.26 (m, 2H).

[0509] Example 42: 5-benzyl-N-((3S)-7-(hexahydro-lH-cyclopenta[c]furan-5-yl)-5-methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-lH-l,2,4-triazole-3-carboxamide -3-yl)-lH-l,2,4-triazole-3-carboxamide

[0510]

[0511] Scheme:

[0512]

[0513] Procedure:

[0514] Step A: A solution of 4-oxocyclopentane-l,2-dicarboxylic acid dimethyl ester (10.0 g, 0.05 mol), ethylene glycol (9.31 g, 0.15 mol), p-toluenesulfonic acid (1.7 g, 0.01 mmol) in toluene (80 mL) was added with active molecular sieves (5.0 g) and stirred at 100 °C for 48 h.

[0515] LCMS monitoring showed the disappearance of the starting material. After removing the molecular sieves by filtration, the residue was concentrated under reduced pressure and the product, 1,4-dioxypyrrolo[4.4]nonane-7,8-dicarboxylic acid dimethyl ester (9.0 g) was obtained after purification on a silica gel column.

[0516] MS (ESI) M / Z: 245.1 [M+H] + .

[0517] Step B: A solution of 1,4-dioxypyrrolo[4.4]nonane-7,8-dicarboxylic acid dimethyl ester (9.0 g, 0.04 mol) in tetrahydrofuran (80 mL) was added with lithium aluminum hydride solid (2.1 g, 0.05 mol) in small portions. The reaction was continued to stir for 1 h in an ice water bath.

[0518] LCMS monitoring showed the disappearance of starting material. The reaction solution was quenched with 1 M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product (1,4-dioxypyrazol[4.4]nonane-7,8-diyl)dimethanol (6.8 g).

[0519] MS (ESI) M / Z: 189.3 [M+H] + .

[0520] Step C: (1,4-Dioxypyrazol[4.4]nonane-7,8-diyl)dimethanol (6.8 g, 36.1 mmol) was dissolved in tetrahydrofuran (80 mL) under an ice water bath, and n-butyllithium in tetrahydrofuran (2.5 M, 14.5 mL, 36.1 mmol) was added slowly. After stirring for half an hour, p-toluenesulfonic acid chloride (6.9 g, 36.1 mmol) was added slowly. After stirring for one hour, n-butyllithium in tetrahydrofuran (2.5 M, 14.5 mL, 36.1 mmol) was added slowly again. The reaction system was allowed to return to room temperature and continue to stir for 16 hours.

[0521] LCMS monitoring showed the disappearance of starting material. The reaction solution was quenched with 1 M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product (1,4-dioxypyrazol[4.4]nonane-7,8-diyl)dimethanol (6.8 g).

[0522] MS (ESI) M / Z: 171.2 [M+H] + .

[0523] Step D: Tetrahydrofuran-1H,3H-spiro[cyclopent[c]furan-5,2'-[1,3]dioxolane] (500.0 mg, 1.2 mmol) was dissolved in acetone: water = 7:1 (8 mL) at room temperature, and Amberlyst 15 ion exchange resin was added. The reaction system was stirred at room temperature for 6 hours.

[0524] LCMS monitoring showed the disappearance of starting material. The reaction solution was quenched with 1 M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product (1,4-dioxypyrazol[4.4]nonane-7,8-diyl)dimethanol (6.8 g).

[0525] MS (ESI) M / Z: 127.3 [M+H] + .

[0526] Step E: Dissolve tetrahydrofuran-5(3H)-one (150.0 mg, 1.2 mmol) and 4-toluenesulfonylhydrazide (220.0 mg, 1.2 mmol) in ethanol (15 mL) at room temperature and stir the reaction system at 80°C for 3 hours.

[0527] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was directly concentrated under reduced pressure to obtain a crude product of 4-methyl-N'-(tetrahydro-1H-cyclopenta[c]furan-5(3H)-ylidene)benzenesulfonylhydrazide (250.0 mg).

[0528] MS (ESI) M / Z: 295.2 [M+H] + .

[0529] Step F: At room temperature, tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine A solution of 1,4-dioxane (22 mL) containing 1,4-dioxane (400 mg, 1.0 mmol) was prepared by dissolving 1,4-dioxane (400 mg, 1.0 mmol). Potassium acetate (317 mg, 3.2 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (315.3 mg, 0.4 mmol), and pinacol diboron (301.0 mg, 1.2 mmol) were added. The reaction system was stirred at 105°C for 6 hours.

[0530] After LCMS monitoring showed that the starting material disappeared, the mixed solution was extracted with ethyl acetate (3 x 50 mL), and the organic phases were combined and washed with saturated brine (2 x 50 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column to obtain the final product, tert-butyl (S)-(5-methyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)carbamate (410 mg).

[0531] MS (ESI) M / Z: 441.3 [M+Na] + .

[0532] Step G: Tert-butyl (S)-(5-methyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine 1-Hydroxy-3-yl)carbamate (410.0 mg, 0.9 mmol) was dissolved in a 6:1 water:methanol solution (21 mL), and sodium periodate (629.3 mg, 2.9 mmol) and ammonium chloride (104.8 mg, 1.9 mmol) were added. The reaction system was stirred at room temperature for 16 hours.

[0533] After LCMS monitoring showed that the starting material disappeared, the mixed solution was concentrated under reduced pressure to remove the methanol in the solution, and then extracted with ethyl acetate (3x50mL). The organic phases were combined, washed with saturated brine (2x 50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to obtain the crude product (S)-(3-(tert-butyloxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -7-yl)boric acid (250.0 mg).

[0534] MS (ESI) M / Z: 359.1 [M+Na] + .

[0535] Step H: (S)-(3-(tert-Butyloxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine A solution of 4-methyl-N'-(tetrahydro-1H-cyclopenta[c]furan-5(3H)-ylidene)benzenesulfonylhydrazide (241.0 mg, 0.82 mmol) and cesium carbonate (726.9 mg, 2.23 mmol) was added to 1,4-dioxane (20 mL). The reaction system was stirred at 100°C for 16 hours.

[0536] After LCMS monitoring showed that the starting material disappeared, the mixed solution was extracted with ethyl acetate (3 x 50 mL), and the organic phases were combined and washed with saturated brine (2 x 50 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column to obtain the final product, tert-butyl ((3S)-7-(hexahydro-1H-cyclopenta[c]furan-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)carbamate (80.0 mg).

[0537] MS (ESI) M / Z: 425.1 [M+Na] + .

[0538] Step I: ((3S)-7-(hexahydro-1H-cyclopenta[c]furan-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)carbamate (80.0 mg, 0.5 mmol) was dissolved in a solution of hydrochloric acid in 1,4-dioxane (10 mL). The reaction was stirred at room temperature for 1 hour.

[0539] LCMS monitoring showed the disappearance of starting material. The reaction was concentrated to give the crude product (3S)-3-amino-7-(hexahydro-lH-cyclopenta[c]furan-5-yl)-5-methyl-2,3- dihydrobenzo[b][l,4]oxazepin-4(5H)-one (40.0 mg).

[0540] MS (ESI) M / Z: 303.2 [M+H] + .

[0541] Step J: (3S)-3-amino-7-(hexahydro-lH-cyclopenta[c]furan-5-yl)-5-methyl-2,3- dihydrobenzo[b][l,4]oxazepin-4(5H)-one (40.0 mg, 0.1 mmol) and 5-benzyl-lH-l,2,4- triazole-3-carboxylic acid (26.7 mg, 0.1 mmol) were dissolved in acetonitrile (20 mL), and to this was added N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (55.3 mg, 0.2 mmol) and N-methylimidazole (21.6 mg, 0.3 mmol). The reaction was stirred at room temperature for 1 hour.

[0542] LCMS monitoring showed the disappearance of starting material, and the reaction was directly concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography. This gave 14.29 mg of 5-benzyl-N-((3S)-7-(hexahydro-lH-cyclopenta[c]furan-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-lH-l,2,4-triazole-3-carboxamide (Compound 42).

[0543] MS (ESI) M / Z: 488.3 [M+H] + .

[0544] 1 ​​​H NMR(400MHz, CDCl3)δ8.37(s,1H),7.31-7.30(m,5H),7.12-7.08(m,3H),5.0 9-5.07(m,1H),4.61-4.58(m,1H),4.44-4.39(m,1H),4.28(s,2H),4.02-3.96 (m,2H),3.85-3.83(m,1H),3.45-3.46(m,1H),3.40(s,3H),2.54-2.48(m,1H) ,2.36-2.24(m,3H),1.96-1.94(m,1H),1.83-1.80(m,1H),1.48-1.38(m,1H).

[0545] Example 43: (S)-5-Benzyl-N-(7-(2-ethyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-1H-1,2,4-triazole-3-carboxamide

[0546]

[0547] (S)-5-Benzyl-N-(7-(1-ethyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-1H-1,2,4-triazole-3-carboxamide

[0548]

[0549] Referring to the synthesis method of Example 8, the purification conditions were as follows: chromatographic column: Xbridge-C18 150 x 19 mm; mobile phase: water (containing 0.1% FA) and acetonitrile, to obtain 30.11 mg of compound 43-P1 (retention time 7.42 min) and 34.96 mg of compound 43-P2 (retention time 7.65 min).

[0550] Compound 43-P1:

[0551] MS (ESI) M / Z: 513.3 [M+H] + .

[0552] 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.62 (s, 1H), 7.34 - 7.22 (m, 6H), 7.10 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 2.8 Hz, 1H), 6.53 (dd, J = 8.8, 2.8 Hz, 1H), 4.88 - 4.79 (m, 1H), 4.47 (t, J = 11.2 Hz, 1H), 4.37 (s, 4H), 4.32 - 4.30 (m, 1H), 4.17 - 4.12 (m, 4H), 3.35 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H).

[0553] Compound 43-P2:

[0554] MS (ESI) M / Z: 513.3 [M+H] + .

[0555] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 8.4 Hz, 1H), 7.34 - 7.21 (m, 7H), 7.11 - 7.09 (m, 1H), 6.67 - 6.64 (m, 1H), 6.54 - 6.49 (m, 1H), 4.88 - 4.81 (m, 1H), 4.54 - 4.43 (m, 3H), 4.37 - 4.31 (m, 3H), 4.15 - 4.11 (m, 4H), 3.41 - 3.35 (m, 3H), 1.41 - 1.37 (m, 3H).

[0556] Example 44: l-benzyl-5-chloro-N-((S)-5-methyl-4-oxo-7-((3aR,6aS)- tetrahydro-lH-furan[3,4-c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin- 3-yl)-lH-l,2,4-triazole-3-carboxamide

[0557] Scheme:

[0558]

[0559] Procedure:

[0560]

[0561] ​Step A: 5-Chloro-lH-l,2,4-triazole-3-carboxylic acid ethyl ester (1 g, 0.006 mol) and bromomethylbenzene (1.2 g, 0.007 mol) were dissolved in N,N-dimethylformamide (10 mL) followed by addition of cesium carbonate (2.4 g, 0.007 mol) and stirred at room temperature for 2 h.

[0562] LCMS monitoring showed disappearance of starting material, which was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue obtained was purified by silica gel column chromatography to get l-benzyl-5-chloro-lH-l,2,4-triazole-3-carboxylic acid ethyl ester (0.6 g).

[0563] MS (ESI) M / Z: 266.1 [M+H] + .

[0564] Step B: l-Benzyl-5-chloro-lH-l,2,4-triazole-3-carboxylic acid ethyl ester (400 mg, 1.506 mmol) was dissolved in a mixture of tetrahydrofuran and water (3: 1 = 12 mL) followed by addition of lithium hydroxide (108.2 mg, 4.517 mmol) and stirred at room temperature for 2 h.

[0565] LCMS monitoring showed disappearance of starting material, which was acidified to pH 6 with dilute hydrochloric acid and lyophilized to get l-benzyl-5-chloro-lH-l,2,4-triazole-3-carboxylic acid (300 mg).

[0566] MS (ESI) M / Z: 238.1 [M+H] + .

[0567] Step C: (S)-3-Amino-5-methyl-7-(3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)-2,3- dihydrobenzo[b][l,4]oxazepine-4(5H)-one (80.0 mg, 0.3 mmol) and l-benzyl-5-chloro-lH-l,2,4- triazole-3-carboxylic acid (69.0 mg, 0.3 mmol) were dissolved in acetonitrile (10 mL) and to this N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (111.0 mg, 0.4 mmol) and N-methylimidazole (43.0 mg, 0.5 mmol) were added. The reaction mixture was stirred at room temperature for 1 h.

[0568] ​LCMS monitoring showed that after the disappearance of the raw materials, the reaction solution was directly concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. 11.84 mg of 1-benzyl-5-chloro-N-((S)-5-methyl-4-oxo-7-((3aR,6aS)- tetrahydro-1H-furan[3,4-c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin- 10 -3-yl)-1H-1,2,4-triazole-3-carboxamide (Compound 44).

[0569] MS (ESI) M / Z: 523.2 [M+H] + .

[0570] 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 8.0 Hz, 1H), 7.41 - 7.34 (m, 3H), 7.28 - 7.26 (m, 2H), 7.03 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.8, 2.4 Hz, 1H), 5.50 (s, 2H), 4.84 - 4.77 (m, 1H), 4.52 - 4.46 (m, 1H), 4.29 - 4.25 (m, 1H), 3.88 - 3.84 (m, 2H), 3.54 - 3.52 (m, 2H), 3.36 (s, 2H), 3.30 (s, 3H), 3.22 - 3.19 (m, 2H), 2.99 - 2.98 (m, 2H).

[0571] Example 45: (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridin-6-yl)-6-fluoro-5-methyl-8-(tetrahydro-1H-furan[3,4-c]pyrrol-5(3H)-yl)-2,3- dihydrobenzo[b][1,4]oxazepine-4(5H)-one -4(5H)-one

[0572]

[0573] Scheme:

[0574]

[0575] Procedure:

[0576] Step A: 1 -benzyl-5-chloro-4-(2-(((3S)-6-fluoro-5-methyl-4-oxo-8-(tetrahydro-1 H- furan[3,4-c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-5- yl)amino)ethyl)-1 H-pyrazole-3-carboxylate (60 mg, 0.10 mmol) was dissolved in toluene (6 mL) at room temperature, trimethylaluminum (22 mg, 0.29 mmol) was added. The reaction was stirred at 100 Celsius for 10 hours. LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine (20 mL x 2) first, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 10 mg of (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridin-6-yl)-6-fluoro-5-methyl-8-(tetrahydro-1 H-furan[3,4-c]pyrrol-5(3H)-yl)-2,3- dihydrobenzo[b][1,4]oxazepine -3-yl)amino)ethyl)-1 H-pyrazole-3-carboxylate (65 mg) was obtained.

[0577] MS (ESI) M / Z: 612.2 [M+H] + .

[0578] Step B: 1 -benzyl-5-chloro-4-(2-(((3S)-6-fluoro-5-methyl-4-oxo-8-(tetrahydro-1 H- furan[3,4-c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-5- yl)amino)ethyl)-1 H-pyrazole-3-carboxylate (60 mg, 0.10 mmol) was dissolved in toluene (6 mL) at room temperature, trimethylaluminum (22 mg, 0.29 mmol) was added. The reaction was stirred at 100 Celsius for 10 hours. LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine (20 mL x 2) first, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to give 10 mg of (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4- c]pyridin-6-yl)-6-fluoro-5-methyl-8-(tetrahydro-1 H-furan[3,4-c]pyrrol-5(3H)-yl)-2,3- dihydrobenzo[b][1,4]oxazepine -3-yl)amino)ethyl)-1 H-pyrazole-3-carboxylate (65 mg) was obtained. ​-4(5H)-ketone (Compound 45)

[0579] MS (ESI) M / Z: 566.2 [M+H] + .

[0580] 1 H NMR (400 MHz, CDC13) δ 7.33 - 7.24 (m, 5H), 6.24 - 6.18 (m, 1H), 6.02 - 5.91 (m, 1H), 5.39 (s, 2H), 4.61 - 4.52 (m, 1H), 4.37 - 4.26 (m, 2H), 4.06 - 3.99 (m, 2H), 3.74 - 3.65 (m, 2H), 3.58 - 3.43 (m, 3H), 3.29 - 3.25 (m, 3H), 3.24 - 3.20 (m, 1H), 3.15 - 2.99 (m, 3H).

[0581] Example 46: 5-benzyl-N-((3S)-8-fluoro-5-methyl-4-oxo-7-(tetrahydro-lH-furo[3,4- c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-lH-l,2,4-triazole-3- carboxamide -3-yl)-lH-l,2,4-triazole-3-carboxamide

[0582]

[0583] Reaction Scheme:

[0584]

[0585] Procedure:

[0586] Step A: Sodium hydride (3.5 g, 88.6 mmol) was dissolved in N,N-dimethylformamide (20 mL), (tert-butoxycarbonyl)-L-serine (8.6 g, 42.2 mmol) was dissolved in N,N-dimethylformamide (40 mL), the sodium hydride solution was added dropwise at 0 degree Celsius, stirred until the foam disappeared, 1-bromo-2,4-difluoro-5-nitrobenzene (10 g, 42.2 mmol) was added dropwise at 0 degree Celsius, slowly raised to room temperature, and the reaction was continued for three hours.

[0587] After LCMS monitoring showed that the raw material disappeared, the reaction solution was poured into ice water, the PH was adjusted to 5-6 with 1M hydrochloric acid, extracted with ethyl acetate (30 mL) three times, washed with saturated brine five times, dried with anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. Purified by silica gel column chromatography to obtain O-(4-bromo-5-fluoro-2-nitrophenyl)-N-(tert-butoxycarbonyl)-L-serine (5 g).

[0588] MS (ESI) M / Z: 444.9 [M+Na] + .

[0589] Step B: Dissolve O-(4-bromo-5-fluoro-2-nitrophenyl)-N-(tert-butoxycarbonyl)-L-serine (5.0 g, 11.8 mmol) in ethanol (50 mL) and water (10 mL), add ammonium chloride (3.1 g, 59.0 mmol) and iron powder (3.2 g, 59.0 mmol), and stir the reaction at 60 °C for 16 hours.

[0590] After LCMS monitoring showed the disappearance of the starting material, the solid was filtered off and the mother liquor was extracted three times with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give O-(2-amino-4-bromo-5-fluorobenzene)-N-(tert-butyloxycarbonyl)-L-serine (3 g). No further purification was required and the next step was carried out directly.

[0591] MS (ESI) M / Z: 415.0 [M+Na] + .

[0592] Step C: Dissolve O-(2-amino-4-bromo-5-fluorobenzene)-N-(tert-butoxycarbonyl)-L-serine (3 g, 7.7 mmol) in dimethyl sulfoxide, add N,N-diisopropylethylamine (1.5 g, 11.55 mmol), and add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.2 g, 8.5 mmol) in batches and stir at room temperature for 3 hours.

[0593] The reaction was complete after LCMS detection. The reaction solution was poured into ice water to precipitate solids, which were filtered and washed twice with water. The filter residue was collected and dried by distillation under reduced pressure to obtain (S)-(7-bromo-8-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine) -3-yl)carbamic acid tert-butyl ester (400 mg).

[0594] MS (ESI) M / Z: 397.0 [M+Na] + .

[0595] Step D: (S)-(7-bromo-8-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine Tert-butyl 1,3-dimethyl-3-yl)carbamate (400 mg, 1.1 mmol) was dissolved in N,N-dimethylformamide, cesium carbonate (1.1 g, 3.3 mmol) was added, iodomethane (156.2 mg, 1.1 mmol) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 16 hours.

[0596] LCMS showed the reaction was complete, the reaction solution was poured into ice water, solid was precipitated, filtered, the filter residue was washed with water twice, the filter residue was collected, the filter residue was dried under reduced pressure, to obtain (S)-(7-bromo-8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-2-yl)(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone tert-butyl carbamate (150 mg). tert-butyl (S)-(7-bromo-8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-2-yl)(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone (150 mg, 0.39 mmol), (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (44 mg, 0.39 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (42 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol) and sodium carbonate (127 mg, 1.2 mmol) were dissolved in tert-butanol / water (10:1, 1 mL), replaced with nitrogen, and the tube was sealed and stirred at 120 degrees Celsius for 16 hours.

[0597] MS (ESI) M / Z: 411.0 [M+Na] + .

[0598] tert-butyl (S)-(7-bromo-8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-2-yl)(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone (150 mg, 0.39 mmol), (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (44 mg, 0.39 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (42 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol) and sodium carbonate (127 mg, 1.2 mmol) were dissolved in tert-butanol / water (10:1, 1 mL), replaced with nitrogen, and the tube was sealed and stirred at 120 degrees Celsius for 16 hours. LCMS showed the reaction was complete, the reaction solution was poured into ice water, solid was precipitated, filtered, the filter residue was washed with water twice, the filter residue was collected, the filter residue was dried under reduced pressure, to obtain (S)-(7-bromo-8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-2-yl)(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone tert-butyl carbamate (150 mg).

[0599] tert-butyl (S)-(7-bromo-8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-2-yl)(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone (150 mg, 0.39 mmol), (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (44 mg, 0.39 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (42 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol) and sodium carbonate (127 mg, 1.2 mmol) were dissolved in tert-butanol / water (10:1, 1 mL), replaced with nitrogen, and the tube was sealed and stirred at 120 degrees Celsius for 16 hours. MS (ESI) M / Z: 411.0 [M+Na] + .

[0600] tert-butyl (S)-(7-bromo-8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-2-yl)(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone (150 mg, 0.39 mmol), (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (44 mg, 0.39 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (42 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol) and sodium carbonate (127 mg, 1.2 mmol) were dissolved in tert-butanol / water (10:1, 1 mL), replaced with nitrogen, and the tube was sealed and stirred at 120 degrees Celsius for 16 hours.

[0601] tert-butyl (S)-(7-bromo-8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-2-yl)(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methanone (150 mg, 0.39 mmol), (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole (44 mg, 0.39 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-I-propyl-11'-biphenyl (42 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol) and sodium carbonate (127 mg, 1.2 mmol) were dissolved in tert-butanol / water (10:1, 1 mL), replaced with nitrogen, and the tube was sealed and stirred at 120 degrees Celsius for 16 hours.

[0602] ​LCMS detected that the reaction was complete, and the solvent was distilled off under reduced pressure to obtain (S)-3-amino-8-fluoro-5-methyl-7-((3aR, 6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxazepine -4(5H)-one (30 mg).

[0603] MS (ESI) M / Z: 322.1 [M+H] + .

[0604] Step G: (S)-3-amino-8-fluoro-5-methyl-7-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxazepine -4(5H)-one (30 mg, 0.09 mmol), 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (19.0 mg, 0.09 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39.2 mg, 0.14 mmol) and methylimidazole (14.8 mmol, 0.18 mmol) were dissolved in acetonitrile (5 mL) and stirred at room temperature for 1 hour.

[0605] After LCMS monitoring showed the disappearance of the starting material, the solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative high performance liquid chromatography to obtain 9 mg of the final product, 5-benzyl-N-((3S)-8-fluoro-5-methyl-4-oxo-7-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-1H-1,2,4-triazole-3-carboxamide (Compound 46).

[0606] MS (ESI) M / Z: 507.2 [M+H] +

[0607] 1H NMR (400 MHz, MeOD) δ 7.45-7.25 (m, 5H), 7.19 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 12.4 Hz, 1H), 5.09-4.99 (m, 1H), 4.64-4.55 (m, 1H), 4.47 (t, J = 10.4 Hz, 1H), 4.34-4.19 (m, 2H), 3.94-3.84 (m, 2H), 3.80-3.75 (m, 2H), 3.69-3.64 (m, 2H), 3.42 (s, 3H), 3.25-3.05 (m, 2H), 3.03-3.01 (m, 1H), 2.91-2.87 (m, 1H).

[0608] Example 47: (S)-5-benzyl-N-(5-methyl-7-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4- d]oxazol-5-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-1,2,4- triazole-3-carboxamide -3-yl)-1 H-1,2,4-triazole-3-carboxamide

[0609]

[0610] Reaction Scheme:

[0611]

[0612] Procedure:

[0613] Step A: tert-Butyl 3-amino-4-hydroxypyrrolidine-1 -carboxylate (7 g, 0.03 mol) was dissolved in dichloromethane (40 mL) solution at -20 °C, acetyl chloride (3 g, 0.04 mol) and triethylamine (4 g, 0.04 mol) were added. The reaction system was stirred at -20 °C for 2 hours. LCMS showed that the reaction was completed. The mixture was extracted with dichloromethane (30 mL x 3), the organic phase was washed with saturated brine (20 mL x 2) first, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product tert-butyl 3-acetylamino-4-hydroxypyrrolidine-1 -carboxylate (6 g).

[0614] MS (ESI) M / Z: 267.1 [M+Na] + .

[0615] Step B: tert-Butyl 3-acetylamino-4-hydroxypyrrolidine-l-carboxylate (6 g, 0.02 mol) was dissolved in dichloromethane (40 mL) at room temperature, and Dess-Martin Oxidizing Reagent (16 g, 0.03 mol) was added. The reaction system was stirred at room temperature for 12 hours. LCMS showed that the reaction was completed. The mixture was extracted with dichloromethane (30 mL x 3), and the combined organic phase was washed with saturated brine (20 mL x 2) first, and then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product tert-butyl 3-acetylamino-4-oxopyrrolidine-l-carboxylate (4 g).

[0616] MS (ESI) M / Z: 243.3 [M+H] + .

[0617] Step C: tert-Butyl 3-acetylamino-4-oxopyrrolidine-l-carboxylate (800 mg, 3.30 mmol) was dissolved in dichloromethane (30 mL) at room temperature, and triphenylphosphine (2.6 g, 9.91 mmol), hexachloroethane (2 g, 8.26 mmol) and triethylamine (2.7 g, 26.41 mmol) were added. The reaction system was stirred at room temperature for 2 days. LCMS showed that the reaction was completed. The mixture was extracted with dichloromethane (30 mL x 3), and the combined organic phase was washed with saturated brine (20 mL x 2) first, and then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product tert-butyl 2-methyl-4,6-dihydro-5H-pyrrolo[3,4-c]oxazole-l-carboxylate (200 mg).

[0618] MS (ESI) M / Z: 225.1 [M+H] + .

[0619] Step D: tert-Butyl 2-methyl-4,6-dihydro-5H-pyrrolo[3,4-c]oxazole-l-carboxylate (800 mg, 0.89 mmol) was dissolved in 1,4-dioxane / hydrochloric acid (6 mL) at room temperature. The reaction system was stirred at room temperature for 2 hours. LCMS showed that the reaction was completed. The mixture was concentrated under reduced pressure to obtain the final product 2-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]oxazole hydrochloride (100 mg).

[0620] MS (ESI) M / Z: 125.2 [M+H] + .

[0621] Step E: tert-Butyl (S)-(5-methyl-7-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4- d]oxazol-5-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)carbamate (60 mg, 0.14 mmol) was dissolved in 1,4-dioxane / HCI (6 mL) at room temperature. The reaction was stirred at room temperature for 1 h. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give the product (S)-3-amino-5-methyl-7-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4- d]oxazol-5-yl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (40 mg). -3-yl)carbamate (116 mg, 0.31 mmol), Pd2dba3(29 mg, 0.03 mmol), brettphos (36 mg, 0.06 mmol) and sodium carbonate (304 mg, 0.93 mmol). The reaction was stirred at 120 degree Celsius for 12 h. LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2) first, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the product tert-butyl (S)-(5-methyl-7-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4- d]oxazol-5-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)carbamate (60 mg). -3-yl)carbamate (60 mg).

[0622] MS (ESI) M / Z: 437.2 [M+Na] + .

[0623] Step E: tert-Butyl (S)-(5-methyl-7-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4- d]oxazol-5-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)carbamate (60 mg, 0.14 mmol) was dissolved in 1,4-dioxane / HCI (6 mL) at room temperature. The reaction was stirred at room temperature for 1 h. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give the product (S)-3-amino-5-methyl-7-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4- d]oxazol-5-yl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (40 mg). -3-yl)carbamate (60 mg, 0.14 mmol) was dissolved in 1,4-dioxane / HCI (6 mL) at room temperature. The reaction was stirred at room temperature for 1 h. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give the product (S)-3-amino-5-methyl-7-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4- d]oxazol-5-yl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (40 mg). -3-yl)carbamate (60 mg, 0.14 mmol) was dissolved in 1,4-dioxane / HCI (6 mL) at room temperature. The reaction was stirred at room temperature for 1 h. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give the product (S)-3-amino-5-methyl-7-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4- d]oxazol-5-yl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (40 mg).

[0624] MS (ESI) M / Z: 315.1 [M+H] + .

[0625] Step E: tert-Butyl (S)-(5-methyl-7-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4- d]oxazol-5-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)carbamate (60 mg, 0.14 mmol) was dissolved in 1,4-dioxane / HCI (6 mL) at room temperature. The reaction was stirred at room temperature for 1 h. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give the product (S)-3-amino-5-methyl-7-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4- d]oxazol-5-yl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (40 mg). -4(5H)-ketone (40 mg, 0.13 mmol) was dissolved in acetonitrile (5 mL), 5-benzyl-1,2,4-triazole-3-carboxylic acid (26 mg, 0.13 mmol), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (54 mg, 0.19 mmol), N-methylimidazole (26 mg, 0.32 mmol) were added. The reaction system was stirred at room temperature for 2 hours. LCMS showed that the reaction was completed. The mixture was extracted with ethyl acetate (20 mL x 3), the organic phase was combined, first washed with saturated brine (20 mL x 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. 6 mg of the final product (S)-5-benzyl-N-(5-methyl-7-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]oxazol-5-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (Compound 47) was obtained. -3-yl)-1H-1,2,4-triazole-3-carboxamide (Compound 47).

[0626] MS (ESI) M / Z: 500.2 [M+H] + .

[0627] 1 H NMR (400 MHz, DMSO-d6) δ 7.22-7.18 (m, 4H), 7.11-7.07 (m, 2H), 6.64 (d, J = 2.8 Hz, 1H), 6.49 (dd, J = 8.8, 2.8 Hz, 1H), 4.83-4.77 (m, 1H), 4.48-4.44 (m, 1H), 4.30-4.24 (m, 3H), 3.90 (s, 2H), 3.37-3.35 (m, 2H), 2.46 (s, 3H), 1.20 (s, 3H).

[0628] Example 48: (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxazepine -4(5H)-ketone

[0629]

[0630] Reaction Scheme:

[0631]

[0632] Procedure:

[0633] Step A: 1-benzyl-5-chloro-4-(2-oxoethyl)pyrazole-3-carboxylic acid ethyl ester (40 mg, 0.13 mmol) was dissolved in dichloroethane (6 mL) at room temperature, and (3S)-3-amino-5-methyl-8-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxazepine was added. -4(5H)-one (40 mg, 0.13 mmol), the reaction system was stirred at room temperature for 1 hour, and sodium acetate borohydride (138 mg, 0.65 mmol) was added. The reaction system was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The mixed solution was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The organic phase was first washed with saturated brine (20 mL×2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product 1-benzyl-5-chloro-4-(2-(((3S)5-methyl-4-oxo-8-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (60 mg).

[0634] MS (ESI) M / Z: 594.2 [M+H] + .

[0635] Step B: 1-benzyl-5-chloro-4-(2-(((3S)5-methyl-4-oxo-8-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester (50 mg, 0.08 mmol) was dissolved in tetrahydrofuran (2 mL) and water (0.2 mL) solution, and lithium hydroxide (2 mg, 0.08 mmol) was added. The reaction system was stirred at room temperature for 10 hours. LCMS showed that the reaction was complete. The mixed solution was acidified by adding hydrochloric acid and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product 1-benzyl-5-chloro-4-(2-(((3S)-5-methyl-4-oxo-8-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid (40 mg).

[0636] MS (ESI) M / Z: 566.2 [M+H]+ .

[0637] Step C: 1-benzyl-5-chloro-4-(2-(((3S)-5-methyl-4-oxo-8-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine (-3-yl)amino)ethyl)-1H-pyrazole-3-carboxylic acid (40 mg, 0.07 mmol) was dissolved in DMF (6 mL), and HATU (40 mg, 0.11 mmol) and DIEA (27 mg, 0.21 mmol) were added. The reaction system was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixed solution was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and washed with saturated brine (20 mL × 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography. 8 mg of the product (3S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-8-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-2,3-dihydrobenzo[b][1,4]oxazepine was obtained. -4(5H)-one (Compound 48).

[0638] MS (ESI) M / Z: 548.2 [M+H] + .

[0639] 1 H NMR(400MHz,DMSO-d6)δ8.47(s,1H),7.38–7.28(m,3H),7.21–7.16(m,2H),6.95– 6.88(m,1H),6.33–6.26(m,2H),5.38(s,2H),3.85–3.77(m,2H),3.70(t,J=6.4Hz, 2H),3.51(dd,J=8.8,3.2Hz,2H),3.27(dd,J=9.6,7.6Hz,3H),3.21(s,3H),3.08(d ,J=9.7Hz,2H),2.99–2.92(m,J=7.4Hz,2H),2.74–2.65(m,1H),2.48–2.41(m,1H).

[0640] Example 50: (S)-5-Benzyl-N-(6-fluoro-5-methyl-8-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-1H-1,2,4-triazole-3-carboxamide

[0641]

[0642] Reaction route:

[0643]

[0644] Steps:

[0645] Step A: At room temperature, tert-butyl (S)-(8-bromo-6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine A solution of 2-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (139.2 mg, 1.1 mmol), tris(dibenzylidene-BASE acetone)dipalladium (94.1 mg, 0.1 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (118.9 mg, 0.2 mmol), and cesium carbonate (1.0 g, 3.1 mmol) was dissolved in 1,4-dioxane (20 mL). The reaction system was stirred at 100°C for 12 hours.

[0646] After LCMS monitoring showed that the starting material disappeared, the mixed solution was extracted with ethyl acetate (3×50 mL), and the organic phases were combined, washed with saturated brine (2×50 mL), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column to obtain the final product, tert-butyl (S)-(6-fluoro-5-methyl-8-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)carbamate (200.0 mg).

[0647] MS (ESI) M / Z: 454.1 [M+Na] + .

[0648] Step B: Tert-butyl (S)-(6-fluoro-5-methyl-8-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine 1,4-dioxane (10 mL) was dissolved in a solution of hydrochloric acid in 1,4-dioxane and the reaction system was stirred at room temperature for 1 hour.

[0649] After LCMS monitoring showed that the starting material disappeared, the reaction solution was concentrated to obtain the crude product (S)-3-amino-6-fluoro-5-methyl-8-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2,3-dihydrobenzo[b][1,4]oxazepine -4(5H)-one (100.0 mg).

[0650] MS (ESI) M / Z: 332.1 [M+H] + .

[0651] Step C: (S)-3-amino-6-fluoro-5-methyl-8-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2,3-dihydrobenzo[b][1,4]oxazepine 4-(5H)-one (50.0 mg, 0.15 mmol) and 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (36.8 mg, 0.18 mmol) were dissolved in acetonitrile (10 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (63.5 mg, 0.22 mmol) and N-methylimidazole (24.8 mg, 0.3 mmol) were added. The reaction system was stirred at room temperature for 1 hour.

[0652] After LCMS monitoring showed the disappearance of the starting material, the reaction solution was directly concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 13.26 mg of (S)-5-benzyl-N-(6-fluoro-5-methyl-8-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-1H-1,2,4-triazole-3-carboxamide (Compound 50).

[0653] MS (ESI) M / Z: 517.2 [M+H] + .

[0654] 1 H NMR (400MHz, DMSO-d6) δ8.29(d,J=7.6Hz,1H),7.59(s,1H),7.32-7.19(m,6H),6.52(dd,J=14.0,2.4Hz,1H),6.38(d,J =1.6Hz,1H),4.96-4.90(m,1H),4.52-4.46(m,1H),4.40-4.33(m,5H),4.07(s,2H),3.85(s,3H),3.18(d,J=1.6Hz,3H).

[0655] Example 51: (S)-1 -benzyl-N-(6-fluoro-5-methyl-8-(2-methyl-2,6-dihydro pyrrolo[3,4- c]pyrazol-5(4H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-1,2,4- triazole-3-carboxamide -3-yl)-1 H-1,2,4-triazole-3-carboxamide

[0656]

[0657] Referring to the synthetic procedure of Example 50, 10.37 mg of (S)-1 -benzyl-N-(6-fluoro-5- methyl-8-(2-methyl-2,6-dihydro pyrrolo[3,4-c]pyrazol-5(4H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-1,2,4-triazole-3-carboxamide (Compound 51) was obtained. -3-yl)-1 H-1,2,4-triazole-3-carboxamide

[0658] MS (ESI) M / Z: 517.2 [M+H] + .

[0659] 1 H NMR (400 MHz, CDC13) δ 8.09 (d, J = 7.2 Hz, 1H), 8.01 (s, 1H), 7.39-7.36 (m, 3H), 7.30-7.27 (m, 2H), 7.22 (s, 1H), 6.25-6.21 (m, 2H), 5.38 (s, 2H), 5.20-5.14 (m, 1H), 4.78-4.74 (m, 1H), 4.45-4.41 (m, 4H), 4.24-4.19 (m, 1H), 3.98 (s, 3H), 3.34 (d, J = 1.6 Hz, 3H).

[0660] Example 52: (S)-5-benzyl-N-(8-chloro-5-methyl-7-(2-methyl-2,6-dihydro pyrrolo[3,4- c]pyrazol-5(4H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-1,2,4-triazole-3- carboxamide -3-yl)-1 H-1,2,4-triazole-3-carboxamide

[0661]

[0662] Scheme:

[0663]

[0664] Procedure:

[0665] Step A: (tert-Butoxycarbonyl)-L-serine (4 g, 0.02 mol) was dissolved in DMF (40 mL) solution at 0 degree Celsius, 60% sodium hydride (1.7 g, 0.04 mol) was added. The reaction system was stirred at 0 degree Celsius for half an hour. 2-chloro-4-fluoro-5-nitro bromobenzene (5 g, 0.02 mmol) was dissolved in DMF (10 mL) solution and added to the reaction system. The reaction system was stirred at 0 degree Celsius for two hours. LCMS showed that the reaction was completed. 1N hydrochloric acid was added to the mixture to adjust pH = 3-4, the mixture was extracted with ethyl acetate (50 mL x 3), the organic phase was combined, the organic phase was first washed with saturated brine (50 mL x 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the final product 4-bromo-5-chloro-2-nitrophenyl-N-tert-butoxycarbonyl-L-serine (5 g).

[0666] MS (ESI) M / Z: 461.0 [M+Na] + .

[0667] Step B: 4-bromo-5-chloro-2-nitrophenyl-N-tert-butoxycarbonyl-L-serine (5 g, 0.01 mol) was dissolved in a mixture of THF (20 mL), ethanol (20 mL) and water (10 mL) at room temperature, iron powder (3 g, 0.05 mol) and ammonium chloride (3 g, 0.05 mmol) were added. The reaction system was stirred at 60 degree Celsius for 12 hours. LCMS showed that the reaction was completed. The mixture was filtered with diatomite, the filtrate was extracted with ethyl acetate (50 mL x 3), the organic phase was combined, the organic phase was first washed with saturated brine (50 mL x 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the final product O-(2-amino-4-bromo-5-chlorophenyl)-N-tert-butoxycarbonyl-L-serine (4 g).

[0668] MS (ESI) M / Z: 431.0 [M+Na] + .

[0669] Step C: O-(2-amino-4-bromo-5-chlorophenyl)-N-tert-butoxycarbonyl-L-serine (3 g, 7.3 mmol) was dissolved in DMSO (50 mL) solution at room temperature, HATU (4 g, 10.95 mmol) and DIEA (3 g, 21.9 mmol) were added. The reaction system was stirred at room temperature for 2 hours. LCMS showed that the reaction was completed. The mixture was extracted with ethyl acetate (30 mL x 3), the organic phase was combined, the organic phase was first washed with saturated brine (30 mL x 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the final product tert-butyl-(7-bromo-8-chloro-4-oxo-2,3,4,5-tetrahydrobenzoxazepin-2-yl)carbamate (3 g). -3-yl)carbamate (2.5 g).

[0670] MS (ESI) M / Z: 413.0 [M+Na] + .

[0671] Step D: At room temperature, tert-butyl-(7-bromo-8-chloro-4-oxo-2,3,4,5-tetrahydrobenzoxazepine) -3-yl) carbamate (2.5 g, 6.4 mmol) was dissolved in DMF (20 mL) solution, and iodomethane (2 g, 12.8 mmol) and potassium carbonate (2.6 g, 19.2 mmol) were added. The reaction system was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixed solution was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was first washed with saturated brine (30 mL × 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the final product tert-butyl-(7-bromo-8-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzoxazine) -3-yl)carbamate (0.5 g).

[0672] MS (ESI) M / Z: 427.0 [M+Na] + .

[0673] Step E: At room temperature, tert-butyl-(7-bromo-8-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzoxazepine) A mixture of 2-methyl-2,4,5,6-tetrahydropyrrolopyrazole (100 mg, 0.81 mmol), 2-methyl-3-hydroxy-1,4-dihydropyrrolopyrazole (300 mg, 0.74 mmol) was dissolved in tert-butanol (10 mL) and water (1 mL). 2-Methyl-2,4,5,6-tetrahydropyrrolopyrazole (100 mg, 0.81 mmol), Pd2(dba)3 (67 mg, 0.07 mmol), brettphos (79 mg, 0.15 mmol), and sodium carbonate (235 g, 2.22 mmol) were added. The reaction was stirred at 120°C for 12 hours. LCMS indicated the reaction was complete. The mixed solution was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was first washed with saturated brine (30 mL × 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the final product tert-butyl-(8-chloro-5-methyl-7-(2-methyl-2,6-dihydropyrrolopyrazol-5-yl)-4-oxo-2,3,4,5-tetrahydrobenzoxazine -3-yl)carbamate (40 mg).

[0674] MS (ESI) M / Z: 448.1 [M+H] + .

[0675] Step F: At room temperature, tert-butyl-(8-chloro-5-methyl-7-(2-methyl-2,6-dihydropyrrolopyrazol-5-yl)-4-oxo-2,3,4,5-tetrahydrobenzoxazepine -3-yl) carbamate (40 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL) solution, and trifluoroacetic acid (1.5 mL) was added. The reaction system was stirred at room temperature for 1 hour. LCMS showed that the reaction was complete. The mixed solution was extracted with ethyl acetate (5 mL x 3), and the organic phases were combined. The organic phase was first washed with saturated brine (5 mL x 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the final product 3-amino-8-chloro-5-methyl-7-(2-methyl-2,6-dihydropyrrolopyrazole-5-yl)-2,3-dihydrobenzoxazine. -4-ketone (30 mg).

[0676] MS (ESI) M / Z: 348.1 [M+H] + .

[0677] Step G: 3-amino-8-chloro-5-methyl-7-(2-methyl-2,6-dihydropyrrolopyrazol-5-yl)-2,3-dihydrobenzoxazepine was added at room temperature. -4-ketone (30 mg, 0.08 mmol) was dissolved in acetonitrile (5 mL) and 5-benzyl-1,2,4-triazole-3-carboxylic acid (18 mg, 0.08 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (36 mg, 0.13 mmol), and N-methylimidazole (18 mg, 0.22 mmol) were added. The reaction system was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete. The mixture was extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with saturated brine (10 mL x 2), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography. 4 mg of the final product (S)-5-benzyl-N-(8-chloro-5-methyl-7-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine was obtained. -3-yl)-1H-1,2,4-triazole-3-carboxamide (Compound 52)

[0678] MS (ESI) M / Z: 533.2 [M+H] + .

[0679] 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.33 (d, J = 7.2 Hz, 2H), 7.30 - 7.24 (m, 5H), 4.91 - 4.83 (m, 1H), 4.67 - 4.49 (m, 5H), 4.39 (dd, J = 9.6, 7.6 Hz, 1H), 4.14 (s, 2H), 3.85 (s, 3H), 3.34 (s, 3H).

[0680] Example 53: (S)-1 -benzyl-5-methyl-N-(5-methyl-7-(2-methyl-2,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-1,2,4- triazole-3-carboxamide

[0681]

[0682] Scheme:

[0683]

[0684] Procedure:

[0685] Step A: Methyl 1 -benzyl-5-bromo- 1 H- 1,2,4-triazole-3-carboxylate (100.0 mg, 0.3 mmol), 2,4,6-trimethyl- 1,3,5,2,4,6-trioxaborinine (84.8 mg, 0.7 mmol), potassium carbonate (140.0 mg, 1.0 mmol) and [1, 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium (49.4 mg, 0.07 mmol) were dissolved in 1,4-dioxane:water = 3:1 (4 mL) at room temperature. The reaction was stirred at 105 °C in a sealed tube for 6 h.

[0686] After LCMS monitoring showed the disappearance of the starting material, extraction was performed with dichloromethane (2 x 50 mL). The aqueous phase was combined, adjusted to pH = 5, and extracted with ethyl acetate (2 x 50 mL). After the organic phase was collected, it was dried over anhydrous sodium sulfate and concentrated to give the crude 1 -benzyl-5-methyl- 1 H- 1,2,4-triazole-3-carboxylic acid (60.0 mg).

[0687] MS (ESI) M / Z: 218.1 [M+H] + .

[0688] ​Step B: 1 -benzyl-5-methyl- 1H- 1,2,4-triazole-3-carboxylic acid (60.0 mg, 0.3 mmol) and 3-amino-5-methyl-7-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2,3- dihydrobenzo[b][l,4]oxazepine-4(5H)-one (86.5 mg, 0.3 mmol) were dissolved in acetonitrile (10 mL) and to this was added N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (116.2 mg, 0.4 mmol) and N-methylimidazole (45.4 mg, 0.5 mmol). The reaction was stirred at room temperature for 1 h. LCMS monitoring showed the disappearance of starting material after which the reaction was directly concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography. This resulted in 0.79 mg of the final product (S)-l-benzyl-5-methyl-N-(5-methyl-7-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-lH-l,2,4-triazole-3-carboxamide (Compound 53).

[0689] LCMS monitoring showed the disappearance of starting material after which the reaction was directly concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography. This resulted in 0.79 mg of the final product (S)-l-benzyl-5-methyl-N-(5-methyl-7-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-lH-l,2,4-triazole-3-carboxamide (Compound 53).

[0690] MS (ESI) M / Z: 513.2 [M+H] + .

[0691] 1 H NMR (400 MHz, CDC13) δ 8.02 (d, J = 7.2 Hz, 1H), 7.37 - 7.31 (m, 3H), 7.18 - 7.16 (m, 3H), 7.11 (d, J = 8.8 Hz, 1H), 6.47 (dd, J = 8.8, 2.8 Hz, 1H), 6.37 (d, J = 2.8 Hz, 1H), 5.33 (s, 2H), 5.16 - 5.10 (m, 1H), 4.74 - 4.70 (m, 1H), 4.46 - 4.37 (m, 4H), 4.20 - 4.15 (m, 1H), 3.95 (s, 3H), 3.47 (s, 3H), 2.39 (s, 3H).

[0692] Example 54: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(2-(trifluoromethyl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)- lH-l,2,4-triazole-3-carboxamide -3-yl)-lH-l,2,4-triazole-3-carboxamide

[0693] ​

[0694] Reaction Scheme:

[0695]

[0696] Procedure:

[0697] Step A: 2,6-Dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester (4.6 g, 0.02 mol) was dissolved in N,N-dimethylformamide (80 mL), after adding sodium hydride (1.06 g, 0.04 mol) and stirring for 30 minutes in ice bath, then adding dibromodifluoromethane (13.85 g, 0.07 mol), the mixture was stirred for 3 hours at 25 degrees Celsius.

[0698] After LCMS monitoring showed that the starting material was consumed, water (30 mL) was added to the mixture, and it was extracted with dichloromethane (2 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 2-(bromodifluoromethyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester (2A) and 1-(bromodifluoromethyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylic acid tert-butyl ester (2B) and 3-(bromodifluoromethyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester (2C) (3.12 g). (Note: the following steps are taken as an example of 54-2A, and the other steps are the same)

[0699] MS (ESI) M / Z: 338.0 [M+H] + .

[0700] Step B: 2-(Bromodifluoromethyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester (2.0 g, 5.9 mmol) obtained after purification was dissolved in dichloromethane (30 mL) and replaced with nitrogen three times, then silver tetrafluoroborate (2.95 g, 15.2 mmol) was added at minus 78 degrees Celsius, and the mixture was stirred for 4 hours at 25 degrees Celsius.

[0701] After LCMS monitoring showed that the starting material was consumed, water (30 mL) was added to the mixture, and it was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 2-(trifluoromethyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester (230.0 mg).

[0702] MS (ESI) M / Z: 278.1 [M+H] + .

[0703] Step C: 2-(trifluoromethyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylic acid tert-butyl ester (230.0 mg, 0.8 mmol) was dissolved in hydrochloric acid solution in 1,4 dioxane (10 mL), the mixture was stirred at 25 degree Celsius for 30 minutes.

[0704] LCMS monitoring showed the starting material was consumed, the mixture was directly concentrated to give 2-(trifluoromethyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (230.0 mg).

[0705] MS (ESI) M / Z: 178.1 [M+H] + .

[0706] Step D: 2-(trifluoromethyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (230.0 mg, 1.3 mmol) was dissolved in 1,4 dioxane, tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (480.6 mg, 1.3 mmol), tris(dibenzylideneacetone)dipalladium (118.2 mg, 0.1 mmol), Xantphos (149.4 mg, 0.3 mmol) and cesium carbonate (1262.1 mg, 3.9 mmol) were added, the mixture was stirred at 100 degree Celsius for 16 hours.

[0707] LCMS monitoring showed the starting material was consumed, water (30 mL) was added to the mixture, extracted with dichloromethane (2 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel to give tert-butyl (S)-(5-methyl-4-oxo-7-(2-(trifluoromethyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (210.0 mg).

[0708] MS (ESI) M / Z: 490.1 [M+Na] + .

[0709] Step E: tert-butyl (S)-(5-methyl-4-oxo-7-(2-(trifluoromethyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (210.0 mg, 0.4 mmol) was dissolved in hydrochloric acid solution in 1,4 dioxane (8 mL), the mixture was stirred at 25 degree Celsius for 30 minutes. ​

[0710] LCMS monitoring showed the disappearance of the starting material, after which direct concentration gave (S)-3-amino-5-methyl-7-(2-(trifluoromethyl)-2,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one -4(5H)-ketone (210.0 mg).

[0711] MS (ESI) M / Z: 368.1 [M+H] + .

[0712] Step F: (S)-3-amino-5-methyl-7-(2-(trifluoromethyl)-2,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (210.0 mg, 0.6 mmol) was dissolved in acetonitrile (15 ml), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (210.0 mg, 0.6 mmol) and N-methylimidazole (93.6 mg, 1.1 mmol) were added and the mixture was stirred at 25 degrees Celsius for 30 minutes.

[0713] The residue obtained was directly concentrated and purified by preparative high performance liquid chromatography. This gave 48.16 mg of the final product (S)-5-benzyl-N-(5-methyl-4-oxo-7-(2-(trifluoromethyl)-2,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-7-yl)-lH-l,2,4-triazole-3- carboxamide (Compound 54). -3-yl)-lH-l,2,4-triazole-3-carboxamide (Compound 54).

[0714] MS (ESI) M / Z: 553.2 [M+H] + .

[0715] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 - 7.87 (m, 1H), 7.33 - 7.23 (m, 6H), 7.15 - 7.10 (m, 1H), 6.78 - 6.68 (m, 1H), 6.64 - 6.50 (m, 1H), 4.89 - 4.82 (m, 1H), 4.72 (s, 1H), 4.50 - 4.29 (m, 3H), 4.34 - 4.29 (m, 1H), 4.12 (s, 2H), 3.87 (s, 1H), 3.35 (d, J = 2.4 Hz, 3H).

[0716] Example 55: (S)-N-(7-(4H-furo[3,4-c]pyrazol-2(6H)-yl)-5-methyl-4-oxo-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide -3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide

[0717]

[0718] Reaction Scheme:

[0719]

[0720] Procedure:

[0721] Step A: Dissolve dihydrofuran-3(2H)-one (2 g, 23.2 mmol) in N,N-dimethylformamide dimethyl acetal (30 mL) and stir at 110 degree Celsius for three hours.

[0722] After LCMS monitoring showed the disappearance of the starting material, the solvent was concentrated under reduced pressure to give (Z)-4-((dimethylamino)methylene)dihydrofuran-3(2H)-one (1.5 g), which was used directly in the next step without further purification.

[0723] MS (ESI) M / Z: 142.2 [M+H] + .

[0724] Step B: Dissolve (Z)-4-((dimethylamino)methylene)dihydrofuran-3(2H)-one (1.5 g, 10.64 mmol), hydrazine hydrochloride (801.6 mg, 11.7 mmol) in acetic acid (40 ml) and stir the reaction solution at room temperature for 48 hours.

[0725] After LCMS monitoring showed the disappearance of the starting material, the solvent was concentrated under reduced pressure, dissolved with dichloromethane, washed with saturated brine twice, dried with anhydrous sodium sulfate, filtered and concentrated to give a crude product. Purify the crude product by silica gel column chromatography to give 2,6-dihydro-4H-furo[3,4-c]pyrazole (900 mg).

[0726] MS (ESI) M / Z: 111.1 [M+H] + .

[0727] Step C: Dissolve 2,6-dihydro-4H-furo[3,4-c]pyrazole (150.0 mg, 1.36 mmol), tert-butyl (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-carbamic acid pinacol ester (400.0 mg, 1.36 mmol) in N,N-dimethylformamide (10 mL) in a microwave tube and heat the reaction solution to 120 degree Celsius for 1 hour. -3-yl)carbamate (457.5 mg, 1.24 mmol), cuprous iodide (25.8 mg, 0.136 mmol), potassium carbonate (563.0 mg, 4.08 mmol) and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (38.6 mg, 0.27 mmol) were dissolved in dioxane, replaced by nitrogen, reacted in a microwave reactor, stirred at 110 degrees Celsius for 5 hours.

[0728] LCMS detected that the reaction was complete, the reaction solution was quenched with water, washed with methanol twice, the solvent was removed by reduced pressure distillation, and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 10) to obtain tert-butyl (S)-(7-(4H-furo[3,4-c]pyrazol-2(6H)-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (457.5 mg, 1.24 mmol), cuprous iodide (25.8 mg, 0.136 mmol), potassium carbonate (563.0 mg, 4.08 mmol) and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (38.6 mg, 0.27 mmol) were dissolved in dioxane, replaced by nitrogen, reacted in a microwave reactor, stirred at 110 degrees Celsius for 5 hours. -3-yl)carbamate (150 mg, yellow oil, purity 100%, yield: 45.0%). 1-cyclobutyl-1H-pyrrolo[3,2-b]pyridin-3-amine (100 mg) was obtained.

[0729] MS (ESI) M / Z: 423.1 [M+Na] + .

[0730] Step D: tert-butyl (S)-(7-(4H-furo[3,4-c]pyrazol-2(6H)-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (150 mg, 0.38 mmol) was dissolved in a hydrochloric acid dioxane solution (10 mL) and stirred at room temperature for 3 hours.

[0731] LCMS detected that the reaction was complete, the solvent was evaporated, (S)-3-amino-7-(4H-furo[3,4-c]pyrazol-2(6H)-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (50 mg) was obtained.

[0732] MS (ESI) M / Z: 301.0 [M+H] + .

[0733] Step E: (S)-3-amino-7-(4H-furo[3,4-c]pyrazol-2(6H)-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (50 mg) was dissolved in a hydrochloric acid dioxane solution (10 mL) and stirred at room temperature for 3 hours. ​​-4(5H)-one (50 mg, 0.17 mmol), 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (40.6 mg, 0.20 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (71.4 mmol, 0.26 mmol) and methylimidazole (27.9 mg, 0.34 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 1 hour.

[0734] After LCMS monitoring showed the disappearance of the starting material, the solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative high performance liquid chromatography to obtain 5.79 mg of the final product (S)-N-(7-(4H-furo[3,4-c]pyrazol-2(6H)-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide (Compound 55).

[0735] MS (ESI) M / Z: 486.2 [M+H] +

[0736] 1 H NMR (400MHz, CDCl3) δ8.05(d,J=7.4Hz,1H),7.63-7.60(m,1H),7.40-7.33(m,2H),7.33-7.27(m,5H),7.10(dd,J=8.7,2.6Hz,1H),5.35( t,J=4.9Hz,1H),5.16(d,J=2.8Hz,2H),4.98(d,J=2.9Hz,2H),4.76(dd,J=9.8,7.3Hz,1H),4.33-4.26(m,1H),4.18(s,2H),3.49(s,3H).

[0737] Example 57: (S)-2-Benzyl-N-(5-methyl-7-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-2H-tetrazole-5-carboxamide

[0738]

[0739] Reaction route:

[0740]

[0741] Steps:

[0742] Step A: Ethyl 2H-tetrazole-5-carboxylate (2.0 g, 14.1 mmol), potassium carbonate (5.8 g, 42.3 mmol) and benzyl bromide (2.9 g, 16.9 mmol) were dissolved in N,N-dimethylformamide (50 ml) and the reaction mixture was stirred at room temperature for 16 hours.

[0743] After LCMS monitoring showed the disappearance of the starting material, water was added to the reaction solution to quench it, extracted three times with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by silica gel column chromatography to give ethyl 2-benzyl-2H-tetrazole-5-carboxylate (900 mg).

[0744] MS (ESI) M / Z: 233.1 [M+H] + .

[0745] Step B: Ethyl 2-benzyl-2H-tetrazole-5-carboxylate (200 mg, 0.9 mmol) and lithium hydroxide (62.1 mg, 2.6 mmol) were dissolved in tetrahydrofuran (10 mL) and water (1 mL), and the reaction solution was stirred at room temperature for 3 hours.

[0746] After LCMS monitoring showed the disappearance of the starting material, the pH was adjusted to 6-7 with dilute hydrochloric acid, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, and filtered to obtain 2-benzyl-2H-tetrazole-5-carboxylic acid (100 mg).

[0747] MS (ESI) M / Z: 205.1 [M+H] + .

[0748] Step C: (S)-3-amino-5-methyl-7-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-2,3-dihydrobenzo[b][1,4]oxazepine -4(5H)-one (75 mg, 0.24 mmol), 2-benzyl-2H-tetrazole-5-carboxylic acid (50 mg, 0.24 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (101 mg, 0.36 mmol), and methylimidazole (40 mg, 0.48 mmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature for 3 hours.

[0749] After LCMS monitoring showed the disappearance of the starting material, the solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative high performance liquid chromatography to obtain 6.45 mg of the final product (S)-2-benzyl-N-(5-methyl-7-(2-methyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-2H-tetrazole-5-carboxamide (Compound 58).

[0750] MS (ESI) M / Z: 500.3 [M+H] +

[0751] 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.43 - 7.37 (m, 5H), 7.09 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 2.8 Hz, 1H), 6.55 - 6.50 (m, 1H), 6.03 (s, 2H), 4.95 - 4.85 (m, 1H), 4.57 - 4.49 (m, 1H), 4.37 (s, 4H), 4.35 - 4.30 (m, 1H), 3.86 (s, 3H), 3.34 (s, 3H).

[0752] Example 59: N-(7-fluoro-2-oxo-8-((3aR,6aS)-tetrahydro-lH-furan[3,4-c]pyrrol-5(3H)-yl)- 2,3,4,5-tetrahydro-lH-benzo[6]azepin-3-yl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2- carboxamide

[0753]

[0754] Reaction Scheme:

[0755]

[0756] Procedure:

[0757] Step A: 7-bromo-6-fluoro-3,4-dihydro-2H-naphthalen-l-one (2200 mg, 9.1 mmol) was dissolved in ethanol (60 mL) and water (15 mL), sodium acetate (1113 mg, 13.58 mmol) and hydroxylamine hydrochloride (943 mg, 13.6 mmol) were added and the reaction mixture was stirred at room temperature for 10 h.

[0758] After LCMS monitoring showed the disappearance of starting material, it was concentrated under reduced pressure, water (50 mL) was added and it was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to get (E)-7-bromo-6-fluoro-3,4-dihydronaphthalen-l(2H)-hydroxylamine (2200 mg).

[0759] MS (ESI) M / Z: 500.3 [M+H] + .

[0760] Step B: (E)-7-bromo-6-fluoro-3,4-dihydronaphthalen-l(2H)-hydroximic acid p- toluenesulfonic acid salt (3000 mg, 7.27 mmol) was dissolved in trifluoroacetic acid (30 mL). The mixture was heated to 50 degree Celsius and stirred for 0.5 h.

[0761] After LCMS monitoring showed the disappearance of starting material, the reaction was diluted with dichloromethane (60 mL) and the organic phase was washed with water (2 x 50 mL), 5% citric acid and brine respectively. The extract was collected and dried over anhydrous sodium sulfate and concentrated to give the crude product (E)-7-bromo-6-fluoro-3,4-dihydronaphthalen-l(2H)-p- toluenesulfonyl hydroxime (3000 mg).

[0762] MS (ESI) M / Z: 412.0 [M+H] + .

[0763] Step C: (E)-7-bromo-6-fluoro-3,4-dihydronaphthalen-l(2H)-p-toluenesulfonyl hydroxime (3000 mg, 7.27 mmol) was dissolved in trifluoroacetic acid (30 mL). The mixture was heated to 50 degree Celsius and stirred for 0.5 h.

[0764] After LCMS monitoring showed the disappearance of starting material, the solvent was removed under reduced pressure, water (40 mL) was added and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product 8-bromo-7-fluoro-l,3,4,5-tetrahydro-2H- benzo[b]azepin-2-one (1800 mg). It was used directly for the next step without further purification.

[0765] MS (ESI) M / Z: 258.0 [M+H] + .

[0766] Step D: 8-bromo-7-fluoro-l,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (1600 mg, 6.19 mmol) was dissolved in dichloromethane (35 mL) and N,N,N',N'-tetramethyl ethylenediamine (1440 mg, 12.40 mmol) was added. Trimethylsilyl iodide (2480 mg, 12.40 mmol) was added dropwise slowly under ice bath, stirred for 1 h, then iodine (2360 mg, 9.30 mmol) was added and the mixture was stirred in ice bath for 1 h.

[0767] LCMS monitoring showed the starting material was consumed, saturated sodium thiosulfate solution was added and stirred for 15 minutes to quench the reaction. Water (40 mL) was added and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give the crude product 8-bromo-7-fluoro-3-iodo-1,3,4,5-tetrahydro-2H- benzo[b]azepin-2-one (2000 mg). No further purification was needed and it was used directly in the next step.

[0768] MS (ESI) M / Z: 384.1 [M+H] + .

[0769] Step E: 8-Bromo-7-fluoro-3-iodo-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (1500 mg, 3.9 mmol) was dissolved in N,N-dimethylformamide (20 mL), sodium azide (305 mg, 4.68 mmol) was added and the mixture was stirred at room temperature for 1 hour. Diluted with ice water (60 mL), solid precipitated out. Filtered, the filter cake was washed with ice water (20 mL), dried to give a white solid. The white solid was dissolved in tetrahydrofuran (20 mL), water (2 mL) and triphenylphosphine (1331 mg, 4.7 mmol) was added. The reaction was stirred at room temperature for 24 hours, concentrated under reduced pressure to give the crude product 3-amino-8-bromo-7-fluoro-1,3,4,5-tetrahydro-2H- benzo[b]azepin-2-one (1000 mg). No further purification was needed and it was used directly in the next step.

[0770] MS (ESI) M / Z: 273.1 [M+H] + .

[0771] Step F: A flask was charged with 3-amino-8-bromo-7-fluoro-1,3,4,5-tetrahydro-2H- benzo[b]azepin-2-one (1000 mg, 5.49 mmol) dissolved in tetrahydrofuran (40 mL), di-tert-butyl dicarbonate (1438 mg, 6.59 mmol) and triethylamine (832 mg, 8.24 mmol). The mixture was stirred at room temperature for 10 hours. LCMS showed the reaction was complete. The mixture was poured into ice water, solid precipitated out. The mixture was filtered, the filter cake was washed with ice water (10) mL and ethyl acetate (10) mL. The solid was dried under vacuum to give tert-butyl (8-bromo-7-fluoro-2-oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-yl)carbamate (1200 mg)

[0772] MS (ESI) M / Z: 395.1 [M+Na] + .

[0773] Step G: tert-Butyl (8-bromo-7-fluoro-2-oxo-2,3,4,5-tetrahydro-lH- benzo[6]azepin-3-yl)carbamate (350 mg, 0.9 mmol) and (3aR,6aS)-hexahydro-lH- furano[3,4-c]pyrrole hydrochloride (127 mg, 1.1 mmol) were dissolved in 1,4- dioxane (8 mL), and tris(dibenzylideneacetone)dipalladium (6 mg, 0.1 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (108 mg, 0.2 mmol) and cesium carbonate (914 mg, 2.8 mmol) were added, and the mixture was sparged with nitrogen three times. The mixture was stirred at 110 °C for 24 h under nitrogen.

[0774] After LCMS monitoring showed the disappearance of starting material, water (30 mL) was added and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography to give tert-butyl (7-fluoro-2-oxo-8-((3aR,6aS)-tetrahydro-lH-furano[3,4- c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydro-lH-benzo[6]azepin-3-yl)carbamate (300 mg).

[0775] MS (ESI) M / Z: 428.3 [M+Na] + .

[0776] Step H: tert-Butyl (7-fluoro-2-oxo-8-((3aR,6aS)-tetrahydro-lH-furano[3,4- c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydro-lH-benzo[6]azepin-3-yl)carbamate (100 mg, 0.25 mmol) was dissolved in hydrochloric acid dioxane (6 mL, 4 M HC1). The solution was stirred at 25 °C for 1 h.

[0777] After LCMS monitoring showed the disappearance of starting material, it was concentrated under reduced pressure to give 3-amino-7-fluoro-8-((3aR,6aS)-tetrahydro-lH- furano[3,4-c]pyrrol-5(3H)-yl)-l,3,4,5-tetrahydro-2H-benzo[6]azepin-2-one (70 mg).

[0778] MS (ESI) M / Z: 306.3 [M+H] + .

[0779] Step I: 3-amino-7-fluoro-8-((3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)-l,3,4,5- tetrahydro-2H-benzo[b]azepin-2-one (20 mg, 0.06 mmol) and 5-benzyl-lH-l,2,4-triazole-3- carboxylic acid (16 mg, 0.07 mmol) were dissolved in acetonitrile (5 mL). N,N,N',N'- tetramethylchloroformamidium hexafluorophosphate (28 mg, 0.1 mmol) and N-methylimidazole (16 mg, 0.2 mmol) were added. The reaction was stirred at 25 °C for 1 h.

[0780] After LCMS monitoring showed the disappearance of the starting material, it was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography. 15 mg of N-(7-fluoro-2-oxo-8-((3aR,6aS)-tetrahydro-lH-furo[3,4-c]pyrrol-5(3H)-yl)- 2,3,4,5-tetrahydro-lH-benzo[b]azepin-3-yl)-5-phenyl-[l,2,4]triazolo[l,5-a]pyridine-2- carboxamide (Compound 59) was obtained.

[0781] MS (ESI) M / Z: 527.1 [M+H] + .

[0782] 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.59 (d, J = 7.6 Hz, 1H), 8.00 - 7.94 (m, 3H), 7.90 - 7.84 (m, 1H), 7.61 - 7.57 (m, 3H), 7.47 (dd, J = 7.2, 1.2 Hz, 1H), 7.11 (d, J = 13.6 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 4.44 - 4.33 (m, 1H), 3.87 - 3.79 (m, 2H), 3.56 - 3.47 (m, 2H), 3.32 - 3.24 (m, 2H), 3.20 - 3.05 (m, 2H), 2.92 (s, 2H), 2.73 - 2.58 (m, 2H), 2.49 - 2.40 (m, 1H), 2.28 - 2.13 (m, 1H).

[0783] Example 60: (5S,7S)-7-fluoro-N-((S)-5-methyl-4-oxo-7-((3aR,6aS)-tetrahydro-lH-furo[3,4- c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)-5-phenyl-6,7-dihydro-5H- pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide -3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazole-2-carboxamide

[0784]

[0785] (5R,7R)-7-Fluoro-N-((S)-5-methyl-4-oxo-7-((3aR,6aS)-tetrahydro-1H-furan[3,4- c]pyrrol-5(3H)-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-phenyl-6,7- dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide -3-yl)-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxamide

[0786]

[0787] Reference Example 8 was purified by preparative high performance liquid chromatography. The purification conditions were as follows, column: Xbridge 5u C18 150 x 30 mm; mobile phase: water (containing 10 mmol / liter trifluoroacetic acid) and acetonitrile. 5 mg of compound 60-P1 (retention time 1.866 min) and 8 mg of compound 60-P2 (retention time 1.889 min) were obtained.

[0788] Compound 60-P1:

[0789] MS (ESI) M / Z: 533.2 [M+H] + .

[0790] 1 H NMR (400 MHz, DMSO-d6) 8.60 (d, J = 8.2 Hz, 1H), 7.45 - 7.36 (m, 3H), 7.24 (d, J = 6.8 Hz, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.8, 2.6 Hz, 1H), 6.30 - 6.15 (m, 1H), 5.71 - 5.65 (m, 1H), 4.86 - 4.76 (m, 1H), 4.52 - 4.44 (m, 1H), 4.30 - 4.24 (m, 1H), 3.88 - 3.84 (m, 2H), 3.77 - 3.72 (m, 1H), 3.56 - 3.50 (m, 2H), 3.38 - 3.32 (m, 2H), 3.29 (s, 3H), 3.23 - 3.18 (m, 2H), 3.00 (s, 2H), 2.75 - 2.64 (m, 1H).

[0791] Compound 60-P2:

[0792] MS (ESI) M / Z: 533.3 [M+H] + .

[0793] 1 H NMR(400MHz, DMSO-d6)δ8.62(d,J=8.2Hz,1H),7.46–7.35(m,3H),7.28–7.22(m,2H),7.03( d,J=8.6Hz,1H),6.69–6.64(m,1H),6.55–6.47(m,1H),6.32–6.12(m,1H),5.68(s,1H),4.8 0(s,1H),4.50(s,1H),4.30–4.25(m,1H),3.90–3.83(m,2H),3.80–3.68(m,1H),3.56–3.50 (m,2H),3.38–3.32(m,2H),3.29(s,3H),3.23–3.17(m,2H),2.99(s,2H),2.73–2.63(m,1H).

[0794] Example 63: N-((3S)-5-methyl-7-((3aR,8aR)-octahydropyrrolo[3,4-b]pyrrolopyrrolidin-2(1H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine -3-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0795]

[0796] Referring to the synthetic method of Example 8, 2.14 mg of N-((3S)-5-methyl-7-((3aR,8aR)-octahydropyrrolo[3,4-b]pyrrolopyrrolidin-2(1H)-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine was obtained. -3-yl)-5-phenyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (Compound 63).

[0797] MS (ESI) M / Z: 564.3 [M+H] + .

[0798] 1H NMR (400 MHz, CD3OD) δ 7.94 - 7.84 (m, 2H), 7.79 - 7.71 (m, 2H), 7.52 - 7.44 (m, 3H), 7.32 (dd, J = 5.2, 3.2 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.65 - 6.60 (m, 1H), 6.57 (dd, J = 8.8, 2.8 Hz, 1H), 4.95 (dd, J = 11.2, 7.6 Hz, 1H), 4.47 - 4.40 (m, 1H), 4.32 - 4.24 (m, 1H), 4.21 (s, 1H), 3.81 (d, J = 11.6 Hz, 1H), 3.57 - 3.46 (m, 1H), 3.40 - 3.34 (m, 2H), 3.32 (d, J = 1.2 Hz, 3H), 3.28 - 3.24 (m, 1H), 3.18 - 3.13 (m, 1H), 2.33 - 1.81 (m, 8H).

[0799] Biological in vitro enzyme activity experiment

[0800] In this experiment, ADP-Glo kinase activity detection method was used to test the inhibitory effect of the compound on RIPK1 kinase activity, and the half inhibitory concentration IC50 of the compound on RIPK1 kinase activity was obtained 50 .

[0801] Experimental materials

[0802] White 384-well microplate, purchased from Greiner Bio-one.

[0803] RIPK1 Enzyme System (containing assay buffer, substrate protein MBP, ATP, DTT, MnCl2) and ADP-Glo Kinase Assay, purchased from Promega Company.

[0804] Microplate reader (SPARK) microplate reader, purchased from TECAN Company.

[0805] 2. Experimental method

[0806] 1) Preparation of enzyme reaction Buffer: dilute the Buffer stock solution contained in the Kit with ddH2O, add DTT and MnCl2. Form enzyme reaction Buffer containing 0.05 mM DTT and 2 mM MnCl2.

[0807] 2) Dilution of RIPK1 enzyme: take GST-hRIPK1 (1-375) enzyme, dilute in enzyme reaction Buffer to form 5 ng / μL enzyme;

[0808] 3) Preparation of substrate / ATP mix: ddH2O dilution to make a mix containing 25 mM ATP and 0.25 mg / ml MBP;

[0809] 3) Preparation of enzyme reaction: 5 μL per well in a 384-well plate. The 5 μL reaction contains 2 μL of GST-hRIPK1 (1-375) enzyme, 2 μL of substrate protein MBP mixed with ATP, and 1 μL of test compound diluted in gradient (DMSO < 1%).

[0810] 5) After 1 h incubation at room temperature, 5 μL of ADP-Glo was added to each well and incubated for another 40 min at room temperature.

[0811] 6) Finally, 10 μL of kinase detection reagent was added to each well and incubated for 10 min at room temperature.

[0812] 7) The chemiluminescence signal of each well was detected by a microplate reader (SPARK) and the data was analyzed by GraphPad Prism software to get the IC 50 .

[0813] The results of the inhibition of kinase activity are shown in Table 1.

[0814] As can be seen from Table 1, the compounds of the present application have a good inhibitory effect on RIPK1 kinase.

[0815] Table 1: Results of enzymatic inhibition

[0816]

[0817]

[0818] Note: The IC50 of the compounds of the present application for the inhibition of RIPK1 activity 50 The data are shown in Table 1. Compounds with IC 50 ≤ 50 nM are identified by A, compounds with 50 < IC 50 ≤ 100 nM are identified by B, compounds with 100 < IC 50 ≤ 1000 nM are identified by C, and compounds with IC 50 > 1000 nM are identified by D.

[0819] Conclusion: As can be seen from Table 1, the compounds of the present application have a good inhibitory effect on RIPK1.

Claims

1. A compound and pharmaceutically acceptable salts selected from:

2. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of claim 2 in the preparation of a medicament for treating a RIPK1-mediated disease.

4. Use according to claim 3, characterized in that The related diseases mediated by the RIPK1 target are cell inflammatory diseases, neurodegenerative diseases, cancers.

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