Compound for inhibiting programmed cell death and preparation method thereof

Abstract

The invention discloses an RIPK1 inhibitor for inhibiting programmed necrosis of cells and a preparation method of the RIPK1 inhibitor. The RIPK1 inhibitor is shown in a general formula I, and X1, X2, X3, X4, X5, Z1, Z2, Z3, L1, L2, L3, R, R1, ring D and n are shown in the specification and claims. The invention also discloses a preparation method of the general formula I and an activity test result of the general formula I for inhibiting programmed cell necrosis and RIPK1. The compound as shown in the general formula I can be used for preparing medicines for treating and preventing inflammation and degenerative diseases. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 202111074627.8, application date September 14, 2021, and invention name “Compounds for inhibiting programmed cell death and preparation methods thereof”. Technical Field

[0002] The present invention provides an inhibitor for inhibiting programmed cell necrosis, and particularly relates to a preparation method thereof and a method and use thereof for treating and preventing inflammatory and degenerative diseases. Background Art

[0003] Programmed cell death is a highly inflammatory form of cell death that can be induced by a variety of promoting factors, such as necrosis factor (TNF) and FAS ligand. This process can occur in a variety of cells and is considered to be the main mode of cell death under pathological conditions. It is directly related to a variety of inflammatory diseases and degenerative diseases. These diseases include neurodegenerative diseases, stroke, coronary heart disease, myocardial infarction, retinal degenerative diseases, inflammatory bowel disease, kidney disease, liver disease, and many other related diseases.

[0004] RIPK1 (receptor interacting protein kinase 1) participates in many key intracellular inflammatory signaling pathways, including not only programmed cell necrosis (necroptosis), but also scientific experiments have confirmed that the protein can cause a wide range of inflammatory cell processes by causing cell rupture. RIPK1 is a major regulator of NF-κB signaling and cellular determinants of death response, among which NF-κB signaling responds to a wide range of inflammatory and pro-death stimuli in human diseases.

[0005] Therefore, RIPK1 inhibitors can provide more effective inhibition of programmed cell necrosis for the prevention and treatment of inflammatory and degenerative diseases related thereto. Summary of the invention

[0006] The purpose of the present invention is to provide a novel RIPK1 inhibitor for inhibiting programmed cell necrosis.

[0007] The present invention provides a compound of general formula I, wherein the compound of general formula I is a compound represented by formula II:

[0008]

[0009] R 1 is H or methyl; R d is H or halogen; Z 1 is N or CH; Ring A is the following structure:

[0010] Ring D is phenyl, halogen-substituted phenyl or thiophene;

[0011] In the tricyclic structure of Formula II, R of the five-membered ring and R of the six-membered ring are independently selected from the group H, halogen, -CN, -C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C 0 -C 6 Alkyleneoxy C 1 -C 6 Alkyl-, C 1 -C 6 Hydroxyalkyl, -C 0 -C 6 Alkylene-SC 1 -C 6 Alkyl-, -C 0 -C 6 Alkylene-C 6 -C 10 Aryl, -C 0 -C 6 Alkylene-5-10 membered heteroaryl, -C 0 -C 6 Alkylene-3-6 membered non-aromatic heterocyclic group, -C 0 -C 6 Alkylene-C 3 -C 6 Cycloalkyl, -C 0 -C 6 Alkylene-CONR a R b , SF 5 , -C 0 -C 6 Alkylene-NR a R b , -C 0 -C 6 Alkylene-NHC(O)R c , -C 0 -C 6 Alkylene-NHC(O)NR a R b , -C 0 -C 6 Alkylene-P(O)Me 2 , -C 0 -C 6 Alkylene C 3 -C 6 Cycloalkoxy, -C 0 -C 6 Alkylene C 1 -C 6Alkoxy, -C 0 -C 6 Alkylene C 1 -C 6 Haloalkoxy, -C 0 -C 6 Alkylene -C≡CR 2 、-OC 1 -C 6 Alkylene -C≡CR 2 , -SC 1 -C 6 Alkylene -C≡CR 2 ,

[0012]

[0013]

[0014] R a , R b are independently hydrogen, substituted or unsubstituted C 1 -C 10 Alkyl, substituted or unsubstituted C 3 -C 10 Cycloalkyl, substituted or unsubstituted C 6 -C 10 Aryl, substituted or unsubstituted C 3 -C 10 Heteroaryl; R a and R b Together with the nitrogen or carbon atom to which they are attached, they may form a three- to eight-membered ring or a four- to eight-membered heterocyclic ring;

[0015] R c Each independently is H, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkoxy, C 0 -C 6 Alkylene hydroxyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclic group;

[0016] R 2 For hydrogen, C 1 -C 10 Alkyl, -C 0 -C6 Alkylene-C 6 -C 10 Aryl, -C 0 -C 6 Alkylene-5-10 membered heteroaryl, -C 0 -C 6 Alkylene-3-10 membered non-aromatic heterocyclic group, -C 0 -C 6 Alkylene-C 3 -C 10 Cycloalkyl.

[0017] The present invention also provides a compound of formula III

[0018]

[0019] wherein the definitions are the same as those in Formula II.

[0020] The third aspect of the present invention provides the use of the compound described in the first aspect for:

[0021] (i) preparing a programmed cell necrosis inhibitor;

[0022] (ii) preparing a medicament for preventing and / or treating a disease mediated by programmed cell death. DETAILED DESCRIPTION

[0023] definition

[0024] 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 (i.e., CH 3 -), ethyl (i.e. CH 3 CH 2 -), n-propyl (i.e. CH 3 CH 2 CH 2 -), isopropyl (i.e. (CH 3 ) 2 CH-), n-butyl (i.e. CH 3 CH 2 CH 2 CH 2 -), isobutyl (i.e. (CH 3 ) 2 CHCH 2 -), sec-butyl (i.e. (CH 3 )(CH 3 CH 2 )CH-), tert-butyl (i.e. (CH 3 ) 3 C-), n-pentyl (i.e. CH 3 CH 2 CH2 CH 2 CH 2 -), neopentyl (i.e. (CH 3 ) 3 CCH 2 -).

[0025] As used herein, the term "aryl" refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6-14) carbon atoms, which has a single ring (such as phenyl) or a condensed ring (such as naphthyl or anthracenyl). If the point of attachment is on the aromatic carbon atom, the condensed ring may be non-aromatic (such as 2-benzoxazolone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, etc.). Preferred aryl groups include phenyl and naphthyl.

[0026] As used herein, the term "alkenyl" refers to an alkenyl group having 2 to 10 (such as 2 to 6 or 2 to 4) carbon atoms, and having at least 1 (such as 1 to 2) unsaturated olefinic bonds (>C=C<). Examples of such groups include vinyl, allyl, but-3-enyl. As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms, having a single ring or multiple rings (including fused systems, bridged ring systems and spiro ring systems). In the fused ring system, one or more rings may be cycloalkyl, heterocyclic, aryl or heteroaryl, as long as the connection point is through the ring of the cycloalkyl group. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.

[0027] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0028] As used herein, the term "heteroaryl" refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring, such heteroaryl groups may be monocyclic (such as pyridyl or furanyl) or fused rings (such as indolizinyl or benzothienyl), wherein the fused ring may be non-aromatic and / or contain one heteroatom, as long as the point of attachment is through the atom of the aromatic heteroaryl. In one embodiment, the ring atoms nitrogen and / or sulfur of the heteroaryl group are optionally oxidized to N-oxide (NO), sulfinyl or sulfonyl. Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, thienyl and furanyl.

[0029] As used herein, the term "substituted heteroaryl" refers to a heteroaryl group substituted with 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from the same substituents as defined for substituted aryl.

[0030] As used herein, the term "heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated, partially saturated or unsaturated group (but not aromatic) having a single ring or fused rings (including bridged ring systems and spiro ring systems) with 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the rings. In a fused ring system, one or more rings can be cycloalkyl, aryl or heteroaryl, as long as the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen atom and / or sulfur atom of the heterocyclic group is optionally oxidized to provide N-oxide, sulfinyl and sulfonyl moieties.

[0031] As used herein, the term "substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclic group substituted with 1 to 5 (e.g., 1 to 3) substituents, the substituents being the same as those defined for substituted cycloalkyl.

[0032] The substituents are selected from, but not limited to, the following chemical groups: halogen, -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, -SF 5 , -C 0-6 Alkylene-NR a R b , -C 0-6 Alkylene-carboxyl, -C 0-6 Alkylene-COR a , -C 0-6 Alkylene-CO 2 R a , -C 0-6 Alkylene-CONR d R e , -C 0-6 Alkylene-SO 2 R a , -C 0-6 Alkylene-SO 2 NR d R e , carbonyl, -C 0-6 Alkylene-CN,-C 3-8 Cycloalkyl-OH,-C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 Alkylene-S(O)(NH)C 1-6 alkyl,-C 0-6Alkylene-S(O)(NCN)C 1-6 alkyl,-C 0-6 Alkylene-NR c S(O) 2 R b ,-C 0-6 Alkylene-NR c S(O) 2 NR c R b ,-C 0-6 Alkylene-NR c C(O)NH 2 ,-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-NRSO 2 R 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- 10Aryl, C 2-10 Heterocyclic, C 2-10 Heteroaromatic ring.

[0033] In this application, C 0-6 Alkylene refers to a group having no alkylene or having C 1-6 Alkylene.

[0034] As used herein, the term "stereoisomer" refers to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

[0035] As used herein, the term "tautomer" refers to alternative forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or tautomeric forms of a heteroaryl group comprising a ring atom attached to the -NH- portion of the ring and the =N- portion of the ring, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0036] "Prodrug" refers to any derivative of an Example compound that, when administered to a subject, is capable of providing, directly or indirectly, an Example compound or its active metabolite or residue. Particularly preferred derivatives and prodrugs are those that, when administered to a subject, increase the bioavailability of an Example compound (e.g., an orally administered compound is more readily absorbed into the blood) or increase 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 invention.

[0037] In the case where the compounds described in the present invention have stereoisomers, the present invention includes all stereoisomers of the compounds. In the case where the compounds described in the present invention have tautomers, the present invention includes all tautomers of the compounds. The present invention also includes deuterated compounds produced by replacing any one or more hydrogen atoms in the compounds with their stable isotope deuterium. The present invention also provides active ingredients within the safe and effective amount range of the compounds of formula I and formula XII, as well as pharmaceutically acceptable carriers. The "active ingredient" described in the present invention refers to the compounds of formula I to formula XII described in the present invention.

[0038] The "active ingredient" and pharmaceutical composition of the present invention can be used as an inhibitor of diseases mediated by programmed cell death. In another preferred embodiment, it is used to prepare a drug for preventing and / or treating diseases mediated by programmed cell death.

[0039] "Safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably, 10-200 mg of active ingredient per dose. Preferably, the "one dose" is one tablet or capsule.

[0040] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of the components in the composition to blend with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Generally, the compounds of the preferred embodiments will be administered in a therapeutically effective amount through any acceptable mode of medicaments with similar effects. The actual dosage of the compounds of the preferred embodiments (i.e., active ingredients) is determined based on multiple factors, such as the severity of the disease to be treated, the age and relative health of the patient, the efficacy of the compound used, the route and form of administration, and other factors. The drug can be administered multiple times a day, preferably once or twice a day. All of these factors are within the consideration of the attending physician.

[0041] For the purpose of the preferred embodiment, the therapeutically effective dose can generally be a total daily dose for a single or divided administration to a patient, for example, about 0.001 to about 1000 mg / kg body weight per day, preferably about 1.0 to about 30 mg / kg body weight per day. The unit dose composition (Dosage unit composition) may contain its dosage factor to form a daily dose. The choice of dosage form depends on various factors, such as the mode of administration and the bioavailability of the drug substance. Generally, the compounds of the preferred embodiments can be administered as pharmaceutical compositions by any of the following routes: oral, systemic administration (such as transdermal, intranasal or by suppository), or parenteral administration (such as intramuscular, intravenous or subcutaneous). The preferred mode of administration is oral, and a convenient daily dose can be adjusted according to the degree of bitterness. The composition can take the form of tablets, pills, capsules, semisolids, powders, sustained-release preparations, solutions, suspensions, elixirs, aerosols or any other suitable composition. Another preferred mode of administering the preferred embodiment compound is inhalation. This is an effective method for delivering therapeutic agents directly to the respiratory tract (see, e.g., U.S. Pat. No. 5,607,915).

[0042] Suitable pharmaceutically acceptable carriers or excipients include: such as treating agents and drug delivery modifiers and promoters, such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, sodium methylcellulose, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting point wax, ion exchange resins, etc., and any combination of two or more thereof. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including petroleum, animal oil, vegetable oil or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly carriers for injectable solutions, include water, saline, aqueous glucose solutions and ethylene glycol. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

[0043] As used herein, the term "pharmaceutically acceptable salt" refers to non-toxic acid or alkaline earth metal salts of compounds of Formula I to Formula XII. These salts can be prepared in situ during the final isolation and purification of compounds of Formula to Formula XIII, or by reacting a suitable organic or inorganic acid or base with a basic or acidic functional group, respectively. Representative salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, gluconate heptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthylsulfonate, oxalate, pamoate, pectinate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, and undecanoate. In addition, nitrogen-containing basic groups can be quaternized by the following reagents: alkyl halides, such as chlorides, bromides and iodides of methyl, ethyl, propyl, butyl; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates; long-chain halides such as chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl; aralkyl halides such as benzyl and phenethyl bromides, etc. Water-soluble or oil-soluble or dispersible products are thus obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, citric acid. Base addition salts can be prepared in situ during the final isolation and purification of the compound of formula I, or by reacting the carboxylic acid portion 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, salts based on alkali and alkaline earth metal cations, such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, and non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines for forming base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0044] The following abbreviations have the indicated meanings. EA: ethyl acetate. DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM: dichloromethane; DIBAL: diisobutylaluminum hydride; DIEA: diisopropylethylamine; DMAP: N,N-dimethylaminopyridine; DME: 1,2-dimethoxyethane; DMF: N,N-dimethylformamide; DMPE: 1,2-bis(dimethylphosphino)ethane; DMSO: dimethyl sulfoxide; DPPB: 1,4-bis(diphenylphosphino)butane; DPPE: 1,2-bis(diphenylphosphino)ethane; DPPF: 1,1'-bis(diphenylphosphino)ferrocene; DPPM: 1,1'-bis(diphenylphosphino)methane; DIAD: diisopropyl azodicarboxylate; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ; HATU: O-(7-nitrobenzotriazole)-1,1,3,3-tetramethyluronium hexafluorophosphate; HMPA: hexamethylphosphoramide; HOAT: N-hydroxy-7-azobenzotriazole; IPA: isopropanol; LDA: lithium diisopropylamide; LHMDS: lithium bis(hexamethyldisilazide)amide; LAH: lithium aluminum hydride; NCS: N-chlorosuccinimide; PE: petroleum ether; PyBOP: benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate; TDA: tris[2-(2-methoxyethoxy)ethyl]amine; DCM: dichloromethane; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; NCS: N-chlorosuccinimide; NMM: N-methylmorpholine; NMP: N-methylpyrrolidone; PPh 3 : triphenylphosphine; RT: room temperature; T3P: propylphosphonic anhydride; TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate.

[0045] Reverse phase HPLC purification conditions: HPLC-MS analysis was performed on a Waters HPLC 2790 using a Waters micromass ZQ 4000 (MAA050 model) as a mass detector and a Waters 2487UV as a detector. The chromatographic column used was Fenome OOB-4605-E0 (5U-XB-C18-100A, 50×4.6 mm). The mobile phase was eluent A (water, 0.05% TFA) and eluent B (CH 3 CN, 0.05% TFA), elution rate is 1 ml / min. The initial condition is 90% A for 1 minute, then 90% A linearly decreases to 10% A within 5 minutes, and then rises from 10% A back to 90% A within 1 minute, and the total running time is 7 minutes. The mobile phase gradient and running time can be adjusted appropriately according to the properties of the compound.

[0046] Chiral HPLC separation conditions: Agilent Technologies 1200 Infinity liquid chromatography system was used, and the chiral column was Daicel CHIRALPAK IG (Cat. No.: IG00EE-AT002). The mobile phase was eluent A (n-hexane) and eluent B (ethanol), the elution rate was 3 ml / min, and the elution condition was a constant proportion of ethanol. Depending on the properties of the compound, the type of chiral column, the proportion of mobile phase ethanol and the running time can be adjusted appropriately.

[0047] With reference to the following examples, it is easier to understand the content of the present invention, which are provided to illustrate the present invention rather than to limit its scope. Unless otherwise specified, percentages and parts are calculated by weight, and the unit is parts by weight.

[0048] Unless otherwise stated, the materials and reagents used in the examples of the present invention are commercially available products.

[0049] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0050] Example 1: Preparation of intermediate Z-7

[0051] Step 1: Preparation of Z-1: 500 mg of 7-nitroindole was dissolved in 10 mL of acetonitrile, methyl acrylate (670.4 mg) and DBU (234.9 mg) were added and reacted at 50°C for 4 h, then the reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was concentrated and subjected to column chromatography to obtain intermediate Z-1. MS ESI: m / z=249.4, [M+H] + .

[0052] Step 2: Preparation of Z-2: Z-1 (330 mg), NH 4 Cl (290.4 mg), iron powder (744.9 mg), dissolved in ethanol (12 mL) and water (4 mL), reacted at room temperature for 1 h, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated the organic phase and column chromatography to obtain intermediate Z-2. MS ESI: m / z = 218.2, [M+H] + .

[0053] Step 3: Preparation of Z-3: Z-2 (250 mg) and lithium hydroxide (140 mg) were dissolved in methanol (10 mL) and water (3 mL). After reacting at room temperature for 1 h, the pH of the reaction solution was adjusted to 5 with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain a crude product Z-3. MS ESI: m / z=205, [M+H] + .

[0054] Step 4: Preparation of Z-4: Z-3, NMI (N-methylimidazole), and TCFH were directly dissolved in DMF (10 mL), reacted at room temperature for 3 h, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the concentrated organic phase was subjected to column chromatography to obtain intermediate Z-4. MSESI: m / z = 187.2, [M+H] + .

[0055] Step 5: Preparation of Z-5: Dissolve Z-4 ​​(100 mg), iodomethane (233.5 mg), and cesium carbonate (185.7 mg) in DMF (5 mL), react for 3 h at room temperature, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate the organic phase, and perform column chromatography to obtain intermediate Z-5. MS ESI: m / z=201.2, [M+H] + .

[0056] Step 6: Preparation of Z-6: Dissolve Z-5 (100 mg), NaHMDS (sodium bis(trimethylsilyl)amide), and isoamyl nitrite in THF (5 mL), react for 3 h in an ice bath, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate the organic phase, and perform column chromatography to obtain intermediate Z-6. MS ESI: m / z=230.2, [M+H] + .

[0057] Step 7: Preparation of Z-7: Dissolve Z-6 (200 mg) and nickel chloride hexahydrate (423.5 mg) in MeOH (8 mL), stir for 30 minutes under ice bath, add sodium borohydride (198.2 mg) under ice bath, react for 3 hours at room temperature, spin dry the reaction solvent, purify by beating with dichloromethane, filter and concentrate the organic phase to obtain intermediate Z-7. MS ESI: m / z=216.2, [M+H] + .

[0058]

[0059] Example 2: T-1

[0060] (±)-5-Benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0061]

[0062] Acid-1 (73.6 mg), NMI (34.3 mg), and TCFH (119.7 mg) were dissolved in 1 mL DMF, stirred for 10 min under ice bath conditions, and then Z-7 (60 mg) was added and reacted at room temperature for 3 h. The reaction was quenched with ice water, extracted three times with EA, and the organic phases were combined, washed three times with water, washed three times with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by HPLC (mobile phase: A:H 2 O(+0.1%CF 3 COOH); B: MeCN; separation conditions: 50% B; flow rate: 10 mL / min; chromatographic column: Waters Prep MSC18, 19×250 mm, 10 μm) was purified and freeze-dried to obtain 5 mg of white solid (T-1).

[0063] 1 H NMR (400 MHz, CDCl 3 )δ8.63(s,1H),7.49(d,J=7.8Hz,1H),7.09-7.32(m,7H),7.06(d,J=7.7Hz,1H) ,6.58(m,1H),4.92(m,1H),4.67(m,1H),4.33(m,1H),4.19(s,2H),3.64(s,3H).

[0064] MS ESI: m / z = 401.1, [M+H] + .

[0065] Example 3: T-2

[0066] (±)-5-Benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)oxazole-2-carboxamide

[0067]

[0068] Using acid-2 (56.6 mg) and Z-7 as raw materials, T-2 was obtained under the same conditions as in Example 2.

[0069] 1 H NMR (400MHz, CD 3OD)δ7.45–7.12(m,10H),7.02(s,1H),6.55(m,1H),4.76(m,1H),4.63(m,1H),4.58(s,1H),4.39(m,1H),4.11(s,2H),3.59(s,3H). MS ESI:m / z=401.1,[M+H] + .

[0070] Example 4: T-3

[0071] (±)-5-Benzyl-N-(7-iodo-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0072]

[0073] Step 1: Preparation of Z-8. Dissolve the intermediate Z-7 (1 eq), di-tert-butyl dicarbonate (1.1 eq), and triethylamine (1.5 eq) in dichloromethane, stir at room temperature for 2 h, add ice water to quench the reaction, extract three times with ethyl acetate, combine the organic phases, wash three times with water, wash three times with saturated brine, dry with anhydrous sodium sulfate, concentrate the organic phase, and separate and purify by rapid column chromatography to obtain the intermediate Z-8.

[0074] Step 2: Preparation of Z-9. Dissolve the intermediate Z-8 (1 eq) and N-iodosuccinimide (1.1 eq) in dichloromethane, stir at room temperature for 30 min, add ice water to quench the reaction, extract three times with ethyl acetate, rinse with a saturated solution of thiosulfuric acid pentahydrate, combine the organic phases, wash three times with water, wash three times with saturated brine, dry over anhydrous sodium sulfate, concentrate the organic phase, and separate and purify by rapid column chromatography to obtain the intermediate Z-9.

[0075] Step 3: Preparation of Z-10: Dissolve intermediate Z-9 (1 eq) and trifluoroacetic acid (10 eq) in dichloromethane, stir at room temperature for 3 h, concentrate the organic phase, and directly separate and purify the intermediate Z-10 by rapid column chromatography. MS ESI: m / z=341.6, [M+H] + .

[0076] Step 4: Preparation of T-3: Using acid-1 (1.5 eq) and Z-9 (1 eq) as raw materials, T-3 was obtained using the same conditions as in Example 2.

[0077] 1 H NMR (400MHz, acetone-d 6)δ8.55(s,1H),7.62(s,1H),7.43–7.21(m,8H),4.88–4.70(m,2H),4.45(m,1H),4.21(s,2H),3.60(s,3H). MS ESI:m / z=527,[M+H] + .

[0078] Example 5: T-4

[0079] (±)-5-Benzyl-N-(1-methyl-7-(methylthio)-2-carbonyl-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0080]

[0081] Step 1: Preparation of Z-11. Dissolve the intermediate Z-8 (1 eq), dimethyl sulfide (1.3 eq), and N-chlorosuccinimide (1.3 eq) in dichloromethane, stir at room temperature for 2 h, add ice water to quench the reaction, extract three times with ethyl acetate, combine the organic phases, wash three times with water, wash three times with saturated brine, dry with anhydrous sodium sulfate, concentrate the organic phase, and separate and purify by rapid column chromatography to obtain the intermediate Z-11.

[0082] Step 2: Preparation of Z-12: Dissolve intermediate Z-11 (1 eq) and trifluoroacetic acid (10 eq) in dichloromethane, stir at room temperature for 3 h, concentrate the organic phase, and directly separate and purify intermediate Z-12 by rapid column chromatography. MS ESI: m / z=262, [M+H] + .

[0083] Step 3: Preparation of T-4: Using acid-1 (1.5 eq) and Z-2 (1 eq) as raw materials, T-4 was obtained using the same conditions as in Example 2.

[0084] 1 H NMR (400MHz, CD 3 OD)δ7.54(m,1H),7.34–7.17(m,7H),4.77(m,1H),4.65–4.59(m,1H),4.37–4.30(m,1H),4.16(s,2H),3.57(s,3H),2.32(s,3H). MS ESI:m / z=447,[M+H] + .

[0085] Example 6: T-5

[0086] (±)-5-Benzyl-N-(9-chloro-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0087]

[0088] Using 5-chloro-7-nitro-indole as the raw material, the intermediate Z-13 was obtained under the same conditions as in Example 1. Using acid-1 (1.5 eq) and Z-13 (1 eq) as the raw materials, the same conditions as in Example 2 were used to obtain T-5.

[0089] 1 H NMR (400 MHz, CDCl 3 )δ8.60(m,1H),7.45(d,J=1.8Hz,1H),7.33–7.27(m,5H),7.08(d,J=3.2Hz,1H),7.03(d,J=1.8Hz, 1H), 6.51 (d, J = 3.1Hz, 1H), 4.91–4.86 (m, 1H), 4.65 (m, 1H), 4.30 (m, 1H), 4.19 (s, 2H), 3.61 (s, 3H). MS ESI:m / z=435,[M+H] + .

[0090] Example 7: T-6

[0091] (±)-5-Benzyl-N-(9-bromo-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0092]

[0093] Using 5-bromo-7-nitro-indole as the starting material, the same conditions as in Example 1 were used to obtain intermediate Z-14, and using acid-1 (1.5 eq) and Z-14 (1 eq) as the starting materials, the same conditions as in Example 2 were used to obtain example T-6.

[0094] 1 H NMR (400 MHz, CDCl 3)δ8.59(m,1H),7.61(d,J=1.6Hz,1H),7.33-7.27(m,5H),7.15(d,J=1.6Hz,1H),7.06(d,J=3.1Hz, 1H), 6.51 (d, J = 3.2Hz, 1H), 4.91–4.84 (m, 1H), 4.65 (m, 1H), 4.29 (m, 1H), 4.19 (s, 2H), 3.61 (s, 3H). MS ESI:m / z=481,[M+H] + .

[0095] Example 8: T-7

[0096] (±)-5-Benzyl-N-(9-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0097]

[0098] Using 5-fluoro-7-nitro-indole as the raw material, the intermediate Z-15 was obtained under the same conditions as in Example 1. Using acid-1 (1.5 eq) and Z-15 (1 eq) as the raw materials, the same conditions as in Example 2 were used to obtain T-7.

[0099] 1 H NMR (400 MHz, DMSO-d 6 )δ8.66(s,1H),7.52(d,J=3.1Hz,1H),7.40–7.19(m,6H),7.09(m,1H),6.55(d, J=3.1Hz,1H),4.70(m,1H),4.59(m,1H),4.41(m,2H),4.13(s,2H),3.50(s,3H). MS ESI: m / z=419, [M+H] + .

[0100] Example 9: T-8

[0101] (±)-5-Benzyl-N-(1-methyl-7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-oxo-1,2,3,4-tetrahydro-[1,4]diazaze[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0102]

[0103] Step 1: Preparation of Z-16: N-methyl-4-alkynylpyrazole (1.3 eq) and intermediate Z-10 (1 eq), CuI (0.05 eq), PdCl2(PPh3)2 (0.1 eq) were dissolved in a mixed solvent of triethylamine and DMF, reacted at 85°C for 0.5 hours, cooled to room temperature, extracted with EA, washed with water three times, concentrated the organic phase, and separated and purified by rapid column chromatography to obtain intermediate Z-16. MS-ESI: m / z=420, [M+H] + .

[0104] Step 2: Preparation of T-8: Using acid-1 (1.5 eq) and Z-16 (1 eq) as raw materials, T-8 was obtained using the same conditions as in Example 2.

[0105] 1 H NMR (400MHz, acetone-d 6 )δ7.88(s,1H),7.68(s,1H),7.60(s,1H),7.58–7.55(m,1H),7.34–7.27(m, 7H),4.86–4.73(m,2H),4.44(m,1H),4.21(s,2H),3.92(s,3H),3.62(s,3H). MS ESI:m / z=505,[M+H] + .

[0106] Example 10: T-9

[0107] (±)-5-Benzyl-N-(1-methyl-9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0108]

[0109] Step 1: Preparation of Z-17: N-methyl-4-alkynylpyrazole (1.3 eq) and intermediate Z-14 (1 eq), CuI (0.05 eq), PdCl 2 (PPh 3 ) 2 (0.1 eq) was dissolved in a mixed solvent of triethylamine and DMF, reacted at 85°C for 3 hours, cooled to room temperature, extracted with EA, washed with water three times, the organic phase was concentrated, and separated and purified by rapid column chromatography to obtain intermediate Z-17. MS-ESI: m / z=420, [M+H] + .

[0110] Step 2: Preparation of T-9: Using acid-1 (1.5 eq) and Z-17 (1 eq) as raw materials, T-9 was obtained using the same conditions as in Example 2.

[0111] 1 H NMR (400MHz, acetone-d 6 )δ8.56(s,1H),7.87(s,1H),7.58(s,1H),7.45(d,J=3.2Hz,1H),7.34 -7.24(m,6H),6.62(d,J=3.2Hz,1H),4.82(m,1H),4.75(m,1H),4.42(m,1H),4.21(s,2H),3.91(s,3H),3.63(s,3H). MS ESI:m / z=505,[M+H] + .

[0112] Example 11: T-10

[0113] (±)-5-Benzyl-N-(1-ethyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0114]

[0115] Step 1: Preparation of Z-18: Use iodoethane and intermediate Z-4 ​​to obtain intermediate Z-18 under the same conditions as in Example 1. MS-ESI: m / z=230, [M+H]+.

[0116] Step 2: Preparation of T-10: Using acid-1 (1.5 eq) and Z-18 (1 eq) as raw materials, T-10 was obtained under the same conditions as in Example 2.

[0117] 1 H NMR (400MHz, CD 3 OD)δ7.47(m,1H),7.35–7.21(m,7H),7.14(m,1H),6.56(m,1H),4.77(m,1H ), 4.65 (m, 1H), 4.32 (m, 1H), 4.18 (q, J = 6.6Hz, 4H), 1.28 (t, J = 7.1Hz, 3H). MSESI:m / z=415,[M+H] + .

[0118] Example 12: T-11

[0119] (±)-5-Benzyl-N-(7-bromo-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi indol-3-yl]-4H-1,2,4-triazole-3-carboxamide

[0120]

[0121] Step 1: Preparation of Z-19: Intermediate Z-19 was obtained by reacting N-bromosuccinimide with intermediate Z-8 under the same conditions as in Example 4. MS-ESI: m / z=296, [M+H] + .

[0122] Step 2: Preparation of T-11: Acid-1 (1.5 eq) and Z-19 (1 eq) were used as raw materials and T-11 was obtained under the same conditions as in Example 2.

[0123] 1 H NMR (400MHz, CD 3 OD)δ7.37–7.20(m,9H),4.80–4.75(m,1H),4.65–4.59(m,1H),4.35(m,1H),4.16(s,2H),3.56(s,3H). MS ESI:m / z=481,[M+H] + .

[0124] Example 13: T-12

[0125] (±)-3-(5-Benzyl-4H-1,2,4-triazole-3-carboxamido)-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indole-6-carboxylate

[0126]

[0127] Using ethyl 7-nitroindole-2-carboxylate as the raw material, the same conditions as in Example 1 were used to obtain intermediate Z-20, and using acid-1 (1.5 eq) and Z-20 (1 eq) as the raw materials, the same conditions as in Example 2 were used to obtain T-12.

[0128] 1 H NMR (400MHz, acetone-d 6)δ8.55(s,1H),7.62(m,1H),7.42(s,1H),7.38–7.26(m,7H),5.37(m,1H),4.86–4.80(m,1H) ,4.43(m,1H),4.39–4.32(q,J=7.1Hz,2H),4.21(s,2H),3.60(s,3H),1.37(t,J=7.1Hz,3H). MS ESI:m / z=473,[M+H] + .

[0129] Example 14: T-13

[0130] (±)-3-(5-Benzyl-4H-1,2,4-triazole-3-carboxamido)-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indole-6-carboxylic acid

[0131]

[0132] T-12 (1 eq) and 2M lithium hydroxide aqueous solution were dissolved in tetrahydrofuran, reacted at 60°C for three hours, neutralized with 2M dilute hydrochloric acid aqueous solution, extracted three times with EA, combined the organic phases, washed three times with water, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated the organic phase, and purified by HPLC to obtain the product T-13.

[0133] 1 H NMR (400MHz, acetone-d 6 )δ8.55(s,1H),7.63(m,1H),7.45(s,1H),7.38–7.30(m,5H),7.25(m,2H),5.44(m,1H),4.83(m,1H),4.40(m,1H),4.21(s,2H),3.61(s,3H).

[0134] MS ESI: m / z = 445, [M + H] + .

[0135] Example 15: T-14

[0136] (±)-5-Benzyl-N-(1-methyl-2-oxo-1,2,3,4,6,7-hexahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0137]

[0138] The intermediate Z-8 (1 eq) and sodium cyanoborohydride (3 eq) were dissolved in acetic acid solution, reacted for 3 h under ice bath conditions, extracted three times with EA, the organic phases were combined, dried over sodium sulfate, and concentrated to obtain the intermediate (Z-21). Acid-1 (1.5 eq) and Z-21 (1 eq) were used as raw materials and T-14 was obtained under the same conditions as in Example 2.

[0139] 1 H NMR (400 MHz, CDCl 3 )δ8.34(s,1H),7.39–7.29(m,4H),6.96-6.90(m,2H),6.75(m,2H),4.87(m, 1H),4.17(s,2H),3.78(m,2H),3.62(m,2H),3.44(s,3H),3.27–3.18(m,2H).

[0140] MS ESI: m / z = 403, [M + H] + .

[0141] Example 16: T-15

[0142] (±)-5-Benzyl-N-(1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0143]

[0144] Step 1: Preparation of Z-22: 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (1.5 eq) and intermediate Z-9 (1 eq), Pd(dppf)Cl2 (0.1 eq), K3PO4 were dissolved in a mixed solvent of dioxane and water, reacted at 95°C overnight under argon protection, cooled to room temperature, extracted with EA, washed with water three times, concentrated the organic phase, and separated and purified by rapid column chromatography to obtain intermediate Z-22.

[0145] Step 2: Preparation of Z-23: Dissolve intermediate Z-22 (1 eq) and trifluoroacetic acid (10 eq) in dichloromethane, stir at room temperature for 3 h, concentrate the organic phase, and directly separate and purify intermediate Z-23 by rapid column chromatography. MS ESI: m / z=296, [M+H] + .

[0146] Step 3: Preparation of T-15: Using acid-1 (1.5 eq) and Z-23 (1 eq) as raw materials, T-15 was obtained using the same conditions as in Example 2.

[0147] 1 H NMR (400 MHz, CDCl 3 )δ7.73(s,1H),7.60(m,2H),7.32(m,4H),7.23–7.07(m,4H),4.91(m,1H),4.65(m,1H),4.34(m,1H),4.20(s,2H),3.98(s,3H),3.63(s,3H). MS ESI:m / z=481,[M+H] + .

[0148] Example 17: T-16

[0149] (±)-5-Benzyl-N-(1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0150]

[0151] T-16 was obtained by reacting 1-methyl-1H-pyrazole-5-boronic acid pinacol ester with intermediate Z-9 under the same conditions as Example 16.

[0152] 1 H NMR (400 MHz, CDCl 3 )δ8.65(s,1H),7.62(s,1H),7.43(m,1H),7.22-7.14(m,8H),6.41(m,1H),4.97–4. 91(m,1H),4.71(m,1H),4.40–4.33(m,1H),4.19(s,2H),3.87(s,3H),3.64(s,3H). MS ESI: m / z=481, [M+H] + .

[0153] Example 18: T-17

[0154] (±)-5-Benzyl-N-(1-methyl-2-oxo-7-(pyridin-3-yl)-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0155]

[0156] T-17 was obtained by reacting 3-pyridineboronic acid pinacol ester with intermediate Z-9 using the same conditions as in Example 16.

[0157] 1H NMR (400 MHz, CDCl 3 )δ8.88(m,1H),8.64(s,1H),8.56(m,1H),7.93(d,J=7.9Hz,1H),7.71(m,1H),7.42–7.30(m,7H) ,7.14(d,J=7.9Hz,1H),4.99(m,1H),4.75(m,1H),4.45–4.36(m,1H),4.20(s,2H),3.66(s,3H). MS ESI:m / z=478,[M+H] + .

[0158] Example 19: T-18

[0159] (±)-5-Benzyl-N-(1-methyl-7-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[[3,2,1-hi]indol-3-yl]-4H-1,2,4-triazole-3-carboxamide

[0160]

[0161] T-18 was obtained by reacting 1-methyl-3-trifluoromethylpyrazole-5-boronic acid pinacol ester with intermediate Z-9 under the same conditions as Example 16.

[0162] 1 H NMR (400 MHz, CDCl 3 )δ8.65(s,1H),7.42(d,J=7.9Hz,1H),7.38–7.29(m,5H),7.24(s,1H),7.17(d,J=7.8Hz,1H) ,6.65(s,1H),5.01(m,1H),4.75(m,1H),4.40(m,1H),4.21(s,2H),3.93(s,3H),3.67(s,3H). MS ESI:m / z=549,[M+H] + .

[0163] Example 20: Preparation of Intermediate Y-8

[0164]

[0165] Step 1: Preparation of Y-1: 4-nitroindole (4000 mg), NH(CH 3 ) 2 (13.58ml, 2mol / l in MeOH), HCHO (2.2ml, 37%), ZnCl 2(5048 mg) and 10 ml of methanol. After stirring at room temperature for 2 h, NH(CH 3 ) 2 (2.46ml), HCHO (0.5ml). After stirring for 4h, LC-MS showed that the raw material was completely consumed, and NaOH solution was added to adjust the pH to about 13, and EA was added to dilute, and the insoluble solid was removed by filtration. The filtrate was extracted with EA, and after the sodium sulfate solid was dried, the solvent was spin-dried to obtain a yellow solid, and then PE / EA 10:1 was used for pulping to obtain 4250mg of a yellow solid. MS ESI: m / z=220, [M+1] + .

[0166] Step 2: Preparation of Y-2: Add Y-1 (4250 mg), diethyl malonate (2.94 ml), ethyl propiolate (1.96 ml) and anhydrous ether (97 ml) into a 250 ml eggplant-shaped bottle under ice bath. Replace the air in the bottle with N 2 After stirring at room temperature for 3 hours, diethyl malonate (0.59 ml) and ethyl propiolate (1.96 ml) were added. After stirring for 4 hours, TLC showed that the reaction was complete, 1N HCl was used for quenching, and EA was used for extraction. The organic phase was dried and concentrated with anhydrous sodium sulfate, and then 5.47 g of yellow solid was obtained by rapid silica gel column chromatography. MSESI: m / z=335, [M+1] + .

[0167] Step 3: Preparation of Y-3. Add Y-2 (5470 mg), Pd / C (3530 mg, 5%) and MeOH (78 ml) to a 250 ml eggplant-shaped bottle. Replace the air in the reaction bottle with hydrogen using a hydrogen balloon, and then stir at room temperature under a hydrogen atmosphere. After about 2 hours, TLC showed that the reaction was complete. Filter through diatomaceous earth, and spin dry the organic phase to obtain 5.04 g of a yellow-brown oil. MS ESI: m / z=305, [M+1] + .

[0168] Step 4: Preparation of Y-4: Formic acid (3.1 ml) and acetic anhydride (1.9 ml) were added to a 10 ml eggplant flask and stirred at room temperature for about 20 min to prepare formic acetic anhydride. Y-3 (4900 mg) and dichloromethane (16 ml) were added to a 50 ml eggplant flask under ice bath, and then the formic acetic anhydride prepared in advance was added dropwise. After stirring at room temperature for 3 hours, a mixed anhydride prepared from 1 ml formic acid and 0.6 ml acetic anhydride was added, and stirring was continued for 2 hours. TLC showed that the reaction was complete. The solvent and excess acid were removed by spin drying under vacuum, and the obtained green solid was dissolved in 64 ml tetrahydrofuran. A tetrahydrofuran solution of borane dimethyl sulfide complex (16.2 ml, 2 mol / l in THF) was added under ice bath. Stir at room temperature overnight, add dilute hydrochloric acid to quench, extract with EA, dry and concentrate with anhydrous sodium sulfate, and obtain 4870 mg of light green oil by rapid silica gel column chromatography. MS ESI: m / z = 319, [M+1] + .

[0169] Step 5: Preparation of Y-5. Add Y-4 (2000 mg), TFA (10 ml) and toluene (52 ml) into a 250 ml eggplant flask. After reflux at 110 °C under nitrogen atmosphere for 26 h, TLC showed that the reaction was complete. After the reaction solution was concentrated, 1225 mg of the target product was obtained by rapid silica gel column chromatography. MS ESI: m / z = 273, [M+1] + .

[0170] Step 6: Preparation of Y-6: Add Y-5 (1225 mg), KOH (1010 mg), water (1.6 ml) and MeOH (10.5 ml) into a 50 ml eggplant-shaped bottle. After stirring at room temperature for 2.5 h, the reaction was completed. The reaction solution was adjusted to acidity with 1N HCl, extracted with EA, and the organic phase was dried with anhydrous sodium sulfate and spin-dried to obtain 1.2163 g of a yellowish brown solid. MS ESI: m / z=245, [M+1] + .

[0171] Step 7: Preparation of Y-7: Add Y-6 (500 mg), DPPA (845.3 mg), DIEA (399.6 mg) and toluene (10 ml) into a 50 ml eggplant-shaped bottle. Replace the air in the bottle with N 2 After that, the mixture was heated and stirred at 85°C for 2h, and then 1.25N NaOH (10ml) solution was added and stirred overnight. The reaction solution was first acidified with hydrochloric acid, and impurities were washed with EA, and then alkalized with NaOH solution, extracted with EA, and anhydrous Na 2 SO 4 After drying and concentration, 274.2 mg of light yellow solid was obtained. MS ESI: m / z=216, [M+1] + .

[0172] Step 8: Preparation of Y-8: Add Y-7 (224 mg), BOC 2 O(340.7mg), NEt 3 (315.1mg,) and THF (5ml). After stirring at room temperature for 6h, the solvent was dried by spin drying, a small amount of EA was added to the solid to dissolve it, and then PE was added to precipitate the product, and 285.7mg of yellow solid was obtained by filtration. Using a CHIRALPAK IG column, eluted with ethanol / n-hexane = 25% to obtain the first peak of S configuration and the second peak of R configuration. MS ESI: m / z = 314, [M-1] - .

[0173] Example 21: T-19

[0174] (±)-5-Benzyl-N-(1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0175]

[0176] Y-7 (20 mg), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (18.9 mg), EDCI (23.4 mg), HOBT (16.6 mg), DIEA (22.8 ul) and ultra-dry DCM (2 ml) were added to a 10 ml reaction tube. The gas was replaced with nitrogen and stirred at room temperature overnight. Saturated NaHCO 3 The solution was quenched, extracted with EA, dried, and crudely purified by flash column chromatography. The crude product was subjected to preparative HPLC (mobile phase: A:H 2 O (+0.1% TFA); B: MeCN; separation conditions: 50% B; flow rate: 18 mL / min; chromatographic column: Waters Prep MSC18, 19×250mm, 10μm) was purified and freeze-dried to obtain 5mg of white solid. Using optically pure Y-7 as raw material, ST-19 and RT-19 can be obtained by the same method.

[0177] 1 H NMR (400 MHz, DMSO-d 6)δ14.37(s,1H),11.19(s,1H),8.67(s,1H),7.39–7.08(m,8H),6.95(d,J=7.6Hz, 1H),4.65–4.54(m,1H),4.13(s,2H),3.50(s,3H),3.24(m,1H),3.09–2.93(m,1H). MS ESI:m / z=401,[M+1] + .

[0178] Example 22: T-20

[0179] (±)-5-Benzyl-N-(1,6-dimethyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0180]

[0181] Step 1: Preparation of Y-9: Add Y-8 (29 mg), K 2 CO 3 (15.2 mg) and DMF (1 ml). The air was replaced with nitrogen and stirred at room temperature overnight. MeI and K were added several times. 2 CO 3 After that, the reaction was completed. TFA was added to quench, and the solvent was removed by spin drying. DCM (2 ml) and TFA (0.4 ml) were added to the solid, stirred overnight to remove BOC, and spin dried, and used directly in the next step. MSESI: m / z = 230, [M+1] + .

[0182] Step 2: Preparation of T-20: Using Y-9 as raw material, 10 mg of white solid was obtained under the same conditions as Example 21.

[0183] 1 H NMR (400 MHz, DMSO-d 6 )δ14.59(s,1H),8.71(m,1H),7.43–7.07(m,8H),6.99(d,J=7.5Hz,1H),4.5 7(m,1H),4.16(s,2H),3.78(s,3H),3.47(s,3H),3.22(m,1H),3.01(m,1H). MS ESI:m / z=415,[M+1] + .

[0184] Example 23: T-21

[0185] (±)-5-Benzyl-N-(1-methyl-2-oxo-6-(phenylsulfonyl)-2,3,4,6-tetrahydro-1H-aza[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0186]

[0187] Step 1: Preparation of Y-10: Add Y-8 (29 mg), NaH (4.4 mg, 60%) and THF (1 ml) into a 10 ml reaction tube. After stirring for a few minutes, add PhSO 2 Cl (35.52 mg). After stirring for 2 h, NaH (10 mg) was added. After stirring for 1 h, the reaction was completed and saturated NaHCO 3 Solution and NH 4 The organic phase was washed twice with anhydrous Na 2 SO 4 Dry and spin dry to obtain the intermediate. Dissolve the intermediate in DCM (1.6 ml), then add TFA (0.4 ml), stir for about 2 h, and the reaction is completed. Spin dry to obtain Y-10. MS ESI: m / z=356, [M+1] + .

[0188] Step 2: Preparation of T-21: Using Y-10 as raw material, 15.7 mg of white solid was obtained under the same conditions as Example 21.

[0189] 1 H NMR (400 MHz, DMSO-d 6 )δ14.39(s,1H),8.69(s,1H),8.06–7.96(m,2H),7.83–7.76(m,2H),7.72m,1H),7.62m,2H),7.44( m,1H),7.38–7.12(m,6H),4.54(m,1H),4.13(s,2H),3.43(s,3H),3.23(m,1H),3.13–2.78(m,1H). MS ESI:m / z=541,[M+1] + .

[0190] Example 24: T-22

[0191] (±)-5-Benzyl-N-(6-(cyclopropylmethyl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0192]

[0193] Step 1: Preparation of Y-11: Add Y-8 (29 mg), NaH (7.4 mg, 60%) and DMF (1 ml) into a 10 ml reaction tube, stir for a few minutes, then add bromomethylcyclopropane (14.9 mg). Stir for 3 h, the reaction is complete, and saturated NH 4 The organic phase was washed twice with anhydrous Na 2 SO 4 Dry and spin dry to obtain 44.5 mg of the intermediate. The intermediate was dissolved in DCM (0.9 ml), TFA (0.3 ml) was added, and the reaction was completed after stirring at room temperature for 4 hours. Y-11 was spin dried and used directly in the next step. MS ESI: m / z = 270, [M+1] + .

[0194] Step 2: Preparation of T-22: Using Y-11 as raw material, 17.8 mg of light yellow solid was obtained under the same conditions as Example 21.

[0195] 1 H NMR (400 MHz, CDCl 3 )8.75(d,J=7.0Hz,1H),7.38–7.12(m,7H),7.04(s,1H),6.90(d,J=7.5Hz,2H),4.98–4.75(m,1H),4.16(s,2H),3.99(dd,J=14.3,6 .7Hz,1H),3.87(dd,J=14.3,6.7Hz,1H),3.61(s,3H),3.39(m,1H),3.18–3.00(m,1H),1.33–1.11(m,1H),0.64(m,2H),0.37(m,2H). MS ESI:m / z=455,[M+1] + .

[0196] Example 25: T-23

[0197] (±)-5-Benzyl-N-(6-cyclopropyl-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0198]

[0199] Step 1: Preparation of Y-12: Add Y-8 (29 mg), cyclopropylboronic acid (9.5 mg), DMAP (33 mg), and Cu(AcO) into a 10 ml reaction tube. 2(20 mg) and toluene (1 ml). The air was replaced with nitrogen, and after stirring at 100°C for 19 h, cyclopropylboronic acid (15 mg), Cu(AcO) 2 (20 mg), continued heating for 17 h, and the reaction was completed. 3 The organic phase was washed with anhydrous Na 2 SO 4 After drying and concentration, 20 mg of the intermediate was obtained by rapid silica gel column chromatography. The intermediate was dissolved in DCM (0.9 ml), TFA (0.3 ml) was added, and the reaction was completed after stirring at room temperature for 4 h. Y-12 was obtained by spin drying and used directly in the next step. MS ESI: m / z=256, [M+1] + .

[0200] Step 2: Preparation of T-23: Using Y-12 as raw material, 10.8 mg of white solid was obtained under the same conditions as Example 21.

[0201] 1 H NMR (400 MHz, CDCl 3 )δ11.75(s,1H),8.72(d,J=6.6Hz,1H),7.36(m,1H),7.32–7.29(m,4H),7.25–7.20(m,2H),6.94(s,1H),6.91(m,1H),4. 96–4.76(m,1H),4.17(s,2H),3.60(s,3H),3.36m,1H),3.33–3.27(m,1H),3.08(m,1H),1.06(m,2H),1.02–0.95(m,2H). MSESI:m / z=441,[M+1] + .

[0202] Example 26: T-24

[0203] (±)-5-Benzyl-N-(1-methyl-2-oxo-6-phenyl-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0204]

[0205] Step 1: Preparation of Y-13: Add Y-8 (29 mg), phenylboronic acid (13.4 mg), DMAP (33 mg), and Cu(AcO) into a 10 ml reaction tube. 2 (20 mg) and toluene (1 ml). The air was replaced with nitrogen, and after stirring at 100°C for 6 h, phenylboric acid (13.4 mg) and Cu(AcO) were added. 2(20 mg), and continued heating for 17 h, and the reaction was completed. 3 The organic phase was washed with anhydrous Na 2 SO 4 After drying and concentration, 10 mg of the intermediate was obtained by rapid silica gel column chromatography. The intermediate was dissolved in DCM (0.9 ml), TFA (0.3 ml) was added, and the reaction was completed after stirring at room temperature for 4 h. Y-13 was obtained by spin drying and used directly in the next step. MS ESI: m / z=292, [M+1] + .

[0206] Step 2: Preparation of T-24: Using Y-13 as raw material, 6.2 mg of white solid was obtained under the same conditions as Example 21.

[0207] 1 H NMR (400 MHz, CDCl 3 )δ8.78(d,J=5.7Hz,1H),7.51~7..10(m,13H),6.98(dd,J=15.8,6.4Hz,1 H),5.02–4.84(m,1H),4.20(s,2H),3.64(s,3H),3.47(m,1H),3.10m,1H). MS ESI:m / z=477,[M+1] + .

[0208] Example 27: T-25

[0209] (±)-5-Benzyl-N-(6-(cyanomethyl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0210]

[0211] Step 1: Preparation of Y-14: Add Y-8 (15 mg), KOH (5.1 mg) and THF (0.5 ml) into a 10 ml reaction tube, stir at room temperature for a few minutes, and then add BrCH 2 CN (7.2 mg). After stirring for 2 h, about half of it was converted into the target product, and KOH and BrCH 2 CN until TLC showed the reaction was complete. 4 Cl solution quenching, EA extraction, organic phase with anhydrous Na 2 SO 4After drying and concentration, 14 mg of the intermediate was obtained by rapid silica gel column chromatography. The intermediate was dissolved in DCM (0.9 ml), TFA (0.3 ml) was added, and the reaction was completed after stirring at room temperature for 2 h. Y-14 was obtained by spin drying and used directly in the next step. MS ESI: m / z=255, [M+1] + .

[0212] Step 2: Preparation of T-25: Using Y-14 as raw material, 3.9 mg of white solid was obtained under the same conditions as in Example 21.

[0213] 1 H NMR (400MHz, acetone-d 6 )δ13.36(s,1H),8.66(d,J=5.0Hz,1H),7.46–7.20(m,8H),7.11(d,J=7.7Hz,1H),5.5 5–5.37(m,2H),4.86–4.62(m,1H),4.20(s,2H),3.60(s,3H),3.41m,1H),3.01(m,1H). MS ESI:m / z=440,[M+1] + .

[0214] Example 28: T-26

[0215] (±)-5-Benzyl-N-(6-(2-fluoroethyl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0216]

[0217] Step 1: Preparation of Y-15. Add Y-8 (30 mg), 1-fluoro-2-iodoethane (62.6 mg), NaH (14.4 mg, 60%) and THF (1 ml) into a 10 ml reaction tube. Replace the air with nitrogen and stir at room temperature for 13 h. Then add NaH (20 mg) and continue stirring for 4 h. The reaction is complete. 4 The organic phase was washed with anhydrous NaCl solution. 2 SO 4 After drying and concentration, 22.5 mg of the intermediate was obtained by rapid silica gel column chromatography. The intermediate was dissolved in DCM (2 ml), TFA (0.5 ml) was added, and the reaction was completed after stirring at room temperature for 2 h. Y-15 was obtained by spin drying and used directly in the next step. MS ESI: m / z = 262, [M+1] + .

[0218] Step 2: Preparation of T-26: Using Y-15 as raw material, 8.8 mg of white solid was obtained under the same conditions as in Example 21.

[0219] 1 H NMR (400 MHz, CDCl 3 )δ12.62(s,1H),8.74(d,J=6.7Hz,1H),7.33–7.07(m,6H),6.91(d,J=7.7Hz,1H),6.88(s,1H),4.95–4.80(m, 1H),4.72(m,1H),4.60(m,1H),4.33(m,2H),4.17(s,2H),3.61(s,3H),3.45–3.31(m,1H),3.22–2.97(m,1H). MS ESI:m / z=447,[M+1] + .

[0220] Example 29: T-27

[0221] (±)-5-Benzyl-N-(6-(2-cyanopropyl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0222]

[0223] Step 1: Preparation of Y-16. Add Y-8 (30 mg), 2-bromo-2-methylpropionitrile (140.6 mg), NaH (16 mg, 60%) and THF (2 ml) into a 10 ml reaction tube. Replace the air with nitrogen, stir at 70 °C for 2 h, add 2-bromo-2-methylpropionitrile (109 mg), continue stirring for 5 h, and the reaction is complete. 4 The organic phase was washed with anhydrous NaCl solution. 2 SO 4 After drying and concentration, 21 mg of the intermediate was obtained by rapid silica gel column chromatography. The intermediate was dissolved in DCM (2 ml), TFA (0.5 ml) was added, and the reaction was completed after stirring at room temperature for 2 h. Y-16 was obtained by spin drying and used directly in the next step. MS ESI: m / z = 283, [M+1] + .

[0224] Step 2: Preparation of T-27: Using Y-16 as raw material, 4 mg of white solid was obtained under the same conditions as Example 21.

[0225] 1 H NMR (400 MHz, CDCl 3)δ8.72(d,J=6.3Hz,1H),7.34–.24(6H),7.12(m,1H),6.93(m,2H),4.94–4.77(m,1H),4.43(m,0.5H),4.26(m 1H), 4.17 (s, 2H), 4.15–4.05 (m, 0.5H), 3.61 (s, 3H), 3.38 (m, 1H), 3.20–2.97 (m, 2H), 1.33 (dd, J = 22.6, 7.1Hz, 3H). MS ESI:m / z=468,[M+1] + .

[0226] Example 30: T-28

[0227] (±)-5-Benzyl-N-(6-(2-methoxyethyl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0228]

[0229] Step 1: Preparation of Y-17. Add Y-8 (30 mg), 2-bromoethyl methyl ether (36 ul), NaH (15.2 mg, 60%) and THF (1 ml) into a 10 ml reaction tube. Replace the air with nitrogen, stir at room temperature overnight, add 2-bromoethyl methyl ether (40 ul), continue stirring for 20 h, and the reaction is complete. 4 Cl solution, and washed with saturated NH 4 The organic phase was washed with anhydrous NaCl solution. 2 SO 4 After drying and concentration, 13 mg of the intermediate was obtained by rapid silica gel column chromatography. The reaction was repeated under similar conditions to obtain a total of 26 mg of the intermediate. The intermediate was dissolved in DCM (2 ml), TFA (0.5 ml) was added, and the reaction was completed after stirring at room temperature for 2 h. Y-17 was obtained by spin drying and used directly in the next step. MS ESI: m / z=274, [M+1] + .

[0230] Step 2: Preparation of T-28: Using Y-17 as raw material, 5 mg of white solid was obtained under the same conditions as Example 21.

[0231] 1 H NMR (400 MHz, CDCl 3)δ8.73(d,J=6.0Hz,1H),7.25–7.09(m,7H),6.91(s,1H),6.87(d,J=7.6Hz,1H),4.87–4.75(m,1H),4.30–4 .17(m,2H),4.14(s,2H),3.66(t,J=5.4Hz,2H),3.58(s,3H),3.32(m,1H),3.30(s,3H),3.12–2.98(m,1H). MS ESI:m / z=459,[M+1] + .

[0232] Example 31: T-29

[0233] (±)-Methyl 2-(3-(5-benzyl-4H-1,2,4-triazole-3-carboxamide)-1-methyl-2-oxo-1,2,3,4-tetrahydro-6H-azacyclo[4,3,2-cd]indol-6-yl)acetate

[0234]

[0235] Step 1: Preparation of Y-18: Add Y-8 (63 mg), NaH (32 mg, 60%) and THF (1 ml) into a 10 ml reaction tube, replace the air with nitrogen, stir for a few minutes, add methyl 2-bromoacetate (306 mg), stir at room temperature overnight, and the reaction is complete. 4 The organic phase was washed with anhydrous NaCl solution. 2 SO 4 After drying and concentration, the intermediate 51 mg was obtained by rapid silica gel column chromatography. The intermediate was dissolved in DCM (2 ml), TFA (0.5 ml) was added, and the reaction was completed after stirring at room temperature for 2 h. Y-18 was obtained by spin drying and used directly in the next step. MS ESI: m / z = 288, [M+1] + .

[0236] Step 2: Preparation of T-29: Using Y-18 as raw material, 30 mg of white solid was obtained under the same conditions as Example 21.

[0237] 1 H NMR (400 MHz, CDCl 3)δ13.47(s,1H),8.75(d,J=6.7Hz,1H),7.25~7.16(m,6H),7.02(d,J=8Hz,1H),6.91(d,J=8Hz,1H),6.69(m,1H),4.85(m,1H), 4.79(d,J=17.7Hz,1H),4.65(d,J=17.7Hz,1H),4.17(s,2H),3.73(s,3H),3.59(s,3H),3.43–3.30(m,1H),3.15–2.97(m,1H). MS ESI:m / z=473,[M+1] + .

[0238] Example 32: T-30

[0239] (±)-2-(3-(5-benzyl-4H-1,2,4-triazole-3-carboxamide)-1-methyl-2-oxo-1,2,3,4-tetrahydro-6H-azacyclo[4,3,2-cd]indol-6-yl)acetic acid

[0240]

[0241] T-29 (8 mg), KOH (4.9 mg), MeOH (0.5 ml), and water (0.1 ml) were added to a 2 ml vial and stirred at room temperature for about 18 h. The mixture was acidified with diluted HCl and dried by spin drying. The mixture was then purified by preparative HPLC (mobile phase: A:H 2 O (+0.1% TFA); B: MeCN; separation conditions: 50% B; flow rate: 18 mL / min; chromatographic column: Waters Prep MSC18, 19×250mm, 10μm) was purified and freeze-dried to obtain 5 mg of white solid.

[0242] 1 H NMR (400 MHz, DMSO-d 6 )δ14.49(s,1H),8.68(s,1H),7.40–7.13(m,8H),6.99(d,J=7.2Hz,1H),4.95(s,2 H),4.69–4.52(m,1H),4.13(s,2H),3.50(s,3H),3.22(m,1H),3.11–2.93(m,1H). MS ESI:m / z=459,[M+1] + .

[0243] Example 33: T-31

[0244] (±)-N-(6-(2-amino-2-oxoethyl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-5-benzyl-4H-1,2,4-triazole-3-carboxamide

[0245]

[0246] T-29 (6 mg), ammonia (0.ml), and MeOH (0.2 ml) were added to a 2 ml vial, stirred at room temperature for about 18 h, and then dried by spin drying. 2 O (+0.1% TFA); B: MeCN; separation conditions: 50% B; flow rate: 18 mL / min; chromatographic column: Waters Prep MSC18, 19×250mm, 10μm) was purified and freeze-dried to obtain 3 mg of white solid.

[0247] 1 H NMR (400 MHz, DMSO-d 6 )δ14.36(s,1H),8.66(s,2H),7.58(s,1H),7.39–7.15(m,8H),7.00(dd,J=6.8,1.5Hz,1H), 4.79(s,2H),4.66–4.57(m,1H),4.13(s,2H),3.50(s,3H),3.22(m,1H),3.10–2.93(m,1H). MS ESI:m / z=458,[M+1] + .

[0248] Example 34: T-32

[0249] (±)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-1-methyl-1,3,4,6-tetrahydro-2H-azacyclo[4,3,2-cd]indol-2-one

[0250]

[0251] Step 1: Preparation of Y-20

[0252]

[0253] Add Y-19 (32 mg), THF (1 ml), HCl (1 ml, 6N) to a 10 ml reaction tube and stir at room temperature overnight. LC-MS shows that the raw material has been completely converted into the product, and it is directly spin-dried for the next step. MS ESI: m / z = 307, [M+1]+ .

[0254] Step 2: Preparation of Y-21

[0255]

[0256] Y-7 (18 mg), Y-20 (30 mg), 2-methylpyridine-N-borane (11.1 mg), MeOH (1 ml) and TFA (0.1 ml) were added to a 10 ml reaction tube, the air was replaced with nitrogen, and the reaction was completed by stirring at room temperature for about 1 day. 4 Cl solution quenching, EA extraction, organic phase with anhydrous Na 2 SO 4 After drying and concentration, 22 mg of the intermediate was obtained by rapid silica gel column chromatography. The intermediate was dissolved in MeOH (1 ml) and water (0.5 ml), KOH (100 mg) was added, and the mixture was stirred at room temperature overnight. 1N HCl was added to quench the reaction, and EA was extracted and dried to obtain 20 mg of solid Y-21. MS ESI: m / z = 478, [M+1] + .

[0257] Step 3: Preparation of T-32: Y-21 (20 mg), TCFH (17 mg), NMI (6.6 mg) and MeCN (1 ml) were added to a 10 ml reaction tube. After stirring at room temperature overnight, TLC showed that the reaction was complete. 4 The mixture was quenched with saturated Cl solution, extracted with EA and concentrated, and subjected to preparative HPLC (mobile phase: A:H 2 O (+0.1% TFA); B: MeCN; separation conditions: 50% B; flow rate: 18 mL / min; chromatographic column: Waters Prep MSC18, 19×250mm, 10μm) was purified and freeze-dried to obtain 6 mg of white solid.

[0258] 1 H NMR (400MHz, acetone-d 6 )δ10.33(s,1H),7.40–7.26(m,5H),7.27–7.13(m,3H),6.95(dd,J=7.6,0.7Hz,1H),5.51(dd,J=11.5,1.5Hz,1H),5.43( s,2H),4.18–4.05(m,1H),3.85–3.73(m,1H),3.57(dd,J=14.0,7.0Hz,2H),3.52(s,3H),3.46–3.37(m,1H),3.25(m,1H). MS ESI:m / z=460,[M+1] + .

[0259] Example 35: T-33

[0260] (±)-5-Benzyl-N-(6-(2-hydroxyethyl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0261]

[0262] Step 1: Preparation of Y-22: Add Y-8 (30 mg), KOH (10 mg) and DMSO (1 ml) to a 10 ml reaction tube, replace the air with nitrogen, stir for a few minutes, add 2-bromoethanol (17.5 mg), and stir at room temperature overnight. 4 The organic phase was washed with anhydrous NaCl solution. 2 SO 4 After drying and concentration, the intermediate was purified by rapid silica gel column chromatography to obtain 19.6 mg. The intermediate was dissolved in DCM (2 ml), TFA (0.5 ml) was added, and the reaction was completed after stirring at room temperature for 2 h. Y-22 was obtained by spin drying and used directly in the next step. MS ESI: m / z = 260, [M+1] + .

[0263] Step 2: Preparation of T-33: Using Y-22 as raw material, 2.4 mg of white solid was obtained under the same conditions as in Example 21.

[0264] 1 H NMR (400 MHz, CDCl 3 )δ8.74(d,J=6.0Hz,1H),7.26(m,7H),6.95(s,1H),6.89(d,J=7.4Hz,1H),4.82(m,1H) ,4.20(m,2H),4.14(s,2H),3.91(m,2H),3.60(s,3H),3.34(m,1H),3.14–2.99(m,1H). MS ESI:m / z=445,[M+1] + .

[0265] Example 36: T-34

[0266] (±)-5-Benzyl-N-(1-methyl-6-(1-methyl-1H-pyrazol-4-yl)-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0267]

[0268] Step 1: Preparation of Y-23: Add Y-8 (30 mg), 1-methyl-4-iodo-pyrazole (29.7 mg), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (7.1 mg), CuI (4 mg), K 3 PO 4 (64 mg) and DMSO (1 ml), the air was replaced with nitrogen, and the mixture was stirred at 90°C overnight. 4 The organic phase was washed with anhydrous NaCl solution. 2 SO 4 After drying and concentration, the intermediate was purified by rapid silica gel column chromatography to obtain 25.4 mg. The intermediate was dissolved in DCM (2 ml), TFA (0.5 ml) was added, and the reaction was completed after stirring at room temperature for 2 h. Y-23 was obtained by spin drying and used directly in the next step. MS ESI: m / z = 296, [M+1] + .

[0269] Step 2: Preparation of T-34: Using Y-23 as raw material, 4 mg of white solid was obtained under the same conditions as Example 21.

[0270] 1 H NMR (400 MHz, DMSO-d 6 )δ14.33(s,1H),8.72(s,1H),8.24(s,1H),7.82(s,1H),7.46(s,1H),7.41–7.17(m,7H),7.08(d,J=6. 9Hz,1H),4..68–4.64(m,1H),4.14(s,2H),3.93(s,3H),3.52(s,3H),3.26(m,1H),3.15–2.92(m,1H). MS ESI:m / z=481,[M+1] + .

[0271] Example 37: T-35

[0272] (±)-5-Benzyl-N-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl)methyl)-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0273]

[0274] Step 1: Preparation of Y-24. Add 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide (29.3 mg), KOH (16 mg) and DMF (2 ml) to a 10 ml reaction tube. After stirring at room temperature for a few minutes, add Y-8 (30 mg). Replace the air with nitrogen. After stirring at room temperature for 20 h, add 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide (29 mg). After stirring at room temperature overnight, add saturated NH 4 Cl solution quenching, EA extraction, organic phase with anhydrous Na 2 SO 4 After drying and concentration, 15 mg of the intermediate was obtained by rapid silica gel column chromatography. The intermediate was dissolved in DCM (2 ml), TFA (0.5 ml) was added, and the reaction was completed after stirring at room temperature for 2 h. Y-24 was obtained by spin drying and used directly in the next step. MS ESI: m / z=310, [M+1] + .

[0275] Step 2: Preparation of T-35: Using Y-24 as raw material, 18 mg of white solid was obtained under the same conditions as Example 21.

[0276] 1 H NMR (400 MHz, CDCl 3 )δ8.71(d,J=6.1Hz,1H),7.44(s,1H),7.31(m,4H),7.21(m3H),7.16(m,1H),6.90(m,2H),5.12(m ,2H),4.92–4.83(m,1H),4.17(s,2H),3.84(s,3H),3.61(s,3H),3.36(m,1H),3.24–2.77(m,1H). MS ESI:m / z=495,[M+1] + .

[0277] Example 38: T-36

[0278] (±)-5-Benzyl-N-(1-methyl-6-(1-methyl-1H-pyrazol-5-yl)-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0279]

[0280] Step 1: Preparation of Y-25: Y-8 (100 mg) and 5-iodo-1-methyl-1H-pyrazole were used as raw materials and 22 mg of solid Y-25 was obtained under the same conditions as in the first step of Example 36. MS ESI: m / z=296, [M+1] + .

[0281] Step 2: Preparation of T-36: Using Y-25 as raw material, 10 mg of white solid was obtained under the same conditions as Example 21.

[0282] 1H NMR (400MHz, CDCl 3 )δ8.74(d,J=6.7Hz,1H),7.62(d,J=1.7Hz,1H),7.34–7.21(m,6H),7.01(d,J=8.0Hz,1H),6.96(s,1H),6.92(d,J =8.0Hz,1H),6.35(d,J=1.7Hz,1H),5.03–4.91(m,1H),4.19(s,2H),3.64(s,6H),3.45(m,1H),3.23–2.95(m,1H).

[0283] MS ESI: m / z = 481, [M+1] + .

[0284] Example 39: T-37

[0285] (±)-5-Benzyl-N-(1-methyl-6-(1-methyl-1H-pyrazol-3-yl)-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0286]

[0287] Step 1: Preparation of Y-26: Y-8 (100 mg) and 3-iodo-1-methyl-1H-pyrazole were used as raw materials and 13 mg of solid Y-26 was obtained under the same conditions as in the first step of Example 36. MS ESI: m / z=296, [M+1] + .

[0288] Step 2: Preparation of T-37: Using Y-26 as raw material, 7.3 mg of light yellow solid was obtained under the same conditions as in Example 21.

[0289] 1 H NMR (400 MHz, CDCl 3)δ8.72(d,J=6.8Hz,1H),7.78(d,J=8.0Hz,1H),7.41(d,J=1.7Hz,1H),7.26~7.35(m,7H),6.97(d,J=8.0Hz,1H ), 6.31(d,J=1.9Hz,1H),4.93(m,1H),4.17(s,2H),3.95(s,3H),3.63(s,3H),3.44(m,1H),3.21–2.99(m,1H). MS ESI:m / z=481,[M+1] + .

[0290] Example 40: T-38

[0291] (±)-5-Benzyl-N-(1-methyl-6-(2-morpholinoethyl)-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0292]

[0293] Step 1: Preparation of Y-27, using Y-8 (50 mg) and 4-(2-bromoethyl)morpholine hydrobromide (48 mg) as raw materials, 52 mg of solid Y-27 was obtained under the same conditions as in the first step of Example 37. MS ESI: m / z=329, [M+1] + .

[0294] Step 2: Preparation of T-38: Add Y-27 (52 mg), 5-benzyl-4H-1,2,4-triazole-3-carboxylic acid (48.7 mg), TCFH (65 mg), NMI (40 ul) and ultra-dry DCM (2 mL) into a 10 ml reaction tube. Replace the gas with nitrogen and stir at room temperature for 5 h. 4 The product was quenched with Cl solution, extracted with EA, and dried by spin drying. The product was initially purified by rapid silica gel column chromatography. Then, the product was purified by preparative HPLC (mobile phase: A:H 2 O (+0.1% TFA); B: MeCN; separation conditions: 60% B; flow rate: 18 mL / min; chromatographic column: Waters Prep MSC18, 19×250mm, 10μm) was purified and freeze-dried to obtain 20mg of white solid.

[0295] 1 H NMR (400 MHz, CDCl 3)δ8.75(d,J=6.8Hz,1H),7.26–7.09(m,7H),6.90-6088(m,2H),4.93–4.72(m,1H),4.32–3.98(m,4H) ,3.78–3.66(m,4H),3.60(s,3H),3.41(m,1H),3.23–2.99(m,1H),2.70(t,J=7.0Hz,2H),2.48(m,4H). MS ESI:m / z=514,[M+1] + .

[0296] Example 41: T-39

[0297] (±)-5-Benzyl-N-(1-methyl-2-oxo-6-pivaloyl-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0298]

[0299] Step 1: Preparation of Y-28: Add Y-8 (50 mg), DCM (2 ml), pivaloyl chloride (100 ul), DMAP (12.5 mg), and triethylamine (144 ul) into a 10 ml reaction tube. Stir at room temperature overnight, then add NaHCO 3 The organic phase was quenched and extracted with EA. 2 SO 4 After drying and concentration, 64 mg of oily intermediate was obtained by rapid silica gel column chromatography. 24 mg of the intermediate was dissolved in DCM (2 ml), and then BBr was added. 3 (0.12 ml, 1N), stirred at room temperature for 5 h, and then washed with NaHCO 3 Quench, extract with EA, and wash the organic phase with anhydrous Na 2 SO 4 After drying and concentration, Y-28 was obtained. MS ESI: m / z=300, [M+1] + .

[0300] Step 2: Preparation of T-39: Using Y-28 as raw material, 3 mg of white solid was obtained under the same conditions as in the second step of Example 40.

[0301] 1 H NMR (400 MHz, CDCl 3)δ8.70(d,J=6.6Hz,1H),8.36(d,J=8.0Hz,1H),7.56(s1H),7.39(t,J=8.2Hz,1H),7. 30(m,5H),7.09(d,J=8.0Hz,1H),4.98–4.80(m,1H),4.18(s,2H),3.60(s,3H),3.39(m 1H),3.14–2.97(m,1H),1.50(s,9H). MS ESI:m / z=485,[M+1] + .

[0302] Example 42: T-40

[0303] (±)-5-Benzyl-N-(1-methyl-2-oxo-6-(3-(trifluoromethyl)pyridin-2-yl)-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0304]

[0305] Step 1: Preparation of Y-29. Add Y-8 (50 mg), 2-bromo-3-(trifluoromethyl)pyridine (66.6 mg), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (11.4 mg), CuI (15.2 mg), K 3 PO 4 (101.9 mg) and toluene (2 ml), the air was replaced with nitrogen, and the mixture was stirred at 110°C for 21 h. 4 The organic phase was washed with anhydrous NaCl solution. 2 SO 4 After drying and concentration, the intermediate 13.1 mg was obtained by rapid silica gel column chromatography. The intermediate was dissolved in DCM (2 ml), TFA (0.5 ml) was added, and the reaction was completed after stirring at room temperature for 2 h. Y-29 was obtained by spin drying and used directly in the next step. MS ESI: m / z=361, [M+1] + .

[0306] Step 2: Preparation of T-40: Using Y-29 as raw material, 6 mg of light yellow solid was obtained under the same conditions as in the second step of Example 40.

[0307] 1 H NMR (400 MHz, CDCl 3)δ8.82(d,J=3.6Hz,1H),8.70(d,J=6.4Hz,1H),8.25(d,J=7.9Hz,1H),7.54(dd,J=12.9,5.2Hz,1H),7.35~7.25(m,5H) ,7.19(d,J=7.9Hz,2H),7.01(d,J=7.6Hz,1H),5.10–4.78(m,1H),4.17(s,2H),3.64(s,3H),3.45(m,1H),3.19(m,1H). MS ESI:m / z=546,[M+1] + .

[0308] Example 43: T-41

[0309] (±)-5-Benzyl-N-(6-(3-methoxypyridin-2-yl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0310]

[0311] Step 1: Preparation of Y-30, using Y-8 (50 mg) and 2-bromo-3-methoxypyridine as raw materials, the temperature was 120°C, and the same conditions as the first step of Example 42 were used to obtain 68.3 mg of the intermediate. 20 mg of the intermediate was dissolved in DCM (2 ml), TFA (0.5 ml) was added, and the reaction was completed after stirring at room temperature for 2 h. Y-30 was obtained by spin drying and used directly in the next step. MS ESI: m / z=323, [M+1] + .

[0312] Step 2: Preparation of T-41: Using Y-30 as raw material, 8 mg of white solid was obtained under the same conditions as in the second step of Example 40.

[0313] 1 H NMR (400 MHz, Acetone-d 6)δ8.55(m,1H),8.07–8.03(m,1H),7.61(d,J=8.3Hz,1H),7.49(s,1H),7.3 5(d,J=8.0Hz,1H),7.31(dd,J=8.3,4.7Hz,1H),7.28–7.17(m,4H),7.14(m 2H), 6.98 (d, J = 8.0Hz, 1H), 4.72 (m, 1H), 4.07 (s, 2H), 3.84 (s, 3H), 3.50 (s, 3H), 3.35 (m, 1H), 3.07–2.87 (m, 1H). MS ESI:m / z=508,[M+1] + .

[0314] Example 44: T-42

[0315] (±)-5-Benzyl-N-(6-(4-(methoxymethyl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0316]

[0317] Step 1: Preparation of Y-31: Y-8 (100 mg) and 3-bromo-4-(methoxymethyl)pyridine were used as raw materials and 100 mg of solid Y-31 was obtained under the same conditions as in the first step of Example 43. MS ESI: m / z=337, [M+1] + .

[0318] Step 2: Preparation of T-42: Using Y-31 as raw material, 40 mg of white solid was obtained under the same conditions as in the second step of Example 40.

[0319] 1 H NMR (400 MHz, Acetone-d 6 )δ13.54(s,1H),8.72(d,J=5.0Hz,1H),8.69(d,J=6.2Hz,1H),8.63(s,1H),7.68(d,J=4.8Hz,1H),7.44–7.18(m,7H),7.12(d,J=7.8H z,1H),6.89(d,J=8.2Hz,1H),4.86(m,1H),4.35–4.23(m,2H),4.20(s,2H),3.63(s,3H),3.49(m,1H),3.29(s,3H),3.20–3.02(m,1H). MS ESI:m / z=522,[M+1] + .

[0320] Example 45: T-43

[0321] (±)-2-(3-(5-benzyl-4H-1,2,4-triazole-3-carboxamide)-1-methyl-2-oxo-1,2,3,4-tetrahydro-6H-azacyclo[4,3,2-cd]indol-6-yl)nicotinate

[0322]

[0323] Step 1: Preparation of Y-32: Y-8 (50 mg) and 2-bromonicotinoic acid methyl ester were used as raw materials and 56 mg of solid Y-32 was obtained under the same conditions as in the first step of Example 43. MS ESI: m / z=351, [M+1] + .

[0324] Step 2: Preparation of T-43: Using Y-32 as raw material, 30 mg of white solid was obtained under the same conditions as in the second step of Example 40.

[0325] 1 H NMR (400MHz, Acetone) δ8.67(dd,J=4.8,1.8Hz,1H),8.55(d,J=5.6Hz,1H),8.27(dd,J=7.8,1.8Hz,1H),7.48(dd,J=7.7,4.8Hz,1H),7.3 1(s,1H),7.28–7.07(m,7H),7.01(d,J=7.8Hz,1H),4.71(m,1H),4.07(s,2H),3.53(s,3H),3.50(s,3H),3.37(m,1H),3.05–2.89(m,1H). MS ESI:m / z=536,[M+1] + .

[0326] Example 46: T-44

[0327] (±)-5-Benzyl-N-(1-methyl-6-(3-methylpyridin-2-yl)-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0328]

[0329] Step 1: Preparation of Y-33, using Y-8 (50 mg) and 2-bromo-3-methylpyridine as raw materials, using the same conditions as in the first step of Example 43 to obtain 46.3 mg of solid Y-33. MS ESI: m / z=307, [M+1] + .

[0330] Step 2: Preparation of T-44: Using Y-33 as raw material, 52.9 mg of white solid was obtained under the same conditions as in Step 2 of Example 40.

[0331] 1 H NMR (400 MHz, Acetone-d 6 )δ8.68(d,J=4.8Hz,1H),8.47(d,J=3.5Hz,1H),7.94(d,J=7.5Hz,2H),7.48(s,1H),7.44(dd,J=7.5,4.8Hz,1H),7.39–7.20(m,6H) ,7.11(d,J=2.9Hz,1H),7.09(d,J=3.4Hz,1H),4.86(m,1H),4.19(s,2H),3.63(s,3H),3.50(m,1H),3.24–3.03(m,1H),2.24(s,3H). MS ESI:m / z=492,[M+1] + .

[0332] Example 47: T-45

[0333] (±)-5-Benzyl-N-(1-methyl-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-oxo-2,3,4,6-tetrahydro-1H-aza[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0334] Step 1: Preparation of S-1: Add methyl 6-bromo-4-indolecarboxylate (25 g), KOH (22.05 g), water (28 ml) and MeOH (169 ml) into a 500 ml round-bottom flask. Stir at room temperature for 3 h, and the reaction is complete. Adjust the pH to about 2 with dilute hydrochloric acid, and a large amount of solid precipitates. Use a Buchner funnel to filter, dry the filter cake in a vacuum oven, extract the filtrate with EA, and remove anhydrous Na 2 SO 4 Dry and spin dry to obtain 23 g of light red solid. MS ESI: m / z = 238, [M-1] - .

[0335] Step 2: Preparation of S-2: Add S-1 (8.62 g), DPPA (10.86 g), TEA (7.47 ml) and THF (180 ml) to a 500 ml round-bottom flask. Replace the air with nitrogen, heat at 70 °C for about 2 h, stop heating, cool to room temperature, add TFA (100 ml), and continue heating for about 2 h. The reaction is complete. Remove part of the solvent, then add EA, wash with water, and wash the organic phase with anhydrous Na 2 SO4 After drying and concentration, 3.65 g of a yellowish brown solid was obtained by rapid silica gel column chromatography. MS ESI: m / z = 239, [M+1] + .

[0336] Step 3: Preparation of S-3: S-2 (3.65 g), dimethylamine (8.4 ml 2N in THF), HCHO (1.36 ml, 37% aqueous solution), ZnCl 2 (3122.6 mg) and MeOH (76 ml). Stir at room temperature overnight, add NaOH (2N) to adjust the pH to alkaline, filter, extract the filtrate with EA, and then wash with anhydrous Na 2 SO 4 Dry and spin dry to obtain 1676 mg of khaki solid. MS ESI: m / z = 296, [M+1] + .

[0337] Step 4: Preparation of S-4: Add S-3 (1676 mg), ethyl nitroacetate (3781 mg) and ultra-dry xylene (28 ml) to a 100 ml eggplant-shaped bottle. Replace the air with nitrogen, heat and stir at 140°C for about 16 hours, and LC-MS shows that the reaction is complete. The reaction solution is spin-dried, then EA is added, and then activated carbon is added for decolorization, filtered, and the activated carbon is washed with ethanol. Combine the organic phases, concentrate, and obtain 561 mg of white solid by rapid silica gel column chromatography. MS ESI: m / z=384, [M+1] + .

[0338] Step 5: Preparation of S-5: S-4 (775 mg), borane dimethyl sulfide complex (2.02 ml, 2N in THF) and THF (10 ml) were added to a 50 ml eggplant flask under ice bath. The air was replaced with nitrogen and stirred at room temperature for about 20 h. LC-MS showed that the reaction was complete. NH 4 Cl saturated solution quenched, EA extracted, the organic phase with anhydrous Na 2 SO 4 After drying and concentration, 330 mg of solid was obtained by flash silica gel column chromatography. MS ESI: m / z=370, [M+1] + .

[0339] Step 6: Preparation of S-6: S-5 (330 mg), zinc powder (1169 mg), AcOH (4 ml) and THF (4 ml) were added to a 10 ml eggplant-shaped bottle and stirred at room temperature for 12 h. LC-MS showed that the reaction was complete. EA was added to dilute the reaction solution, and then filtered. The filtrate was washed with saturated NaHCO 3 The organic phase was washed with anhydrous Na 2 SO 4After drying and concentration, 120 mg of solid intermediate was obtained. The intermediate was dissolved in THF (4 ml) and then (Boc) 2 O (85.1 mg) and TEA (54 ul). Stir at room temperature for about 6 hours, and the reaction is complete. The organic phase is concentrated and then purified by rapid silica gel column chromatography to obtain 130 mg of solid. MS ESI: m / z = 440, [M+1] + .

[0340] Step 7: Preparation of S-7: S-6 (130 mg), MeOH (2 ml), water (0.5 ml) and KOH (67.2 mg) were added to a 10 ml reaction tube. After stirring at room temperature for about 6 h, the reaction was completed, diluted HCl was added to acidify, and then extracted with EA. The organic phase was washed with Na 2 SO 4 Dry and spin dry to obtain 121 mg of solid. MS ESI: m / z=412, [M+1] + .

[0341] Step 8: Preparation of S-8: S-7 (125 mg) was dissolved in MeCN (3 ml) under ice bath, and then TCFH (102 mg) and NMI (36 ul) were added. After stirring at room temperature for 2 h, TCFH (10 mg) and NMI (5 ul) were added. After stirring for 3 h, the reaction was terminated. 4 Cl saturated solution quenched, EA extracted, the organic phase with anhydrous Na 2 SO 4 After drying and concentration, 66 mg of white solid was obtained by flash silica gel column chromatography. MS ESI: m / z=392, [M-1] - .

[0342] Step 9: Preparation of S-9: S-8 (60 mg), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (22.8 mg), CuI (30.5 mg), NaI (48 mg) and 1,4-dioxane (2 ml) were added to a 10 ml reaction tube. The air was replaced with nitrogen and heated at 110 °C for 3 days. NH 4 Cl saturated solution quenched, EA extracted, the organic phase with anhydrous Na 2 SO 4 After drying and concentration, 53 mg of white solid was obtained by rapid silica gel column chromatography, in which the ratio of raw material to product was about 1:1. The mixture was dissolved in DCM (2 ml), and then CF 3 COOH (0.4 ml), stirred at room temperature for about 3 h, the reaction was completed, and 38 mg of the mixture was obtained by spin drying, which was directly used in the next step. MS ESI: m / z = 342, [M+1] + .

[0343] Step 10: Preparation of S-10: S-9 (38 mg, including bromide), N-methyl-4-alkynylpyrazole (14 mg), Pd(PPh) were added to a 10 ml reaction tube. 3 Cl 2 (8.4 mg), CuI (2.3 mg), NEt 3 (1 ml) and DMF (1 ml). The air was replaced with nitrogen and heated at 70°C for 2 h. The reaction was completed. NH 4 Cl saturated solution quenched, EA extracted, the organic phase with anhydrous Na 2 SO 4 After drying and concentration, 22.4 mg of solid (containing a small amount of bromide) was obtained by flash silica gel column chromatography. MS ESI: m / z = 320, [M+1] + .

[0344] Step 11: Preparation of T-45: Using S-10 as raw material, 2 mg of white solid was obtained under the same conditions as in Example 21.

[0345] 1 H NMR (400 MHz, DMSO-d 6 )δ11.36(s,1H),8.69(s,1H),8.06(s,1H),7.69(s,1H),7.28(m,7H),7.02(s,1H ),4.68–4.47(m,1H),4.13(s,2H),3.86(s,3H),3.23(m,1H),3.10–2.93(m,1H). MS ESI:m / z=505,[M+1] + .

[0346]

[0347] (±)-2-(3-(5-benzyl-4H-1,2,4-triazole-3-carboxamide)-1-methyl-2-oxo-1,2,3,4-tetrahydro-6H-azacyclo[4,3,2-cd]indol-6-yl)nicotinic acid

[0348]

[0349] Using T-43 (10 mg) as raw material, 3.2 mg of white solid was prepared under the same conditions as in Example 32.

[0350] 1 H NMR (400 MHz, Acetone-d 6)δ8.77(d,J=2.7Hz,1H),8.67(d,J=5.6Hz,1H),7.56m,1H),7.47(s,1H),7.32(m,7H),7.10(d ,J=7.5Hz,1H),4.83(m,1H),4.20(s,2H),3.61(s,3H),3.59–3.53(m,1H),3.51–3.42(m,1H). MS ESI:m / z=522,[M+1] + .

[0351] Example 49: T-47

[0352] (±)-5-Benzyl-N-(6-(3-hydroxypyridin-2-yl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0353]

[0354] Step 1: Preparation of Y-34, using Y-8 (30 mg) and 2-bromo-3-(methoxymethoxy)pyridine as raw materials, using the same conditions as in the first step of Example 43 to obtain 28.6 mg of solid Y-34. MS ESI: m / z=309, [M+1] + .

[0355] Step 2: Preparation of T-47: Using Y-34 as raw material, 6.9 mg of white solid was obtained under the same conditions as in Step 2 of Example 40.

[0356] 1 H NMR (400 MHz, Acetone-d 6 )δ8.69(d,J=6.1Hz,1H),8.12(dd,J=4.8Hz,J=1.2Hz,1H),7.66(s,1H),7.58(d,J=8.0Hz,1H),7.53(d,J=8.3Hz,1H ),7.41–7.19(m,7H),7.09(d,J=7.8Hz,1H),4.91–4.74(m,1H),4.19(s,3H),3.62(s,3H),3.49(m,1H),3.08m,1H). MS ESI:m / z=494,[M+1] + .

[0357] Example 50: T-48

[0358] (±)-5-Benzyl-N-(6-(4-(hydroxymethyl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0359]

[0360] Step 1: Preparation of Y-35, using Y-8 (30 mg) and (3-bromopyridin-4-yl)methanol as raw materials, using the same

[0361] The same conditions as in the first step produced 21 mg of solid Y-35. The Ullmann reaction required a longer reaction time. MSESI:

[0362] m / z=323,[M+1] + .

[0363] Step 2: Preparation of T-48. When Y-35 was used as raw material and the product was prepared under the same conditions as in Step 2 of Example 40, the amino group and hydroxyl group of Y-35 reacted with triazolecarboxylic acid. Therefore, the product was extracted and then hydrolyzed with lithium hydroxide monohydrate (20 mg), MeOH (2 ml), and water (0.3 ml). Then, it was purified under the same conditions as in Step 2 of Example 40 to obtain 6.7 mg of a white solid.

[0364] 1 H NMR (400 MHz, Acetone-d 6 )δ8.72(d,J=4.8Hz,1H),8.69(s,1H),8.59(m,1H),7.81(d,J=4.8Hz,1H),7.42–7.20(m,7H),7.12(d,J=7.8Hz, 1H), 6.87 (d, J = 8.0Hz, 1H), 4.87 (s, 1H), 4.50s, 2H), 4.20 (s, 2H), 3.63 (s, 3H), 3.49 (m, 1H), 3.23–3.01 (m, 1H). MS ESI:m / z=508,[M+1] + .

[0365] Example 51: T-49

[0366] (±)-5-Benzyl-N-(6-(3-(hydroxymethyl)pyridin-2-yl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0367]

[0368] Step 1: Preparation of Y-36, using Y-8 (30 mg) and (2-bromopyridin-3-yl)methanol as raw materials, using the same

[0369] The same conditions as in the first step gave 24 mg of solid Y-36. The Ullmann reaction also required a longer reaction time. MSESI: m / z = 323, [M+1] + .

[0370] Step 2: Preparation of T-49: Using Y-36 as raw material, 5.3 mg of white solid was obtained under the same conditions as in Example 21.

[0371] 1 H NMR (400 MHz, Acetone-d 6 )δ8.68(m,1H),8.54(d,J=2.9Hz,1H),8.23(d,J=7.0Hz,1H),7.59–7.48(m,2H),7.40–7.16(m,7H),7.1 1(d,J=7.4Hz,1H),4.84(m,1H),4.68–4.43(s,3H),4.20(s,2H),3.63(s,3H),3.48(m,1H),3.07(m,1H). MS ESI:m / z=508,[M+1] + .

[0372] Example 52: T-50

[0373] (±)-3-(3-(5-benzyl-4H-1,2,4-triazole-3-carboxamide)-1-methyl-2-oxo-1,2,3,4-tetrahydro-6H-azacyclo[4,3,2-cd]indol-6-yl)pyrazine-2-carboxylic acid methyl ester

[0374]

[0375] Step 1: Preparation of Y-37, using Y-8 (50 mg) and 3-bromopyrazine-2-carboxylic acid methyl ester as raw materials, 58.3 mg of solid Y-37 was obtained using the same conditions as in the first step of Example 43. MS ESI: m / z=352, [M+1] + .

[0376] Step 2: Preparation of T-50: Using Y-37 as raw material, 53.6 mg of white solid was obtained under the same conditions as in Step 2 of Example 40.

[0377] 1 H NMR (400 MHz, DMSO-d 6)δ14.38(s,1H),8.91(d,J=2.2Hz,1H),8.82(d,J=2.2Hz,1H),8.69(bs,1H),7.52(s,1H),7.42(d,J=8.2Hz,1H),7.38–7.2 2(m,6H),7.17(d,J=7.8Hz,1H),4.75–4.63(m,1H),4.14(s,2H),3.72(s,3H),3.53(s,3H),3.29(m,1H),3.19–2.95(m,1H).

[0378] MS ESI: m / z = 537, [M+1] + .

[0379] Example 53: T-51

[0380] (±)-5-(3-(5-benzyl-4H-1,2,4-triazole-3-carboxamide)-1-methyl-2-oxo-1,2,3,4-tetrahydro-6H-azacyclo[4,3,2-cd]indol-6-yl)pyrimidine-4-carboxylic acid methyl ester

[0381]

[0382] Step 1: Preparation of Y-38, using Y-8 (50 mg) and 5-bromo-4-pyrimidinecarboxylic acid methyl ester as raw materials, 26.5 mg of solid Y-38 was prepared under the same conditions as in the first step of Example 43. MS ESI: m / z=352, [M+1] + .

[0383] Step 2: Preparation of T-51: Using Y-38 as raw material, 19 mg of light yellow solid was obtained under the same conditions as in Step 2 of Example 40.

[0384] 1 H NMR (400MHz, acetone-d 6 )δ9.36(s,1H),9.26(s,1H),8.67(bs,1H),7.40(s,1H),7.32(m,5H),7.26(m,1H),7.16(d,J=7.8Hz,1H),7 .09(d,J=8.1Hz,1H),4.84(m,1H),4.20(s,2H),3.68(s,3H),3.63(s,3H),3.48(m,1H),3.20–3.02(m,1H). MS ESI:m / z=537,[M+1] + .

[0385] Example 54: T-52

[0386] (±)-5-Benzyl-N-(6-(3-cyclopropylpyridin-2-yl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0387]

[0388] Step 1: Preparation of Y-39, using Y-8 (50 mg) and 2-bromo-3-cyclopropylpyridine as raw materials, using the same

[0389] 57.6 mg of solid Y-39 was obtained under the same conditions as in the first step. MS ESI: m / z=333, [M+1] + .

[0390] Step 2: Preparation of T-52: Using Y-39 as raw material, 56 mg of white solid was obtained under the same conditions as in Step 2 of Example 40.

[0391] 1 H NMR (400MHz, acetone-d 6 )δ8.67(d,J=4.6Hz,1H),8.43–8.40(m,1H),7.61(d,J=8.0Hz,1H),7.57(s,1H),7.42(dd,J=7.6,4.6Hz,1H),7.28(m,8H),7.11(d, J=7.6Hz,1H),4.87(s,1H),4.19(s,2H),3.63(s,3H),3.51(m,1H),3.19–3.02(m,1H),1.77(m,1H),1.08–0.89(m,2H),0.80(m,2H). MS ESI:m / z=518,[M+1] + .

[0392] Example 55: T-53

[0393] (±)-5-Benzyl-N-(6-(3-(difluoromethyl)pyridin-2-yl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0394]

[0395] Step 1: Preparation of Y-40, using Y-8 (50 mg) and 2-bromo-3-(difluoromethyl)pyridine as raw materials, 58 mg of solid Y-40 was obtained under the same conditions as in the first step of Example 43. MS ESI: m / z=343, [M+1] + .

[0396] Step 2: Preparation of T-53: Using Y-40 as raw material, 80 mg of white solid was obtained under the same conditions as in the second step of Example 40.

[0397] 1 H NMR (400MHz, acetone-d 6 )δ8.82(d,J=4.8Hz 1H),8.66(d,J=5.2Hz,1H),8.38(d,J=7.7Hz,2H),7.74(dd,J=7.6,4.8Hz,1H),7.48(s,1H),7.41–7.19(m,7H),7.1 6(d,J=7.4Hz,1H),6.92(t,J=54.1Hz,1H),4.87(s,1H),4.20(s,2H),3.63(s,3H),3.50(m,1H),3.20–3.02(m,1H). MS ESI:m / z=528,[M+1] + .

[0398] Example 56: T-54

[0399] (±)-5-Benzyl-N-(6-(3-(fluoromethyl)pyridin-2-yl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0400]

[0401] Step 1: Preparation of Y-41 Using Y-8 (50 mg) and 2-bromo-3-(fluoromethyl)pyridine as raw materials, 51.2 mg of solid Y-41 was prepared under the same conditions as in the first step of Example 43. MS ESI: m / z=325, [M+1] + .

[0402] Step 2: Preparation of T-54 Using Y-41 as raw material, 73 mg of white solid was obtained under the same conditions as in the second step of Example 40.

[0403] 1 H NMR (400MHz, acetone-d 6)δ8.67(m,2H),8.22(d,J=7.0Hz,1H),7.70–7.56(m,1H),7.49(s,1H),7.40–7.17(m,7H),7.14(m,1 H), 5.46 (d, J = 47.4Hz, 2H), 4.86 (m, 1H), 4.19 (s, 2H), 3.63 (s, 3H), 3.49 (m, 1H), 3.20–3.01 (m, 1H). MS ESI:m / z=510,[M+1] + .

[0404] Example 57: T-55

[0405] (±)-5-Benzyl-N-(6-(3-(2-hydroxypropan-2-yl)pyridin-2-yl)-1-methyl-2-oxy-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0406]

[0407] Step 1: Preparation of Y-43 Add Y-42 (30 mg) and THF (1 ml) to a 10 ml reaction tube, and add MeMgBr (0.07 ml, 3 M in THF) under ice bath. Stir at room temperature for 1 h, then add MeMgBr (0.2 ml, 3 M in THF), and stir for 2 h before the reaction is complete. 4 The mixture was quenched with a saturated solution of Cl and then extracted with EA. The organic phase was spin-dried to give 22 mg of crude product. The crude product was dissolved in DCM (2 ml) and then MeOH was added. 3 SiCl, stirred at room temperature for about 1 h, and then 4 The solution was quenched with a saturated solution of Cl and then extracted with EA. The organic phase was washed with anhydrous Na 2 SO 4 After drying, the product was spin dried to obtain 17 mg of Y-43, which was used directly in the next step. MS ESI: m / z = 351, [M+1] + .

[0408] Step 2: Preparation of T-55 Using Y-43 as raw material, 7 mg of white solid was prepared under the same conditions as in the second step of Example 40.

[0409] 1 H NMR (400MHz, acetone-d 6)δ8.32–8.28(m,1H),8.19(s,1H),8.01(d,J=8.0Hz,1H),7.68(d,J=7.6Hz,1H),7.35(m,5H),7.24(m,1H),6.97(dd,J=7.6,4.9Hz,1H),6 .90(d,J=8.0Hz,1H),5.57(d,J=3.6Hz,1H),4.80(m,1H),4.17(s,2H),3.59(m,1H),3.43(s,3H),2.62(m,1H),1.70(s,3H),1.52(s,3H). MS ESI:m / z=536,[M+1] + .

[0410] Example 58: Intermediate Y-45

[0411] Y-44 (40 mg), KOH (37.3 mg), MeOH (1 ml) and water (0.2 ml) were added to a 10 ml reaction tube and stirred at room temperature overnight. NH 4 The mixture was diluted with a saturated solution of Cl, and then the pH was adjusted to acidic with 2N HCl, and then extracted with EA and dried to obtain 58 mg of Y-45. MS ESI: m / z = 435, [M-1] - .

[0412]

[0413] (±)-2-(3-(5-benzyl-4H-1,2,4-triazole-3-carboxamide)-1-methyl-2-oxy-1,2,3,4-tetrahydro-6H-azacyclo[4,3,2-cd]indol-6-yl)-N-methylnicotinamide

[0414]

[0415] Step 1: Preparation of Y-46

[0416] Y-45 (32 mg) and methylamine hydrochloride were used as raw materials and the same conditions as in the second step of Example 40 were used to obtain 26.4 mg of solid Y-46. MS ESI: m / z=350, [M+1] + .

[0417] Step 2: Preparation of T-56

[0418] Using Y-46 as the starting material, 27 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0419] 1 H NMR (400MHz, acetone-d 6)δ8.66(d,J=3.3Hz,1H),8.11(d,J=7.1Hz,1H),7.60(d,J=8.2Hz,1H),7.54–7.45(m,2H),7.42(s,1H),7.39–7.1 9(m,6H),7.12(d,J=7.6Hz,1H),4.81(m,1H),4.19(s,2H),3.62(s,3H),3.46(m,1H),3.05(mz,1H),2.72(s,3H). MSESI:m / z=535,[M+1] + .

[0420] Example 60: T-57

[0421] (±)-2-(3-(5-benzyl-4H-1,2,4-triazole-3-carboxamide)-1-methyl-2-oxy-1,2,3,4-tetrahydro-6H-azacyclo[4,3,2-cd]indol-6-yl)-N,N-dimethylnicotinamide

[0422]

[0423] Step 1: Preparation of Y-47

[0424] Y-45 (26 mg) and dimethylamine were used as raw materials and the same conditions as in the second step of Example 40 were used to obtain 13.3 mg of solid Y-47. MS ESI: m / z=364, [M+1] + .

[0425] Step 2: Preparation of T-57

[0426] Using Y-47 as the starting material, 10.9 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0427] 1 H NMR (400 MHz, DMSO-d 6 )δ14.34(s,1H),8.71(d,J=4.6Hz,1H),8.04(d,J=7.6Hz,1H),7.60(d,J=8.4Hz,1H),7.58–7.52(m,1H),7.40–7.20(m,8H),7 .14(d,J=7.8Hz,1H),4.65(m,1H),4.14(s,2H),3.53(s,3H),3.26(s,1H),3.15–2.95(m,1H),2.84(s,3H),2.49–2.40(m,3H). MS ESI:m / z=549,[M+1] + .

[0428] Example 61: T-58

[0429] (±)-5-Benzyl-N-(6-(3-(1-hydroxyethyl)pyridin-2-yl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0430]

[0431] Step 1: Preparation of Y-48

[0432] Y-8 (50 mg) and 1-(2-bromopyridin-3-yl)ethane-1-ol were used as raw materials, and solid Y-48 was obtained under the same conditions as in the first step of Example 43. Since the reaction was not completely purified, the next step was charged according to the theoretical yield. MS ESI: m / z=325, [M+1] + .

[0433] Step 2: Preparation of T-58

[0434] Using Y-48 as the starting material and the same conditions as in Example 21, 10.4 mg of a white solid was obtained.

[0435] 1 H NMR (400MHz, acetone-d 6 )δ8.68(m,1H),8.58–8.47(m,1H),8.30(d,J=7.9Hz,1H),7.58(m,1H),7.46(s,1H),7.42–7.30(m,4H),7.27–7.19(m,2H),7.08(m 2H), 4.95 (m, 1H), 4.88 (m, 1H), 4.20 (s, 2H), 3.63 (s, 3H), 3.49 (m, 1H), 3.14 (m, 1H), 1.26 (dd, J = 22.0, 6.3Hz, 3H). MS ESI:m / z=522,[M+1] + .

[0436] Example 62: T-59

[0437] (±)-N-(6-(3-acetylpyridin-2-yl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-5-benzyl-4H-1,2,4-triazole-3-carboxamide

[0438]

[0439] Step 1: Preparation of Y-49

[0440] Using Y-8 (50 mg) and 1-(2-bromopyridin-3-yl)ethan-1-one as raw materials, 42.3 mg of solid Y-49 was obtained using the same conditions as in the first step of Example 43. MS ESI: m / z=335, [M+1] + .

[0441] Step 2: Preparation of T-59

[0442] Using Y-49 as the starting material, 37 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0443] 1 H NMR (400 MHz, DMSO-d 6 )δ14.33(s,1H),8.77(d,J=3.2Hz,1H),8.67(bs,1H),8.29(d,J=6.3Hz,1H),7.64(dd,J=7.7,4.8Hz,1H),7.47(s,1H),7 .40–7.22(m,7H),7.14(d,J=7.0Hz,1H),4.67(m,1H),4.15(s,2H),3.53(s,3H),3.28(m,1H),3.10(m,1H),2.13(s,3H). MS ESI:m / z=520,[M+1] + .

[0444] Example 63: T-60

[0445] (±)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-1-methyl-6-(3-(trifluoromethyl)pyridin-2-yl)-1,3,4,6-tetrahydro-2H-azepin[4,3,2-cd]indol-2-one

[0446]

[0447] Step 1: Preparation of Y-50: Y-29 (50 mg) was used as the starting material and 31.5 mg of solid Y-50 was obtained under the same conditions as in Step 2 of Example 34. MS ESI: m / z=623, [M+1] + .

[0448] Step 2: Preparation of T-60: Using Y-50 as raw material, 20 mg of white solid was obtained under the same conditions as in the third step of Example 34.

[0449] 1 H NMR (400 MHz, Acetone-d 6)δ8.90(d,J=4.0Hz,1H),8.48(d,J=7.9Hz,1H),7.84–7.78(m,1H),7.31(m,7H),7.10(dd,J=8.0,4.2Hz,2H),5.59(d,J=11.5Hz,1H),5.4 4(s,2H),4.22–4.03(m,1H),3.80(m,1H),3.55(s,3H),3.53–3.44(m,1H),3.33(d,J=14.5Hz,1H),3.00–2.89(m,1H),2.89–2.82(m,1H). MS ESI:m / z=605,[M+1] + .

[0450] Example 64: T-61

[0451] (±)-2-(3-(5-benzyl-4H-1,2,4-triazole-3-carboxamide)-1-methyl-2-oxy-1,2,3,4-tetrahydro-6H-azacyclo[4,3,2-cd]indol-6-yl)nicotinamide

[0452]

[0453] T-51 (30 mg) and ammonia methanol solution (2 ml, 7 N) were added to a 2 ml vial and stirred at 50 °C for about 3 days. The mixture was then spin-dried and subjected to preparative HPLC (mobile phase: A:H 2 O (+0.1% TFA); B: MeCN; separation conditions: 50% B; flow rate: 18 mL / min; chromatographic column: Waters Prep MSC18, 19×250 mm, 10 μm) was purified and freeze-dried to obtain 23 mg of white solid.

[0454] 1 H NMR (400 MHz, Acetone-d 6 )δ8.65(d,J=2.8Hz,1H),8.17(d,J=7.4Hz,1H),7.56(d,J=8.2Hz,1H),7.49(dd,J=6.4,4.2Hz,1H),7.47(s,1H),7.40–7 .18(m,7H),7.10(d,J=7.7Hz,1H),6.97(s,1H),4.80(m,1H),4.19(s,2H),3.60(s,2H),3.43(m,1H),3.15–2.93(m,1H).

[0455] MS ESI: m / z = 521, [M+1] + .

[0456] Example 65: T-62

[0457] (±)-5-Benzyl-N-(6-(3-chloropyridin-2-yl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0458]

[0459] Step 1: Preparation of Y-51, using Y-8 (30 mg) and 2-bromo-3-chloropyridine as raw materials, using the same conditions as in the first step of Example 43 to obtain 25 mg of solid Y-51. MS ESI: m / z=327, [M+1] + .

[0460] Step 2: Preparation of T-62: Using Y-51 as raw material, 38 mg of white solid was obtained under the same conditions as in the second step of Example 40.

[0461] 1 H NMR (400MHz, acetone-d 6 )δ8.68(d,J=5.6Hz,1H),8.60(dd,J=4.6,1.5Hz,1H),8.19(dd,J=8.0,1.5Hz,1H),7.59–7.56(m,1H),7.55(d,J=4.7 Hz,1H),7.41–7.18(m,7H),7.13(d,J=7.4Hz,1H),4.86(m,1H),4.11(s,2H),3.63(s,3H),3.48(m,1H),3.09(m,1H).

[0462] MS ESI: m / z = 512, [M+1] + .

[0463] Example 66: T-63

[0464] (±)-5-Benzyl-N-(1-methyl-2-oxo-6-(3-(trifluoromethyl)pyridin-2-yl)-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)oxazole-2-carboxamide

[0465]

[0466] Using Y-29 (23.5 mg) and freshly prepared Y-52 as starting materials, 17 mg of a white solid was prepared using the same conditions as in the second step of Example 40.

[0467] 1 H NMR (400 MHz, Acetone-d 6 )δ8.91(d,J=3.3Hz,1H),8.57(bs,1H),8.49(d,J=7.9Hz,1H),7.82(dd,J=7.2,5.0Hz,1H),7.42(s,1H),7.40–7.2 1(m,6H),7.18–7.08(m,2H),7.06(s,1H),4.96–4.65(m,1H),4.15(s,2H),3.62(s,3H),3.47(m,1H),3.12(m,1H). MSESI:m / z=546,[M+1] + .

[0468] Example 67: T-64

[0469] (±)-5-Benzyl-N-(6-(3-methoxy-6-methylpyridin-2-yl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0470]

[0471] Step 1: Preparation of Y-53, using Y-8 (30 mg) and 2-bromo-3-methoxy-6-methylpyridine as raw materials, using the same conditions as in the first step of Example 43 to obtain 31 mg of solid Y-53. MS ESI: m / z=337, [M+1] + .

[0472] Step 2: Preparation of T-64: Using Y-53 as raw material, 38 mg of white solid was obtained under the same conditions as in Step 2 of Example 40.

[0473] 1 H NMR (400MHz, acetone-d 6 )δ8.68(d,J=5.8Hz,1H),7.63(d,J=8.3Hz,1H),7.60(s,1H),7.49(d,J=8.2Hz,1H),7.34(m,4H),7.30–7.21(m,3H),7. 09(d,J=7.8Hz,1H),4.89–4.81(m,1H),4.20(s,2H),3.91(s,3H),3.62(s,3H),3.47(m,1H),3.07(m,1H),2.49(s,3H).

[0474] MS ESI: m / z = 522, [M+1] +.

[0475] Example 68: T-65

[0476] (±)-5-Benzyl-N-(6-(3-isopropylpyridin-2-yl)-1-methyl-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0477]

[0478] Step 1: Preparation of Y-54, using Y-8 (30 mg) and 2-bromo-3-isopropylpyridine as raw materials, using the same

[0479] 30 mg of solid Y-54 was obtained under the same conditions as in the first step. MS ESI: m / z=335, [M+1] + .

[0480] Step 2: Preparation of T-65: Using Y-54 as raw material, 41 mg of white solid was obtained under the same conditions as in Step 2 of Example 40.

[0481] 1 H NMR (400MHz, acetone-d 6 )δ8.69(d,J=5.3Hz,1H),8.55–8.42(m,1H),8.08(d,J=7.9Hz,1H),7.55(dd ,J=7.8,4.6Hz,1H),7.42(s,1H),7.34(m,4H),7.25(m,2H),7.09(d,J=7.8Hz ,1H),6.97(d,J=8.2Hz,1H),4.88(m,1H),4.25(s,2H),3.63(s,3H),3.50(m, 1H), 3.13 (m, 1H), 2.90 (m, 1H), 1.21 (d, J = 6.8Hz, 3H), 1.17 (d, J = 6.8Hz, 3H). MS ESI: m / z = 520, [M+1] + .

[0482] Example 69: T-66

[0483] (±)-2-(3-(5-benzyl-4H-1,2,4-triazole-3-carboxamide)-1-methyl-2-oxo-1,2,3,4-tetrahydro-6H-azacyclo[4,3,2-cd]indol-6-yl)nicotinate

[0484]

[0485] Step 1: Preparation of Y-55: Y-55 (30 mg), cyclopropanol (20.3 mg), DCC (21.6 mg), DMAP (4.3 mg) and DCM (2 ml) were added to a 10 ml reaction bottle. After stirring at room temperature overnight, NH 4 The saturated solution of Cl was quenched, and then extracted with EA. The organic phase was dried by spin drying and then subjected to rapid silica gel column chromatography to obtain 30 mg of a white solid. The solid was dissolved in DCM (2 ml) and TFA (0.5 ml), stirred at room temperature for 2 h, and then dried by spin drying to obtain 23.7 mg of solid Y-55. MS ESI: m / z=377, [M+1] + .

[0486] Step 2: Preparation of T-66: Using Y-55 as raw material, 16.6 mg of white solid was obtained under the same conditions as in Step 2 of Example 40.

[0487] 1 H NMR (400MHz, acetone-d 6 )δ8.81–8.78(m,1H),8.67(bs,1H),8.40(dd,J=7.8,1.8Hz,1H),7.63(dd,J=7.8,4.8Hz,1H),7.47(s,1H),7.40–7.21(m,6H),7.16 (m,2H),4.85(m,1H),4.20(s,2H),4.06(m,1H),3.64(s,3H),3.51(m,1H),3.07(m,1H),0.56–0.47(m,2H),0.19(m,1H),0.08m,1H). MS ESI:m / z=562,[M+1] + .

[0488] Example 70: T-67

[0489] (±)-5-Benzyl-N-(6-(3-ethoxypyridin-2-yl)-1-methyl-2-oxy-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0490]

[0491] Step 1: Preparation of Y-56: Y-8 (30 mg) and 2-bromo-3-ethoxypyridine were used as raw materials and the same conditions as in the first step of Example 43 were used to obtain 26.2 mg of solid Y-56. MS ESI: m / z=337, [M+1] + .

[0492] Step 2: Preparation of T-67: Using Y-56 as raw material, 21.8 mg of white solid was obtained under the same conditions as in Step 2 of Example 40.

[0493] 1 H NMR (400MHz, acetone-d 6 )δ8.66(d,J=5.6Hz,,1H),8.16(d,J=4.7Hz,1H),7.70(d,J=8.0Hz,1H),7.66(s,1H),7.51(d,J=8.1Hz,1H),7.43–7.20(m,7H),7 .10(d,J=7.8Hz,1H),4.85(m,1H),4.31–4.20(m,2H),4.19(s,2H),3.62(s,3H),3.49(m,1H),3.07(m,1H),1.37(t,J=6.9Hz,3H). MS ESI:m / z=522,[M+1] + .

[0494] Example 71: T-68

[0495] (±)-5-Benzyl-N-(1-methyl-6-(3-(methylsulfonyl)pyridin-2-yl)-2-oxo-2,3,4,6-tetrahydro-1H-azepin[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0496]

[0497] Step 1: Preparation of Y-57, using Y-8 (30 mg) and 2-bromo-3-(methylsulfonyl)pyridine as raw materials, using the same conditions as in the first step of Example 43 to obtain 15.7 mg of solid Y-57. MS ESI: m / z=371, [M+1] + .

[0498] Step 2: Preparation of T-68: Using Y-57 as raw material, 21.6 mg of white solid was obtained under the same conditions as in Step 2 of Example 40.

[0499] 1 H NMR (400MHz, acetone-d 6)δ8.91(d,J=2.9Hz,1H),8.68(d,J=7.9Hz,2H),7.87(dd,J=7.9,4.8Hz,1H),7.60(s,1H),7.44–7.19(m,6 H),7.15(d,J=8.1Hz,2H),4.87(m,1H),4.23(s,2H),3.63(s,3H),3.49(m,1H),3.14(m,1H),2.86(s,3H). MS ESI:m / z=556,[M+1] + .

[0500] Example 72: T-69

[0501] (±)-5-Benzyl-N-(1-methyl-2-oxo-6-(pyridin-2-yl)-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0502]

[0503] Step 1: Preparation of Y-58, using Y-8 (30 mg) and 2-bromopyridine as raw materials, using the same conditions as in the first step of Example 43 to obtain 26 mg of solid Y-58. MS ESI: m / z=293, [M+1] + .

[0504] Step 2: Preparation of T-69: Using Y-58 as raw material, 30.4 mg of white solid was obtained under the same conditions as in Step 2 of Example 40.

[0505] 1 H NMR (400MHz, acetone-d 6 )δ8.67(bs,1H),8.60(d,J=3.0Hz,1H),8.28(d,J=8.4Hz,1H),8.00(t,J=7.5Hz,1H),7.87(s,1H),7.75(d,J=8.3Hz,1H),7.42 –7.28(m,6H),7.25(d,J=6.1Hz,1H),7.17(d,J=7.8Hz,1H),4.83(m,1H),4.20(s,2H),3.62(s,3H),3.49(m,1H),3.06(m,1H). MS ESI:m / z=478,[M+1] + .

[0506] Example 73: T-70

[0507] (±)-N-(1-methyl-2-oxo-6-(3-(trifluoromethyl)pyridin-2-yl)-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4-phenoxypicolinamide

[0508]

[0509] Using Y-29 (14 mg) and Y-59 as raw materials, 17 mg of white solid was prepared under the same conditions as in the second step of Example 40.

[0510] 1 H NMR (400MHz, acetone-d 6 )δ9.41(d,J=5.2Hz,1H),8.91(d,J=3.5Hz,1H),8.58(d,J=5.5Hz,1H),8.49(d,J=6.7Hz,1H),7.82(dd,J=7.3,4.9Hz,1H),7.59–7.47 (m,3H),7.41(s,1H),7.33(t,J=7.5Hz,1H),7.27(t,J=8.0Hz,1H),7.22(m,2H),7.12(m,3H),4.94–4.80(m,1H),3.64(s,3H),3.48(m 1H),3.08(m,1H). MS ESI:m / z=558,[M+1] + .

[0511] Example 74: Preparation of Intermediate R-7

[0512] Step 1: Preparation of R-1. Add 4-nitro-indole (11 g) and pyridine (150 ml) to a 500 ml reaction bottle, then dissolve pyridinium tribromide in pyridine (50 ml) and add to the reaction bottle under ice bath. After stirring at room temperature overnight, the reaction is complete. After removing part of the solvent, water and EA are added to extract the product. The organic phase is subjected to rapid silica gel column chromatography to obtain 15.62 g of yellow solid R-1. MS ESI: m / z=241, [M+1] + .

[0513] Step 2: Preparation of R-2: Add R-1 (15.62 g) and (Boc) into a 250 ml reaction bottle. 2 O (15.5 g), DMAP (0.79 g) and THF (100 ml). Stir at room temperature for 2 h. The reaction is complete. The reaction solution is spin-dried and 21.23 g of yellow solid R-2 is obtained by rapid silica gel column chromatography.

[0514] Step 3: Preparation of R-3, add zinc powder (43.56g), DMF (50ml) and 1,2-dibromoethane (1.9ml) to a 500ml reaction bottle. After stirring at 50℃ for 30min, stop heating, wait for it to cool to room temperature, and add TMSCl (0.68ml). After stirring at room temperature for 30min, dissolve (R)-N-tert-butyloxycarbonyl-3-iodoalanine methyl ester (43.84g) in DMF (50ml), and then add it to the reaction solution. After stirring at room temperature for 2h, let it stand for 30min. After the excess zinc powder settles, take out the supernatant and add R-2 (22.72g), Pd(OAc) 2 (1.50 g) and Sphos (2.74 mg) were placed in a 500 ml reaction bottle. After stirring at 35 °C for 3 h, the reaction was completed. 4 The reaction was quenched with Cl solution and extracted with EA. The organic phase was spin-dried and 10.21 g of yellow solid R-3 was obtained by rapid silica gel column chromatography. MS ESI: m / z=364, [(M-Boc)+1] + .

[0515] Step 4: Preparation of R-4: R-3 (4000 mg), Pd / C (1839 mg, 10% active ingredient, 55% water content) and MeOH (43 ml) were added to a 100 ml reaction bottle. 2 The mixture was stirred at room temperature overnight under an atmosphere, then filtered through celite, dried by rotation, and the impurities remaining in the previous step were removed by rapid silica gel column chromatography to obtain 2.995 g of light yellow solid R-4. MS ESI: m / z=424, [M+1] + .

[0516] Step 5: Preparation of R-5, R-4 (2998 mg) was dissolved in MeOH (30 ml) and water (5 ml), and then lithium hydroxide monohydrate (1162.6 mg) was added. After stirring at room temperature for about 3 h, NH 4 Cl saturated solution was diluted, and then the pH was adjusted to acidic with 2N HCl and extracted with EA. The organic phase was washed with anhydrous Na 2 SO 4 After drying, the intermediate was obtained by spin drying. The intermediate was dissolved in MeCN (30 ml), and then TCFH (2912.4 mg) and NMI (2.76 ml) were added. After stirring at room temperature for 2 h, the reaction was completed and NH 4 After quenching with a saturated Cl solution, EA was used for extraction. The organic phase was purified by rapid silica gel column chromatography to obtain 2588.6 mg of solid R-5. MS ESI: m / z = 400, [M-1] - .

[0517] Step 6: Preparation of R-6: R-5 (2807 mg) was dissolved in DMF (30 ml), and then Cs 2 CO 3 (2738.4 mg) and MeI (1192.8 mg). After stirring at room temperature for 5 h, the reaction was complete. 4 The reaction was quenched with a saturated solution of Cl and extracted with EA. The organic phase was purified by rapid silica gel column chromatography to obtain 2900 mg of colorless solid R-6. MS ESI: m / z=316, [(M-Boc)+1] + .

[0518] Step 7: Preparation of R-7: R-6 (2900 mg) was dissolved in DCM (35 ml), and then TFA (8 ml) was added. After stirring at room temperature for 2 h, the reaction solution was spin-dried. The intermediate was dissolved in THF (30 ml), and then (Boc) was added. 2 O (1600 mg), stirred at room temperature for 20 min, the reaction was completed. The reaction solution was spin-dried and 1876 mg of colorless solid R-7 was obtained by rapid silica gel column chromatography. Using R-7 as a raw material and the same conditions as in Example 72, the S enantiomer of this structure can be obtained. MS ESI: m / z = 314, [M-1] - .

[0519]

[0520] Example 75: Preparation of Intermediate L-7

[0521] Step 1: Preparation of L-1. Add 4-nitro-7-azaindole (1000 mg) and pyridine (10 ml) to a 50 ml reaction bottle, then dissolve pyridinium tribromide in pyridine (5 ml) and add to the reaction bottle under ice bath. After stirring at room temperature for 3 hours, the reaction is completed. After removing part of the solvent, water and EA are added to extract the product. The organic phase is subjected to rapid silica gel column chromatography to obtain 1.09 g of yellow solid L-1. MS ESI: m / z=242, [M+1] + .

[0522] Step 2: Preparation of L-2: Add L-1 (1090 mg) and (Boc) into a 50 ml reaction bottle. 2 O (1800.2 mg), DMAP (55 mg) and THF (10 ml). After stirring at room temperature overnight, the reaction solution was spin-dried and purified by flash silica gel column chromatography to obtain 1.197 g of yellow solid L-2.

[0523] Step 3: Preparation of L-3, add zinc powder (2288.3 mg), DMF (8 ml) and 1,2-dibromoethane (0.1 ml) to a 50 ml reaction bottle. After stirring at 50 ° C for 30 minutes, stop heating, wait for it to cool to room temperature, and add TMSCl (35 ul). After stirring at room temperature for 30 minutes, dissolve (R)-N-tert-butyloxycarbonyl-3-iodoalanine methyl ester (2533.3 mg) in DMF (8 ml) and then add it to the reaction solution. After stirring at room temperature for 2 hours, let it stand for 30 minutes. After the excess zinc powder settles, take out the supernatant and add L-2 (1197 mg), Pd (OAc) 2 (78 mg) and Sphos (144 mg) were placed in a 50 ml reaction bottle. After stirring at 35 °C for 4 h, the reaction was completed. NH 4 The reaction was quenched with Cl solution and extracted with EA. The organic phase was spin-dried and 404 mg of yellow solid L-3 was obtained by rapid silica gel column chromatography. MS ESI: m / z=365, [M+1] + .

[0524] Step 4: Preparation of L-4: Add L-3 (404 mg), Pd / C (236.9 mg, 10% active ingredient, 55% water content) and MeOH (5 ml) into a 10 ml reaction bottle. 2 Stir at room temperature overnight under atmosphere, then filter through celite and spin dry to obtain L-4, which is used directly in the next step. MS ESI: m / z=335, [M+1] + .

[0525] Step 5: Preparation of L-5: L-4 was dissolved in MeOH (20 ml) and water (0.5 ml), and then lithium hydroxide monohydrate (186.5 mg) was added. After stirring at room temperature for 3 h, NH 4 The saturated solution of Cl was diluted, and then the pH was adjusted to acidic with 2N HCl and extracted with EA. The organic phase was washed with anhydrous Na 2 SO 4 After drying, the intermediate was obtained by spin drying. The intermediate was dissolved in MeCN (10 ml), and then TCFH (467.2 mg) and NMI (0.44 ml) were added. After stirring at room temperature for 2 h, the reaction was completed and NH 4 After quenching with a saturated Cl solution, EA was used for extraction. The organic phase was purified by rapid silica gel column chromatography to obtain 75 mg of solid L-5. MS ESI: m / z = 303, [M+1] + .

[0526] Step 6: Preparation of L-6: L-5 (75 mg) was dissolved in THF (5 ml), and then (Boc) was added 2O (266.2 mg) and DMAP (13.5 mg), stirred at room temperature overnight, and NH 4 The reaction was quenched with a saturated solution of Cl and extracted with EA. The organic phase was purified by rapid silica gel column chromatography to obtain 100 mg of solid L-6. MS ESI: m / z = 403, [M+1] + .

[0527] Step 7: Preparation of L-7: Dissolve L-6 in DMF (2 ml), then add Cs 2 CO 3 (162.2 mg) and MeI (42.4 mg). After stirring at room temperature for 1 h, the reaction was complete. 4 The reaction was quenched with a saturated solution of Cl and extracted with EA. The organic phase was purified by rapid silica gel column chromatography to obtain 93 mg of light yellow solid L-7. MS ESI: m / z = 417, [M+1] + .

[0528]

[0529] Example 76: T-71

[0530] (S)-5-Benzyl-N-(6-methyl-7-oxo-6,7,8,9-tetrahydro-2H-2,3,6-triazabenzo[cd]azulene-8-yl)-4H-1,2,4-triazole-3-carboxamide

[0531]

[0532] Step 1: Preparation of L-8, L-7 (30 mg) was dissolved in DCM (2 ml), then TFA (0.5 ml) was added, and after stirring at room temperature for 2 h, the reaction solution was spin-dried to obtain L-8, which was directly used in the next step. MS ESI: m / z=217, [M+1] + .

[0533] Step 2: Preparation of T-71: Using L-8 as raw material, 43.9 mg of white solid was obtained under the same conditions as in the second step of Example 40.

[0534] 1 H NMR (400 MHz, Acetone-d 6)δ13.36(s,1H),10.69(s,1H),8.61(s,1H),8.25(d,J=5.4Hz,1H),7.38–7.29(m,5H),7.24(m,1H ), 6.97 (d, J = 5.4Hz, 1H), 4.84 (m, 1H), 4.19 (s, 2H), 3.61 (s, 3H), 3.43 (m, 1H), 3.24–2.94 (m, 1H). MS ESI:m / z=402,[M+1] + .

[0535] Example 77: Preparation of Intermediate S-7

[0536]

[0537] S-7 (33 mg) was prepared by using 4-nitro-1H-indazole (1 g) as the starting material and the same operation as in Example 75. As in Example 75, the Negishi reaction in the third step was poor.

[0538] Example 78: T-72

[0539] (S)-5-Benzyl-N-(6-methyl-7-oxo-6,7,8,9-tetrahydro-2H-azacyclo[4,3,2-cd]indazol-8-yl)-4H-1,2,4-triazole-3-carboxamide

[0540]

[0541] Using S-7 (33 mg) as starting material, the same operation as in Example 76 was adopted to obtain 20.8 mg of a white solid.

[0542] 1 H NMR (400MHz, acetone-d 6 )δ12.19(s,2H),8.66(s,1H),7.51–7.39(m,1H),7.34(m,5H),7.25(m,1H),7.02(d,J=7 .5Hz,1H),4.86(m,1H),4.20(s,2H),3.66–3.59(m,1H),3.62(s,3H),3.37–3.15(m,1H).

[0543] MS ESI: m / z = 402, [M+1] + .

[0544] Example 79: T-73

[0545] (±)-5-Benzyl-N-(1-methyl-6-(1-methyl-1H-1,2,4-triazol-3-yl)-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0546] Step 1: Preparation of Y-60, using Y-8 (30 mg) and 3-bromo-1-methyl-1,2,4-thiazole as raw materials, using the same conditions as the first step of Example 43 (when removing the protecting group, using 4N HCl dioxane solution instead) to obtain 15.1 mg of solid Y-60. MS ESI: m / z=297, [M+1] + .

[0547] Step 2: Preparation of T-73: Using Y-60 as raw material, 10 mg of white solid was obtained under the same conditions as in the second step of Example 40.

[0548] 1 H NMR (400MHz, acetone-d 6 )δ13.31(s,1H),8.65(bs,1H),8.36(s,1H),8.27(d,J=8.2Hz,1H),7.84(s,1H),7.41(d,J=8.1Hz,1H),7.35(m,4H),7.22 (d,J=21.3Hz,1H),7.16(d,J=7.8Hz,1H),4.81(m,1H),4.20(s,2H),4.03(s,3H),3.62(s,3H),3.49(m,1H),3.04(m,1H). MS ESI:m / z=482,[M+1] + .

[0549]

[0550] Example 80: T-74

[0551] (±)-5-Benzyl-N-(1-methyl-6-(1-methyl-1H-imidazol-5-yl)-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0552]

[0553] Step 1: Preparation of Y-61, using Y-8 (30 mg) and 5-iodo-1-methyl-1H-imidazole as raw materials, using the same

[0554] The same conditions as in the first step (4N HCl dioxane solution was used for deprotection) gave 18.6 mg of solid Y-61. MS ESI: m / z = 296, [M+1] + .

[0555] Step 2: Preparation of T-74: Using Y-61 as raw material, 12 mg of white solid was obtained under the same conditions as in Step 2 of Example 40.

[0556] 1 H NMR (400MHz, acetone-d 6 )δ8.67(bs,1H),7.69(s,1H),7.40–7.28(m,6H),7.25(m,1H),7.13(m,1H),6.96(d,J=8.0H z,1H),4.84(m,1H),4.20(s,2H),3.63(s,3H),3.48(m,1H),3.45(s,3H),3.18–3.00(m,1H). MS ESI:m / z=481,[M+1] + .

[0557] Example 81: T-75

[0558] (±)-5-Benzyl-N-(1-methyl-6-(3-(N-methylsulfamoyl)pyridin-2-yl)-2-oxo-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0559]

[0560] Step 1: Preparation of Y-62: Y-8 (30 mg), 2-chloro-N-methylpyridine-3-sulfonamide and KI (1 eq) were used as raw materials and the same conditions as in the first step of Example 80 were used to obtain 15.8 mg of solid Y-62. MS ESI: m / z=386, [M+1] + .

[0561] Step 2: Preparation of T-75: Using Y-62 as raw material, 8 mg of white solid was obtained under the same conditions as in Step 2 of Example 40.

[0562] 1 H NMR (400MHz, acetone-d 6)δ8.83(dd,J=4.7,1.7Hz,1H),8.65(d,J=5.0Hz,1H),8.61(dd,J=7.9,1.7 Hz,1H),7.77(dd,J=7.9,4.7Hz,1H),7.55(s,1H),7.34(m,4H),7.26(m,2H ),7.18(d,J=8.0Hz,1H),7.12(d,J=7.7Hz,1H),6.14(s,1H),4.85(m,1H), 4.21 (s, 2H), 3.62 (s, 3H), 3.46 (m, 1H), 3.05 (m, 1H), 2.47 (d, J = 4.4Hz, 3H). MS ESI:m / z=571,[M+1] + .

[0563] Example 82: T-76

[0564] (±)-5-Benzyl-N-(7-cyano-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0565]

[0566] Step 1: Preparation of Z-24. Dissolve the intermediate Z-8 (1 eq) and chlorosulfonyl isocyanate (1.1 eq) in acetonitrile and react for 2 h in an ice bath. Add DMF (25 eq) and continue to react for 2 h in an ice bath. Extract with EA, wash three times with water, concentrate the organic phase, and separate and purify by rapid column chromatography to obtain the intermediate Z-24.

[0567] Step 2: Preparation of Z-25: Dissolve intermediate Z-24 (1 eq) and trifluoroacetic acid (10 eq) in dichloromethane, stir at room temperature for 3 h, concentrate the organic phase, and directly separate and purify intermediate Z-25 by rapid column chromatography. MS ESI: m / z = 241, [M+H] + .

[0568] Step 3: Preparation of T-76: Using acid-1 (1.5 eq) and Z-25 (1 eq) as raw materials, Example 82 (T-76) was obtained using the same conditions as Example 2.

[0569] 1 H NMR (400MHz, acetone-d 6)δ8.23(s,1H),7.59–7.51(m,2H),7.44–7.30(m,6H),7.26(m,2H),4.88-4.83(m,2H),4.59–4.50(m,1H),4.21(s,2H),3.62(s,3H). MS ESI:m / z=426,[M+H] + .

[0570] Example 83: T-77

[0571] (±)-5-Benzyl-N-(1-methyl-2-oxo-7-(2-(trifluoromethyl)pyridin-4-yl)-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0572]

[0573] T-77 was obtained by reacting 2-trifluoromethylpyridine-4-boronic acid pinacol ester with intermediate Z-9 using the same conditions as Example 16.

[0574] 1 H NMR (400MHz, acetone-d 6 )δ8.76(d,J=5.2Hz,1H),8.58(s,1H),8.19(s,1H),8.14(s,1H),8.05(d,J=5.3Hz,1H),7.94(m,1H ),7.41–7.30(m,6H),7.26(m,2H),4.88-4.84(m,2H),4.58–4.51(m,1H),4.22(s,2H),3.64(s,3H).

[0575] MS ESI: m / z = 546, [M+H] + .

[0576] Example 84: T-78

[0577] 5-Benzyl-N-(7-(2-methoxypyridin-3-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0578]

[0579] T-78 was obtained by reacting 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine with intermediate Z-9 under the same conditions as Example 16.

[0580] 1 H NMR (400MHz, acetone-d 6 )δ8.58(s,1H),8.12(dd,J=4.9,1.7Hz,1H),7.99(dd,J=7.3,1.7Hz,1H),7.77(s,1H),7.62(m,1H),7.34(m,4H),7.28–7.1 9(m,3H),7.08(dd,J=7.3,5.0Hz,1H),4.89(m,1H),4.84–4.76(m,1H),4.47(m,1H),4.21(s,2H),3.97(s,3H),3.63(s,3H). MS ESI:m / z=508,[M+H] + .

[0581] Example 85: T-79

[0582] (±)-5-Benzyl-N-(7,10-dibromo-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0583]

[0584] Step 1: Preparation of Z-26. Dissolve the intermediate Z-8 (1 eq) and N-bromosuccinimide (1.1 eq) in dichloromethane. After reacting at room temperature for 1 h, quench the reaction with a saturated sodium thiosulfate solution, extract with EA, wash with water three times, concentrate the organic phase, and separate and purify by rapid column chromatography to obtain the intermediate Z-26.

[0585] Step 2: Preparation of Z-27: Dissolve intermediate Z-26 (1 eq) and trifluoroacetic acid (10 eq) in dichloromethane, stir at room temperature for 3 h, concentrate the organic phase, and directly separate and purify intermediate Z-27 by rapid column chromatography. MS ESI: m / z=374, [M+H] + .

[0586] Step 3: Preparation of T-79

[0587] Using acid-1 (1.5 eq) and Z-27 (1 eq) as raw materials, the same conditions as Example 2 were used to obtain Example 85 (T-79).

[0588] 1 H NMR (400MHz, acetone-d 6)δ8.51(s,1H),7.70(s,1H),7.41(d,J=8.4Hz,1H),7.34(m,4H),7.26(m,1H),7.17(d, J=8.4Hz,1H),4.85(m,1H),4.77–4.70(m,1H),4.45(m,1H),4.21(s,2H),3.58(s,3H). MS ESI:m / z=560,[M+H] + .

[0589] Example 86: T-80

[0590] (±)-5-Benzyl-N-(7-(3-(methoxymethyl)phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0591]

[0592] T-80 was obtained by reacting 2-(3-(methoxymethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane with intermediate Z-9 under the same conditions as in Example 16.

[0593] 1 H NMR (400MHz, acetone-d 6 )δ8.58(s,1H),7.78(m,1H),7.68(s,2H),7.63(m,1H),7.45(m,1H),7.39–7.30(m,4H),7.29–7.21( m,4H),4.87(m,1H),4.81(m,1H),4.53(s,2H),4.47(m,1H),4.21(s,2H),3.63(s,3H),3.39(s,3H). MS ESI:m / z=521,[M+H] + .

[0594] Example 87: T-81

[0595] 5-Benzyl-N-(7-(1,4-dimethyl-1H-pyrazol-5-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0596]

[0597] T-81 was obtained by reacting 1,4-dimethylpyrazole-5-boronic acid pinacol ester with intermediate Z-9 under the same conditions as in Example 16.

[0598] 1 H NMR (400MHz, acetone-d 6 )δ8.59(s,1H),7.59(s,1H),7.34(m,5H),7.29–7.21(m,4H),4.91(m,1H) ,4.88–4.81(m,1H),4.51(m,1H),4.21(s,2H),3.72(s,3H),3.64(s,3H).

[0599] MS ESI: m / z = 495, [M+H] + .

[0600] Example 88: T-82

[0601] 5-Benzyl-N-(1-methyl-2-oxo-7-(3-(trifluoromethyl)pyridin-2-yl)-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0602] Step 1: Preparation of Z-28: Dissolve the intermediate Z-8 (1 eq) and N-bromosuccinimide (1.1 eq) in dichloromethane, react for 1 h at room temperature, quench the reaction with a saturated sodium thiosulfate solution, extract with EA, wash three times with water, concentrate the organic phase, and separate and purify the intermediate Z-28 by rapid column chromatography. MS ESI: m / z=396, [M+H] + .

[0603] Step 2: Preparation of Z-29: intermediate Z-28 (1 eq), pinacol borane (2 eq), Pd 2 (dba) 3 (0.02eq), Xphos (0.02eq), and triethylamine (3eq) were dissolved in ultra-dry 1,4-dioxane solution, and reacted under nitrogen protection at 110°C for 3 hours. The reaction solution was cooled to room temperature, extracted with EA, washed with water three times, and the organic phase was concentrated. The intermediate Z-29 was separated and purified by rapid column chromatography.

[0604] Step 3: Preparation of Z-30: 2-bromo-3-trifluoromethylpyridine (1.5 eq) and intermediate Z-29 (1 eq), Pd(dppf)Cl 2 (0.1eq), K 3 PO 4Dissolve in a mixed solvent of dioxane and water, react at 95°C overnight under argon protection, cool to room temperature, extract with EA, wash three times with water, concentrate the organic phase, separate and purify by rapid column chromatography to obtain intermediate Z-30.

[0605] Step 4: Preparation of Z-31: Dissolve intermediate Z-30 (1 eq) and TFA (10 eq) in dichloromethane, stir at room temperature for 3 h, concentrate the organic phase, and directly separate and purify intermediate Z-31 by rapid column chromatography. MS ESI: m / z=361, [M+H] + .

[0606] Step 5: Preparation of T-82: Using acid-1 (1.5 eq) and Z-31 (1 eq) as raw materials, the same conditions as Example 2 were used to obtain Example 88 (T-82).

[0607] 1 H NMR (400MHz, acetone-d 6 )δ8.96(m,1H),8.56(s,1H),8.26(m,1H),7.81(m,1H),7.73(s,1H),7.54(m,1H),7.34(m ,4H),7.29–7.21(m,3H),4.94–4.83(m,2H),4.55–4.46(m,1H),4.21(s,2H),3.64(s,3H). MS ESI:m / z=546,[M+H] + .

[0608]

[0609] Example 89: T-83

[0610] (±)-5-Benzyl-N-(1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-oxazole-2-carboxamide

[0611]

[0612] T-83 was obtained by reacting 1-methyl-1H-pyrazole-5-boronic acid pinacol ester with intermediate Z-9 and acid-2 under the same conditions as in Example 16.

[0613] 1 H NMR (400MHz, acetone-d 6)δ8.46(s,1H),7.66(s,1H),7.49(m,2H),7.32(m,4H),7.25(m,3H),7.08(s,1H),6 .45(m,1H),4.88–4.75(m,2H),4.48(m,1H),4.15(s,2H),3.89(s,3H),3.61(s,3H). MS ESI:m / z=481,[M+H] + .

[0614] Example 90: T-84

[0615] (±)-5-Benzyl-N-(1-methyl-2-oxo-7-(2-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0616]

[0617] T-84 was obtained by reacting 2-trifluoromethylphenylboronic acid pinacol ester with intermediate Z-9 using the same conditions as in Example 16.

[0618] 1 H NMR (400MHz, acetone-d 6 )δ8.58(s,1H),7.89(d,J=8.1Hz,1H),7.76(t,J=7.4Hz,1H),7.68–7.57(m,2H),7.48(s,1H),7.34(q,J=8.0Hz,4H),7.27–7 .22(m,3H),7.22–7.16(m,1H),4.89(d,J=6.7Hz,1H),4.83(d,J=12.5Hz,1H),4.53–4.45(m,1H),4.21(s,2H),3.64(s,3H). MS ESI:m / z=555,[M+H] + .

[0619] Example 91: T-85

[0620] (±)-5-Benzyl-N-(7-(2,6-dimethoxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diaza[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0621]

[0622] T-85 was obtained by reacting 2,6-dimethoxyphenylboronic acid pinesol ester with intermediate Z-9 under the same conditions as in Example 16.

[0623] 1 H NMR (400MHz, acetone-d 6 )δ8.45(s,1H),7.49–7.44(m,1H),7.41–7.34(m,1H),7.30(m,4H),7.23(m,1H),7.14(m,2H),6.78(m,1H),6.73( m,1H),6.55(s,1H),4.81(m,1H),4.21(m,1H),4.15(s,2H),4.09(m,1H),3.78(s,3H),3.75(s,3H),3.62(s,3H). MS ESI:m / z=537,[M+H] + .

[0624] Example 92: T-86

[0625] 5-Benzyl-N-(7-(3,5-dimethylisoxazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepin[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0626]

[0627] T-86 was obtained by reacting 3,5-dimethylisoxazole-4-boronic acid pinacol ester with intermediate Z-9 under the same conditions as in Example 16.

[0628] 1 H NMR (400MHz, acetone-d 6 )δ8.58(s,1H),7.51(s,1H),7.38–7.19(m,8H),4.92–4.84(m,1H),4.81(m, 1H),4.52–4.43(m,1H),4.21(s,2H),3.63(s,3H),2.37(s,3H),2.20(s,3H).

[0629] MS ESI: m / z = 496, [M+H] + .

[0630] Example 93: T-87

[0631] (±)-5-Benzyl-N-(7-(2-methoxyphenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepin[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0632]

[0633] T-87 was obtained by reacting 2-methoxyphenylboronic acid pinacol ester with intermediate Z-9 using the same conditions as in Example 16.

[0634] 1 H NMR (400MHz, acetone-d 6 )δ8.58(s,1H),7.60(s,1H),7.59–7.52(m,2H),7.38–7.28(m,5H),7.27–7.11(m,4H),7.05(m, 1H),4.93–4.86(m,1H),4.79(m,1H),4.49–4.40(m,1H),4.21(s,2H),3.85(s,3H),3.63(s,3H). MS ESI:m / z=507,[M+H] + .

[0635] Example 94: T-88

[0636] (±)-5-Benzyl-N-(7-(isoxazol-4-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepin[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0637]

[0638] T-88 was obtained by reacting 4-isoxazole boronic acid pinacol ester with intermediate Z-9 using the same conditions as in Example 16.

[0639] 1 H NMR (400MHz, acetone-d 6 )δ9.21(s,1H),8.91(s,1H),8.56(s,1H),7.79(s,1H),7.72(m,1H),7.40–7.30(m,4H) ,7.30–7.21(m,3H),4.85(m,1H),4.78(m,1H),4.46(m,1H),4.21(s,2H),3.63(s,3H). MS ESI:m / z=468,[M+H] + .

[0640] Example 95: T-89

[0641] (±)-3-(2-Benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydro-[1,4]diazepin[3,2,1-hi]indol-2(1H)-one

[0642] T-89 was obtained using the intermediate amine of Example 89 as a raw material and Y-20 under the same conditions as Example 34.

[0643] 1 H NMR (400MHz, acetone-d 6 )δ7.62(s,1H),7.50–7.44(m,2H),7.39–7.28(m,5H),7.25(m,2H),6.44(m,1H),5.52–5.46(m,1H),5.45(s,2H) ,5.06–4.99(m,1H),4.90(m,1H),4.08–4.01(m,1H),3.88(s,3H),3.77–3.70(m,1H),3.56(s,3H),2.83(m,2H). MS ESI:m / z=541,[M+H] + .

[0644]

[0645] Example 96: T-90

[0646] (±)-5-Benzyl-N-(7-(1-isopropyl-1H-pyrazol-5-yl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-1,4-diazepin[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0647]

[0648] T-90 was obtained by reacting 1-isopropylpyrazole-5-boronic acid pinacol ester with intermediate Z-9 under the same conditions as in Example 16.

[0649] 1 H NMR (400MHz, acetone-d 6)δ8.57(s,1H),7.62(s,1H),7.56(d,J=1.8Hz,1H),7.43–7.27(m,6H),7.27–7.20(m,2H),6.35(d,J=1.8Hz, 1H), 4.94–4.79 (m, 2H), 4.68 (p, J = 6.7Hz, 1H), 4.48 (m, 1H), 4.25 (s, 2H), 3.63 (s, 3H), 1.43 (t, J = 6.8Hz, 6H). MS ESI:m / z=509,[M+H] + .

[0650] Example 97: T-91

[0651] (±)-5-Benzyl-N-(1-methyl-7-(3-methylthien-2-yl)-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepin[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0652]

[0653] T-90 was obtained by reacting 3-methylthiophene-2-boronate with intermediate Z-9 using the same conditions as in Example 16.

[0654] 1 H NMR (400 MHz, DMSO-d 6 )δ7.60(s,1H),7.47(m,1H),7.38(d,J=5.1Hz,1H),7.31–7.11(m,7H),6.97(d,J=5.1Hz, 1H),4.71(m,1H),4.64–4.56(m,1H),4.41(m,1H),4.08(s,2H),3.45(s,3H),2.19(s,3H). MS ESI:m / z=497,[M+H] + .

[0655] Example 98: Preparation of Intermediate Z-40

[0656]

[0657] Step 1: Preparation of Z-33: 7-nitroindole (1 eq), methyl bromoacetate (1.1 eq), and cesium carbonate (1.5 eq) were dissolved in DMF under ice bath conditions, stirred at room temperature for 2 h, and quenched with water. The reaction was extracted with EA, washed with water three times, and the organic phase was concentrated. The intermediate Z-33 was separated and purified by rapid column chromatography. MS ESI: m / z=235, [M+H] + .

[0658] Step 2: Preparation of Z-34: Dissolve the intermediate Z-33 (1 eq) in ultra-dry toluene, slowly add diisobutylaluminum hydride (1.5 eq) at -70°C, stir for 4 h at -70°C, add methanol and stir for 0.5 h to quench the reaction. Extract with EA, add 2M sodium hydroxide aqueous solution, wash three times with water, concentrate the organic phase, separate and purify by rapid column chromatography to obtain the intermediate Z-34. MS ESI: m / z=205, [M+H] + .

[0659] Step 3: Preparation of Z-35: Dissolve intermediate Z-34 (1 eq), tetraisopropyl titanate (2.5 eq), and R-(+)-tert-butylsulfenamide (1.2 eq) in ultra-dry tetrahydrofuran solution, stir at room temperature for 6 h, extract with EA, wash three times with water, concentrate the organic phase, and separate and purify by rapid column chromatography to obtain intermediate Z-35. MS ESI: m / z=308, [M+H] + .

[0660] Step 4: Preparation of Z-36: Dissolve the intermediate Z-35 (1 eq) in ultra-dry DMF solution, slowly add trimethylsilyl cyanide (3 eq) at -70°C, cool to room temperature and stir for 12 h, extract with EA, wash three times with water, concentrate the organic phase, separate and purify by rapid column chromatography to obtain the intermediate Z-36. MS ESI: m / z=335, [M+H] + .

[0661] Step 5: Preparation of Z-37: Dissolve the intermediate Z-36 (1 eq) and iron powder (8 eq) in ethanol solution, add an aqueous solution of ammonium chloride (4 eq) at room temperature, stir for 4 h at room temperature, filter with diatomaceous earth, extract with EA, wash three times with water, concentrate the organic phase, and separate and purify the intermediate Z-37 by rapid column chromatography. MS ESI: m / z=305, [M+H] + .

[0662] Step 6: Preparation of Z-38: Dissolve the intermediate Z-37 (1 eq) in 4N hydrochloric acid methanol solution, stir at 100°C for 1 h, cool to room temperature, extract with EA, wash three times with water, concentrate the organic phase, and separate and purify the intermediate Z-38 by rapid column chromatography. MS ESI: m / z=202, [M+H] + .

[0663] Step 7: Preparation of Z-39. Dissolve the intermediate Z-38 (1 eq) in dichloromethane, slowly add triethylamine (1 eq) and di-tert-butyl dicarbonate (1.2 eq), stir at room temperature for 3 h, extract with EA, wash with water three times, concentrate the organic phase, and separate and purify by rapid column chromatography to obtain the intermediate Z-39.

[0664] Step 8: Preparation of Z-40: Dissolve the intermediate Z-39 (1 eq) in ultra-dry DMF, add cesium carbonate (1.5 eq) and iodomethane (1.2 eq), stir for 3 h at room temperature, extract with EA, wash three times with water, concentrate the organic phase, separate and purify by flash column chromatography to obtain the intermediate Z-40. MS ESI: m / z=216, [M+H] + .

[0665] Example 99: T-92

[0666] Methyl (S)-2-(3-(5-benzyl-4H-1,2,4-triazole-3-carboxamide)-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepin[3,2,1-hi]indol-7-yl)-2-oxoacetic acid

[0667]

[0668] Step 1: Preparation of Z-41. Dissolve the intermediate Z-40 (1 eq) and oxalyl chloride (1.1 eq) in anhydrous ether, stir for 2.5 h in an ice bath, quench with water, spin dry, and directly dissolve in a mixed solution of dichloromethane and methanol. Add trimethylsilyldiazomethane (2 eq), stir at room temperature for 3 h, extract with EA, wash with water three times, concentrate the organic phase, and separate and purify by rapid column chromatography to obtain the intermediate Z-41.

[0669] Step 2: Preparation of Z-42: Dissolve intermediate Z-41 (1 eq) and TFA (10 eq) in dichloromethane, stir at room temperature for 3 h, concentrate the organic phase, and directly separate and purify intermediate Z-42 by rapid column chromatography. MS ESI: m / z=302, [M+H] + .

[0670] Step 3: Preparation of T-92

[0671] Using acid-1 (1.5 eq) and Z-42 (1 eq) as raw materials, T-92 was obtained using the same conditions as in Example 2.

[0672] 1 H NMR (400MHz, acetone-d 6 )δ8.56(s,2H),8.21(m,1H),7.45–7.25(m,7H),4.90(m,2H),4.56(m,1H),4.22(s,2H),3.93(s,3H),3.62(s,3H). MS ESI:m / z=487,[M+H] + .

[0673] Example 100: T-93

[0674] (S)-5-Benzyl-N-(1-methyl-2-oxo-7-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-[1,4]diazepin[3,2,1-hi]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0675]

[0676] Step 1: Preparation of Z-43: Dissolve the intermediate Z-40 (1 eq) and trifluoroacetic acid (1.5 eq) in DMF, stir at room temperature for 2 h, add water to quench the reaction, extract with EA, wash with water three times, concentrate the organic phase, and separate and purify the intermediate Z-43 by rapid column chromatography.

[0677] Step 2: Preparation of Z-44: Dissolve intermediate Z-43 (1 eq) and trifluoroacetic acid (10 eq) in dichloromethane, stir at room temperature for 3 h, concentrate the organic phase, and directly separate and purify intermediate Z-44 by rapid column chromatography. MS ESI: m / z=312, [M+H] + .

[0678] Step 3: Preparation of T-93: Using acid-1 (1.5 eq) and Z-44 (1 eq) as raw materials, T-93 was obtained using the same conditions as in Example 2.

[0679] 1 H NMR (400MHz, acetone-d 6 )δ8.57(s,2H),8.21(m,1H),7.52–7.39(m,2H),7.34(m,4H),7.26(m,1H),4.97(m,2H),4.62(m,1H),4.23(s,2H),3.63(s,3H). MS ESI:m / z=497,[M+H] + .

[0680] Example 101: T-94

[0681] (S)-3-(5-Benzyl-4H-1,2,4-triazole-3-carboxamide)-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazacyclo[3,2,1-hi]indole-7-carboxylic acid

[0682]

[0683] T-92 (1 eq) was dissolved in tetrahydrofuran solution, 2 M sodium hydroxide aqueous solution (3 eq) was added, and the mixture was stirred at room temperature for 3 h. Water was added to quench the reaction, and the mixture was extracted with EA and washed with water three times. The organic phase was concentrated and separated and purified by flash column chromatography and HPLC to obtain T-94.

[0684] 1 H NMR (400MHz, acetone-d 6 )δ8.56(s,1H),8.13(s,1H),8.06(m,1H),7.39–7.22(m,7H),4.90–4.85(m,1H),4.83(m,1H),4.55–4.44(m,1H),4.21(s,2H),3.62(s,3H). MSESI:m / z=445,[M+H] + .

[0685] Example 102: T-95

[0686] Methyl (S)-3-(5-benzyl-4H-1,2,4-triazole-3-carboxamide)-1-methyl-2-oxo-1,2,3,4-tetrahydro-[1,4]diazepin[3,2,1-hi]indole-7-carboxylate

[0687]

[0688] T-94 (1 eq) was directly dissolved in a mixed solution of dichloromethane and methanol, trimethylsilyldiazomethane (2 eq) was added, stirred at room temperature for 3 h, extracted with EA, washed with water three times, the organic phase was concentrated, and T-95 was separated and purified by flash column chromatography and HPLC, respectively.

[0689] 1 H NMR (400MHz, acetone-d 6 )δ8.55(s,1H),8.13(s,1H),8.03(m,1H),7.40–7.22(m,7H),4.90–4.80(m,2H),4.21(m,1H),3.86(s,3H),3.61(s,3H). MS ESI:m / z=459,[M+H] + .

[0690] Example 103: T-96

[0691] (S)-5-Benzyl-N-(1-methyl-2-oxo-6-(3-(trifluoromethyl)pyridin-2-yl)-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0692]

[0693] Using R-7 (400 mg) as the starting material and the same conditions as in Example 42, 520 mg of white solid T-96 can be obtained.

[0694] 1 H NMR (400MHz, acetone-d 6 )δ8.92(d,J=4.5Hz,1H),8.67(d,J=5.7Hz,1H),8.50(d,J=7.9Hz,1H),7.83(dd,J=7.6,4.9Hz,1H),7.43(s, 1H),7.30(m,6H),7.17–7.07(m,2H),4.86(m,1H),4.19(s,2H),3.63(s,3H),3.49(m,1H),3.20–3.05(m,1H). MS ESI:m / z=546,[M+1] + .

[0695] Example 104: T-97

[0696] (±)-5-Benzyl-N-(1-methyl-2-oxo-6-(3-(2,2,2-trifluoroethyl)pyridin-2-yl)-2,3,4,6-tetrahydro-1H-azacyclo[4,3,2-cd]indol-3-yl)-4H-1,2,4-triazole-3-carboxamide

[0697]

[0698] Step 1: Preparation of Y-63, using Y-8 (30 mg) and 2-bromo-3-(2,2,2-trifluoroethyl)pyridine as raw materials, using the same conditions as in the first step of Example 80 to obtain 33.9 mg of solid Y-64. MS ESI: m / z=375, [M+1] + .

[0699] Step 2: Preparation of T-97: Using Y-64 as raw material, 40 mg of white solid was obtained under the same conditions as in Step 2 of Example 40.

[0700] 1 H NMR (400MHz, acetone-d 6)δ8.67(m,2H),8.19(d,J=7.9Hz,1H),7.63(dd,J=7.6,4.6Hz,1H),7.48(s,1H),7.40–7.18(m,6H),7.13(d,J=7.8Hz, 1H),7.02(d,J=8.2Hz,1H),4.87(m,1H),4.19(s,2H),3.82–3.65(m,2H),3.63(s,3H),3.50(m,1H),3.21–3.08(m,1H). MS ESI:m / z=560,[M+1] + .

[0701] Activity test:

[0702] 1. Cell activity test (TNFα induced FADD-deficient human leukemia Jurkat cell programmed necrosis system.

[0703] (1) Cell culture: Jurkat fadd-deficient cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum (FBS), 100 U / mL penicillin, 100 U / mL streptomycin, and 5% CO. 2 All cells were cryopreserved in complete medium containing 5-10% DMSO. The medium was changed 3-4 times a week.

[0704] (2) Experimental materials: Reagents:

[0705] RPMI 1640 culture medium (GIBCO, USA), fetal bovine serum (GIBCO, USA), Humanrecombinant TNF (Novoprotein C008), Cell Titer-Glo Kit (Promega, USA), Nec-1s synthesized by Ma Dawei's research group at Shanghai Institute of Organic Chemistry, compound GSK2982772 (Biodeoxyglucose Reagents, Inc.).

[0706] (3) Experimental consumables:

[0707] Cell culture dishes (100 / 60 / 35 mm) from BD or Corning, USA; cell culture plates (384 / 96 / 24 / 6 wells) from BD or Corning, USA; centrifuge tubes (15 / 50 ml) from BD or Corning, USA.

[0708] (4) Experimental plan: The TNFα-induced Jurkat fadd-deficient cell programmed necrosis system was used to screen compounds with RIPK1 kinase inhibitory activity.

[0709] Fadd deficient Jurkat cells were evenly inoculated into 384-well plates, 1w / well / 40μL complete medium, 5μL of the compound to be tested was added to each well, the starting concentration of the compound was set to 25μM (the starting concentration of some compounds with better activity was 0.5μM), three-fold gradient dilution, a total of 12 gradient points, and 3 replicates for each compound. A blank control group and a control group stimulated by TNFα alone were added. After adding the compound, the mixture was centrifuged and mixed, and placed at 37°C with 5% CO 2 The cells were incubated in a cell culture incubator for 1 hour, and then 5 μL of 5 ng / mL TNFα was added to stimulate necrosis. After centrifugation and mixing, the cells were placed in a cell culture incubator and incubated for 13 hours (until the cell death rate in the TNF-α group alone reached 65%). The total volume of each well was 50 μL. The cell survival rate was then detected according to the following steps.

[0710] Remove the CellTiter- Buffer, equilibrated to room temperature, and then used CellTiter- Buffer dissolves CellTiter- Substrate, obtained CellTiter- Reagent can be used directly in experiments.

[0711] Add 15 μL of room temperature equilibrated CellTiter- Reagent, keep in dark for 15 min, and then use an enzyme reader (Enspire multifunctional enzyme reader, PerkinElmer, USA) to detect chemiluminescence. The value of the blank control group was taken as 100%, and the relative change of ATP in the experimental group was calculated and the IC value of the compound was obtained by fitting with Graphpad Prism software. 50 :A(<0.01uM),B(0.01-0.1uM),C(0.1-1.0uM),D(>1uM).

[0712] Table 1 Results of Jurkat Fadd(- / -) inhibitory activity test

[0713] Compound No. <![CDATA[IC 50 ]]> Compound No. <![CDATA[IC 50 ]]> Compound No. <![CDATA[IC 50 ]]> T-1 A T-33 B T-65 B T-2 A T-34 A T-66 A T-3 B T-35 A T-67 A T-4 B T-36 A T-68 A T-5 C T-37 A T-69 A T-6 C T-38 A T-70 A T-7 B T-39 B T-71 A T-8 A T-40 A T-72 A T-9 A T-41 A T-73 B T-10 B T-42 A T-74 A T-11 B T-43 A T-75 B T-12 C T-44 A T-76 B T-13 D T-45 A T-77 C T-14 B T-46 C T-78 A T-15 A T-47 C T-79 D T-16 A T-48 A T-80 B T-17 B T-49 A T-81 A T-18 A T-50 A T-82 A T-19 A T-51 B T-83 A ST-19 A T-52 A T-84 B RT-19 C T-53 A T-85 C T-20 B T-54 A T-86 A T-21 C T-55 B T-87 B T-22 B T-56 B T-88 B T-23 C T-57 C T-89 B T-24 B T-58 B T-90 A T-25 A T-59 A T-91 B T-26 B T-60 A T-92 D T-27 B T-61 B T-93 C T-28 A T-62 A T-94 D T-29 A T-63 A T-95 C T-30 C T-64 A T-96 A T-31 C T-97 A T-32 A

[0714] 2. RIPK1 inhibitory activity test

[0715] The RIPK1 activity inhibition test was performed by NANOSYN Testing Services, Inc. (3100 Central Expressway, Santa Clara, CA 95051, USA). The test compound was dissolved in DMSO, the highest test concentration was 1 μM, and then diluted 3 times in sequence. The concentration of DMSO in the test medium was kept at 1%, and a total of 12 test concentrations were obtained to obtain IC 50 .

[0716] Table 2 RIPK1 activity inhibition test results

[0717]

[0718]

[0719] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A compound represented by the structure represented by general formula II or a pharmaceutically acceptable salt thereof, R 1 is H or methyl; R d is H or halogen; Z 1 N or CH; Ring A is the following structure: Ring D is phenyl or phenyl substituted with halogen; In the tricyclic structure of formula II, R of the five-membered ring and R of the six-membered ring are each independently selected from the group H, halogen, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -C0-C6 alkyleneoxy C1-C6 alkyl-, C1-C6 hydroxyalkyl, -C0-C6 alkylene-S-C1-C6 alkyl-, -C0-C6 alkylene-C6-C 10 Aryl, -C0-C6 alkylene-5-10 membered heteroaryl, -C0-C6 alkylene-3-6 membered non-aromatic heterocyclic group, -C0-C6 alkylene-C3-C6 cycloalkyl, -C0-C6 alkylene-CONR a R b 、SF5、-C0-C6 alkylene-NR a R b 、-C0-C6 alkylene-NHC(O)R c 、-C0-C6 alkylene-NHC(O)NR a R b , -C0-C6 alkylene-P(O)Me2, -C0-C6 alkylene C3-C6 cycloalkyloxy, -C0-C6 alkylene C1-C6 alkoxy, -C0-C6 alkylene C1-C6 haloalkoxy, -C0-C6 alkylene-C≡CR 2 、-O-C1-C6 alkylene-C≡CR 2 、-S-C1-C6 alkylene-C≡CR 2 , R a , R b are independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, or substituted or unsubstituted C3-C 10 Heteroaryl; R a and R b Together with the nitrogen or carbon atom to which they are attached, they may form a three- to eight-membered ring or a four- to eight-membered heterocyclic ring; R c Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 cycloalkyloxy, C0-C6 alkylene hydroxyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclic group; R 2 is hydrogen, C1-C 10 Alkyl, -C0-C6 alkylene-C6-C 10 Aryl, -C0-C6 alkylene-5-10 membered heteroaryl, -C0-C6 alkylene-3-10 membered non-aromatic heterocyclic group, -C0-C6 alkylene-C3-C 10 Cycloalkyl.

2. A compound represented by the structure represented by general formula III or a pharmaceutically acceptable salt thereof, characterized in that: The structure shown in general formula III is as follows, R 1 is H or methyl; R d is H or halogen; Z 1 N or CH; Ring A is the following structure: Ring D is phenyl or phenyl substituted with halogen; In the tricyclic structure of formula III, R of the five-membered ring and R of the six-membered ring are each independently selected from the group consisting of H, halogen, -CN, -C1-C6 alkyl, -C1-C6 haloalkyl, -C0-C6 alkyleneoxy C1-C6 alkyl-, C1-C6 hydroxyalkyl, -C0-C6 alkylene-S-C1-C6 alkyl-, -C0-C6 alkylene-C6-C 10 Aryl, -C0-C6 alkylene-5-10 membered heteroaryl, -C0-C6 alkylene-3-6 membered non-aromatic heterocyclic group, -C0-C6 alkylene-C3-C6 cycloalkyl, -C0-C6 alkylene-CONR a R b 、SF5、-C0-C6 alkylene-NR a R b 、-C0-C6 alkylene-NHC(O)R c 、-C0-C6 alkylene-NHC(O)NR a R b , -C0-C6 alkylene-P(O)Me2, -C0-C6 alkylene C3-C6 cycloalkyloxy, -C0-C6 alkylene C1-C6 alkoxy, -C0-C6 alkylene C1-C6 haloalkoxy, -C0-C6 alkylene-C≡CR 2 、-O-C1-C6 alkylene-C≡CR 2 、-S-C1-C6 alkylene-C≡CR 2 and the following groups: When R is attached to a nitrogen atom, R is not a halogen; R a , R b are independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C6-C 10 Aryl, or substituted or unsubstituted C3-C 10 Heteroaryl; R a and R b The nitrogen atom or carbon atom to which they are attached may together form a three- to eight-membered ring or a four- to eight-membered heterocyclic ring; R c Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 cycloalkyloxy, C0-C6 alkylene hydroxyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclic group; R 2 is hydrogen, C1-C 10 Alkyl, -C0-C6 alkylene-C6-C 10 Aryl, -C0-C6 alkylene-5-10 membered heteroaryl, -C0-C6 alkylene-3-10 membered non-aromatic heterocyclic group, -C0-C6 alkylene-C3-C 10 Cycloalkyl.

3. A compound, characterized in that The compound is selected from the group consisting of:

4. The use of the compound according to any one of claims 1 to 3, characterized in that Used for: (i) preparing RIPK1 inhibitors; (ii) preparing inhibitors of programmed cell death; (iii) preparing a drug for preventing or treating a disease mediated by RIPK1.

Images