A compound for inhibiting apoptosis of cells and a method for preparing the same

Abstract

Disclosed are a RIPK1 inhibitor for inhibiting cell programmed necrosis and a preparation method thereof. The RIPK1 inhibitor of the present application is shown in general formula I, wherein X, Y, Z, L, R 1 , R 2 , R 3 , R 4 , ring A, ring B and n are shown in the description and claims. The present application also discloses a preparation method of general formula I and test results of its inhibiting cell programmed necrosis and RIPK1 activity. The compound of general formula I described in the present application can be used for preparing a drug for treating and preventing inflammatory and degenerative diseases.

Description

Technical Field

[0001] This invention provides an inhibitor for inhibiting programmed cell death, specifically relating to its preparation method and methods and uses for treating and preventing inflammatory and degenerative diseases. Background Technology

[0002] Programmed cell death (PCD) is a highly inflammatory form of cell death that can be induced by various promoting factors, such as necrosis factor (TNF) and FAS ligand. This process can occur in a variety of cell types and is considered a major mode of cell death under pathological conditions, directly associated with a range of inflammatory and degenerative diseases. These diseases include neurodegenerative diseases, stroke, coronary artery disease, myocardial infarction, retinal degeneration, inflammatory bowel disease, kidney disease, liver disease, and many other related conditions.

[0003] RIPK1 (receptor-interacting protein kinase 1) participates in many key intracellular inflammatory signaling pathways, including necroptosis. Scientific experiments have confirmed that this protein can induce a wide range of inflammatory cellular processes by causing cell rupture. RIPK1 is a major regulator of NF-κB signaling and death response, which are key cellular determinants in response to a wide range of inflammatory and death-promoting stimuli in human diseases.

[0004] Therefore, RIPK1 inhibitors can provide more effective inhibition of programmed cell death, and can be used to prevent and treat related inflammatory and degenerative diseases. Summary of the Invention

[0005] The purpose of this invention is to provide a novel RIPK1 inhibitor that inhibits programmed cell death.

[0006] Another object of the present invention is to provide a method for preparing the inhibitor.

[0007] A first aspect of the invention provides a compound as represented by general formula I, or various isomers thereof (such as stereoisomers or tautomers thereof) and a pharmaceutically acceptable salt or prodrug:

[0008]

[0009] In the formula: Y is CH2 or CH2CH2; Z is O, NR 4A CR a R b Or it may not exist; ring B is a C3-C6 cycloalkyl, phenyl, C3-C6 cycloalkylphenyl, 5-6 membered heteroaryl or 5-6 membered non-aromatic heterocyclic group;

[0010] Each R1 Independently, H, halogen, -OH, -CN, -COOH, C1-C6 alkyl, -C0-C6 alkyleneoxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C 10 Alkoxyalkyl, C2-C 10 Haloalkoxyalkyl, C1-C6 hydroxyalkyl, -C0-C6 alkylene-S-C1-C6 alkyl-, -C0-C6 alkylene-C6-C 10 aryl, -C0-C6 alkylene-X-C6-C 10 Aryl, -C0-C6 alkylene-5-10 heteroaryl, -C0-C6 alkylene-X-5-10 heteroaryl, -C0-C6 alkylene-3-10 non-aromatic heterocyclic, -C0-C6 alkylene-C3-C 10 Cycloalkyl, -C0-C6 alkylene, -C3-C 10 Cycloalenyl, -C0-C6 alkylene-COR c -C0-C6 alkylene-CO2C1-C6 alkyl, -C0-C6 alkylene-CONR a R b -C0-C6 alkylene-SO2NR a R b -C0-C6 alkylene-S(O)2R c -C0-C6 alkylene-NR a R b -C0-C6 alkylene-C(O)NR a R b -C0-C6 alkylene-NHC(O)R c -C0-C6 alkylene-NHC(O)C(O)NR a R b -C0-C6 alkylene-NHC(O)C(O)OR a -C0-C6 alkylene-NHC(O)NR a R b , -P(O)Me2, -P(O)(OMe)2, -C≡CR 6 ;

[0011] R 2 H, halogen, -CN, C1-C6 alkyl, -C0-C6 alkylene, -C6-C 10Aryl, -C0-C6 alkylene-5-10 heteroaryl, -C0-C6 alkylene-3-10 non-aromatic heterocyclic, C1-C6 haloalkyl, -C0-C6 alkylene-C3-C6 cycloalkyl, -C0-C6 alkylene-C3-C6 cycloalkoxy, -C0-C6 alkylene-C1-C6 alkoxy, -C0-C6 alkylene-C1-C6 haloalkoxy, -C0-C6 alkylene-NR a R b -C≡CR 6 -CH=CH-R 6 ;R 2 For not replaced or by 1, 2, 3 or 4 Rs f replace;

[0012] R 3 It is H, C1-C6 alkyl or -C0-C3 alkylene or -C3-C6 cycloalkyl;

[0013] R 4A H, C1-C6 alkyl, C1-C6 haloalkyl;

[0014] n is 0, 1, 2, or 3;

[0015] Ring A is C6-C 10 Aromatic rings or 5-10 heterocyclic aromatic rings;

[0016] L is a C0-C6 alkylene, C2-C6 alkenyl, C3-C6 cycloalkylene, benzene ring, 5-6 membered heteroaromatic ring, or 5-6 membered non-aromatic heterocycle; L is optionally surrounded by 1-3 Rs. 5 replace;

[0017] R 5 Each can be independently represented as H, halogen, -OH, -CN, carbonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy.

[0018] Each R 6 Independently hydrogen, C1-C 10 Alkyl, -C0-C6 alkylene -C6-C 10 Aryl, -C0-C6 alkylene-5-10 heteroaryl, -C0-C6 alkylene-3-10 non-aromatic heterocyclic, -C0-C6 alkylene-C3-C 10 cycloalkyl, or -C0-C6 alkylene-C1-C 10 Alkoxy; R 6 Each independently represents either unsubstituted or replaced by 1, 2, 3, or 4 Rs. f replace;

[0019] R fEach occurrence is independently a halogen, -OH, carbonyl, -CN, -COOH, C1-C6 alkyl, -C0-C6 alkyleneoxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C 10 Alkoxyalkyl, C2-C 10 Haloalkoxyalkyl, C1-C6 hydroxyalkyl, -C0-C6 alkylene, -C3-C 10 Cycloalkyl, -C0-C6 alkylene-S-C1-C6 alkyl, -SF5, -C0-C6 alkylene-COR c -C0-C6 alkylene-CO2C1-C6 alkyl, -C0-C6 alkylene-CONR a R b -C0-C6 alkylene-SO2NR a R b -C0-C6 alkylene-S(O)2R c -C0-C6 alkylene-NR a R b -C0-C6 alkylene-C(O)NR a R b -C0-C6 alkylene-NHC(O)R c -C0-C6 alkylene-NHC(O)C(O)NR a R b -C0-C6 alkylene-NHC(O)C(O)OR a -C0-C6 alkylene-NHC(O)NR a R b -C0-C6 alkylene-P(O)Me2, -C0-C6 alkylene-P(O)(OMe)2; two adjacent R f Or two R atoms bonded to the same carbon atom f Together they form three- to eight-membered rings or four- to eight-membered heterocyclic rings;

[0020] R a R b R c Each can be independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 alkenyl, substituted or unsubstituted C6-C 10 aryl, or substituted or unsubstituted C3-C 10 heteroaryl; R a and R bThe nitrogen or carbon atoms connected to them can form three- to eight-membered rings or four- to eight-membered heterocycles; the three- to eight-membered rings or four- to eight-membered heterocycles can be formed by one or more R... e replace;

[0021] R e Independently, it can be a halogen, -OH, -CN, carbonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy, with two adjacent R groups. e Or two R atoms bonded to the same carbon atom e Together they form three- to eight-membered rings or four- to eight-membered heterocyclic rings;

[0022] Each of the above heterocycles and heteroaryl groups has 1, 2, 3, or 4 heteroatoms, selected from sulfur, oxygen, N, NH, or NR. g ;

[0023] R g For C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, or C3-C 10 Mixed aromatics;

[0024] Each X is independently O, S, SO, S(O)2, NH, CO, CH2, CF2, CH(CH3), CH(OH) or N(CH3).

[0025] In another preferred embodiment, the heteroaryl group is selected from, but not limited to: thienyl, pyridyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrimidinyl, thiazolyl, isothiazolyl, indolyl, triazolyl, tetrazolyl, thiadiazolyl, and oxadiazolyl.

[0026] In another preferred embodiment, the compound of general formula I is the compound shown in formula II:

[0027]

[0028] Among them, Z 1 and Z 3 Each can be independently N or CR 7 ;

[0029] R 7 H, halogen, methyl, halomethyl; Z 2 For N or CR 1 ;

[0030] R 1 R 2 R 3 The definitions of X, Y, Z, L, ring B, and n are as described in general formula I.

[0031] In another preferred embodiment, the compound of general formula I is the compound shown in formula III:

[0032]

[0033] Z 4 and Z 5 Each independently as CR 1 , O, S, N or NR 1 ;R 1 R 2 R 3 The definitions of X, Y, Z, L, ring B, and n are as described in general formula I.

[0034] In another preferred embodiment, the compound of general formula I is the compound shown in formula IV:

[0035]

[0036] Among them, each R 1 and R 2 The definition is as stated in general formula I;

[0037] X is O, S, or CH2;

[0038] n is 0, 1, or 2; m is 0, 1, 2, 3, or 4.

[0039] In another preferred embodiment, the compound of general formula I is the compound shown in formula V:

[0040]

[0041] Among them, each R 1 R 2 The definitions of X, Z, L, ring B, and n are as described in general formula I.

[0042] In another preferred embodiment, the compound of general formula I is the compound shown in formula VI:

[0043]

[0044] Among them, each R 1 and R 2 The definition is as stated in general formula I;

[0045] X is O, S, or CH2;

[0046] n is 0, 1, or 2;

[0047] m can be 0, 1, 2, 3, or 4.

[0048] In another preferred embodiment, the compound of general formula I is the compound shown in formula VII:

[0049]

[0050] Where R 1 and R 2 The definition is as stated in general formula I;

[0051] X is O, S, or CH2;

[0052] n is 0, 1, or 2;

[0053] m is an integer of 0, 1, 2, 3 or up to 4.

[0054] In another preferred embodiment, R in compounds of formulas I to VII 2 Selected from the following groups:

[0055]

[0056]

[0057] In another preferred embodiment, the compound of general formula I is:

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096] In another preferred embodiment, the compounds of formulas I to VII include all stereoisomers.

[0097] In another preferred embodiment, the stereoisomer is a cis-trans isomer.

[0098] In another preferred embodiment, the compound is a racemic mixture.

[0099] In another preferred embodiment, the stereoisomer is an enantiomer.

[0100] In another preferred embodiment, any one or more hydrogen atoms in the compound may be replaced by deuterium atoms.

[0101] In another preferred embodiment, the compounds of formulas I to VII include their prodrugs.

[0102] In another preferred embodiment, the pharmaceutically acceptable salts of formulas I to VII are selected from the group consisting of: hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate (toluenesulfonate), 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, and mandelate.

[0103] A second aspect of the present invention provides a method for preparing the compound of general formula I described in the first aspect, wherein the method is selected from one of the following schemes.

[0104] Option 1:

[0105]

[0106] Use containing R 6The fast-acting compound (a) of the group is reacted with an aryl halide (formula Ia-1, wherein the halogen is Cl, Br, or I) under Sonogashira coupling conditions to prepare compound (formula I). ​​Typically, the coupling reaction is carried out in the presence of a metal catalyst (including, but not limited to, a combination of palladium and copper catalysts) and a base, and in a suitable solvent at a specific temperature (e.g., about 85°C to 120°C). The reaction can also be promoted by microwave irradiation. The palladium catalysts include, but are not limited to, bis(triphenyltantalum)palladium(II) dioxide, allyl palladium(II) oxide dimer, [1,1'-bis(diphenylphosphino)ferrocene]palladium dioxide ((dppf)PdCl2), and palladium(II) acetate. The copper catalysts include, but are not limited to, cuprous iodide. Examples of suitable bases that can be used include, but are not limited to, triethylamine, pyridine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Non-limiting examples of solvents include N,N-dimethylformamide, dimethylacetamide, methanol, ethanol, acetonitrile, dimethoxyethane, dimethyl sulfoxide, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, and toluene.

[0107] Option 2:

[0108]

[0109] Use containing R 6 The alkynyl compound (a) of the group is coupled with an aryl halide (Formula Ib-1, where the halogen is Cl, Br, or I) under the Sonogashira coupling conditions described in Scheme 1 to obtain an intermediate (Formula Ib-2). Subsequently, the Boc protecting group is removed under acidic conditions to obtain a free amine (Formula Ib-3). Then, using an amide condensation reagent, the generated free amine (Formula Ib-3) is condensed with the corresponding acid (Formula III) to obtain the target product (Formula I).

[0110] Option 3:

[0111]

[0112] Boc-L-serine is reacted with a suitable substituted 1-fluoro-2-nitrobenzene using a base to give I-1. The nitro group is then reduced to an amine I-2 (reduction conditions include, but are not limited to, Zn / AcOH, Fe / NH4Cl / EtOH, Zn / NH4Cl / EtOH), and intramolecular condensation is performed using a condensation reagent to give an intermediate (Formula I-3) (condensation reagents include, but are not limited to, HOAT, HOBT, HATU, EDCI, BOP, TCFH, NMI). The compound I-3 is methylated to give I-4, followed by removal of the Boc protecting group under acidic conditions (e.g., but not limited to, CF3CO2H, HCl) to give the free amine I-5. The resulting free amine is then condensed with a suitable acid (b) using an amide condensation reagent (condensation reagents include, but are not limited to, HOAT, EDCI, HATU) to give the intermediate (Formula I-6). Finally, an intermediate containing R is used... 6 The alkynyl compound (a) was treated with Sonogashira coupling conditions I-6 to give the final product I.

[0113] Option 4:

[0114]

[0115] Compound I-5 reacts with methyl oxaloyl chloride to give (Formula I-8), followed by hydrolysis under alkaline conditions (including but not limited to ethanol / aqueous solution of lithium hydroxide) to give (Formula I-9). I-9 condenses with a suitable amine (c) to give an intermediate (Formula I-10). Finally, it reacts with a compound containing R... 6 The alkynyl compound (a) was reacted under Sonogashira coupling conditions I-10 to give the final product I.

[0116] Option 5:

[0117]

[0118] By using a suitable starting material (d) in an acid-mediated Schmidt reaction with sodium azide or via a Beckmann rearrangement reaction of the ketoxime formed after reaction with NH₂OH, a suitably substituted 1,3,4,5-tetrahydro-1-benzozazepine-2-one (Formula I-14) can be obtained. Then, I-14 is converted to α-iodophenyllactam (Formula I-15) via a trimethyliodosilane-mediated iodination reaction, followed by conversion to α-aminophenyllactam with sodium azide, and then Staudinge reduction with triphenylphosphine to generate α-aminophenyllactam (Formula I-16). This is then condensed with an amide condensing agent and a suitable acid (b) to give product I-17. Methylation under basic conditions yields the final product I.

[0119] Option Six:

[0120]

[0121] Compound I-4 is deprotected under acidic conditions (e.g., but not limited to TFA, HCl) to yield the free amine I-5. Different alkynyl compounds (formula a) are reacted with I-4 or I-5 under Sonogashira coupling conditions to yield I-18 or I-19. These are then condensed with a suitable acid (b) using an amide condensing agent (e.g., but not limited to HOAT, EDCI, HATU) to give the final product I.

[0122] Option Seven:

[0123]

[0124] Boc-L-cysteine ​​is reacted with a suitably substituted 1-fluoro-2-nitrobenzene using a base to give I-20. The nitro group is then reduced to an amine I-21 (reduction conditions include, but are not limited to, Zn / AcOH, Fe / NH4Cl / EtOH, Zn / NH4Cl / EtOH), followed by intramolecular condensation using a condensation reagent to give an intermediate of formula I-22 (condensation reagents include, but are not limited to, HOAT, HOBT, HATU, EDCI, BOP, TCFH / NMI). The compound of formula I-22 is methylated to give I-23, followed by deprotection of the Boc group under acidic conditions (e.g., but not limited to TFA, HCl) to give trifluoroacetate I-24. I-23 or I-24 is then reacted with compounds containing different R groups. 6 The alkynyl compound (a) was reacted under Sonogashira coupling conditions to give I-25 or I-26, respectively. Then, it was condensed with an acid (b) using an amide condensing agent (such as, but not limited to, HOAT, EDCI, HATU, TCFH) to give the final product I.

[0125] Option 8:

[0126]

[0127] Under alkaline conditions, Boc-L-cysteine ​​reacts with a suitably substituted thiophene derivative I-27 to give I-28. Nitro reduction of compound I-28 yields I-29, which is then subjected to intramolecular condensation to give compound I-30. I-30 is alkylated to give I-31, which is then reacted with NIS to give iodide I-31. Under acidic conditions, deprotection of the Boc group yields I-35. Then, following Scheme 7, a Sonogashira coupling reaction and an amide condensation reaction are performed (condensation reagents include, but are not limited to, HOAT, EDCI, HATU, and TCFH) to give the final product I.

[0128] A third aspect of the invention provides the use of the compounds of general formulas I to VII described in the first aspect for:

[0129] (i) Preparation of inhibitors of programmed cell necrosis;

[0130] (ii) To prepare drugs for the prevention and / or treatment of diseases mediated by programmed cell death.

[0131] In another preferred embodiment, the cell-mediated programmed necrosis includes cancer, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, Sjögren's syndrome, systemic scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, non-alcoholic fatty liver disease, autoimmune hepatitis, autoimmune hepatobiliary diseases, and primary scleroderma. Inflammation, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-related febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-related periodic syndrome, and periodontitis.

[0132] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0133] definition

[0134] The term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, including straight-chain and branched hydrocarbon groups, such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), tert-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).

[0135] As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6 to 14) carbon atoms, having a monocyclic (e.g., phenyl) or fused (e.g., naphthyl or anthracene) ring. If the bonding point is on an aromatic carbon atom, the fused ring may be non-aromatic (e.g., 2-benzoxazolone, 2H-1,4-benzoxazine-3(4H)-one-7-yl, etc.). Preferred aryl groups include phenyl and naphthyl.

[0136] As used herein, the term "alkenyl" refers to an alkenyl group having 2 to 10 (e.g., 2 to 6 or 2 to 4) carbon atoms and having at least one (e.g., 1 to 2) unsaturated alkene bond (>C=C<). Examples of such groups include vinyl, allyl, and but-3-alkenyl. As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms and having a monocyclic or polycyclic structure (including fused, bridged, and spirocyclic systems). In fused-ring systems, one or more rings may be cycloalkyl, heterocyclic, aryl, or heteroaryl, as long as the linking site is a ring through a cycloalkyl ring. Suitable examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

[0137] As used in this article, the term "halogenated" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0138] As used herein, the terms "heteroaryl" and "heteroary ring" refer to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur within the ring. Such a heteroaryl can be monocyclic (e.g., pyridyl or furanyl) or fused-ring (e.g., indolizinyl or benzothiophene), wherein the fused ring can be non-aromatic and / or contain one heteroatom, provided that the connecting point is through an atom of an aromatic heteroaryl. In one embodiment, the ring atom nitrogen and / or sulfur of the heteroaryl is optionally oxidized to N-oxide (NO), sulfinyl, or sulfonyl. Preferably, the heteroaryl includes pyridyl, pyrroleyl, indolyl, thiophene, and furanyl.

[0139] As used herein, the term "substituted heteroaryl" refers to a heteroaryl group substituted by 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the same substituents as defined for substituted aryl.

[0140] As used herein, the terms "heterocyclic," "heterocyclic," "heterocyclic alkyl," or "heterocyclic group" refer to a saturated, partially saturated, or unsaturated group (but not aromatic) having a monocyclic or fused ring (including bridged and spirocyclic systems) containing 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In fused ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided the junction passes through a non-aromatic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to provide an N-oxide, a sulfinyl group, and a sulfonyl moiety.

[0141] As used herein, the terms “substituted heterocyclic” or “substituted heterocyclic alkyl” or “substituted heterocyclic group” refer to a heterocyclic group substituted by 1 to 5 (e.g., 1 to 3) substituents, which are the same substituents defined as substituted cycloalkyl.

[0142] The substituents are selected from, but not limited to, the following chemical groups: halogens, -C 1-6 Alkyl, -C 3-8 cycloalkyl, -C 1-6 Haloalkyl, -C 3-8 Halogenated cycloalkyl, -C 1-6 Alkoxy, -C 3-8 Cycloalkoxy, -C 1-6 Alkylthio, -C 0-6 Alkylene -OH, nitro, aldehyde, -SF5, -C 0-6 Alkylene-NR a R b -C 0-6 alkylene-carboxyl group, -C 0-6 Alkylene-COR a -C 0-6 Alkylene-CO2R a -C 0-6 Alkylene-CONR d R e -C 0-6 Alkylene-SO2R a -C 0-6 Alkylene-SO2NR d R e -P(O)(OMe)2; carbonyl, -C 0-6 Alkylene-CN,-C 3-8 cycloalkyl-OH,-C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkylene-S(O)(NH)C 1-6 alkyl,-C 0-6 Alkylene-S(O)(NCN)C 1-6 alkyl,-C0-6 Alkylene-NR c S(O)2R b ,-C 0-6 Alkylene-NR c S(O)2NR c R b ,-C 0-6 Alkylene-NR c C(O)NH2,-C 0-6 Alkylene-NR c C(O)R b ,-C 0-6 Alkylene-NR c C(O)NR d R e ,-C 0-6 Alkylene-NR c C(O)OR b ,-C 0-6 Alkylene-NRSO2R b C(O)-R b ,-C 0-6 Alkylene-P(O)R c R b ,-C 0-6 Alkylene-P(O)(OR) c (OR) b ),-C 0-6 Alkylene-C(O)C 1-6 alkyleneamino, C 1-6 Heteroalkyl, C 5-10 Carbon ring, C 5- 10 aryl, C 2-10 Heterocyclic, C 2-10 Mixed fragrance ring.

[0143] In this application, C 0-6 Alkylene refers to a compound that does not have an alkylene group or has a C group. 1-6 Alkylene.

[0144] As used herein, the term "stereoisomer" refers to a compound with one or more stereocenters that differ in chirality. Stereoisomers include enantiomers and diastereomers.

[0145] As used herein, the term "tautomer" refers to an alternative form of a compound with different proton positions, such as enol-ketone and imine-enamine tautomers, or a heteroaryl tautomer containing a ring atom connected to both the -NH- and =N- portions of the ring, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetraazoles.

[0146] "Prodrug" refers to any derivative of the compounds of the examples that, when administered to a subject, can directly or indirectly provide the compounds of the examples or their active metabolites or residues. Particularly preferred derivatives and prodrugs are those that, when administered to a subject, improve the bioavailability of the compounds of the examples (e.g., more readily absorbed into the bloodstream than orally administered compounds) or enhance the delivery of the parent compound to biological compartments (e.g., the brain or lymphatic system) relative to the parent species. Prodrugs include ester forms of the compounds of the present invention.

[0147] In the presence of stereoisomers of the compounds described in this invention, this invention includes all stereoisomers of the compounds.

[0148] In the presence of tautomers of the compounds described in this invention, this invention includes all tautomers of the compounds.

[0149] The present invention also includes deuterated compounds produced by replacing any one or more hydrogen atoms in the said compound with its stable isotope deuterium.

[0150] The present invention also provides active ingredients within safe and effective ranges for compounds of formulas I and VII, as well as pharmaceutically acceptable carriers.

[0151] The "active ingredient" mentioned in this invention refers to the compounds of general formulas I to VII described in this invention.

[0152] The "active ingredient" and pharmaceutical composition described in this invention can be used as inhibitors of diseases mediated by programmed cell death. In another preferred embodiment, it is used to prepare a medicament for the prevention and / or treatment of diseases mediated by programmed cell death.

[0153] "Safe and effective dose" refers to an amount of active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably 10-200 mg of active ingredient per dose. Preferably, "one dose" refers to one tablet or capsule.

[0154] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the active ingredient of the present invention without significantly reducing the efficacy of the active ingredient.

[0155] Typically, the compounds of preferred embodiments are administered in a therapeutically effective amount, via any acceptable mode of administration of an agent with similar effects. The actual dosage of the compound (i.e., the active ingredient) of preferred embodiments is determined based on several factors, such as the severity of the disease to be treated, the patient's age and relative health, the potency of the compound used, the route and form of administration, and other factors. The drug may be administered multiple times a day, preferably once or twice daily. All these factors are taken into consideration by the attending physician.

[0156] For the purposes of preferred embodiments, the therapeutically effective dose can typically be a total daily dose administered to a patient in a single dose or in divided doses, for example, about 0.001 to about 1000 mg / kg body weight daily, preferably about 1.0 to about 30 mg / kg body weight daily. A dosage unit composition may include its dosage factor to form a daily dose. The choice of dosage form depends on various factors, such as the administration method and the bioavailability of the pharmaceutical substance. Generally, the compounds of preferred embodiments can be administered as pharmaceutical compositions via any of the following routes: oral, systemic (e.g., transdermal, intranasal, or via suppositories), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). Oral administration is preferred, allowing for adjustment of the convenient daily dose according to the degree of bitterness. The composition may be in the form of tablets, pills, capsules, semi-solids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition. Another preferred method of administering the compounds of preferred embodiments is by inhalation. This is an effective method of delivering the therapeutic agent directly to the respiratory tract (see, for example, U.S. Patent No. 5,607,915).

[0157] Suitable pharmaceutically acceptable carriers or excipients include processing agents and drug delivery modifiers and accelerators, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low-melting-point waxes, ion exchange resins, and any combination of two or more thereof. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils, including petroleum, animal, vegetable, or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous glucose solutions, and ethylene glycol. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, MackPub.Co., New Jersey (1991), and are incorporated herein by reference.

[0158] As used herein, the term "pharmaceutically acceptable salt" refers to a nontoxic acid or alkaline earth metal salt of a compound of formula I. These salts can be prepared in situ during the final isolation and purification of the compound of formula I, or by reacting a suitable organic or inorganic acid or base with a basic or acidic functional group. Representative salts include, but are not limited to: acetates, adipates, alginates, citrates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butates, camphorates, camphorsulfonates, diglucose, cyclopentanepropionates, dodecyl sulfates, ethanesulfonates, gluconate-heptate, glycerol phosphates, hemisulfates, heptate, hexanoates, fumarates, hydrochlorides, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactates, maleates, methanesulfonates, nicotinates, 2-naphthylsulfonate, oxalates, dihydroxynaphthyl salts, pectates, thiocyanates, 3-phenylpropionates, picrates, neopentate, propionates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, and undecanoates. Furthermore, nitrogen-containing basic groups can be quaternized with reagents such as: alkyl halides, such as chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl groups; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and dipentyl sulfates; long-chain halides, such as chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearyl groups; and aralkyl halides, such as benzyl and phenethyl bromides. This yields water-soluble, oil-soluble, or dispersible products. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, and citric acid. Base addition salts can be prepared in situ during the final separation and purification of compounds of general formula I, or by reacting the carboxylic acid moiety with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate) or ammonia, or an organic primary, secondary, or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal-based cations, such as salts of sodium, lithium, potassium, calcium, magnesium, and aluminum, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Other representative organic amines used to form base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine.

[0159] The following abbreviations have the meanings indicated. EA: Ethyl acetate. DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM: Dichloromethane; DIBAL: Diisobutylaluminum hydrogenate; DIEA: Diisopropylethylamine; DMAP: N,N-dimethylaminopyridine; DME: 1,2-dimethoxyethane; DMF: N,N-dimethylformamide; DMPE: 1,2-bis(dimethylphosphine)ethane; DMSO: Dimethyl sulfoxide; DPPB: 1,4-bis(diphenylphosphine)butane; DPPE: 1,2-bis(diphenylphosphine)ethane; DPPF: 1,1'-bis(diphenylphosphine)ferrocene; DPPM: 1,1'-bis(diphenylphosphine)methane; DIAD: Diisopropyl azodicarbonate; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; HATU: O-(7-nitrogen... Benzotriazole-1,1,3,3-Tetramethylurea hexafluorophosphate; HMPA: Hexamethylphosphoramide; HOAT: N-hydroxy-7-azobenzotriazole; IPA: Isopropanol; LDA: Lithium diisopropylaminodimethyl ...

[0160] Reversed-phase HPLC purification conditions: A Waters Micromass ZQ 4000 (MAA050) was used as the mass detector, and a Waters 2487UV was used as the detector. HPLC-MS analysis was performed on a Waters HPLC 2790. The column used was a Finomax OOB-4605-E0 (5U-XB-C18-100A, 50 × 4.6 mm). The mobile phase consisted of eluent A (water, 0.05% TFA) and eluent B (CH3CN, 0.05% TFA), with an elution rate of 1 mL / min. The initial conditions were 90% A for 1 min, followed by a linear decrease from 90% A to 10% A within 5 min, and then a recovery from 10% A to 90% A within 1 min, for a total run time of 7 min. The mobile phase gradient and run time could be adjusted appropriately according to the properties of the compound.

[0161] The following examples will make it easier to understand the content of this invention. These embodiments are given to illustrate the invention and not to limit its scope. Unless otherwise stated, percentages and parts are by weight and in parts by weight.

[0162] Unless otherwise stated, the materials and reagents used in the embodiments of this invention are commercially available products.

[0163] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0164] Example 1

[0165] (S)-N 1 -Benzyl-N 2 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0166]

[0167] At room temperature, intermediates NN-1 (1 eq), M-5 (1 eq), and HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea hexafluorophosphate, 1.2 eq) were dissolved in dichloromethane (0.1 M reactant concentration). DIEA (3 eq) was added under ice bath conditions. After 10 minutes, the ice bath was removed, and the mixture was stirred at room temperature for 2 hours. The reaction was then quenched with ice water. The mixture was extracted three times with EA, and the organic phases were combined, washed three times with water, three times with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated. The product was then separated and purified by rapid column chromatography to obtain the product in Example 1 (T-1).

[0168] 1 H NMR (400MHz, DMSO-d6) δ9.34(t,J=6.4Hz,1H),8.84(d,J=7.5Hz,1H),7.53-7.45(m,3H),7. 34–7.21(m,3H),4.71-4.60(m,2H),4.43-4.40(m,1H),4.31(d,J=6.5Hz,2H),3.28(s,3H).

[0169] MS-ESI: m / z = 434.0 [M+H] + .

[0170] Example 2

[0171] (S)-N 1 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -Phenethyloxalamide

[0172]

[0173] Using NN-2 and M-5 as raw materials, Example 2 (T-2, yellow solid) was obtained under the same conditions as in Example 1.

[0174] 1 H NMR(400MHz, CDCl3) δ8.16(d,J=7.1Hz,1H),7.33–6.98(m,10H),4.74(dt,J=11.2,7.3Hz,1H),4.52(dd,J=9.7,7 .4Hz, 1H), 4.17 (dd, J=11.0, 10.1Hz, 1H), 3.49 (ddd, J=13.5, 6.9, 2.9Hz, 2H), 3.32 (s, 3H), 2.77 (t, J=7.1Hz, 2H).

[0175] MS-ESI: m / z = 446.1 [M+H] + .

[0176] Example 3

[0177] (S)-N 1 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -Methyl-N 2 -Phenethyloxalamide

[0178]

[0179] At room temperature, intermediate M-7 (1 eq), N-methylphenylethylamine (1 eq), and HATU (1.2 eq) were dissolved in dichloromethane (0.1 M reactant concentration). DIEA (3 eq) was added under ice bath conditions. After 10 minutes, the ice bath was removed, and the mixture was stirred at room temperature. After 1 hour, the reaction was quenched with ice water. The mixture was extracted three times with EA, and the organic phases were combined. The organic phases were washed three times with water and three times with saturated brine. The organic phases were dried over anhydrous sodium sulfate, concentrated, and separated into a yellow solid by rapid column chromatography. Example 3 (T-3).

[0180] 1H NMR(400MHz, DMSO-d6)δ9.08(dd,J=20.6,7.9Hz,1H),7.56–7.46(m,3H),7.34–7.18(m,5H),4.70(ddd,J=10.2,7.9,3.9Hz,1H),4.54–4. 33(m,2H),3.67–3.56(m,1H),3.55–3.41(m,2H),3.34(s,1H),3.30(s,1H),3.28(s,1H),2.94(s,1H),2.85(s,2H),2.79(t,J=7.9Hz,1H). MS-ESI:m / z=460.0[M+H] + .

[0181] Example 4

[0182] N1-((S)-8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -(1,2,3,4-tetrahydronaphth-2-yl)oxalamide

[0183]

[0184] Example 4 was obtained using M-7 and (±)1,2,3,4-tetrahydro-2-naphthylamine as raw materials under the same conditions as in Example 3.

[0185] 1 H NMR(400MHz, CDCl3)δ8.28(d,J=7.3Hz,1H),7.40-7.36(m,2H),7.28(d,J=8 .2Hz,1H),7.16–7.03(m,5H),4.81(dt,J=11.2,7.4Hz,1H),4.66–4.55(m,1H ),4.28-4.21(m,2H),3.40(s,3H),3.12(dd,J=16.2,5.1Hz,1H),2.97-2.83 (m,2H),2.71(dd,J=16.3,8.8Hz,1H),2.16–2.07(m,1H),1.89–1.74(m,1H). MS-ESI: m / z = 472.0 [M+H] + .

[0186] Example 5

[0187] (S)-N 1 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(2-Fluorophenylethyl)oxalamide

[0188]

[0189] Example 5 was obtained using M-7 and o-fluorophenylethylamine as raw materials under the same conditions as in Example 3.

[0190] 1H NMR(400MHz, CDCl3)δ8.23(d,J=6.4Hz,1H),7.40–7.31(m,3H),7.25–7.13(m,2H),7.11–6.98(m,3H),4.82(dt,J=11.3,7.1Hz,1H) ,4.60(dd,J=9.8,7.3Hz,1H),4.24(dd,J=11.3,9.8Hz,1H),3.56(ddd,J=13.4,7.0,1.9Hz,2H),3.39(s,3H),2.89(t,J=7.0Hz,2H).

[0191] MS-ESI: m / z = 463.9 [M+H] + .

[0192] Example 6

[0193] (S)-N 1 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(4-Fluorophenylethyl)oxalamide

[0194]

[0195] Using M-7 and 4-fluorophenylethylamine as raw materials, and under the same conditions as in Example 3, the mixture was analyzed by HPLC (mobile phase: A: H2O (+0.1% FA); B: MeCN; separation conditions: 60% B; flow rate: 10 mL / min; column: Water). Example 6 was obtained by purifying MSCs (18, 19 × 250 mm, 10 μm).

[0196] 1H NMR(400MHz, CDCl3)δ8.22(d,J=7.2Hz,1H),7.42–7.33(m,2H),7.16–7.06(m,3H),7.02–6.95(m,2H),4.81(dt,J=11.3,7.4Hz,1H) ,4.60(dd,J=9.8,7.3Hz,1H),4.24(dd,J=11.2,9.9Hz,1H),3.54(ddd,J=13.4,7.1,4.7Hz,2H),3.40(s,3H),2.82(t,J=7.1Hz,2H).

[0197] MS-ESI: m / z = 464.0 [M+H] + .

[0198] Example 7

[0199] (S)-N 1 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(2-chlorophenylethyl)oxalamide

[0200]

[0201] Using M-7 and 2-chlorophenylethylamine as raw materials, and under the same conditions as in Example 3, Example 7 (T-7) was obtained.

[0202] 1 H NMR (400MHz, CDCl3) δ8.24(d,J=7.2Hz,1H),7.39-7.34(m,4H),7.21–7.15(m,3H),7.09(d,J=8.5Hz,1H),4.82(dt,J=11.3,7 .3Hz, 1H), 4.60 (dd, J = 9.8, 7.3Hz, 1H), 4.24 (dd, J = 11.3, 9.8Hz, 1H), 3.61-3.56 (m, 2H), 3.39 (s, 3H), 2.99 (t, J = 7.1Hz, 2H).

[0203] MS-ESI: m / z = 480.1 [M+H] + .

[0204] Example 8

[0205] (S)-N 1 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(3-chlorophenylethyl)oxalamide

[0206]

[0207] Using M-7 and 3-chlorophenylethylamine as raw materials, and under the same conditions as in Example 3, Example 8 (T-8) was obtained.

[0208] 1 H NMR(400MHz, CDCl3)δ8.23(d,J=7.3Hz,1H),7.41–7.33(m,2H),7.31-7.28(m,1H),7.23-7.18(m,3H),7.10–7.05(m,2H),4.81(dt,J=11.2,7 .4Hz, 1H), 4.60 (dd, J = 9.8, 7.3Hz, 1H), 4.24 (dd, J = 11.2, 9.9Hz, 1H), 3.56 (ddd, J = 13.6, 7.1, 2.1Hz, 2H), 3.40 (s, 3H), 2.82 (t, J = 7.2Hz, 2H). MS-ESI:m / z=480.0[M+H] + .

[0209] Example 9

[0210] N 1 -((S)-8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -((S)-2-hydroxy-2-phenylethyl)oxalamide

[0211]

[0212] At room temperature, intermediates M-7 (1 eq), (R)-(+)-2-phenylglycine (1 eq), EDCI (1.5 eq), and HOAT (1.1 eq) were dissolved in DMF (0.09 M) and stirred for 1 h. The reaction was quenched with water under ice bath conditions. The reaction solution was extracted with EA, washed three times with water, three times with saturated brine, dried over anhydrous sodium sulfate, and the concentrated organic phase was separated by preparative HPLC to obtain Example 9 (T-9, yellow solid).

[0213] 1H NMR(400MHz, CDCl3)δ8.26(d,J=7.5Hz,1H),7.74–7.64(m,1H),7.42–7.27(m,7H),7.09(d,J=8.5Hz,1H),4.87-4.79(m,2H),4 .59(dd,J=9.8,7.4Hz,1H),4.25(dd,J=11.2,10.0Hz,1H),3.72(ddd,J=13.9,7.3,3.5Hz,1H),3.49–3.31(m,4H),2.75(s,1H).

[0214] MS-ESI: m / z = 464.0 [M+H] + .

[0215] Example 10

[0216] (S)-N 1 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(2,3-dihydro-1H-indan-2-yl)oxalamide

[0217]

[0218] Using M-7 and 2-aminoindane hydrochloride as raw materials, and under the same conditions as in Example 9, Example 10 (T-10) was obtained.

[0219] 1 H NMR(400MHz, CDCl3)δ8.26(d,J=7.3Hz,1H),7.43–7.40(m,1H),7.38(dd,J=8.5,2.2Hz,1 H),7.35(d,J=2.2Hz,1H),7.24–7.16(m,4H),7.09(d,J=8.5Hz,1H),4.80(dt,J=11.2,7. 4Hz,1H),4.74–4.67(m,1H),4.59(dd,J=9.8,7.3Hz,1H),4.24(dd,J=11.2,9.9Hz,1H),3 .40(s,3H),3.36(dd,J=7.2,2.4Hz,1H),3.31(dd,J=7.2,2.5Hz,1H),2.92–2.81(m,2H). MS-ESI:m / z=458.0[M+H] + .

[0220] Example 11

[0221] (S)-N 1-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(2-(pyridin)-3-yl)ethyl)oxalamide

[0222]

[0223] Using M-7 and 3-(2-aminoethyl)pyridine as raw materials, and under the same conditions as in Example 9, Example 11 (T-11) was obtained.

[0224] 1 H NMR(400MHz, CDCl3)δ8.52–8.44(m,2H),8.22(d,J=7.1Hz,1H),7.54-7.50(m,1H),7 .38(dd,J=8.5,2.2Hz,1H),7.35(d,J=2.1Hz,1H),7.33-7.31(m,1H),7.25-7.22(m,1 H),7.09(d,J=8.5Hz,1H),4.81(dt,J=11.2,7.4Hz,1H),4.60(dd,J=9.8,7.3Hz,1H), 4.24(dd,J=11.2,9.9Hz,1H),3.62–3.53(m,2H),3.40(s,3H),2.87(t,J=7.1Hz,2H).

[0225] MS-ESI: m / z = 447.1 [M+H] + .

[0226] Example 12

[0227] (S)-N 1 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(3-Fluorophenylethyl)oxalamide

[0228]

[0229] Using M-7 and 3-fluorophenylethylamine as raw materials, and under the same conditions as in Example 9, Example 12 was obtained.

[0230] 1H NMR (400MHz, CDCl3) δ8.24(d,J=7.4Hz,1H),7.37(dd,J=8.5,2.2Hz,1H),7.35( d,J=2.2Hz,1H),7.29-7.23(m,1H),7.09(d,J=8.5Hz,1H),6.99–6.80(m,4H),4 .81(dt,J=11.3,7.4Hz,1H),4.59(dd,J=9.8,7.3Hz,1H),4.25(dd,J=11.3,9.8 Hz, 1H), 3.56 (ddd, J = 13.5, 7.1, 2.8Hz, 2H), 3.39 (s, 3H), 2.84 (t, J = 7.1Hz, 2H). MS-ESI: m / z = 461.9 [MH] - .

[0231] Example 13

[0232] (S)-N 1 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(4-chlorophenylethyl)oxalamide

[0233]

[0234] Using M-7 and 4-chlorophenylethylamine as raw materials, and under the same conditions as in Example 9, Example 13 (T-13) was obtained.

[0235] 1 H NMR (400MHz, CDCl3) δ8.23(d,J=7.3Hz,1H),7.41–7.33(m,2H),7.30-7.24(m,2H),7.14-7.06(m,4H),4.81(dt,J=11.3,7.4 Hz, 1H), 4.60 (dd, J = 9.7, 7.4Hz, 1H), 4.24 (dd, J = 11.1, 10.0Hz, 1H), 3.59–3.46 (m, 2H), 3.39 (s, 3H), 2.82 (t, J = 7.1Hz, 2H).

[0236] MS-ESI: m / z = 480.0 [M+H] + .

[0237] Example 14

[0238] (S)-N 1 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2-(3-methoxyphenylethyl)oxalamide

[0239]

[0240] Using M-7 and 3-methoxyphenylethylamine as raw materials, and under the same conditions as in Example 9, Example 14 (T-14) was obtained.

[0241] 1 H NMR (400MHz, CDCl3) δ8.24(d,J=7.4Hz,1H),7.37(dd,J=8.5,2.2Hz,1H),7.35( d,J=2.2Hz,1H),7.24–7.19(m,1H),7.09(d,J=8.5Hz,1H),6.83–6.68(m,3H),4. 81(dt,J=11.3,7.4Hz,1H),4.59(dd,J=9.8,7.3Hz,1H),4.24(dd,J=11.3,9.8Hz ,1H),3.78(s,3H),3.59–3.51(m,2H),3.39(s,3H),2.80(t,J=11.3,7.2Hz,2H). MS-ESI: m / z = 478.1 [M+H] + .

[0242] Example 15

[0243] (S)-N 1 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(2-chloro-6-fluorobenzyl)oxalamide

[0244]

[0245] Using M-7 and 2-chloro-6-fluorobenzylamine as raw materials, and under the same conditions as in Example 9, Example 15 (T-15) was obtained.

[0246] 1H NMR (400MHz, CDCl3) δ8.26 (d, J=6.8Hz, 1H), 7.53-7.49 (m, 1H), 7.37 (dd, J=8 .5,2.2Hz,1H),7.35(d,J=2.2Hz,1H),7.26–7.15(m,2H),7.08(d,J=8.5Hz,1 H),7.05–6.98(m,1H),4.80(dt,J=11.1,7.2Hz,1H),4.71–4.63(m,2H),4.59 (dd, J = 9.8, 7.3 Hz, 1H), 4.23 (dd, J = 11.2, 9.9 Hz, 1H), 3.39 (d, J = 1.7 Hz, 3H). MS-ESI: m / z = 484.0 [M+H] + .

[0247] Example 16

[0248] (S)-N 1 -(8-cyano-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -Phenethyloxalamide

[0249]

[0250] Add 50 mg of the product from Example 2, 13.4 mg of zinc cyanide, 32.4 mg of PdPPh3, and 3 mL of DMF to the reaction vessel. React in a microwave reactor at 100 °C for one hour. Then, add a saturated sodium bicarbonate solution at 0 °C. Extract the organic phase with EA and wash it three times with water. Concentrate under reduced pressure and separate by preparative HPLC (mobile phase: A, H2O (+0.1% TFA); B, MeCN; separation conditions: 53% B; flow rate: 24 mL / min; column: Water). MSC18, 19×250mm, 10μm), yielded Example 16 (T-16, white solid).

[0251] 1H NMR (400MHz, CDCl3) δ8.17(d,J=7.4Hz,1H),7.48(dd,J=8.3,1.8Hz,1H),7.42(d,J =1.8Hz,1H),7.23(d,J=7.6Hz,3H),7.19(s,1H),7.17(d,J=7.2Hz,1H),7.13–7.09( m,2H),4.74(dt,J=11.4,7.4Hz,1H),4.55(dd,J=9.8,7.3Hz,1H),4.24(dd,J=11.3, 9.9Hz, 1H), 3.50 (ddd, J = 13.6, 7.1, 1.8Hz, 2H), 3.37 (s, 3H), 2.78 (t, J = 7.1Hz, 2H). MS-ESI:m / z=338.9[M+H] + .

[0252] Example 17

[0253] (S)-N 1 -(5-methyl-4-oxo-8-(pyridin-4-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N2-phenylacetamide

[0254]

[0255] first step:

[0256] 4-Alynylpyridine (31.8 mg) was reacted with intermediate M-4 (40 mg), CuI (5.1 mg), PdCl2(PPh3)2 (9.5 mg), triethylamine (1 ml), and DMF (2 ml) in a microwave reactor at 85 °C for 3 hours. After cooling to room temperature, the mixture was extracted with EA, washed three times with water, and the solvent was removed by vacuum rotary evaporation. The mixture was then separated by preparative HPLC (mobile phase: A, H2O (+0.1% FA); B, MeCN; separation conditions: 51% B; flow rate: 24 mL / min; column: Water). MSC18 (19 × 250 mm, 10 μm) yielded a white solid, M-8. MS-ESI: m / z = 394.1 [M+H] + .

[0257] Step Two:

[0258] Dissolve M-8 in a THF:TFA ratio of 5:2 and react at room temperature for 1 hour. Dry the solvent to obtain intermediate M-9. Proceed directly to the next step without purification.

[0259] Step 3:

[0260] Intermediate M-9 (16 mg) was dissolved in DMF (1 ml), and intermediate NN-2, EDCI (15.7 mg), and HOAT (8.2 mg) were added. After reacting for 1 hour, water was added under ice bath and extracted with EA. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum rotary evaporation. The mixture was separated by preparative HPLC to obtain Example 17 (T-17, white solid).

[0261] 1 H NMR (400MHz, CDCl3) δ8.63 (d, J = 5.5 Hz, 2H), 8.26 (d, J = 7.4 Hz, 1H), 7.42 (dd, J = 8. 3,1.8Hz,1H),7.38(dd,J=8.3,3.8Hz,3H),7.30(t,J=7.3Hz,3H),7.25–7.15(m,4H ),4.84(dt,J=11.2,7.4Hz,1H),4.62(dd,J=9.8,7.4Hz,1H),4.27(dd,J=11.1,10 .0Hz, 1H), 3.57 (ddd, J = 13.4, 7.0, 3.7Hz, 2H), 3.43 (s, 3H), 2.84 (t, J = 7.1Hz, 2H). MS-ESI: m / z = 469.2 [M+H] + .

[0262] Example 18

[0263] (S)-N 1 -(5-methyl-4-oxo-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N2-phenylacetamide

[0264]

[0265] The preparation method of Example 18 is the same as that of Example 17, and the raw materials are M-4 and 2-alkynylpyridine.

[0266] Intermediate M-10: MS-ESI: m / z = 394.1 [M+H] + .

[0267] Intermediate M-11:

[0268] Example 18 (T-18): 1H NMR (400MHz, CDCl3) δ8.78 (s, 1H), 8.58 (d, J = 3.7Hz, 1H), 8.26 (d, J = 7.3Hz, 1H), 7.82 (dt,J=7.9,1.9Hz,1H),7.42(dd,J=8.3,1.9Hz,1H),7.36(d,J=1.8Hz,1H),7.35–7.27 (m,4H),7.25–7.14(m,4H),4.84(dt,J=11.2,7.3Hz,1H),4.62(dd,J=9.8,7.4Hz,1H) ,4.26(dd,J=11.2,9.9Hz,1H),3.63–3.49(m,2H),3.43(s,3H),2.84(t,J=7.1Hz,2H).

[0269] MS-ESI: m / z = 469.2 [M+H] + .

[0270] Example 19

[0271] (S)-N 1 -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azaxazon-3-yl)-N 2 -(2-(thien-2-yl)ethyl)oxalamide

[0272]

[0273] The preparation method of Example 19 is the same as that of Example 17. M-5 and 3-methylbutynol-3 were reacted under Sonogashira coupling conditions to obtain intermediate M-12, which was then condensed with intermediate NN-4 in one step to obtain the target compound T-19.

[0274] 1 H NMR(400MHz, CDCl3)δ8.24(d,J=7.4Hz,1H),7.48–7.39(m,1H),7.31–7.27 (m,1H),7.24(s,1H),7.18–7.11(m,2H),6.96–6.90(m,1H),6.85–6.80(m,1 H),4.80(dt,J=11.2,7.4Hz,1H),4.58(dd,J=9.6,7.5Hz,1H),4.29–4.19( m,1H),3.65–3.50(m,2H),3.40(s,3H),3.06(t,J=6.8Hz,2H),1.63(s,6H).

[0275] Example 20

[0276] (S)-N 1 -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azaxazon-3-yl)-N 2 -Phenethyloxalamide

[0277]

[0278] The preparation method of Example 20 is the same as that of Example 19. The target product T-20 was obtained by one-step condensation of intermediate M-12 and intermediate NN-2.

[0279] 1 H NMR(400MHz, CDCl3)δ8.24(d,J=7.4Hz,1H),7.36–7.27(m,4H),7.25–7.20(m,2H),7.20–7.11(m,3H),4.79(dt,J=11.2,7.5 Hz,1H),4.58(dd,J=9.7,7.5Hz,1H),4.27–4.19(m,1H),3.63–3.50(m,2H),3.40(s,3H),2.84(t,J=7.1Hz,2H),1.63(s,6H).

[0280] Example 21

[0281] (S)-N 1 -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -Phenethyloxalamide

[0282]

[0283] For the preparation method of intermediate N-5, please refer to the preparation method of intermediate M-5.

[0284] Using N-5 and NN-2 as raw materials, and employing the same method as in Example 17, the samples were purified by HPLC to obtain Example 21 (T-21).

[0285] 1H NMR (400MHz, CDCl3) δ8.17(d,J=7.4Hz,1H),7.30–7.18(m,5H),7.16(d,J=7.3Hz,1H),7.11(d,J=7.0Hz,2H),6.99(d,J=8.7Hz,1H),4.74(dt,J=11 .3,7.5Hz,1H),4.50(dd,J=9.8,7.4Hz,1H),4.17(dd,J=11.2,9.9Hz,1H),3.49(ddd,J=13.5,7.1,1.7Hz,2H),3.33(s,3H),2.77(t,J=7.1Hz,2H).

[0286] MS-ESI: m / z = 448.0 [M+H] + .

[0287] Example 22

[0288] (S)-N 1 -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(2-(thiophene)-3-yl)ethyl)oxalamide

[0289]

[0290] Using N-5 and NN-3 as raw materials, and employing the same method as in Example 1, Example 22 (T-22) was obtained.

[0291] 1 H NMR (400MHz, CDCl3) δ8.24 (d, J = 7.5Hz, 1H), 7.37-7.33 (m, 3H), 7.28 (dd, J = 4. 9,2.9Hz,1H),7.06(dt,J=8.9,1.2Hz,1H),7.02–6.99(m,1H),6.94(dd,J=4.9 ,1.3Hz,1H),4.82(dt,J=11.3,7.5Hz,1H),4.58(dd,J=9.8,7.4Hz,1H),4.24( dd,J=11.3,9.8Hz,1H),3.61–3.52(m,2H),3.40(s,3H),2.88(t,J=7.0Hz,2H).

[0292] MS-ESI: m / z = 452.0 [M+H] + .

[0293] Example 23

[0294] (S)-N1 -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(2-(thiophene)-2-yl)ethyl)oxalamide

[0295]

[0296] Using N-5 and NN-4 as raw materials, and employing the same method as in Example 1, Example 23 (T-23) was obtained.

[0297] 1 H NMR (400MHz, CDCl3) δ8.25(d,J=7.4Hz,1H),7.44(t,J=6.1Hz,1H),7.37–7.32(m,2H),7.16(dd,J=5.1,1.0Hz,1H),7.06(d,J=8.5Hz,1 H),6.93(dd,J=5.1,3.4Hz,1H),6.83(d,J=3.3Hz,1H),4.82(dt,J=11.3,7.5Hz,1H),4.58(dd,J=9.8,7.4Hz,1H),4.24(dd,J=11.2,9.9

[0298] Hz, 1H), 3.58 (ddd, J = 13.2, 6.8, 1.4Hz, 2H), 3.40 (s, 3H), 3.06 (t, J = 6.8Hz, 2H).

[0299] MS-ESI: m / z = 452.0 [M+H] + .

[0300] Example 24

[0301] (S)-N 1 -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(2-chloro-6-fluorobenzyl)oxalamide

[0302]

[0303] Using N-5 and NN-5 as raw materials, and employing the same method as in Example 1, Example 24 (T-24) was obtained.

[0304] 1H NMR (400MHz, CDCl3) δ8.25 (d, J = 7.5Hz, 1H), 7.52 (s, 1H), 7.39–7.33 (m, 2H), 7.25–7.19 (m, 2H), 7.09–6.98 (m, 2H), 4. 80(dt,J=11.2,7.4Hz,1H),4.75–4.61(m,2H),4.57(dd,J=9.8,7.4Hz,1H),4.22(dd,J=11.1,9.9Hz,1H),3.40(s,3H). MS-ESI:m / z=484.0[M+H] + .

[0305] Example 25

[0306] (S)-N 1 -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(2,6-dichlorophenylethyl)oxalamide

[0307]

[0308] Using N-5 and NN-6 as raw materials, dissolved in 1.0 mL of DMF, HATU (38.0 mg, 0.10 mmol) and DIPEA (19.4 mg, 0.15 mmol) were added. After stirring overnight at room temperature, 10.0 mL of saturated ammonium chloride and 15.0 mL of ethyl acetate were added. The organic phase was washed three times with 10.0 mL of saturated ammonium chloride and then twice with 10.0 mL of saturated brine. The organic phase was retained and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, the organic phase was concentrated, and purified by rapid column chromatography to a 0-25% ethyl acetate petroleum ether solution, finally yielding Example 25 (T-25).

[0309] 1 H NMR (400MHz, CDCl3) δ8.21(d,1H),7.41-7.35(m,2H),7.30-7.28(m,2H),7.13-7.08(m,2H),4.84-4. 79(m,1H),4.63-4.58(t,1H),4.25-4.20(t,1H),3.63-3.58(m,2H),3.39(s,3H),3.24-3.21(t,2H). MS(ESI+):m / z=514.0[M+1] + .

[0310] Example 26

[0311] (S)-N 1-(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(2,6-dichlorophenylethyl)oxalamide

[0312]

[0313] Using M-5 and NN-6 as raw materials, and employing the same method as in Example 25, Example 26 (T-26) was obtained.

[0314] 1 H NMR(400MHz, CDCl3)δ8.21(d,1H),7.42-7.39(m,1H),7.36-7.28(m,4H),7.13-7.09(m,1H),7.06(d,1H),4. 86-4.79(m,1H),4.61-4.57(dd,1H),4.24-4.19(t,1H),3.63-3.58(m,2H),3.40(s,3H),3.24-3.21(t,2H). MS(ESI+):m / z=514.0[M+1] + .

[0315] Example 27

[0316] (S)-N 1 -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxenyl)-N 2 -(2,6-dichlorobenzyl)oxalamide

[0317]

[0318] Using N-5 and NN-7 as raw materials, and employing the same method as in Example 25, Example 27 (T-27) was obtained.

[0319] 1 H NMR(400MHz, CDCl3)δ8.25(d,1H),7.48-7.46(m,1H),7.35-7.32(m,4H),7.22-7.19(t,1 H),7.08(d,1H),4.85-4.75(m,3H),4.60-4.56(dd,1H),4.25-4.20(t,1H),3.40(s,3H).

[0320] MS(ESI+): m / z = 500[M+1] + .

[0321] Example 28

[0322] (S)-N 1 -(8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -(2,6-dichlorobenzyl)oxalamide

[0323]

[0324] Using M-5 and NN-7 as raw materials, and employing the same method as in Example 25, Example 28 (T-28) was obtained.

[0325] 1 H NMR(400MHz, CDCl3)δ8.26(d,1H),7.48-7.46(m,1H),7.39-7.32(m,4H),7.23-7.19(t,1 H),7.08(d,1H),4.86-4.75(m,3H),4.62-4.57(dd,1H),4.26-4.21(t,1H),3.39(s,3H).

[0326] MS(ESI+): m / z = 500[M+1] + .

[0327] Example 29

[0328] (S)-N 1 -(5-methyl-4-oxo-7-(pyridin-4-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N2-(2-(thiophene-2-yl)ethyl)oxalamide

[0329]

[0330] Using intermediates N-8 and N-9, the preparation method of Example 29 (T-29) is the same as that of Example 17.

[0331] 1H NMR (400MHz, CDCl3) δ8.63 (dd, J=4.5, 1.5Hz, 1H), 8.26 (d, J=7.5Hz, 1H), 7.44–7.3 6(m,5H),7.19(dd,J=7.5,1.3Hz,1H),7.16(dd,J=5.1,1.0Hz,1H),6.94(dd,J=5.1 ,3.4Hz,1H),6.84(d,J=3.2Hz,1H),4.85(dt,J=11.3,7.3Hz,1H),4.63(dd,J=9.7, 7.3Hz, 1H), 4.28 (dd, J=11.2, 9.9Hz, 1H), 3.64–3.55 (m, 2H), 3.07 (t, J=6.7Hz, 2H).

[0332] MS-ESI: m / z = 475.1 [M+H] + .

[0333] Example 30

[0334] (S)-N 1 -(5-methyl-4-oxo-7-(pyridin-4-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N2-phenylacetamide

[0335]

[0336] In Example 21, 40 mg of 4-alkynylpyridine (26.4 mg), PdCl2(PPh3)2 (7.9 mg), and CuI (4.3 mg) were dissolved in DMF (2 ml) and triethylamine (1 ml). The mixture was heated to 85°C under argon protection and reacted for 3 hours. After cooling to room temperature, the solvent was removed by vacuum rotary evaporation. The mixture was then separated by HPLC (mobile phase: A, H2O (+0.1% TFA); B, MeCN; separation conditions: 55% B; flow rate: 10 mL / min; column: Water). Example 30 was obtained by using MSC18, 19×250mm, 10μm.

[0337] 1 H NMR (400MHz, CDCl3) δ8.32–8.23(m,1H),7.51–7.28(m,8H),7.24–7.13(m,4H),4.91–4.78(m, 1H),4.67–4.55(m,1H),4.35–4.22(m,1H),3.65–3.51(m,2H),3.45(s,3H),2.91–2.75(m,2H).

[0338] Example 31

[0339] (S)-N 1 -(2-Chloro-6-fluorobenzyl)-N 2 -(5-methyl-4-oxo-7-(pyridin-4-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0340]

[0341] Example 31 was obtained using the same method as in Example 30, with the raw materials of Example 24 and 4-alkynylpyridine.

[0342] 1 H NMR (400MHz, CDCl3) δ8.65(s,1H),8.28(d,J=7.3Hz,1H),7.54(t,J=5.5Hz,1H),7.46–7.35(m,4H),7.25–7.14( m,3H),7.02(t,J=8.2Hz,1H),4.83(dt,J=11.2,7.3Hz,1H),4.76–4.57(m,3H),4.33–4.21(m,1H),3.44(s,3H).

[0343] Example 32

[0344] (S)-N 1 -(7-(cyclopropylethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -Phenethyloxalamide

[0345]

[0346] Example 32 was obtained using the same method as Example 30, with the raw materials of Example 21 and cyclopropaneacetylene.

[0347] 1 H NMR(400MHz, CDCl3)δ8.23(d,J=7.3Hz,1H),7.34–7.27(m,3H),7.25–7.15(m,5H),7.06(d,J=8.8Hz,1H),4.80(dt,J=11.0,7.3Hz,1H),4.62–4 .54(m,1H),4.27–4.16(m,1H),3.61–3.52(m,2H),3.39(s,3H),2.84(t, J=7.1Hz,2H),1.50–1.41(m,1H),0.94–0.85(m,2H),0.85–0.78(m,2H).

[0348] Example 33

[0349] (S)-N 1 -(5-methyl-7-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -(2-(thien-2-yl)ethyl)oxalamide

[0350]

[0351] The preparation methods for intermediates N-10 and N-11 are described in Example 17. N-11 and NN-4 were obtained in Example 33 by one-step amide condensation.

[0352] 1 H NMR (400MHz, CDCl3) δ8.25(d,J=7.2Hz,1H),7.66(s,1H),7.57(s,1H),7.39(t,J=6.1H z,1H),7.35–7.31(m,2H),7.18–7.11(m,2H),6.93(dd,J=5.1,3.4Hz,1H),6.83(dd,J= 3.4,0.8Hz,1H),4.84(dt,J=11.3,7.4Hz,1H),4.62(dd,J=9.7,7.3Hz,1H),4.25(dd,J=11. 2,9.8Hz,1H),3.93(s,3H),3.59(qd,J=6.8,1.8Hz,2H),3.43(s,3H),3.07(t,J=6.7Hz,2H).

[0353] MS-ESI: m / z = 478.1 [M+H] + .

[0354] Example 34

[0355] (S)-N 1 -(5-methyl-7-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4-[azapyroxen-3-yl)-N 2 -Phenethyloxalamide

[0356]

[0357] Example 34 was obtained using N-11 and NN-2 as raw materials and the same method as in Example 33.

[0358] 1H NMR(400MHz, CDCl3)δ8.25(d,J=7.2Hz,1H),7.66(s,1H),7.57(s,1H),7.39(t,J=6.1Hz, 1H),7.35–7.31(m,2H),7.18–7.11(m,2H),6.93(dd,J=5.1,3.4Hz,1H),6.83(dd,J=3.4, 0.8Hz, 1H), 4.84 (dt, J=11.3, 7.4Hz, 1H), 4.62 (dd, J=9.7, 7.3Hz, 1H), 4.25 (dd, J=11.2, 9.8Hz, 1H), 3.93 (s, 3H), 3.59 (qd, J = 6.8, 1.8Hz, 2H), 3.43 (s, 3H), 3.07 (t, J = 6.7Hz, 2H).

[0359] MS-ESI: m / z = 478.1 [M+H] + .

[0360] Example 35

[0361] (S)-N 1 -(2-Chloro-6-fluorobenzyl)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0362]

[0363] Example 35 was obtained using N-11 and NN-5 as raw materials and the same method as in Example 33.

[0364] 1 H NMR(400MHz, CDCl3)δ8.28(d,J=7.3Hz,1H),7.64(s,1H),7.57(s,1H),7.35–7.29(m,2H),7.25–7.17(m,2H),7.15–7.09(m,1H),7.01(t, J=8.4Hz,1H),4.81(dt,J=11.0,7.4Hz,1H),4.74–4.55(m,3H),4.24(t,J=10.5Hz,1H),4.12(q,J=7.1Hz,1H),3.92(s,3H),3.41(s,3H).

[0365] Example 36

[0366] (S)-N 1-(5-methyl-7-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -(2-(thien-3-yl)ethyl)oxalamide

[0367]

[0368] Example 36 was obtained using N-11 and NN-3 as raw materials and the same method as in Example 33.

[0369] 1 H NMR(400MHz, CDCl3)δ8.26(d,J=7.4Hz,1H),7.65(s,1H),7.57(s,1H),7.34–7 .30(m,2H),7.30–7.27(m,1H),7.16–7.11(m,1H),7.01(s,1H),6.93(d,J=4.1H z,1H),4.83(dt,J=11.2,7.4Hz,1H),4.61(dd,J=9.7,7.4Hz,1H),4.30–4.21( m, 1H), 3.92 (s, 3H), 3.56 (q, J = 6.6Hz, 2H), 3.42 (s, 3H), 2.88 (t, J = 7.0Hz, 2H).

[0370] Example 37

[0371] (S)-N 1 -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azaxazon-3-yl)-N 2 -(2-(thien-2-yl)ethyl)oxalamide

[0372]

[0373] The preparation method of Example 37 is the same as that of Example 17. The raw material is N-5 and 3-methylbutynol-3, which are reacted under Sonogashira coupling conditions to obtain intermediate N-12, and then condensed with intermediate NN-4 in one step to obtain the target compound (T-37).

[0374] 1H NMR(400MHz, CDCl3)δ8.25(d,J=7.3Hz,1H),7.49–7.40(m,1H),7.29–7.27(m,1H) ),7.19–7.13(m,1H),7.13–7.08(m,1H),6.96–6.90(m,1H),6.86–6.80(m,1H),4 .81(dt,J=11.2,7.3Hz,1H),4.59(dd,J=9.7,7.4Hz,1H),4.24(dd,J=11.1,10.0 Hz, 1H), 3.58 (q, J = 6.6Hz, 2H), 3.40 (s, 3H), 3.06 (t, J = 6.8Hz, 2H), 1.62 (s, 6H).

[0375] Example 38

[0376] (S)-N 1 -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azaxazon-3-yl)-N 2 -Phenethyloxalamide

[0377]

[0378] The preparation method of Example 38 is the same as that of Example 37, which is to obtain the target compound (T-38) by one-step condensation of intermediate N-12 and intermediate NN-4. 1 H NMR (400MHz, CDCl3) δ8.24(d,J=7.3Hz,1H),7.33–7.26(m,4H),7.25–7.09(m,5H),4.80(dt,J=11.2,7.4Hz,1H),4.59(dd,J =9.7,7.3Hz,1H),4.24(dd,J=11.2,9.9Hz,1H),3.62–3.51(m,3H),3.41(s,3H),2.83(dd,J=13.3,6.2Hz,2H),1.63(s,6H).

[0379] Example 39

[0380] (S)-N 1 -(7-(cyclopropylethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -(2-(thien-2-yl)ethyl)oxalamide

[0381]

[0382]

[0383] The preparation method of Example 39 is the same as that of Example 17. The raw material N-5 is reacted with cyclopropaneacetylene under Sonogashira coupling conditions to obtain intermediate N-13, which is then condensed with intermediate NN-4 in one step to obtain the target compound (T-39).

[0384] 1 H NMR(400MHz, CDCl3)δ8.24(d,J=7.1Hz,1H),7.46–7.39(m,1H),7.25–7.19(m,2H),7.1 8–7.13(m,1H),7.09–7.04(m,1H),6.96–6.90(m,1H),6.85–6.80(m,1H),4.80(dt,J=11 .0,7.4Hz,1H),4.63–4.54(m,1H),4.23(t,J=10.5Hz,1H),3.73(dd,J=13.9,6.9Hz,1H ), 3.58 (dd, J = 12.9, 6.3 Hz, 2H), 3.39 (s, 3H), 0.95–0.85 (m, 2H), 0.82 (d, J = 2.8 Hz, 2H).

[0385] Example 40

[0386] (S)-N 1 -(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)-N 2 -Phenethyloxalamide

[0387]

[0388] The preparation method of Example 40 (T-40) can be referred to Example 1. The preparation method of intermediate O-5 can be referred to the literature (J.Med.Chem.2017,60,1247-1261). 1 H NMR (400MHz, CDCl3) δ8.27(d,J=7.4Hz,1H),7.34(s,1H),7.32–7.27(m,2H),7.25–7.20(m,4H),7.19–7.14(m,3H),4.82(dt,J=11 .2,7.5Hz,1H),4.60(dd,J=9.8,7.4Hz,1H),4.23(dd,J=11.2,9.8Hz,1H),3.63–3.47(m,2H),3.41(s,3H),2.83(t,J=7.1Hz,2H). MS-ESI:m / z=368.2[M+H] + .

[0389] Example 41

[0390] (±)-N 1 -(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-3-yl)-N 2 -Phenethyloxalamide

[0391]

[0392] The preparation method of Example 41 (T-41) can be referred to Example 1. The preparation method of intermediate P-5 can be referred to the patent (BANDYOPADHYAY, Heterocyclic amides as kinase inhibitors.WO 2014 / 125444).

[0393] 1 H NMR (400MHz, CDCl3) δ8.22(d,J=7.6Hz,1H),7.51(s,1H),7.36(t,J=4.9Hz,1H),7.30(t,J=7.3Hz,3H),7.25–7.16(m,5H),7.00(d,J=7.5Hz,1H),4 .48(dt,J=11.4,7.7Hz,1H),3.65–3.47(m,2H),3.07–2.94(m,1H),2.84( t, J=7.1Hz, 2H), 2.71 (ddd, J=17.0, 11.2, 6.2Hz, 2H), 2.12–1.99 (m, 1H). MS-ESI:m / z=352.0[M+H] + .

[0394] Example 42

[0395] (±)-N 1 -(1-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]aza-3-yl)-N 2 -Phenethyloxalamide

[0396]

[0397] Under ice bath conditions, 50 mg of Example 41 was dissolved in 2 ml of DMF, 64.9 mg of cesium carbonate was added, followed by 0.011 ml of MeI. The mixture was stirred at 0°C for 5 min, then allowed to react at room temperature for 2 h. After 2 h, EA was added first, followed by ice water. The mixture was extracted three times with EA, and the organic phases were combined. The organic phases were washed three times with water and three times with saturated brine. Anhydrous sodium sulfate was added to dry the organic phase, which was then concentrated. The white solid of Example 42 (T-42) was obtained by preparative HPLC. 1H NMR(400MHz, CDCl3)δ8.29(d,J=7.5Hz,1H),7.40-7.34(m,1H),7.34–7.26(m,3H),7.25-7.20(m,2H),7.20-7.14(m,4H),4.41 (dt,J=11.1,7.6Hz,1H),3.61–3.46(m,2H),3.41(s,3H),2.85(dt,J=14.2,7.6Hz,3H),2.66-2.55(m,2H),2.04–1.93(m,1H). MS-ESI:m / z=366.1[M+H] + .

[0398] Example 43

[0399] (S)-N 1 -(7-(cyclopropylethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)-N 2 -Phenethyloxalamide

[0400]

[0401] The preparation method of intermediate Q-7 is described in Example 17, using intermediate Q-4 and cyclopropaneacetylene as raw materials.

[0402] At room temperature, intermediates NN-2 (1 eq), Q-7 (1 eq), and TCFH (N,N,N',N'-tetramethylchloromethamidine hexafluorophosphate, 1.2 eq) were dissolved in DMF (0.1 M reactant concentration). NMI (N-methylimidazole) (2.6 eq) was added under ice bath cooling, the temperature was slowly increased, and the mixture was stirred at room temperature for 4 h. The reaction was then quenched with ice water. The mixture was extracted twice with EA, and the organic phases were combined, washed 10 times with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, and the organic phase was concentrated. The target product, Example 43 (T-43), was obtained by rapid column chromatography.

[0403] 1H NMR (400MHz, CDCl3) δ8.30(d,J=7.7Hz,1H),7.53(d,J=7.9Hz,1H),7.30(m,3H),7.2 5(d,J=1.7Hz,1H),7.24–7.19(m,2H),7.17(d,J=7.0Hz,2H),4.53(dt,J=11.5,7.2H z,1H),3.69(dd,J=11.0,6.7Hz,1H),3.62–3.47(m,2H),3.39(s,3H),2.90(t,J=11. 3Hz, 1H), 2.83 (t, J = 7.1Hz, 2H), 1.50–1.42 (m, 1H), 0.91 (m, 2H), 0.86–0.79 (m, 2H).

[0404] MS-ESI: m / z = 448.2 [M+H] + .

[0405] Example 44

[0406] (S)-N 1 -(5-methyl-4-oxo-7-(pyridin-4-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)-N2-phenylacetamide

[0407]

[0408] The synthesis method of intermediate Q-9 can be found in Example 17. Using intermediate Q-9 and intermediate NN-2 as raw materials, the same condensation conditions as in Example 42 were used, and the mixture was further pulped with methyl tert-butyl ether to obtain Example 44 (T-44, white solid).

[0409] 1 H NMR (400MHz, CDCl3) δ8.64(d,J=4.9Hz,2H),8.32(d,J=7.8Hz,1H),7.67(d,J= 7.9Hz,1H),7.46-7.36(m,5H),7.15(d,J=4.5Hz,1H),6.96–6.90(m,1H),6.83 (d,J=2.9Hz,1H),4.58(dt,J=11.5,7.0Hz,1H),3.74(dd,J=11.0,6.6Hz,1H), 3.65–3.51(m,2H),3.45(s,3H),3.06(t,J=6.8Hz,2H),2.97(t,J=11.3Hz,1H). MS-ESI: m / z = 485.2 [M+H] + .

[0410] Example 45

[0411] (S)-N 1 -(5-methyl-7-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)-N2-phenylacetamide

[0412]

[0413]

[0414] The synthesis method of intermediate Q-17 is the same as in Example 17. Using intermediates NN-2 and Q-11 as raw materials, Example 45 (T-45, white solid) was obtained under the same condensation conditions as in Example 42.

[0415] 1 H NMR (400MHz, CDCl3) δ8.32(d,J=7.4Hz,1H),7.66(s,1H),7.59(m,2H),7.39–7.27(m,5H),7.24-7.19(m,1H),7.17(d,J=7.3Hz,2H),4.56(dt, J=14.6,7.4Hz,1H),3.93(s,3H),3.72(dd,J=10.9,6.7Hz,1H),3.61-3.51(m,2H),3.42(s,3H),2.93(t,J=11.2Hz,1H),2.83(t,J=7.0Hz,2H). MS-ESI:m / z=488.2[M+H] + .

[0416] Example 46

[0417] (S)-N 1 -(5-methyl-7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)-N 2 -Phenethyloxalamide

[0418]

[0419] Using intermediate Q-13 as a raw material, Boc removal was performed under the same conditions as in Example 42 to obtain elimination product intermediate Q-13, which was a brown oily substance with MS-ESI: m / z = 273.1 [M+H]. + .

[0420] Using intermediates NN-2 and Q-13 as raw materials, Example 46 (T-46, white solid) was obtained under the same condensation conditions as Example 42.

[0421] 1 H NMR (400MHz, CDCl3) δ8.31(d,J=7.8Hz,1H),7.58(d,J=8.0Hz,1H),7.35–7.27(m,5H),7.24–7.19(m,1H),7.17(d,J=7.2Hz,2H),5.44(s,1H),5.37( s,1H),4.59–4.50(m,1H),3.71(dd,J=11.0,6.7Hz,1H),3.61-3.49(m,2H) ,3.41(s,3H),2.93(t,J=11.3Hz,1H),2.83(t,J=7.1Hz,2H),1.99(s,3H). MS-ESI:m / z=448.2[M+H] + .

[0422] Example 47

[0423] (S)-N 1 -(7-(cyclopropylethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)-N 2 -(2-(thien-2-yl)ethyl)oxalamide

[0424]

[0425] Using intermediates Q-7 and NN-4 as raw materials, and employing the same condensation conditions as in Example 42, Example 47 (T-47) was obtained. 1 H NMR (400MHz, CDCl3) δ8.30(d,J=7.6Hz,1H),7.53(d,J=8.0Hz,1H),7.41-7.35(m,1H),7.22( d,J=8.0Hz,1H),7.15(d,J=5.1Hz,1H),6.94–6.90(m,1H),6.82(d,J=3.3Hz,1H),4.54(dt,J =11.5,7.3Hz,1H),3.70(dd,J=11.0,6.7Hz,1H),3.63-3.52(m,2H),3.39(s,3H),3.05(t,J= 6.7Hz,2H),2.91(t,J=11.3Hz,1H),1.50-1.41(m,1H),0.95–0.86(m,2H),0.86–0.79(m,2H). MS-ESI:m / z=454.1[M+H] + .

[0426] Example 48

[0427] (S)-N 1 -(5-methyl-7-(3-methylbut-3-en-1-yn-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)-N 2 -(2-(thien-2-yl)ethyl)oxalamide

[0428]

[0429] Using intermediates NN-4 and Q-13 as raw materials, and after condensation under the same conditions as in Example 42, the mixture was pulped with methyl tert-butyl ether to obtain Example 48 (T-48, white solid). 1 H NMR(400MHz, CDCl3)δ8.31(d,J=7.4Hz,1H),7.59(d,J=8.0Hz,1H),7.41-7.35(m,1H) ,7.34–7.28(m,2H),7.15(dd,J=5.1,1.1Hz,1H),6.94-6.91(m,1H),6.82(m,1H),5.4 4(s,1H),5.38–5.35(s,1H),4.60–4.51(m,1H),3.72(dd,J=11.0,6.7Hz,1H),3.62-3 .52(m,2H),3.41(s,3H),3.05(t,J=6.8Hz,2H),2.93(t,J=11.3Hz,1H),1.99(s,3H). MS-ESI:m / z=454.1[M+H] + .

[0430] Example 49

[0431] (S)-N 1 -(5-methyl-4-oxo-7-(pyridin-4-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)-N2-(2-(thien-2-yl)ethyl)oxalamide

[0432]

[0433] Using intermediates Q-9 and NN-4 as raw materials, and after being pulped with methyl tert-butyl ether under the same conditions as in Example 1, Example 49 (T-49, white solid) was obtained.

[0434] 1H NMR (400MHz, CDCl3) δ8.64(d,J=4.9Hz,2H),8.32(d,J=7.8Hz,1H),7.67(d,J =7.9Hz,1H),7.42(m,5H),7.15(d,J=4.5Hz,1H),6.96–6.90(m,1H),6.83(d, J=2.9Hz,1H),4.58(dt,J=11.5,7.0Hz,1H),3.74(dd,J=11.0,6.6Hz,1H),3. 65–3.51(m,2H),3.45(s,3H),3.06(t,J=6.8Hz,2H),2.97(t,J=11.3Hz,1H). MS-ESI: m / z = 491.1 [M+H] + .

[0435] Example 50

[0436] (S)-N 1 -(5-methyl-7-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-yl)-N 2 -(2-(thien-2-yl)ethyl)oxalamide

[0437]

[0438] Using intermediates Q-11 and NN-4 as raw materials, Example 50 (T-50, white solid) was obtained under the same conditions as in Example 42.

[0439] 1 H NMR (400MHz, CDCl3) δ8.32(d,J=7.7Hz,1H),7.66(s,1H),7.59(d,J=11.6H z,2H),7.41-7.30(m,3H),7.16-7.12(m,1H),6.95–6.89(m,1H),6.84-6.80 (m,1H),4.57(dt,J=11.4,7.5Hz,1H),3.93(s,2H),3.76-3.68(m,1H),3.6 3-3.51(m,2H),3.42(s,3H),3.05(t,J=6.7Hz,2H),2.93(t,J=11.3Hz,1H). MS-ESI: m / z = 494.1 [M+H] + .

[0440] Example 51

[0441] (S)-N 1-(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)-N 2 -Phenethyloxalamide

[0442]

[0443] Using intermediate Q-5 as a raw material, intermediate Q-14 was obtained by the synthesis method of Example 37, and then it underwent a condensation reaction with intermediate NN-2 to obtain Example 51 (T-51, white solid).

[0444] 1 H NMR (400MHz, CDCl3) δ8.30(d,J=7.7Hz,1H),7.58(d,J=7.9Hz,1H),7.30(m,4H),7.22(m,1H),7.17(d,J=7.1Hz,2H),4.53(dt,J=11. 6,7.4Hz,1H),3.70(dd,J=11.0Hz,6.7Hz,1H),3.55m,2H),3.40(s,3H),2.92(t,J=11.3Hz,1H),2.84(d,J=7.1Hz,2H),1.63(s,6H).

[0445] MS-ESI: m / z = 466.2 [M+H] + .

[0446] Example 52

[0447] (S)-N 1 -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)-N 2 -(2-(thien-2-yl)ethyl)oxalamide

[0448]

[0449] Using intermediates NN-2 and Q-14 as raw materials, and after condensation under the same conditions as in Example 42, the mixture was pulped with methyl tert-butyl ether to obtain Example 52 (T-52, white solid).

[0450] 1H NMR (400MHz, CDCl3) δ8.30(d,J=7.8Hz,1H),7.58(d,J=7.9Hz,1H),7.41-7.34(m,1H ),7.33-7.28(m,2H),7.15(dd,J=5.1,0.9Hz,1H),6.93(dd,J=5.0,3.5Hz,1H),6.82( d,J=2.6Hz,1H),4.54(dt,J=11.5,7.2Hz,1H),3.71(dd,J=11.0,6.7Hz,1H),3.63–3 .52(m,2H),3.41(s,3H),3.06(t,J=6.8Hz,2H),2.93(t,J=11.3Hz,1H),1.63(s,6H).

[0451] MS-ESI: m / z = 472.2 [M+H] + .

[0452] Example 53

[0453] (S)-N 1 -(5-methyl-7-(1-methyl-1H-pyrazol-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)-N 2 -Phenethyloxalamide

[0454]

[0455] Step 1: tert-butyl(S)-(5-methyl-7-(1-methyl-1H-pyrazol-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-ylcarbamate

[0456]

[0457] (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa]-3-yl)tert-butyl carbamate (150.0 mg, 0.41 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (118.0 mg, 0.57 mmol) were dissolved in dioxane (4.0 mL) and water (1.5 mL) under nitrogen protection. Potassium carbonate (167.0 mg, 1.21 mmol) and Pd(dppf)Cl2 (27.7 mg, 0.04 mmol) were added. The reaction mixture was heated to 100 °C and reacted for 2 hours. The reaction mixture was poured into ice water (10.0 mL), extracted with EA (20.0 mL), dried over sodium sulfate, filtered, and concentrated to dryness. Column chromatography was used for separation and purification (mobile phase gradient: 0-80% ethyl acetate / petroleum ether) to obtain 173.0 mg of the target compound.

[0458] MS(ESI+): m / z = 373.2[M-Boc+1] + .

[0459] Step 2: (S)-3-amino-5-methyl-7-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrobenzo[b][1,4]oxazoline-4(5H)-one

[0460]

[0461] The product from the first step (173.0 mg, 0.46 mmol) was dissolved in dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added dropwise to the reaction system. After reacting for 1 hour, the reaction solution was evaporated to dryness, dissolved again in dichloromethane (10.0 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The organic phase was collected, dried over sodium sulfate, filtered, and concentrated to dryness to give 114.0 mg of the target compound.

[0462] MS(ESI+): m / z = 273.1 [M+1] + .

[0463] Step 3: (S)-N 1 -(5-methyl-7-(1-methyl-1H-pyrazol-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)-N 2 -Phenethyloxalamide

[0464]

[0465] The product from step three (21.3 mg, 0.11 mmol) was dissolved in 1.0 mL of DMF, and HATU (41.8 mg, 0.11 mmol) and DIPEA (28.4 mg, 0.22 mmol) were added. The reaction mixture was stirred overnight at room temperature. Then, 10.0 mL of saturated ammonium chloride and 15.0 mL of ethyl acetate were added. The organic phase was washed three times with 10.0 mL of saturated ammonium chloride and twice with 10.0 mL of saturated brine. The organic phase was retained and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was evaporated to dryness. The solution was then purified by column chromatography (using a mobile phase gradient of 0-100% ethyl acetate in petroleum ether) to obtain 33.0 mg of the target compound.

[0466] 1 H NMR(400MHz, CDCl3)δ8.25(d,1H),7.72(s,1H),7.60(s,1H),7.31-7.28(m,4H),7.24-7.21(m,1H),7.19-7.15(m,3H),4.90-4.84(m,1 H),4.62-4.58(t,1H),4.25-4.20(t,1H),3.97(s,3H),3.60-3.54(m,2H),3.45(s,3H),2.86-2.82(m,2H).MS(ESI+):m / z=448.2[M+1] + .

[0467] Example 54

[0468] (S)-N 1 -(5-methyl-7-(1-methyl-1H-pyrazol-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)-N 2 -(2-(thien-2-yl)ethyl)oxalamide

[0469]

[0470] The target compound was obtained by using 2-oxo-2-(((2-(thiophen-2-yl)ethyl)amino)acetic acid instead of 2-oxo-2-(phenylethylamino)acetic acid and the product of step 2 in Example 53 as starting materials, under the same reaction conditions and methods.

[0471] 1H NMR(400MHz, CDCl3)δ8.26(d.1H),7.72(s,1H),7.60(s,1H),7.41-7.38(m,1H),7.31-7.29(m,1H),7.17-7.158(m,2H),6.94-6.92(m,1H),6 .83-6.82(m,1H),4.91-4.85(m,1H),4.63-4.59(t,1H),4.26-4.21(t ,1H),3.97(s,3H),3.62-3.56(m,2H),3.45(s,3H),3.08-3.05(m,2H).

[0472] MS(ESI+): m / z = 454.1 [M+1] + .

[0473] Example 55

[0474] (S)-N 1 -(5-methyl-7-(1-methyl-1H-pyrazol-5-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)-N 2 -Phenethyloxalamide

[0475]

[0476] Step 1: tert-butyl(S)-(5-methyl-7-(1-methyl-1H-pyrazol-5-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-ylcarbamate

[0477]

[0478] (S)-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa]-3-yl)tert-butyl carbamate (150.0 mg, 0.41 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (118.0 mg, 0.57 mmol) were dissolved in dioxane (4.0 mL) and water (1.5 mL) under nitrogen protection. Potassium carbonate (167.0 mg, 1.21 mmol) and Pd(dppf)Cl2 (27.7 mg, 0.04 mmol) were added. The reaction mixture was heated to 100 °C and reacted for 2 hours. The reaction mixture was then poured into ice water (10.0 mL), extracted with EA (20.0 mL), dried over sodium sulfate, filtered, and concentrated to dryness. Column chromatography was used for separation and purification (mobile phase gradient 0-80% ethyl acetate / petroleum ether) to give 180.0 mg of the target compound.

[0479] MS(ESI+): m / z = 373.2[M-Boc+1] + .

[0480] Step 2: (S)-3-amino-5-methyl-7-(1-methyl-1H-pyrazol-5-yl)-2,3-dihydrobenzo[b][1,4]oxazoline-4(5H)-one

[0481]

[0482] The product from the first step (180.0 mg, 0.48 mmol) was dissolved in dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added dropwise to the reaction system. After reacting for 1 hour, the reaction solution was directly evaporated to dryness. It was then dissolved in dichloromethane (10.0 mL), and the pH was adjusted to 8 with a saturated sodium bicarbonate aqueous solution. The organic phase was collected, dried over sodium sulfate, filtered, and concentrated to dryness to give 137.0 mg of the target compound. MS (ESI+): m / z = 273.1 [M+1] + .

[0483] Step 3 (S)-N 1 -(5-methyl-7-(1-methyl-1H-pyrazol-5-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)-N 2 -Phenethyloxalamide

[0484]

[0485] Using the product from the second step as a raw material, the target compound was obtained under the same reaction conditions and methods as in the third step of Example 53.

[0486] 1 H NMR(400MHz, CDCl3)δ8.25(d,1H),7.54-7.53(m,1H),7.33-7.29(m,3H),7.25-7.21(m,3H),7.19-7.17(d,2H),4.94 -4.88(m,1H),4.66-4.62(t,1H),4.31-4.26(t,1H),3.91(s,3H),3.61-3.55(m,2H),3.45(s,3H),2.87-2.83(m,2H).

[0487] MS(ESI+): m / z = 448.2[M+1] + .

[0488] Example 56

[0489] (S)-N 1-(5-methyl-7-(1-methyl-1H-pyrazol-5-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)-N 2 -(2-(thien-2-yl)ethyl)oxalamide

[0490]

[0491] The target compound was obtained by using 2-oxo-2-(((2-(thiophen-2-yl)ethyl)amino)acetic acid instead of 2-oxo-2-(phenylethylamino)acetic acid and the product of step 2 in Example 55 as starting materials, under the same reaction conditions and methods as step 3 in Example 53.

[0492] 1 H NMR(400MHz, CDCl3)δ8.28(d,1H),7.54-7.53(m,1H),7.41-7.38(m,1H),7.27-7.26(m,3H),7.16(d,1H),6.95-6.93(m,1H),6.84-6.83(m,1H ),6.326.31(m,1H),4.95-4.88(m,1H),4.67-4.63(m,1H),4.32-4.27( m,1H),3.91(s,3H),3.63-3.57(m,2H),.45(s,3H),3.09-3.06(m,2H).

[0493] MS(ESI+): m / z = 454.1 [M+1] + .

[0494] Example 57

[0495] (S)-N 1 -(2,6-Dibromobenzyl)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)oxalamide

[0496]

[0497] Step 1: 1,3-Dibromo-2-(bromomethyl)benzene

[0498] 1,3-Dibromo-2-methylbenzene (2.50 g, 10.0 mmol) was dissolved in carbon tetrachloride (40.0 mL), AIBN (164.0 mg, 1.0 mmol) was added, followed by NBS (1.78 g, 10.0 mmol). Nitrogen gas was then added to replace the nitrogen atmosphere. The reaction mixture was heated to 80 °C and maintained for 14 hours. The reaction system was then cooled to room temperature, filtered through diatomaceous earth, evaporated to dryness, and purified by column chromatography (mobile phase gradient 0-5% ethyl acetate / petroleum ether) to give 2.75 g of the target compound. 1 H NMR (400MHz, CDCl3): δ7.55(d,2H),7.04-7.00(t,1H),4.83(s,2H).

[0499] Step 2: N-[(2,6-dibromophenyl)methyl]-N-[(tert-butoxy)carbonyl]tert-butyl carbamate

[0500] 1,3-Dibromo-2-(bromomethyl)benzene (2.65 g, 8.03 mmol) was dissolved in DMF (25.0 mL), potassium carbonate (2.22 g, 16.06 mmol) was added, followed by N-[(tert-butoxy)carbonyl]carbamate tert-butyl ester (2.09 g, 9.64 mmol). The mixture was stirred overnight, heated to 45 °C, and stirred for 1 hour. The solid was filtered off with diatomaceous earth. Ethyl acetate (40 mL) was added, followed by washing with water (20 mL x 3), then with saturated brine (20 mL). The mixture was dried over sodium sulfate, filtered, and evaporated to dryness. Column chromatography was used for purification (mobile phase gradient 0-10% ethyl acetate in petroleum ether solution) to give 3.45 g of the target compound. MS (ESI+): m / z = 464.0 [M+1] + .

[0501] Step 3 (2,6-dibromophenyl)methylamine

[0502] The product from the second step (3.45 g, 7.42 mmol) was dissolved in dichloromethane (30 mL). Under ice bath conditions, TFA (6.0 mL) was added, and the mixture was stirred for 1 hour under ice bath conditions. The reaction mixture was directly evaporated to dryness, dissolved in dichloromethane (10 mL), and the pH was adjusted to approximately 9 with 1 M sodium hydroxide aqueous solution. The mixture was extracted with dichloromethane (10 mL x 2), and the organic phases were combined and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was evaporated to dryness. Then, column chromatography was used for purification (mobile phase gradient of 0-5% methanol in dichloromethane solution), finally yielding 1.85 g of the target compound. MS (ESI+): m / z = 264.0 [M+1] + .

[0503] Step 4: methyl 2-((2,6-dibromobenzyl)amino)-2-oxyacetate

[0504]

[0505] (2,6-Dibromophenyl)methylamine (1.85 g, 6.98 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled in a dry ice bath at -40 °C. DIPEA (2.25 g, 17.45 mmol) was added directly to the reaction system in one batch, while monomethyl oxaloyl chloride (1.07 g, 8.73 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to return to room temperature naturally and stirred overnight. 2.0 mL of saturated ammonium chloride aqueous solution and 10.0 mL of ethyl acetate were added. The mixture was separated, and the organic phase was washed with 10.0 mL of saturated brine and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated to dryness. The solution was purified by column chromatography (fluidity gradient 0-30-80% ethyl acetate in petroleum ether solution) to give 2.32 g of the target compound. MS (ESI+): m / z = 349.9 [M+1] + .

[0506] Step 5: 2-((2,6-dibromobenzyl)amino)-2-oxyacetic acid

[0507]

[0508] The product from step four (2.32 g, 6.61 mmol) was dissolved in a mixture of 20.0 mL tetrahydrofuran and 6.0 mL water, cooled in an ice bath, and then lithium hydroxide solution (4.95 mL, 2 M, 9.92 mmol) was added. The mixture was stirred overnight, and the pH was adjusted to 6 with 1 M dilute hydrochloric acid. The reaction mixture was then evaporated to dryness, and the solution was removed three times with toluene to obtain 2.2 g of crude product of the target compound.

[0509] Step 6 (S)-N 1 -(2,6-Dibromobenzyl)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)oxalamide

[0510]

[0511] The product of step 5 (34.0 mg, 0.08 mmol) and (S)-3-amino-5-methyl-7-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxa-4(5H)-one (20.0 mg, 0.068 mmol) were dissolved in 1.0 mL of DMF, and HATU (33.0 mg, 0.088 mmol) and DIPEA (26.0 mg, 0.08 mmol) were added. 0.20 mmol) was added, and the reaction was stirred overnight at room temperature. 10.0 mL of saturated ammonium chloride and 15.0 mL of ethyl acetate were added. The organic phase was washed three times with 10.0 mL of saturated ammonium chloride, and then twice with 10.0 mL of saturated brine. The organic phase was retained and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was evaporated to dryness. The solution was then purified by column chromatography (using a mobile phase gradient of 0-80% ethyl acetate in petroleum ether), finally yielding 12.0 mg of the target compound.

[0512] 1 H NMR (400MHz, CDCl3): δ8.28(d,1H),7.65(s,1H),7.57-7.52(m,3H),7.48-7.46(m,1H),7.34-7.32(m,2H),7.13(d,1H),7.06 -7.03(t,1H),4.87-4.81(m,3H),4.63-4.59(m,1H),4.27-4.22(m,1H),3.92(s,3H),3.43(s,3H).MS(ESI+):m / z=614.0[M+1] + .

[0513] Example 58

[0514] (S)-N 1 -(2-bromo,6-chlorobenzyl)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)oxalamide

[0515]

[0516] Step 1: 2-((2-bromo,6-chlorobenzyl)amino)-2-oxyacetic acid

[0517]

[0518] The target compound was obtained using 1-bromo-3-chloro-2-methylbenzene as a starting material and under the same reaction conditions as the first to fifth steps of Example 57.

[0519] Step 2 (S)-N 1-(2-bromo,6-chlorobenzyl)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)oxalamide

[0520]

[0521] The target compound was obtained using 2-((2-bromo,6-chlorobenzyl)amino)-2-oxyacetic acid and S)-3-amino-5-methyl-7-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxa-4 as starting materials under the same reaction conditions as in step 6 of Example 57. 1 H NMR (400MHz, CDCl3) δ8.28(d,1H),7.65(s,1H),7.56(s,1H),7.52-7.47(m,2H),7.38-7.32(m,3H),7.15-7.11(m,2 H),4.84-4.79(m,3H),4.63-4.59(m,1H),4.27-4.22(m,1H),3.92(s,3H),3.42(s,3H).MS(ESI+):m / z=570.0[M+1] + .

[0522] Example 59

[0523] (S)-N 1 -(2,6-Dimethoxybenzyl)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)oxalamide

[0524]

[0525] Step 1: Methyl 2-((2,6-dimethoxybenzyl)amino)-2-oxyacetate

[0526]

[0527] Compound (2,6-dimethoxyphenyl)methylamine (0.96 g, 5.74 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled in a dry ice bath at -40 °C under a nitrogen atmosphere. DIPEA (1.85 g, 14.35 mmol) was added directly to the reaction system in a single batch, while monomethyl oxaloyl chloride (0.879 g, 7.18 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to return to room temperature naturally, and stirring continued overnight. Then, 2.0 mL of saturated ammonium chloride aqueous solution and 10.0 mL of ethyl acetate were added. The mixture was separated, and the organic phase was washed with 10.0 mL of saturated brine and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off, and the filtrate was concentrated and purified by column chromatography (mobile phase gradient 0-30-80% ethyl acetate in petroleum ether solution) to give 1.13 g of the target compound.

[0528] MS(ESI+): m / z = 254.0 [M+1] + .

[0529] Step 2: 2-((2,6-dimethoxybenzyl)amino)-2-oxoacetic acid

[0530]

[0531] The product from the first step (1.13 g, 4.47 mmol) was dissolved in a mixture of 15.0 mL tetrahydrofuran and 5.0 mL water, cooled in an ice bath, and then a solution of lithium hydroxide (1.34 mL, 4 M, 5.36 mmol) was added. After stirring overnight, 1 M dilute hydrochloric acid was added to adjust the pH to 6. The reaction was then directly evaporated to dryness, and the product was rinsed three times with toluene to obtain 1.20 g of crude product of the target compound.

[0532] MS(ESI+): m / z = 240.0 [M+1] + .

[0533] Step 3 (S)-N 1 -(2,6-Dimethoxybenzyl)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)oxalamide

[0534]

[0535] Using the product of the second step and S)-3-amino-5-methyl-7-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxa-4 as starting materials, the target compound was obtained under the same reaction conditions as in step 6 of Example 57.

[0536] 1H NMR (400MHz, CDCl3): δ8.29(d,1H),7.65(s,2H),7.56(s,1H),7.32-7.31(m,2H),7.24-7.20(m,1H),7.13-7.11(m,1H),6.54(d, 2H),4.86-4.79(m,1H),4.64-4.54(m,3H),4.25-4.20(m,1H),3.92(s,3H),3.83(s,6H),3.42(s,3H).MS(ESI+):m / z=518.0[M+1] + .

[0537] Example 60

[0538] (S)-N 1 -(2,6-Dimethylbenzyl)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)oxalamide

[0539]

[0540] Step 1 (2,6-dimethylphenyl)methylamine

[0541] 2,6-Dimethylbenzyl nitrile (1.31 g, 10.0 mmol) was dissolved in methanol (30 mL) and ammonia (10 mL), Raney nickel (1.5 g) was added, and the mixture was heated to 50 °C and stirred overnight. The reaction solution was then filtered through diatomaceous earth and evaporated to dryness to obtain 1.40 g of crude target compound.

[0542] MS(ESI+): m / z = 136.0 [M+1] + .

[0543] Step 2: 2-((2,6-dimethylbenzyl)amino)-2-oxoacetic acid

[0544]

[0545] The target compound was obtained from (2,6-dimethylphenyl)methylamine under the same reaction conditions as in steps four and five of Example 57.

[0546] Step 3 (S)-N 1 -(2,6-Dimethylbenzyl)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-3-yl)oxalamide

[0547]

[0548] The target compound was obtained using the product of the second step and (S)-3-amino-5-methyl-7-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxa-4 as starting materials under the same reaction conditions as in step 6 of Example 57.

[0549] MS(ESI+): m / z = 486.2[M+1] + .

[0550] Example 61

[0551]

[0552] (S)-N 1 -(3-Fluorophenylethyl)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0553]

[0554] Example 61 was obtained by rapid column chromatography purification (eluent: petroleum ether / ethyl acetate: 1 / 2-2 / 3) of a one-step amide condensation (NN-8) of (S)-3-amino-5-methyl-7-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxa-4(N-11) and 2-((3-fluorophenylethyl)amino)-2-oxoacetic acid) to obtain 2 ...

[0555] 1 H NMR(400MHz, CDCl3)δ8.25(d,J=7.5Hz,1H),7.65(s,1H),7.57(s,1H),7.41–7.30(m,4H),7.18–7.11(m,1H),7.01–6.87(m,4H),4 .91–4.78(m,1H),4.61(t,J=8.6Hz,1H),4.25(t,J=10.5Hz,1H),3.93(s,3H),3.61–3.52(m,2H),3.43(s,3H),2.89–2.81(m,2H).

[0556] MS-ESI: m / z = 490.2 [M+H] + .

[0557] Example 62

[0558]

[0559] (S)-N 1 -(2,6-Dichlorobenzyl)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0560]

[0561] Example 62 was obtained by one-step amide condensation of intermediates (S)-3-amino-5-methyl-7-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxa-4(N-11) and NN-7, followed by rapid column chromatography purification (eluent: methanol / dichloroethane: 1 / 20-1 / 10).

[0562] 1 H NMR(400MHz, CDCl3)δ8.29(d,J=7.3Hz,1H),7.65(s,1H),7.57(s,1H),7.50(t,J=5.4Hz,1H),7.36–7.29(m,4H),7.24–7.1 7(m,1H),7.16–7.10(m,1H),4.88–4.73(m,3H),4.60(dd,J=9.6,7.5Hz,1H),4.29–4.19(m,1H),3.92(s,3H),3.42(s,3H).

[0563] MS-ESI: m / z = 526.1 [M+H] + .

[0564] Example 63

[0565]

[0566] (S)-N 1 -(benzyloxy)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0567]

[0568] Example 63 was obtained by one-step amide condensation of intermediate (S)-3-amino-5-methyl-7-(((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,3-dihydrobenzo[b][1,4]oxa-4(N-11) and 2-((benzyloxy)amino)-2-oxoacetic acid) followed by rapid column chromatography purification (eluent: methanol / dichloroethane: 1 / 20-1 / 10).

[0569] 1 H NMR (400MHz, CDCl3) δ9.49 (s, 1H), 8.23 ​​(d, J = 7.2Hz, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.43–7.29 (m, 8H), 7.16–7.10 (m, 1H) ),4.95(s,2H),4.81(dt,J=11.1,7.4Hz,1H),4.59(dd,J=9.6,7.5Hz,1H),4.30–4.20(m,1H),3.92(s,3H),3.43(s,3H).

[0570] MS-ESI: m / z = 474.2 [M+H] + .

[0571] Example 64

[0572] (S)-N 1 -(3-fluorophenylethyl)-N 2 -(5-methyl-7-((1-methyl-1-hydro-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazoline-3-yl)oxalamide

[0573]

[0574] Example 64 (white side solid) was obtained using intermediates 2-oxo-2-(3-fluorophenylethylamine)-acetic acid and (S)-5-methyl-7-((1-methyl-1-hydro-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazinone-2,2,2-trifluoroacetic acid 3-ammonium salt as raw materials under the same conditions as in Example 43.

[0575] 1H NMR (400MHz, CDCl3) δ8.32 (d, J = 7.5Hz, 1H), 7.66 (s, 1H), 7.62-7.56 (m, 2H ),7.39–7.27(m,3H),7.26-7.22(m,1H),6.98–6.84(m,3H),4.56(dt,J=11 .4,7.0Hz,1H),3.93(s,3H),3.72(dd,J=11.0,6.6Hz,1H),3.55(dt,J=13. 7,7.0Hz,2H),3.42(s,3H),2.93(t,J=11.0Hz,1H),2.83(t,J=7.1Hz,2H). MS-ESI:m / z=506.2[M+H] + .

[0576] Example 65

[0577] (S)-N 1 -(2-Chloro-6-fluorobenzyl)-N 2 -(5-methyl-7-((1-methyl-1-hydro-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazoline-3-yl)oxalamide

[0578]

[0579] Example 65 (white side solid) was obtained using intermediate NN-5 and (S)-5-methyl-7-((1-methyl-1-hydro-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazinone-2,2,2-trifluoroacetic acid 3-ammonium salt as raw materials under the same conditions as in Example 43.

[0580] 1 H NMR (400MHz, CDCl3) δ8.34(d,J=8.0Hz,1H),7.65(s,1H),7.62–7.47(m,3H),7.36–7.30(m,2H),7.25–7.17(m,2H),7.01(t,J=8. 4Hz,1H),4.73–4.61(m,2H),4.55(dt,J=11.4,7.3Hz,1H),3.93(s,3H),3.75–3.67(m,1H),3.41(s,3H),2.92(t,J=11.3Hz,1H).

[0581] MS-ESI: m / z = 526.0 [M+H] +

[0582] Example 66

[0583] (S)-N 1 -(3-fluorophenylethyl)-N 2 -(5-methyl-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)oxalamide

[0584]

[0585] Example 66 was obtained using intermediates (S)-3-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]thiazoline-4(5-hydrogen) and 2-oxo-2-(3-fluorophenylethylamine)-acetic acid as raw materials under the same conditions as in Example 43.

[0586] 1 H NMR (400MHz, CDCl3) δ8.31(d,J=7.7Hz,1H),8.02(s,1H),7.58(d,J=7.9Hz,1H),7.35–7.21(m,3H),7.04–6.80(m,3H),4.60–4.47(m,1H),3.70(dd, J=10.9,6.8Hz,1H),3.54(tq,J=13.6,6.8Hz,2H),3.41(s,3H),2.93(t,J= 11.4Hz,1H),2.83(t,J=7.0Hz,1H),1.63(s,6H).MS-ESI:m / z=484.2[M+H] + .

[0587] Example 67

[0588] (S)-N 1 -(2-Chloro-6-fluorobenzyl)-N 2 -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)oxalamide

[0589]

[0590] Example 67 was obtained using intermediates (S)-3-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]thiazoline-4(5-hydrogen) and NN-5 as raw materials under the same conditions as in Example 43.

[0591] 1H NMR (400MHz, CDCl3) δ8.33(d,J=7.8Hz,1H),7.58(d,J=7.9Hz,1H),7.54(t,J=5.7Hz,1H),7.32–7.18(m,4H),7.05-6.98(m,1H), 4.72–4.60(m,2H),4.52(dt,J=11.5,7.2Hz,1H),3.69(dd,J=11.0,6.7Hz,1H),3.40(s,3H),2.92(t,J=11.7Hz,1H),1.62(s,6H).

[0592] MS-ESI: m / z = 504.1, 506.1 [M+H] + .

[0593] Example 68

[0594] N 1 -((3S)-7-(3-hydroxy-3-((5-methylisoxazol-3-yl)but-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -Phenethyloxalamide

[0595]

[0596] The preparation method of Example 68 is the same as that of Example 17, using N-4 and 2-(5-methylisoxazol-3-yl)but-3-yn-2-ol as the raw materials. MS-ESI: m / z = 517.2 [M+H] + .

[0597] Example 69

[0598] (S)-N 1 -(5-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -Phenethyloxalamide

[0599]

[0600] Example 34 (12.0 mg) and Pd / C (2.0 mg) were added to a reaction flask containing THF (2.0 mL), purging with hydrogen. The reaction was stirred overnight at room temperature. Pd / C was filtered off with diatomaceous earth, the reaction mixture was evaporated to dryness, and column chromatography (0-40% ethyl acetate / petroleum ether) was performed to give the title compound (9.0 mg). MS-ESI: m / z = 476.2 [M+H] + .

[0601] Example 70

[0602] (S,E)-N 1 -(5-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)vinyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -Phenethyloxalamide

[0603]

[0604] first step:

[0605] 1-Methyl-4-vinyl-1H-pyrazole (20.0 mg), N-4 (63.0 mg), DIPEA (48.0 mg), Pd(OAc)2 (2.0 mg), tri-o-methylphenylphosphine (8.0 mg), and DMF (2.0 mL) were added to a reaction flask. After addition, the air in the reaction system was purged with nitrogen, and the reaction was heated to 120 °C and reacted for 14 hours. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (20.0 mL) and water (10.0 mL). The organic phase was collected and dried over sodium sulfate. The intermediate was purified by column chromatography (0-80% ethyl acetate / petroleum ether) to give 68 mg of the intermediate. MS-ESI: m / z = 399.2 [M+H] + .

[0606] Step Two:

[0607] The intermediate from the previous step (65.0 mg) was dissolved in dichloromethane (5.0 mL), cooled in an ice bath, and TFA (1.0 mL) was added. The mixture was stirred at this temperature for 1 hour, and TLC showed that the reaction was complete. The reaction solution was evaporated to dryness, and ethyl acetate (10.0 mL) and a saturated sodium bicarbonate solution (5.0 mL) were added for extraction. The organic phase was collected to give the crude intermediate (57.0 mg). MS-ESI: m / z = 299.1 [M+H] + .

[0608] Step 3:

[0609] The intermediate from the previous step (30.0 mg), along with intermediate NN-2 (29.0 mg), HATU (57.0 mg), DIPEA (32.0 mg), and DMF (1.5 mL), were placed in a reaction flask and stirred at room temperature for 2 hours. Column chromatography (0-60% ethyl acetate / petroleum ether) yielded the target compound (25.0 mg). MS-ESI: m / z = 474.2 [M+H] + .

[0610] Example 71

[0611] (S)-N 1 -(2,6-Difluorobenzyl)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxan-3-yl)oxalamide

[0612]

[0613] The preparation method for Example 71 is the same as that in Example 17. MS-ESI: m / z = 494.2 [M+H] + .

[0614] Example 72

[0615] (S)-N 1 -(2,4,6-,trifluorobenzyl)-N 2 -(5-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxan-3-yl)oxalamide

[0616]

[0617] The preparation method for Example 72 is the same as that in Example 17. MS-ESI: m / z = 512.1 [M+H] + .

[0618] Example 73

[0619] (S,E)-N 1 -(5-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)vinyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)-N 2 -Phenethyloxalamide

[0620]

[0621]

[0622] The preparation method of Example 73, using compound Q-4 as a starting material, is the same as that in Example 70. MS-ESI: m / z = 490.2 [M+H] + .

[0623] Example 74

[0624] (R,E)-N 1 -(5-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)vinyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)-N2 -(2,4,6-trifluorobenzyl)oxalamide

[0625]

[0626] The preparation method for Example 74 is the same as that for Example 73. MS-ESI: m / z = 530.1 [M+H] + .

[0627] Example 75

[0628] (S)-N 1 -(5-methyl-4-oxo-7-(pyridin-3-ylethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)-N 2 - phenacetin

[0629]

[0630] Using Q4 and 3-alkynylpyridine as raw materials, the preparation method of Example 75 is the same as that in Example 44. MS-ESI: m / z = 485.2 [M+H] + .

[0631] Example 76

[0632] (R)-N 1 -(5-methyl-4-oxo-7-((2-(trifluoromethyl)pyridin-4-yl)ethynyl)-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)-N 2 -Phenethyloxalamide

[0633]

[0634] Using Q4 and 3-trifluoromethyl-4-ynylpyridine as raw materials, the preparation method of Example 76 is the same as that in Example 44. MS-ESI: m / z = 553.1 [M+H] + .

[0635] Example 77

[0636] N 1 -((R)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -(1-Phenylethyl)oxalamide

[0637]

[0638] The preparation method of Example 77 is the same as that of Example 51, using 2-oxo-2-((1-phenylethyl)amine)acetic acid and Q-14 as raw materials.

[0639] MS-ESI: m / z = 466.1 [M+H] +

[0640] Example 78

[0641] N 1 -(cyclopropyl(phenyl)methyl)-N 2 -((R)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0642]

[0643] Using 2-((cyclopropyll(phenyl)methyl)amine)-2-oxoacetic acid and Q-14 as raw materials, the preparation method of Example 78 is the same as that in Example 51. MS-ESI: m / z = 492.1.

[0644] Example 79

[0645] N 1 -(1-(2-chloro-6-fluorophenyl)ethyl)-N 2 -((R)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0646]

[0647] The preparation method of Example 79 is the same as that in Example 51, using 2-((1-(2-chloro-6-f-fluorophenyl)ethyl)amine)-2-oxoacetic acid and Q-14 as raw materials. MS-ESI: m / z = 518.1.

[0648] Example 80

[0649] (R)-N 1 -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazaphen-3-yl)-N 2 -(2-Phenylacetyl-2-yl)oxalamide

[0650]

[0651] The preparation method of Example 80 is the same as that of Example 51, using 2-oxo-2-((2-phenylprop-2-yl)amino)acetic acid and Q-14 as raw materials.

[0652] MS-ESI: m / z = 480.1.

[0653] Example 81

[0654] N 1 -(1-(2-chloro-6-fluorophenyl)ethyl)-N 2 -((R)-5-methyl-7-((1-methyl-1-hydro-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0655]

[0656] The preparation method of Example 81 is the same as that of Example 51, using 2-((1-(2-chloro-6-f-fluorophenyl)ethyl)amine)-2-oxoacetic acid and Q-11 as raw materials. MS-ESI: m / z = 541.1.

[0657] Example 82

[0658] N 1 -((2-chloro-6-fluorophenyl)(cyclopropyl)methyl)-N 2 -((R)-5-methyl-7-((1-methyl-1-hydro-pyrazol-4-yl)acetylene)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazolin-3-yl)oxalamide

[0659]

[0660] The preparation method of Example 82 is the same as that in Example 51, using 2-((cyclopropyll(2-chloro-6-fluorobenzene)methyl)amine)-2-oxoacetic acid and Q-11 as raw materials. MS-ESI: m / z = 566.0.

[0661] Example 83

[0662] (R)-4-((5-methyl-4-oxo-3-(2-oxo-2-(phenethyl)acetamide)-2,3,4,5-tetrahydrobenzo[b][1,4]azaxazon-7-yl)ethynyl)-1-hydropyrazole-1-salt 2,2,2-trifluoroacetate

[0663]

[0664] Step 1: (R)-7-((1-hydropyrazol-4-yl)ethynyl)-3-amine-5-methyl-2,3-dihydrobenzo[b][1,4]azapyr-4(5-hydro)-one

[0665]

[0666] Q-ZH-1 was prepared from 4-iodine-1-hydropyrazole using the preparation method described in Q-11.

[0667] Step 2: Using Q-ZH-1 and NN-2 as raw materials, the preparation method of Example 83 is the same as that in Example 51. MS-ESI: m / z = 474.1.

[0668] Example 84

[0669] N 1 -((R)-5-methyl-7-((1-methyl-1-hydropyrazol-4-yl)acetylene)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azaxazon-3-yl)-N 2 -((S)-1-phenylethyl)oxalamide

[0670]

[0671] Using (S)-2-oxo-2-((1-phenylethyl)amine)acetic acid and Q-11 as raw materials, the preparation method of Example 84 is the same as that in Example 51.

[0672] MS-ESI:MS-ESI:m / z=488.1.

[0673] Example 85

[0674] (R)-N 1 -(5-methyl-7-((1-methyl-1-hydro-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azaxazopyro-3-yl)-N 2 -(1-Phenycyclopropyl)oxalamide

[0675]

[0676] Step 1: 1-Phenylocyclopropylamine

[0677] Benzonitrile (1 mL) was dissolved in tetrahydrofuran (60 mL). Tetraisopropyl titanate (1.65 mL) was slowly added under dry ice-ethanol bath cooling, followed by slow dropwise addition of ethyl magnesium bromide (2 M, 5.2 mL). After the reaction mixture was slowly heated to room temperature, boron trifluoride diethyl ether solution (6 mL, 48%) was slowly added dropwise. The reaction was then quenched with 40 mL of 1N hydrochloric acid under ice bath cooling, and alkalized with NaOH (10%, 120 mL) aqueous solution. The organic phase was separated, and the aqueous phase was extracted with diethyl ether (50 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solid was filtered off and concentrated to give 1-phenylcyclopropylamine (1.1 g). MS-ESI: m / z = 134.1

[0678] Step 2: 2-Oxo-2-((1-Phenylocyclopropyl)amino)acetic acid

[0679] The target product was prepared using 1-phenylcyclopropylamine as a raw material, following the preparation method of NN-2.

[0680] Step 3: Using 2-oxo-2-((1-phenylcyclopropyl)amino)acetic acid and Q-11 as raw materials, the preparation method of Example 84 is the same as that in Example 51. MS-ESI: m / z = 500.1.

[0681] Example 86

[0682] 2,2,2-Trifluoroacetic acid 1-methyl-4-(((R)-5-methyl-3-(2-(methyl(phenethyl)amine)-2-oxoacetamide)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azaxazopyron-7-yl)acetylene)-1H-pyrazole-1-salt

[0683]

[0684] Step 1: 2-(methyl(phenylethyl)amine)-2-oxoacetic acid

[0685] NN-2 (96 mg) was dissolved in DMF (2 mL), and then cesium carbonate (0.475 mg) was added under ice bath cooling. Iodomethane (0.08 mL) was slowly added dropwise, and the mixture was stirred for 1 hour and 20 minutes. The solution was then quenched with water, extracted with ethyl acetate, washed with brine, concentrated, and then treated with THF / H2O. 2- Hydrolysis with O / LiOH, acidification with dilute hydrochloric acid, extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, and filtration to concentrate the target compound. MS-ESI: m / z = 208.1

[0686] Step 2: Using 2-(methyl(phenylethyl)amine)-2-oxoacetic acid and Q-11 as raw materials, the preparation method of Example 85 is the same as that in Example 51. MS-ESI: m / z = 502.1

[0687] Example 87

[0688] N 1 -((R)-5-methyl-7-((1-methyl-1-hydropyrazol-4-yl)acetylene)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azaxazon-3-yl)-N 2 -((R)-1-phenylethyl)oxalamide

[0689]

[0690] Step 1: (R)-2-oxo-2-((1-phenylethyl)amine)acetic acid

[0691] The target product was prepared using (R)-1-phenylethyl-1-amine as a raw material, following the preparation method of NN-2.

[0692] Step 2: Using (R)-2-oxo-2-((1-phenylethyl)amine)acetic acid and Q-11 as raw materials, the preparation method of Example 86 is the same as that in Example 51. MS-ESI: m / z = 488.1

[0693] Example 88

[0694] N 1 -((R)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -((S)-1-phenylethyl)oxalamide

[0695]

[0696] Step 1: (S)-2-oxo-2-((1-phenylethyl)amine)acetic acid

[0697] The target product was prepared using (S)-1-phenylethyl-1-amine as a raw material, following the preparation method of NN-2.

[0698] Step 2: Using (S)-2-oxo-2-((1-phenylethyl)amine)acetic acid and Q-14 as raw materials, the preparation method of Example 87 is the same as that in Example 51. MS-ESI: m / z = 466.1.

[0699] Example 89

[0700] N 1 -((R)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -((R)-1-phenylethyl)oxalamide

[0701]

[0702] The preparation method of Example 87 is the same as that in Example 51, using (R)-2-oxo-2-((1-phenylethyl)amine)acetic acid and Q14 as raw materials. MS-ESI: m / z = 466.1.

[0703] Example 90

[0704] (R)-N 1 -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -(1-Phenylocyclopropyl)oxalamide

[0705]

[0706] The preparation method of Example 89 is the same as that in Example 51, using 2-oxo-2-((1-phenylcyclopropyl)amino)acetic acid and Q-14 as raw materials. MS-ESI: m / z = 478.1.

[0707] Example 91

[0708] (R)-N 1 -(5-methyl-4-oxo-7-((1-phenyl-1-hydro-pyrazol-4-yl)acetylene)-2,3,4,5-tetrahydrobenzo[b][1,4]azaxazopyro-3-yl)-N 2 -Phenethyloxalamide

[0709]

[0710] Step 1: (R)-3-amino-5-methyl-7-((1-phenyl-1-hydropyrazole-4-yl)vinyl)-2,3-dihydrobenzo[b][1,4]azaporide-4(5-hydro)-one

[0711]

[0712] 0.0163 g of tert-butyl(R)-(7-((1-hydro-pyrazol-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydro[b][1,4]thiazoline-3-yl)carbamate was added, followed by the addition of phenylboronic acid (0.0146 g) and CuAcO (0.123 g), dissolved in dichloromethane (2 mL), and pyridine (0.02 mL). After reacting in dry air for one day, phenylboronic acid (35 mg) was added, and the reaction was continued for another day. The mixture was diluted with ethyl acetate, quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to column chromatography. The resulting product was prepared by the same detert-butyloxycarbonylation method as Q-11 to obtain Q-ZH-2.

[0713] Step 2: Using Q-ZH-2 and NN-2 as raw materials, the preparation method of Example 90 is the same as that in Example 51. MS-ESI: m / z = 550.1.

[0714] Example 92

[0715] (R)-N 1 -(5-methyl-4-oxo-7-((1-cyclopropyl-1-hydro-pyrazole-4-yl)acetylene)-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)-N 2 -Phenethyloxalamide

[0716]

[0717] Step 1: (R)-3-amino-5-methyl-7-((1-cyclopropyl-1-hydropyrazole-4-yl)vinyl)-2,3-dihydrobenzo[b][1,4]azepine-4(5-hydro)-one

[0718]

[0719] Q-ZH-3 was prepared by the Q-ZH-2 method using tert-butyl(R)-(7-((1-hydro-pyrazol-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydro[b][1,4]thiazoline-3-yl)carbamate and cyclopropylboronic acid.

[0720] Step 2: Using Q-ZH-3 and NN-2 as raw materials, the preparation method of Example 91 is the same as that in Example 51. MS-ESI: m / z = 514.0.

[0721] Example 93

[0722] (R)-N 1 -(1-(2-chloro-6-fluorophenyl)cyclopropyl)-N 2-(5-methyl-7-((1-methyl-1-hydro-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0723]

[0724] Example 91 was obtained using 2-chloro-6-benzonitrile as a starting material and the same synthesis method as in Example 84. MS-ESI: m / z = 552.1.

[0725] Example 94

[0726] N 1 -((R)-7-((1-Cyclopropyl-1-hydro-pyrazole-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azaxazopyro-3-yl)-N 2 -((S)-1-phenylethyl)oxalamide

[0727]

[0728] The preparation method of Example 92 is the same as that of Example 51, using Q-ZH-3 and (S)-2-oxo-2-((1-phenylethyl)amine)acetic acid as raw materials.

[0729] MS-ESI: m / z = 515.0.

[0730] Example 95

[0731] (R)-N 1 -(2-(2-chloro-6-fluorophenyl)prop-2-yl)-N 2 -(5-methyl-7-((1-methyl-1-hydro-pyrazol-4-yl)ethynyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0732]

[0733] Step 1: 2-(2-Chloro-6-fluorophenyl)prop-2-amine

[0734] In a dry system, cerium trichloride (6.512 g) was mixed with tetrahydrofuran (200 mL), cooled in a dry ice-ethanol bath (-72 °C), and under nitrogen protection, methyllithium (1.3 M) (20 mL) was slowly added dropwise. After reacting for 1 hour, a tetrahydrofuran solution containing 2-chloro-6-fluorobenzonitrile (1.023 g) (7 mL) was slowly added dropwise. After stirring at -72 °C for 4 hours, the temperature was raised to 0 °C, and the mixture was quenched with 20 mL of saturated ammonium chloride. The mixture was filtered, concentrated, and then subjected to column chromatography to obtain 2-(2-chloro-6-fluorophenyl)prop-2-amine (90 mg).

[0735] Step 2: 2-((2-(2-chloro-6-fluorophenyl)prop-2-yl)amine)-2-oxoacetic acid

[0736] The target product was prepared by referring to the preparation method of NN-2, using the product from the first stage as raw material.

[0737] Step 3: Using the products from Step 1 and Step 2 as raw materials, the preparation method of Example 93 is the same as that in Example 51. MS-ESI: m / z = 554.1.

[0738] Example 96

[0739] (R)-N 1 -(2-(2-chloro-6-fluorophenyl)prop-2-yl)-N 2 -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0740]

[0741] The preparation method of Example 94 is the same as that of Example 51, using 2-((2-(2-chloro-6-fluorophenyl)prop-2-yl)amine)-2-oxoacetic acid and Q14 as raw materials.

[0742] MS-ESI: m / z = 532.1.

[0743] Example 97

[0744] N 1 -((2-chloro-6-fluorophenyl)(cyclopropyl)methyl)-N 2 -((R)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0745]

[0746] Using Q14 as raw material, the preparation method of Example 97 is the same as that in Example 51. MS-ESI: m / z = 546.0.

[0747] Example 98

[0748] (R)-N 1 -(1-(2-chloro-6-fluorophenyl)cyclopropyl)-N 2 -(7-(3-hydroxy-3-methylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyroxen-3-yl)oxalamide

[0749]

[0750] The preparation of Example 98 using 2-chloro-6-benzonitrile and Q-14 raw materials is described in Examples 84 and 51. MS-ESI: m / z = 530.1.

[0751] Preparation of intermediate M-7

[0752] (S)-2-(((8-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]azapyro-3-yl)amino)-2-oxoacetic acid

[0753]

[0754]

[0755] Step 1: Under nitrogen protection at -5℃, 6.336 g of 60% sodium hydride was dissolved in 60 ml of DMF. Then, an anhydrous N-Boc-L-serine solution dissolved in DMF was slowly added dropwise to the system. After reacting for 2 hours, 18.22 g of 2-fluoro-4-bromonitrobenzene was slowly added to the solution. The reaction was continued at 0℃ for 1 hour, then at room temperature for 3 hours. EA (80 ml) was added to the reaction solution, and the solution was slowly poured into a 0.5 M ice-cold hydrochloric acid conical flask. The system was tested with pH paper until it reached a weakly acidic state. Extraction was performed with ethyl acetate, followed by washing with water and saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated, and separated by rapid column chromatography (25%-55% EA in PE) to obtain the yellow intermediate M-1. MS ESI: m / z = 402.2 [MH] - .

[0756] Step 2: Dissolve 1g of M-1 in ethanol / water (10ml / 3ml), add 538.78mg of ammonium chloride and 1.38g of iron powder, react at 80℃ for 20min, filter while hot with diatomaceous earth to remove insoluble matter, and concentrate the filtrate to obtain product M-2. MS-ESI: m / z=372.9[MH] - .

[0757] Step 3: Dissolve 5.61 g M-2 in 30 ml DMSO, then add 4.15 ml TEA, followed by slowly adding 11.602 g HATU. React at room temperature for 3.5 hours. Add 300 ml ice water to the system; a yellow solid precipitates. Stir the system in an ice bath for 30 minutes, filter, wash the solid with water, collect the solid, and dry it to obtain intermediate M-3. MS-ESI: m / z = 355.0 [MH] - .

[0758] Step 4: Nitrogen protection. Under ice bath conditions, M-3 (2.138 g) was dissolved in DMF (10 ml), cesium carbonate (2.739 g) was added, followed by MeI (0.458 mL). The mixture was stirred at 0 °C for 5 min, and then reacted at room temperature for 3 h. Ice water (40 ml) was added to the system, and a large amount of solid precipitated out. The solid was filtered, washed with water (40 ml x 3), washed with diethyl ether (10 ml x 2), and dried to obtain white solid M-4.

[0759] 1 H NMR (400MHz, CDCl3) δ7.34(dd,J=8.4,2.2Hz,1H),7.31(d,J=2.1Hz,1H),7.06(d,J=8.4Hz,1H),5.46(d,J=7.0Hz,1H ), 4.64(dt,J=11.1,7.1Hz,1H), 4.56(dd,J=9.5,7.2Hz,1H), 4.17(dd,J=11.1,9.6Hz,1H), 3.38(s,3H), 1.40(s,9H). MS-ESI: m / z=370.0[MH] - .

[0760] Step 5: At room temperature, intermediate M-4 (2.5 g) was dissolved in dichloromethane / trifluoroacetic acid (15 ml / 3 ml) and reacted for 2 hours. The solvent was removed by vacuum rotary evaporation. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the product was extracted with ethyl acetate (30 ml x 5). The extract was dried over anhydrous copper sulfate, and the solvent was removed by vacuum rotary evaporation to obtain an orange-yellow solid product M-5. MS-ESI: m / z = 271.1 [M+H] + .

[0761] Step 6: Select a two-necked flask as the reaction vessel. The system is strictly dehydrated and protected with argon. Add intermediate M-5 (1g), ultra-dry THF (20mL), and triethylamine (590μL) to the system. Replace the argon three times. Under dry ice and ethanol bath cooling, slowly inject oxaloyl chloride monomethyl ester (381μL). Stir for five minutes and then return to room temperature. Continue stirring for 10 minutes. After 0.5h, add MeOH (0.2eq) under ice bath. A white solid precipitates out. Filter to remove the solid, wash with methyl tert-butyl ether, concentrate the filtrate, and purify by rapid column chromatography (30-35% EA in PE) to obtain orange solid product M-6.

[0762] 1H NMR (400MHz, DMSO-d6) δ9.14 (d, J=7.9Hz, 1H), 7.56–7.44 (m, 3H), 4.75–4. 63(m,1H),4.62–4.53(m,1H),4.48–4.37(m,1H),3.79(s,3H),3.28(s,3H).

[0763] MS-ESI: m / z = 359.0 [M+H] + .

[0764] Step 7: Dissolve intermediate M-6 (800 mg) in a mixed solution of THF and water (THF:H2O = 4:1, 16 ml), add LiOH (54.9 mg), stir at room temperature, and after 2 h, neutralize with 6 M HCl to pH = 4. Concentrate the reaction solution, filter to remove inorganic salts, and obtain intermediate M-7, which is directly added to the next step of the reaction.

[0765] 1H NMR (400MHz, CDCl3) δ8.21(d,J=6.7Hz,1H),7.41(dd,J=8.5,2.2Hz,1H),7.38(d,J=2.1Hz,1H),7.12(d,J=8.5Hz,1H ), 6.98 (s, 1H), 4.82 (dt, J = 11.2, 7.3Hz, 1H), 4.66 (dd, J = 9.8, 7.4Hz, 1H), 4.28 (dd, J = 11.1, 9.9Hz, 1H), 3.42 (s, 4H).

[0766] MS-ESI: m / z = 345.0 [M+H] + .

[0767] Preparation of intermediate N-5

[0768] (S)-3-amino-7-bromo-5-methyl-2,3-dihydrobenzo[b][1,4]azaxazopon-4(5H)-one

[0769]

[0770] The synthesis method of intermediate N-5 is basically the same as that of intermediate M-5.

[0771] Preparation of intermediate Q-5

[0772] (R)-3-amino-7-bromo-5-methyl-2,3-dihydrobenzo[b][1,4]thiazin-4(5H)-one

[0773]

[0774] The synthetic route of intermediate Q-5 is basically the same as that of M-5.

[0775] Step 1: At room temperature, L-Boc-cysteine ​​(14.5 g, 65.531 mmol) was dissolved in 80 mL of ethanol, and then NaHCO3 (34 g, 242 mmol) was slowly added. Under N2 protection, 4-bromo-1-fluoro-nitrobenzene (8.3 mL, 66.4 mmol) was slowly added dropwise to the reaction solution, and the reaction was heated to 80 °C. The reaction was refluxed for 2.5 hours, and the reaction was confirmed to be complete by LC-MS. The reaction solution was concentrated, washed with diethyl ether (30 mL x 2), acidified with 1N HCl to pH=2, extracted with DCM (300 mL * 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a brown oily substance (Q-1).

[0776] MS-ESI: m / z = 320.9 [M+H-Boc] + .

[0777] Step 2: Dissolve intermediate Q-2 (0.47 g), zinc powder (0.962 g), and ammonium chloride (0.962 g, 14.683 mmol) in methanol (20 mL). Heat the reaction mixture at 75 °C for 2.5 hours. After filtration, wash the residue with hot methanol solution. Concentrate the filtrate and separate it using water and dichloromethane (30 mL x 3). Wash the organic phase with saturated brine, dry it with anhydrous sodium sulfate, and filter again. Concentrate the filtrate to obtain a white solid, which is intermediate Q-2.

[0778] MS-ESI: m / z = 334.9 [M+H-Bu] + .

[0779] Step 3: Intermediate Q-2 (0.502 g, 1.278 mmol) was dissolved in DMF (20 mL), followed by the addition of N,N,N',N'-tetramethylchloro Methylamidine hexafluorophosphate Salt (i.e., TCFH, 0.49 g, 1.289 mmol) was added dropwise, followed by the slow addition of N-methylimidazole (0.16 mL g, 2.0078 mmol). The reaction was stirred overnight, and the reaction progress was monitored by plate chromatography and LC-MS. After the reaction was completed, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with water (10 mL x 5) and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by rapid column chromatography to obtain a white solid as intermediate Q-3.

[0780] MS-ESI: m / z = 316.9 [M+H- t Bu] + .

[0781] Step 4: Using intermediate Q-3 as a starting material, methylation was performed under the same synthetic conditions as intermediate M-4 to obtain intermediate Q-4. MS-ESI: m / z = 331.0 [M+H- t Bu] + .

[0782] Step 5: Using intermediate Q-4 as raw material, remove Boc under the same conditions as intermediate M-5 to obtain intermediate Q-5.

[0783] MS-ESI: m / z = 287.0 [M+H] + .

[0784] Preparation of intermediate NN 1-7

[0785]

[0786] Step 1: Select a two-necked flask as the reaction vessel. Under argon protection, add amine (1 eq), THF (to make the amine concentration 1M), and triethylamine (1.2 eq) to the system. Under dry ice and ethanol bath conditions, slowly inject oxaloyl chloride monomethyl ester (1.1 eq). After stirring for 10 minutes, remove the ice bath, return to room temperature, and continue stirring for 10 minutes. After 40 minutes, add MeOH (0.2 eq) under ice bath conditions, concentrate the reaction solution, filter to remove the solid, wash the solid with methyl tert-butyl ether, concentrate the filtrate, and perform rapid column chromatography (20-30% EA in PE) to obtain the solid product.

[0787] R2 of intermediate MM-1: The product is a white solid.

[0788] 1 H NMR (400MHz, DMSO-d6) δ9.47 (s, 1H), 7.40–7.15 (m, 5H), 4.33 (d, J = 6.3Hz, 2H), 3.78 (s, 3H). MS-ESI:m / z=194.1[M+H] + .

[0789] The R2 of intermediate MM-2 is: The product is a white solid.

[0790] 1 H NMR (400MHz, DMSO-d6) δ9.02 (s, 1H), 7.30 (dd, J = 10.4, 4.3Hz, 2H), 7.25–7.16 (m, 3H), 3.76 (s, 3H), 3.41–3.31 (m, 2H), 2.78 (t, J = 7.5Hz, 2H). MS-ESI:m / z=208.1[M+H] + .

[0791] The R2 of intermediate MM-3 is: The product is a pale yellow solid. MS-ESI: m / z 214.1 [M+H] + .

[0792] The R2 of intermediate MM-4 is: The product is a pale yellow solid. MS-ESI: m / z 214.0 [M+H] + .

[0793] The R2 of intermediate MM-5 is: The product is a yellow solid. MS-ESI: m / z 246.0 [M+H] + .

[0794] The R2 of intermediate MM-6 is: The product is a white solid. MS (ESI+): m / z = 276 [M+1] + .

[0795] The R2 of intermediate MM-7 is: The product is a white solid. MS (ESI+): m / z = 262 [M+1] + .

[0796] The R2 of intermediate MM-8 is: The product is a white solid. MS (ESI+): m / z = 226.1 [M+1] + .

[0797] The R2 of intermediate MM-9 is: The product is a white solid. MS (ESI+): m / z = 208.0 [M+1] + .

[0798] Step Two:

[0799] Intermediate MM 1-7 (1 eq) was dissolved in a mixed solution of tetrahydrofuran and water (THF:H2O = 4:1), and LiOH (3 eq) was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was then concentrated and neutralized with 6M HCl to pH 4. The reaction solution was then concentrated and filtered to remove inorganic salts, yielding intermediate NN 1-7.

[0800] Intermediate NN-2: MS-ESI: m / z = 180.1 [M+H] + .

[0801] Intermediate NN-2: MS-ESI: m / z = 194.1 [M+H] + .

[0802] Intermediate NN-3: MS-ESI: m / z = 197.9 [MH] - .

[0803] Intermediate NN-4: MS-ESI: m / z = 197.9 [MH] - .

[0804] Intermediate NN-5: MS-ESI: m / z = 232.0 [M+H] + .

[0805] Intermediate NN-6: MS-ESI: m / z = 262.0 [M+H] + .

[0806] Intermediate NN-7: MS-ESI: m / z = 248.0 [M+H] + .

[0807] Intermediate NN-8: MS-ESI: m / z = 212.1 [M+H] + .

[0808] Intermediate NN-9: MS-ESI: m / z = 194.1 [M+H] + .

[0809] Example 99

[0810] Activity test:

[0811] 1. Cell viability test (TNFα-induced FADD-deficient human leukemia cell Jurkat cell programmed necrosis system).

[0812] (a) Cell culture: Jurkat fadd-deficient cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum (FBS), 100 U / mL penicillin, and 100 U / mL streptomycin. All cells were cultured in a 37°C incubator containing 5% CO2. All cells were cryopreserved using complete medium containing 5-10% DMSO. The medium was changed and passaged 3-4 times per week.

[0813] (2) Experimental materials: Reagents:

[0814] RPMI 1640 medium (GIBCO, USA), fetal bovine serum (GIBCO, USA), human recombinant TNF (Novoprotein C008), Cell Titer-Glo Kit (Promega, USA), Nec-1s synthesized by Ma Dawei's research group at the Shanghai Institute of Organic Chemistry, and compound GSK2982772 (BYD Reagents).

[0815] (3) Experimental consumables:

[0816] Cell culture dishes (100 / 60 / 35mm) from BD or Corning, USA; cell culture plates (384 / 96 / 24 / 6 wells) from BD or Corning, USA; centrifuge tubes (15 / 50ml) from BD or Corning, USA.

[0817] (4) Experimental protocol: The TNFα-induced Jurkat fadd-deficient cell programmed necrosis system was used to screen for compounds with RIPK1 kinase inhibitory activity.

[0818] Fadd deficient Jurkat cells were uniformly seeded into 384-well plates. One week per well, 40 μL of complete culture medium was used. 5 μL of the test compound was added to each well, with an initial concentration of 25 μM (0.5 μM for some compounds with good activity). A three-fold serial dilution was performed, resulting in 12 dilutions. Each compound was used in triplicate. A blank control group and a control group stimulated with TNF-α alone were added. After adding the compound, the cells were centrifuged and incubated at 37°C with 5% CO2 for 1 hour. Then, 5 μL of 5 ng / mL TNF-α was added to stimulate necrosis. After centrifugation, the cells were incubated for a total of 13 hours (until the TNF-α-only group reached a cell death rate of 65%). The total volume per well was 50 μL. Cell viability was then assessed according to the following steps.

[0819] Take out the kit Buffer, equilibrate to room temperature, and then use. Buffer dissolution Substrate, obtained Reagent can be used directly in experiments.

[0820] Add 15 μL of room temperature equilibrated solution to each well. After being incubated in the dark for 15 minutes, the chemiluminescence of the compound was detected using an Enspire multi-functional microplate reader (PerkinElmer, USA). Using the blank control group as 100%, the relative changes in ATP in the experimental groups were calculated, and the IC50 of the compound was obtained by fitting the data using Graphpad Prism software. 50 .

[0821] Table 1 Results of Jurkat Fadd (- / -) inhibitory activity assay in cells

[0822] Example number <![CDATA[IC 50 (nM)]]> Example 1 255 Example 2 116 Example 3 4300 Example 4 196 Example 5 360 Example 6 1090 Example 7 1259 Example 8 1856 Example 9 841 Example 10 124 Example 11 3330 Example 12 190 Example 13 593 Example 14 2654 Example 15 83 Example 16 352 Example 17 249 Example 18 1045 Example 19 14 Example 20 7 Example 21 65 Example 22 46 Example 23 43 Example 24 136 Example 25 1130 Example 26 3020 Example 27 200 Example 28 160 Example 29 0.1 Example 30 <0.1 Example 31 16 Example 32 0.6 Example 33 <0.1 Example 34 <0.1 Example 35 <0.1

[0823] Example 36 0.06 Example 37 6.7 Example 38 13 Example 39 1.8 Example 40 152 Example 41 1418 Example 42 319 Example 43 <0.1 Example 44 <0.1 Example 45 <0.1 Example 46 <0.1 Example 47 <0.1 Example 48 <0.1 Example 49 <0.1 Example 50 <0.1 Example 51 <0.1 Example 52 <0.1 Example 53 32 Example 54 42 Example 55 184 Example 56 74 Example 57 7.8 Example 58 2.8 Example 59 >1000 Example 60 485 Example 61 <1 Example 62 1.3 Example 63 77.8 Example 64 <1 Example 65 156.6 Example 66 126.2 Example 67 542.8 Example 68 1.6 Example 69 21 Example 70 3.2 Example 71 3.4 Example 72 4.1 Example 73 <1 Example 74 43 Example 75 <1 Example 76 19 Example 77 <1 Example 78 <1 Example 79 <1

[0824] Example 80 <1 Example 81 <1 Example 82 9.4 Example 83 <1 Example 84 <1 Example 85 <1 Example 86 9.5 Example 87 <1 Example 88 <1 Example 89 <1 Example 90 2.7 Example 91 1.89 Example 92 <1 Example 93 <1 Example 94 3.1 Example 95 53 Example 96 1.74 Example 97 <1 Example 98 3.3

[0825] 2. RIPK1 inhibitory activity test

[0826] The RIPK1 activity inhibition assay was performed by NANOSYN Test Services (3100 Central Expressway, Santa Clara, CA 95051). The test compound was dissolved in DMSO, with a maximum test concentration of 1 μmol, followed by sequential 3-fold dilutions. The concentration of DMSO in the test medium was maintained at 1%, for a total of 12 test concentrations. IC50 values ​​were obtained. 50 .

[0827] Table 2 Results of RIPK1 activity inhibition test

[0828] Example number <![CDATA[IC 50 (nM)]]> Staurosporine (kinase inhibitor standard) 79.8 GSK2982772 (positive control) 11.1 Example 33 4.5 Example 34 5.9 Example 32 19.5 Example 44 5.1

[0829] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of general formula I or a pharmaceutically acceptable salt thereof: I In the formula: Y is CH2; Z is NR 4A or is absent; n is 0, 1, 2, or 3; Ring B is phenyl, C3-C6 cycloalkylphenyl, or 5-6 heteroaryl; Each R 1 H, halogen, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C 10 Alkoxyalkyl, C1-C6 hydroxyalkyl, C0-C6 alkylene, C6-C 10 aryl, -C0-C6 alkylene-X-C6-C 10 Aryl, -C0-C6 alkylene-5-10 heteroaryl, -P(O)Me2, -P(O)(OMe)2, -C≡CR 6 ; R 2 H, halogen, -CN, C1-C6 alkyl, -C0-C6 alkylene, -C6-C 10 Aryl, -C0-C6 alkylene-5-10 heteroaryl, C1-C6 haloalkyl, -C≡CR 6 -CH=CH-R 6 ;R 2 For not replaced or by 1, 2, 3 or 4 Rs f replace; R 3 R is H, or C1-C6alkyl; R 4A R is H, C1-C6alkyl; Ring A is C6-C10aryl 10 aromatic ring; L is C0-C6alkylene, or C3-C6cycloalkylene; L is optionally substituted with 1-3 R 5 R 5 each independently H, -OH, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy; Each R 6 Independently hydrogen, C1-C 10 Alkyl, -C0-C6 alkylene -C6-C 10 Aryl, -C0-C6 alkylene-5-10 heteroaryl, -C0-C6 alkylene-C3-C 10 cycloalkyl; R 6 Each independently represents either unsubstituted or replaced by 1, 2, 3, or 4 Rs. f replace; R f Each occurrence is independently a halogen, -OH, -CN, C1-C6 alkyl, -C0-C6 alkyleneoxy-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -C0-C6 alkylene-C3-C 10 cycloalkyl; R e Independent of halogen, -OH, Each of the above heteroaryl groups has one or two heteroatoms selected from sulfur, oxygen, N, NH or NR. g ; R g For C1-C 10 Alkyl, or C1-C 10 Heteroalkyl; X can be O, S, or CH2 independently.

2. The compound according to claim 1, characterized in that, The compound has the structure shown in general formula II. II In the formula: Z 1 and Z 3 Each independently as CR 7 ; R 7 It can be H, halogen, methyl or halomethyl; Z 2 For CR 1 ; Each R 1 R 2 R 3 The definitions of X, Y, Z, L, ring B, and n are as described in general formula I of claim 1.

3. The compound according to claim 1, characterized in that, The halogens are fluorine, chlorine, bromine, and iodine.

4. The compound according to claim 1, characterized in that, The compound has the structure shown in general formula IV. IV In the formula: Each R 1 and R 2 The definition is as described in general formula I of claim 1; X is O, S, or CH2; n is 1 or 2; m can be 0, 1, 2, 3, or 4.

5. The compound according to claim 1, characterized in that, The heteroaryl groups include pyridyl, pyrroleyl, thiophenyl, and furanyl.

6. The compound according to claim 1, characterized in that, The compound has the structure shown in general formula VI. WE In the formula, each R 1 and R 2 The definition is as described in general formula I of claim 1; X is O, S, or CH2; n is 1 or 2; m is 1 or 2.

7. The compound according to claim 1, characterized in that, The compound has the structure shown in general formula VII. VII Among them, R 1 and R 2 The definition is as described in general formula I of claim 1; X is O, S, or CH2; n is 0, 1, or 2; m is 1 or 2.

8. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of: 。 9. The compound according to any one of claims 1-8, characterized in that, The pharmaceutically acceptable salts of the compounds of general formulas I to VII are selected from the group consisting of: hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, 1-therasulfonate, 2-therasulfonate, acetate, trifluoroacetate, malate, tartrate, thiazoline, lactate, oxalate, hyaluronate, fumarate, maleate, benzoate, salicylate, phenylacetate, and mandelate.

10. The compound according to any one of claims 1-8, characterized in that, In the compound, any one or more hydrogen atoms may be replaced by deuterium atoms.

11. Use of the compound according to any one of claims 1 to 10, characterized in that, Used for: (i) Preparation of RIPK1 inhibitors; (ii) Preparation of inhibitors of programmed cell necrosis; (iii) To prepare a medicament for the prevention and / or treatment of diseases mediated by programmed cell death, wherein the diseases are selected from the group consisting of: cancer, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, non-alcoholic fatty liver disease, autoimmune hepatobiliary diseases, nephritis, celiac disease, autoimmune ITP, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, multiple sclerosis, tumor necrosis factor receptor-related periodic syndrome, and periodontitis.

12. The use as described in claim 11, characterized in that, The diseases mediated by programmed cell necrosis are selected from the group consisting of: autoimmune hepatitis, primary sclerocholangitis, or a combination thereof.

13. The use as described in claim 11, characterized in that, The diseases mediated by programmed cell death include leukemia.

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