Compound for inhibiting programmed cell death and preparation method thereof

Abstract

The present invention discloses a RIPK1 inhibitor for inhibiting programmed cell necrosis and a preparation method thereof. The RIPK1 inhibitor of the present invention is shown in general formula I, wherein X 1 , X 2 , X 3 , X 4 , X 5 , Z 1 , Z 2 , Z 3 , L 1 , L 2 , L 3 , R, R 1 , ring D and n are as shown in the specification and claims. The present invention also discloses a preparation method of the general formula I and its activity test results of inhibiting programmed cell necrosis and RIPK1. The general formula I compound of the present invention can be used to prepare drugs for treating and preventing inflammatory and degenerative diseases.

Description

Technical Field

[0001] 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

[0002] 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.

[0003] 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.

[0004] 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

[0005] The purpose of the present invention is to provide a novel RIPK1 inhibitor for inhibiting programmed cell necrosis.

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

[0007] The first aspect of the present invention provides a compound as shown in general formula I, or various isomers and pharmaceutically acceptable salts thereof:

[0008]

[0009] Where:

[0010] Z 1 , Z 2 and Z 3 Independent for N, C(R);

[0011] R is independently H, halogen, -OH, -CN, -COOH, C1-C6 alkyl, -C0-C6 alkyleneoxy, C1-C6 alkyl-, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C 10 Alkoxyalkyl, C2-C 10 Halogenated alkoxyalkyl, C1-C6 hydroxyalkyl, -C0-C6 alkylene-S-C1-C6 alkyl-, -C0-C6 alkylene-C6-C 10 Aryl, -C0-C6 alkylene-X-C6-C 10 Aryl, -C0-C6 alkylene-5-10 membered heteroaryl, -C0-C6 alkylene-X-5-10 membered heteroaryl, -C0-C6 alkylene-3-10 membered non-aromatic heterocyclic group (wherein the heteroatom can be independently one or more sulfur, oxygen, NH or NR g ), -C0-C6 alkylene-C3-C 10 Cycloalkyl, -C0-C6 alkylene-C3-C 10 Cycloalkenyl, -C0-C6 alkylene-COR c 、-C0-C6 alkylene-CO2C1-C6 alkyl、-C0-C6 alkylene-CONR a R b 、-C0-C6 alkylene-SO2NR a R b 、-C0-C6 alkylene-S(O)2R c 、SF5、-C0-C6 alkylene-NR a R b 、-C0-C6 alkylene-NHC(O)R c 、-C0-C6 alkylene-NHC(O)C(O)NR a R b 、-C0-C6 alkylene-NHC(O)C(O)OR a 、-C0-C6 alkylene-NHC(O)NR a R b , -P(O)Me2, -P(O)(OMe)2, -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 、、-C0-C6 alkylene-CH=CH-R 2 ; R may be unsubstituted or substituted with 1 to 4 R fSubstitution; when R is attached to a nitrogen atom, R is not a halogen.

[0012] R can be specifically selected from the following groups:

[0013]

[0014]

[0015]

[0016] X is O, S, SO, S(O)2, NH, C(O), CH2, CF2, CH(CH3), CH(OH) or N(CH3);

[0017] R 1 and R 1a are independently H, C1-C6 alkyl or -C0-C3 alkylene-C3-C6 cycloalkyl;

[0018] 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 (which may be sulfur, oxygen, NH or NR g ), -C0-C6 alkylene-C3-C 10 Cycloalkyl, or -C0-C6 alkylene-C1-C 10 Alkoxy; R 2 are each independently unsubstituted or substituted with 1 to 4 R f replace;

[0019] R f is independently halogen, -OH, carbonyl, -CN, -COOH, C1-C6 alkyl, -C0-C6 alkyleneoxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C 10 Alkoxyalkyl, C2-C 10 Halogenated alkoxyalkyl, C1-C6 hydroxyalkyl, -C0-C6 alkylene-S-C1-C6 alkyl, -SF5, -C0-C6 alkylene-COR c 、-C0-C6 alkylene-CO2C1-C6 alkyl、-C0-C6 alkylene-CONR a R b 、-C0-C6 alkylene-SO2NR a R b 、-C0-C6 alkylene-S(O)2R c 、-C0-C6 alkylene-NRa R b 、-C0-C6 alkylene-C(O)NR a R b 、-C0-C6 alkylene-NHC(O)R c 、-C0-C6 alkylene-NHC(O)C(O)NR a R b 、-C0-C6 alkylene-NHC(O)C(O)OR a 、-C0-C6 alkylene-NHC(O)NR a R b , -C0-C6 alkylene-P(O)Me2, -C0-C6 alkylene-P(O)(OMe)2; two adjacent R f or two R attached to the same carbon atom f Together they form a three- to eight-membered ring or a four- to eight-membered heterocyclic ring which may contain heteroatoms such as sulfur, oxygen, NH or NR g ;

[0020] R a , R b are independently hydrogen, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl, substituted or unsubstituted C2-C 10 Alkenyl, substituted or unsubstituted C6-C 10 Aryl, or substituted or unsubstituted C3-C 10 Heteroaryl; R a and R b The nitrogen atom or carbon atom to which they are attached may form a three- to eight-membered ring or a four- to eight-membered heterocyclic ring, which may contain heteroatoms such as sulfur, oxygen, NH or NR g The three- to eight-membered ring or four- to eight-membered heterocyclic ring may be one or more R e replace;

[0021] R c Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C 10 Cycloalkenyl, C1-C6 alkoxy, C1-C6 cycloalkoxy, C0-C6 alkylene hydroxyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclic group, -C0-C6 alkylene CF3, -C1-C6 alkylene CN, -C1-C6 alkylene-C1-C6 alkoxy, C1-C6 alkylene NR a R b 、C1-C6 alkylene NR b C(O)R a、C1-C6 alkylene NR b S(O)2R a , C1-C6 alkylene carboxyl, -C1-C6 alkylene CO2, C1-C6 alkyl, C1-C6 alkylene COR a 、-C0-C6 alkylene CONR a R b , the C6-C 10 Aryl, 5-10 membered heteroaryl, 3-10 membered non-aromatic heterocyclic group, C3-C6 cycloalkyl, or C3-C 10 The cycloalkenyl groups are each independently unsubstituted or substituted by one or two substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C0-C6 alkylene, NR a R b , -C0-C6 alkylene CN, -C0-C6 alkylene OH;

[0022] R g C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, or C3-C 10 heteroaryl;

[0023] X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from C, CR, N and NR, provided that the valence bond rules are met;

[0024] Select from the following structures:

[0025]

[0026] The above-mentioned 3-10 membered non-aromatic heterocyclic group may also be selected from the following bicyclic or spirocyclic structures:

[0027]

[0028] L 1 For the following structure:

[0029]

[0030] Ring A is a substituted or unsubstituted benzene ring, a 5-6 membered heteroaromatic ring, or a 5-6 membered non-aromatic heterocyclic ring; Ring A may be furan, thiophene, isoxazole, oxazole, thiazole, oxadiazole, pyrrole, pyrazole, imidazole, triazole, or tetrazole;

[0031] Preferably, ring A is the following structure:

[0032]

[0033] Ring A may be substituted by one or two halogens, -CN, C1-C6 alkyl or C1-C6 haloalkyl;

[0034] Ring B is a substituted or unsubstituted 5-7 membered heterocyclic ring containing a nitrogen atom;

[0035] Ring C is a substituted or unsubstituted benzene ring or a 5-6-membered heteroaromatic ring;

[0036] Y1 and Y2 are independently a carbon atom or a nitrogen atom;

[0037] Preferably, For the following structure:

[0038]

[0039] R d is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0040] R e is H, C1-C6 alkyl or C1-C6 haloalkyl;

[0041] L 2 O, NR g , CR a R b or does not exist;

[0042] L 3 is C0-C6 alkylene, C2-C6 alkenylene, C3-C6 cycloalkylene, benzene ring, 5-6 membered heteroaromatic ring or 5-6 membered non-aromatic heterocycle; L 3 Can be 1-3 R 5 replace;

[0043] R 5 Each is independently H, halogen, -OH, -CN, carbonyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy;

[0044] Ring D is C3-C6 cycloalkyl, phenyl, naphthyl, C3-C6 cycloalkylphenyl, 5-6 membered heteroaryl or 5-6 membered non-aromatic heterocyclic group;

[0045] R 10 Independently selected from halogen, CN, C1-C6 alkyl, C1-C6 haloalkyl, OC1-C6 alkyl, or C3-C6 cycloalkyl;

[0046] n is 0, 1, 2 or 3.

[0047] In another preferred embodiment, the compound of general formula I is a compound represented by formula II:

[0048]

[0049] wherein R is independently defined as described in Formula I; R 1 is H, methyl or ethyl.

[0050] R d Each is independently H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0051] Ring A is the following structure:

[0052]

[0053] Ring D is a benzene ring or thiophene;

[0054] R 10 is halogen or -CN.

[0055] n is 0, 1, 2 or 3.

[0056] In another embodiment, the compound of formula I is a compound of formula III:

[0057]

[0058] wherein R is independently defined as described in Formula I, with the proviso that when R is attached to a nitrogen atom, R is not a halogen; R 1 is H, methyl or ethyl.

[0059] W is N or CR d ;

[0060] R d is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0061] Ring A is the following structure:

[0062]

[0063] Ring D is a benzene ring or thiophene;

[0064] R 10 are independently halogen or -CN;

[0065] n is 0, 1, 2 or 3.

[0066] In another embodiment, the compound of formula I is a compound of formula IV:

[0067]

[0068] wherein R is independently defined as described in Formula I; R 1 R is H, methyl or ethyl. d Each is independently H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0069] Ring A is the following structure:

[0070]

[0071] Ring D is a benzene ring or thiophene;

[0072] R 10 are independently halogen or -CN;

[0073] n is 0, 1, 2 or 3.

[0074] In another preferred embodiment, the compound of general formula I is a compound represented by formula V:

[0075]

[0076] Where R and R 10 Each is independently defined as described in Formula I; R 1 is H, methyl or ethyl.

[0077] For the following structure:

[0078]

[0079] R d Each is independently H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0080] R e is H, C1-C6 alkyl or C1-C6 haloalkyl;

[0081] Ring D is a benzene ring or thiophene;

[0082] R 10 are independently halogen or -CN.

[0083] n is 0, 1, 2 or 3.

[0084] In another preferred embodiment, the compound of general formula I is a compound represented by formula VI:

[0085]

[0086] Where R and R 10 Each is independently defined as described in Formula I, with the proviso that when R is attached to a nitrogen atom, R is not a halogen; R 1 is H, methyl or ethyl.

[0087] For the following structure:

[0088]

[0089] R d are independently H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0090] R e is H, C1-C6 alkyl or C1-C6 haloalkyl;

[0091] Ring D is a benzene ring or thiophene;

[0092] R 10 are independently halogen or -CN.

[0093] n is 0, 1, 2 or 3.

[0094] In another preferred embodiment, the compound of general formula I is a compound represented by formula VII:

[0095]

[0096] wherein R is independently defined as described in Formula I, with the proviso that when R is attached to a nitrogen atom, R is not a halogen; R 1 is H, methyl or ethyl.

[0097] For the following structure:

[0098]

[0099] R d are independently H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0100] R e is H, C1-C6 alkyl or C1-C6 haloalkyl;

[0101] Ring D is a benzene ring or thiophene;

[0102] R 10 are independently halogen or -CN.

[0103] n is 0, 1, 2 or 3.

[0104] In another preferred embodiment, the compound of general formula I is a compound represented by formula VIII:

[0105]

[0106] wherein R is independently defined as described in Formula I; R 1 is H, methyl or ethyl.

[0107] Ring D is a benzene ring or thiophene;

[0108] R d is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0109] R 10 are independently halogen or -CN;

[0110] n is 0, 1, 2 or 3.

[0111] In another preferred embodiment, the compound of general formula I is a compound represented by formula IX:

[0112]

[0113] wherein R is independently defined as described in Formula I, with the proviso that when R is attached to a nitrogen atom, R is not a halogen; R 1 is H or methyl;

[0114] R 10 is halogen or -CN;

[0115] R d is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0116] Ring D is a benzene ring or thiophene;

[0117] n is 0, 1, 2 or 3.

[0118] In another embodiment, the compound of general formula I is a compound represented by formula X:

[0119]

[0120] wherein R is independently defined as described in Formula I; R 1 is H, methyl or ethyl.

[0121] Ring D is a benzene ring or thiophene;

[0122] R d is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0123] R 10 is halogen or -CN;

[0124] n is 0, 1, 2 or 3.

[0125] In another embodiment, the compound of general formula I is a compound represented by formula XI:

[0126]

[0127] wherein R is independently defined as described in Formula I; R 1is H, methyl or ethyl.

[0128] Ring D is a benzene ring or thiophene;

[0129] R d is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0130] R 10 is halogen or -CN;

[0131] n is 0, 1, 2 or 3.

[0132] In another embodiment, the compound of formula I is a compound represented by formula XII:

[0133]

[0134] wherein R is independently defined as described in Formula I; R 1 is H, methyl or ethyl.

[0135] Ring D is a benzene ring or thiophene;

[0136] R d is H, halogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0137] R 10 is halogen or -CN;

[0138] n is 0, 1, 2 or 3.

[0139] In another preferred embodiment, in the compounds of general formula I to general formula XII, R is selected from the following groups: halogen,

[0140]

[0141]

[0142] In another preferred embodiment, the compounds of Formula I to Formula XII are:

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172] In another preferred embodiment, the compounds of Formula I to Formula XII include all stereoisomers.

[0173] In another preferred embodiment, the stereoisomers are cis-trans isomers.

[0174] In another preferred embodiment, the compound is an optically pure isomer.

[0175] In another preferred embodiment, the compound is a racemate.

[0176] In another preferred embodiment, the stereoisomers are enantiomers.

[0177] In another preferred embodiment, any one or more hydrogen atoms in the compound may be replaced by a deuterium atom.

[0178] In another preferred embodiment, the compounds of Formula I to Formula XII include prodrugs thereof.

[0179] In another preferred embodiment, the pharmaceutically acceptable salts of Formula I to Formula XII are selected from the following group: hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate (toluenesulfonate), 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, and mandelate.

[0180] The second aspect of the present invention provides a method for preparing the compounds of Formula I to Formula XII described in the first aspect, wherein the method is selected from one of the following schemes.

[0181] Option 1:

[0182]

[0183] Methyl acrylate is reacted with a suitably substituted 7-nitroindole with a base to obtain I-1, and then the nitro group is reduced to amine I-2 (reduction conditions are for example but not limited to Zn / AcOH, Fe / NH4Cl / EtOH, Zn / NH4Cl / EtOH, Pd / C / H2 / MeOH), and an intramolecular condensation is carried out using a condensation reagent to obtain an intermediate (Formula I-4) (the condensation reagent is for example but not limited to HOAT, HOBT, HATU, EDCI, BOP, TCFH / NMI), and Formula I -4 compound is alkylated to obtain I-5, which is reacted with isoamyl nitrite under alkaline conditions to obtain intermediate I-6, and then the oxime is reduced to amine I-7 (reduction conditions are such as but not limited to Pd / C / H2 / MeOH, Ni / C / H2 / MeOH, NaBH4 / NiCl2(H2O)6 / MeOH), which is subjected to chiral separation and then condensed with acid (a) using an amide condensation reagent (condensation reagent is such as but not limited to HOAT, EDCI, HATU, TCFH) to obtain the final product I.

[0184] Option 2:

[0185]

[0186] Use a suitably substituted 7-nitroindole to reduce the nitro group to amine II-1 (reduction conditions include but are not limited to Zn / AcOH, Fe / NH4Cl / EtOH, Zn / NH4Cl / EtOH, Pd / C / H2 / MeOH), react II-1 with an acyl chloride under alkaline conditions to obtain an intermediate (Formula II-2), and under alkaline conditions obtain the ring-closed intermediate I-4, and the final product I is obtained in the same manner as in Scheme 1.

[0187] Option 3:

[0188]

[0189] A suitably substituted 4-nitroindole is used to react with dimethylamine and formaldehyde in a Mannich reaction with Lewis acid or Bronsted acid catalysis to obtain III-1, which is then reacted with a malonic acid diester under propiolate catalysis or heating conditions to obtain III-2. The nitro group is then reduced to an amine III-3 (reduction conditions are, for example, but not limited to, Zn / AcOH, Fe / NH4Cl / EtOH, Zn / NH4Cl / EtOH, Pd / C / H2 / MeOH). The resulting amine is then reacted with an anhydride to obtain an amide, and the amide is reduced to an alkylamine III-4, or directly proceeds to the next step. Acid catalysis is added to toluene to perform ring closure to obtain III-5, which is then subjected to ester hydrolysis and curtius rearrangement and amino protection to obtain III-7. Using III-7 as an intermediate, different substitutions are performed by nucleophilic substitution or coupling reaction under alkaline conditions. After removing the protecting group, an amide condensation reagent (condensation reagent is, for example, but not limited to, HOAT, EDCI, HATU, TCFH) is used to condense with acid (a) to obtain the final product III. Depending on the reaction conditions, III-7, III-8 or III can be chirally resolved.

[0190] Option 4:

[0191]

[0192] Select a suitable 4-carboxylic acid methyl ester halogenated indole as the raw material, first perform ester hydrolysis, then perform curtius rearrangement, and quench with formic acid to obtain IV-2. Then perform a mannich reaction to obtain IV-3, and react with nitroacetic acid ester under heating conditions to obtain IV-4. Subsequently, formamide is reduced with borane dimethyl sulfide, and then the nitro group is reduced (reduction conditions such as but not limited to Zn / AcOH, Fe / NH4Cl / EtOH, Zn / NH4Cl / EtOH, Ranney Ni / H2 / MeOH) and the amino group is protected. After the ester hydrolysis of IV-6, an amide condensation reagent (condensation reagent such as but not limited to HOAT, EDCI, HATU, TCFH) is used and the protecting group is removed to obtain IV-8. Then Sonogashira coupling is performed to obtain IV-9, which is subjected to chiral resolution and then condensed with acid (a) using an amide condensation reagent (condensation reagent such as but not limited to HOAT, EDCI, HATU, TCFH) to obtain the final product IV.

[0193] Option 5:

[0194]

[0195] Using amine as raw material, first reductive amination is carried out to obtain V-1, then ester hydrolysis is carried out to obtain acid V-2, and finally an amide condensation reagent (condensation reagent is for example but not limited to HOAT, EDCI, HATU, TCFH) is used to obtain the final product V.

[0196] Option 6:

[0197]

[0198] Using appropriately substituted 4-nitroindole as a raw material, a halogen is introduced at the 3-position of indole using a halogenating agent, and then a suitable protecting group such as Boc is selected to protect the nitrogen of the indole. Then, Negishi coupling is performed with (R)-N-tert-butyloxycarbonyl-3-iodoalanine methyl ester to obtain VI-3. After the nitro group of VI-3 is reduced to an amino group (reduction conditions such as but not limited to Zn / AcOH, Fe / NH4Cl / EtOH, Zn / NH4Cl / EtOH, Ranney Ni / H2 / MeOH), the ester is hydrolyzed, and then an amide condensation reagent (condensation reagents such as but not limited to HOAT, EDCI, HATU, TCFH) is used to obtain VI-5. VI-5 reacts with a suitable alkyl iodide to obtain VI-6, and then a protecting group conversion is performed to obtain the intermediate VI-7. VI-7 introduces a substituent on the indole nitrogen atom under different conditions, then removes the protecting group, and then uses an amide condensation reagent (condensation reagent is, for example but not limited to, HOAT, EDCI, HATU, TCFH) to condense with acid (a) to obtain the final product I.

[0199] Option 7:

[0200]

[0201] Using a suitably substituted 4-nitroindole as a raw material, a halogen is introduced at the 3-position of indole using a halogenating agent, and then a suitable protecting group such as Boc is selected to protect the nitrogen of the indole. Then, Negishi coupling is performed with (R)-N-tert-butyloxycarbonyl-3-iodoalanine methyl ester to obtain VII-3. After the nitro group of VII-3 is reduced to an amino group (reduction conditions such as but not limited to Zn / AcOH, Fe / NH4Cl / EtOH, Zn / NH4Cl / EtOH, Ranney Ni / H2 / MeOH), the ester is hydrolyzed, and then an amide condensation reagent (condensation reagents such as but not limited to HOAT, EDCI, HATU, TCFH) is used to obtain VII-5. The nitrogen atom of the indole of VII-5 is protected using a suitable protecting group such as Boc, and then reacted with a suitable alkyl iodide to obtain VII-7, and then the protecting group is transformed to obtain the intermediate VII-8. VII-8 is subjected to different conditions to introduce a substituent on the indole nitrogen atom, and then the protecting group is removed, and then condensed with the acid (a) using an amide condensation reagent (condensation reagents include but are not limited to HOAT, EDCI, HATU, TCFH) to obtain the final product VII.

[0202] Option 8:

[0203]

[0204] Using a suitably substituted 4-nitroindazole as a raw material, a halogen is introduced at the 3-position of indole using a halogenating agent, and then a suitable protecting group such as Boc is selected to protect the nitrogen of the indole. Then, Negishi coupling is performed with (R)-N-tert-butyloxycarbonyl-3-iodoalanine methyl ester to obtain VIII-3. After the nitro group of VIII-3 is reduced to an amino group (reduction conditions such as but not limited to Zn / AcOH, Fe / NH4Cl / EtOH, Zn / NH4Cl / EtOH, Ranney Ni / H2 / MeOH), the ester is hydrolyzed, and then an amide condensation reagent (condensation reagents such as but not limited to HOAT, EDCI, HATU, TCFH) is used to obtain VIII-5. The nitrogen atom of VIII-5 is protected using a suitable protecting group such as Boc, and then reacted with a suitable alkyl iodide to obtain VIII-7, and then the protecting group is transformed to obtain the intermediate VIII-8. VIII-8 is subjected to different conditions to introduce a substituent on the indazole nitrogen atom, and then the protecting group is removed, followed by condensation with the acid (a) using an amide condensation reagent (condensation reagents include but are not limited to HOAT, EDCI, HATU, TCFH) to obtain the final product VIII.

[0205] Option Nine:

[0206]

[0207] Methyl bromoacetate is reacted with a suitably substituted 7-nitroindole using a base to obtain IX-1, and then the ester group is reduced to an aldehyde IX-2. IX-2 is reacted with a suitable chiral tert-butylsulfonimide to obtain IX-3. A cyano group is introduced using trimethylsilyl cyanide to obtain IX-4. Its nitro group is reduced to an amino group IX-5, and then the compounds of different chirality are purified using column chromatography (reduction conditions such as but not limited to Zn / AcOH, Fe / NH4Cl / EtOH, Zn / NH4Cl / EtOH, Pd / C / H2 / MeOH). The suitable chiral compound IX-5 is heated in a methanol solution of hydrochloric acid for intramolecular ring closure to obtain an intermediate IX-6, the amino group therein is protected with a suitable protecting group to obtain IX-7, and then reacted with a suitable alkyl iodide to obtain IX-8, and the protecting group is further removed to obtain an intermediate IX-9, which is then condensed with an acid (a) using an amide condensation reagent (condensation reagents such as but not limited to HOAT, EDCI, HATU, TCFH) to obtain the final product I.

[0208] The third aspect of the present invention provides the use of the compounds of formula I to formula XII described in the first aspect for:

[0209] (i) preparing a programmed cell necrosis inhibitor;

[0210] (ii) preparing a medicament for preventing and / or treating a disease mediated by programmed cell death.

[0211] In another preferred embodiment, the disease mediated by programmed cell necrosis is cancer, new coronavirus infection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, Sjögren's syndrome, scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, nonalcoholic fatty liver hepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary scleroderma cholangitis, nephritis, celiac disease, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease, Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, multiple sclerosis, type I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-1 converting enzyme-associated febrile syndrome, chronic obstructive pulmonary disease, tumor necrosis factor receptor-associated periodic syndrome, and periodontitis.

[0212] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0213] definition

[0214] 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., CH3-), ethyl (i.e., CH3CH2-), n-propyl (i.e., CH3CH2CH2-), isopropyl (i.e., (CH3)2CH-), n-butyl (i.e., CH3CH2CH2CH2-), isobutyl (i.e., (CH3)2CHCH2-), sec-butyl (i.e., (CH3)(CH3CH2)CH-), tert-butyl (i.e., (CH3)3C-), n-pentyl (i.e., CH3CH2CH2CH2CH2-), and neopentyl (i.e., (CH3)3CCH2-).

[0215] 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.

[0216] 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.

[0217] As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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, -SF5, -C 0-6 Alkylene-NR a R b , -C 0-6 Alkylene-carboxyl, -C 0-6 Alkylene-COR a , -C 0-6 Alkylene-CO2Ra , -C 0-6 Alkylene-CONR d R e , -C 0-6 Alkylene-SO2R a , -C 0-6 Alkylene-SO2NR 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 0-6 Alkylene-S(O)(NCN)C 1-6 alkyl,-C 0-6 Alkylene-NR c S(O)2R b ,-C 0-6 Alkylene-NR c S(O)2NR c R b ,-C 0-6 Alkylene-NR c C(O)NH2,-C 0-6 Alkylene-NR c C(O)R b ,-C 0-6 Alkylene-NR c C(O)NR d R e ,-C 0-6 Alkylene-NR c C(O)OR b ,-C 0-6 Alkylene-NRSO2R b C(O)-R b ,-C 0-6 Alkylene-P(O)R c R b ,-C 0-6 Alkylene-P(O)(OR c )(OR b ),-C 0-6 Alkylene-C(O)C 1-6 Alkyleneamino, C 1-6 Heteroalkyl, C 5-10 Carbon ring, C 5- 10Aryl, C 2-10 Heterocyclic, C 2-10 Heteroaromatic ring.

[0223] In this application, C 0-6 Alkylene refers to a group having no alkylene or having C 1-6 Alkylene.

[0224] As used herein, the term "stereoisomer" refers to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

[0225] 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.

[0226] "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.

[0227] When the compounds described in the present invention exist as stereoisomers, the present invention includes all stereoisomers of the compounds.

[0228] When the compounds described in the present invention exist in tautomers, the present invention includes all tautomers of the compounds.

[0229] The present invention also includes deuterated compounds produced by replacing any one or more hydrogen atoms in the compounds with its stable isotope deuterium.

[0230] The present invention also provides active ingredients within a safe and effective amount range of the compounds of formula I and formula XII, and pharmaceutically acceptable carriers.

[0231] The "active ingredient" described in the present invention refers to the compounds of Formula I to Formula XII described in the present invention.

[0232] 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.

[0233] "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.

[0234] "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 means that the components in the composition can be mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.

[0235] Typically, the compounds of the preferred embodiments will be administered in a therapeutically effective amount, by any acceptable mode of administration of a medicament having a similar effect. The actual dosage of the compounds (i.e., active ingredients) of the preferred embodiments is determined according to a number of 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.

[0236] 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).

[0237] 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.

[0238] 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.

[0239] 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: isopropyl alcohol; LDA: lithium diisopropylamide; LHMDS: lithium bis(hexamethyldisilazide)amide; LAH: lithium aluminum hydride; NCS: N-chlorosuccinimide; PE: petroleum ether; PyBOP: benzotriazol-1-yloxytripyrrolidino 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; PPh3: triphenylphosphine; RT: room temperature; T3P: propylphosphonic anhydride; TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate.

[0240] Reverse phase HPLC purification conditions: Waters micromass ZQ 4000 (MAA050 model) was used as the mass detector, Waters 2487UV was used as the detector, and HPLC-MS analysis was performed on a Waters HPLC 2790. 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 (CH3CN, 0.05% TFA), and the elution rate was 1 ml / min. The initial condition was 90% A for 1 minute, then 90% A linearly decreased to 10% A within 5 minutes, and then rose from 10% A to 90% A within 1 minute, and the total running time was 7 minutes. According to the properties of the compound, the mobile phase gradient and running time can be adjusted appropriately.

[0241] 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.

[0242] 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.

[0243] Unless otherwise stated, the materials and reagents used in the examples of the present invention are commercially available products.

[0244] 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.

[0245] Example 1: Preparation of intermediate Z-7

[0246]

[0247] Step 1: Preparation of Z-1

[0248] 500 mg of 7-nitroindole was dissolved in 10 mL of acetonitrile, and methyl acrylate (670.4 mg) and DBU (234.9 mg) were added to react at 50°C for 4 h. The reaction solution was then 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.

[0249] MS ESI: m / z = 249.4, [M+H] + .

[0250] Step 2: Preparation of Z-2

[0251] Z-1 (330 mg), NH4Cl (290.4 mg), and iron powder (744.9 mg) were dissolved in ethanol (12 mL) and water (4 mL). After reacting at room temperature for 1 h, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic phase was concentrated and subjected to column chromatography to obtain intermediate Z-2.

[0252] MS ESI: m / z = 218.2, [M+H] + .

[0253] Step 3: Preparation of Z-3

[0254] 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 the crude product Z-3.

[0255] MS ESI: m / z = 205, [M+H] + .

[0256] Step 4: Preparation of Z-4

[0257] 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 organic phase was concentrated and subjected to column chromatography to obtain intermediate Z-4.

[0258] MS ESI: m / z = 187.2, [M+H] + .

[0259] Step 5: Preparation of Z-5

[0260] Z-4 (100 mg), iodomethane (233.5 mg), and cesium carbonate (185.7 mg) were dissolved in DMF (5 mL), reacted at room temperature for 3 h, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was concentrated and subjected to column chromatography to obtain intermediate Z-5.

[0261] MS ESI: m / z = 201.2, [M+H] + .

[0262] Step 6: Preparation of Z-6

[0263] Z-5 (100 mg), NaHMDS (sodium bis(trimethylsilyl)amide), and isoamyl nitrite were dissolved in THF (5 mL), reacted for 3 h under ice bath conditions, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was concentrated and subjected to column chromatography to obtain intermediate Z-6.

[0264] MS ESI: m / z = 230.2, [M+H] + .

[0265] Step 7: Preparation of Z-7

[0266] Dissolve Z-6 (200 mg) and nickel chloride hexahydrate (423.5 mg) in MeOH (8 mL), stir for 30 minutes under ice bath conditions, add sodium borohydride (198.2 mg) under ice bath conditions, 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.

[0267] MS ESI: m / z = 216.2, [M+H] + .

[0268] Example 2: T-1

[0269] (±)-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

[0270]

[0271] Acid-1 (73.6 mg), NMI (34.3 mg), and TCFH (119.7 mg) were dissolved in 1 mL DMF. After stirring for 10 min under ice bath conditions, 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: H2O (+0.1% CF3COOH); 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).

[0272] 1 H NMR (400MHz, CDCl3) 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).

[0273] MS ESI: m / z = 401.1, [M+H] + .

[0274] Example 3: T-2

[0275] (±)-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

[0276]

[0277] Using acid-2 (56.6 mg) and Z-7 as raw materials, T-2 was obtained under the same conditions as in Example 2.

[0278] 1 H NMR (400MHz, CD3OD) 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).

[0279] MS ESI: m / z = 401.1, [M+H] + .

[0280] Example 4: T-3

[0281] (±)-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

[0282]

[0283] Step 1: Preparation of Z-8

[0284] The intermediate Z-7 (1 eq), di-tert-butyl dicarbonate (1.1 eq), and triethylamine (1.5 eq) were dissolved in dichloromethane, stirred at room temperature for 2 h, and the reaction was quenched by adding ice water. The mixture was extracted three times with ethyl acetate, 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. The intermediate Z-8 was separated and purified by rapid column chromatography.

[0285] Step 2: Preparation of Z-9

[0286] The intermediate Z-8 (1 eq) and N-iodosuccinimide (1.1 eq) were dissolved in dichloromethane, stirred at room temperature for 30 min, and the reaction was quenched by adding ice water. The mixture was extracted three times with ethyl acetate, rinsed with a saturated solution of thiosulfuric acid pentahydrate, 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. The intermediate Z-9 was separated and purified by rapid column chromatography.

[0287] Step 3: Preparation of Z-10

[0288] Intermediate Z-9 (1 eq) and trifluoroacetic acid (10 eq) were dissolved in dichloromethane and stirred at room temperature for 3 h. After the organic phase was concentrated, it was directly separated and purified by rapid column chromatography to obtain intermediate Z-10.

[0289] MS ESI: m / z = 341.6, [M+H] + .

[0290] Step 4: Preparation of T-3

[0291] Using acid-1 (1.5 eq) and Z-9 (1 eq) as raw materials, T-3 was obtained under the same conditions as Example 2.

[0292] 1 H NMR (400MHz, acetone-d6) 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).

[0293] MS ESI: m / z = 527, [M+H] + .

[0294] Example 5: T-4

[0295] (±)-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

[0296]

[0297] Step 1: Preparation of Z-11

[0298] The intermediate Z-8 (1 eq), dimethyl sulfide (1.3 eq), and N-chlorosuccinimide (1.3 eq) were dissolved in dichloromethane, stirred at room temperature for 2 h, and the reaction was quenched by adding ice water. The mixture was extracted three times with ethyl acetate, 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. The intermediate Z-11 was separated and purified by rapid column chromatography.

[0299] Step 2: Preparation of Z-12

[0300] Intermediate Z-11 (1 eq) and trifluoroacetic acid (10 eq) were dissolved in dichloromethane and stirred at room temperature for 3 h. After the organic phase was concentrated, intermediate Z-12 was directly separated and purified by rapid column chromatography.

[0301] MS ESI: m / z = 262, [M+H] + .

[0302] Step 3: Preparation of T-4

[0303] Using acid-1 (1.5 eq) and Z-2 (1 eq) as raw materials, T-4 was obtained under the same conditions as Example 2.

[0304] 1 H NMR (400MHz, CD3OD) 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).

[0305] MS ESI: m / z = 447, [M + H] + .

[0306] Example 6: T-5

[0307] (±)-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

[0308]

[0309] 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.

[0310] 1 H NMR (400MHz, CDCl3) 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).

[0311] MS ESI: m / z = 435, [M + H] + .

[0312] Example 7: T-6

[0313] (±)-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

[0314]

[0315] 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.

[0316] 1 H NMR (400MHz, CDCl3) 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).

[0317] MS ESI: m / z = 481, [M+H] + .

[0318] Example 8: T-7

[0319] (±)-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

[0320]

[0321] 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.

[0322] 1 H NMR(400MHz,DMSO-d6)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).

[0323] MS ESI: m / z = 419, [M+H] + .

[0324] Example 9: T-8

[0325] (±)-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

[0326]

[0327] Step 1: Preparation of Z-16

[0328] N-methyl-4-alkynylpyrazole (1.3eq) and intermediate Z-10 (1eq), CuI (0.05eq), PdCl2(PPh3)2 (0.1eq) 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.

[0329] MS-ESI: m / z = 420, [M+H] + .

[0330] Step 2: Preparation of T-8

[0331] Using acid-1 (1.5 eq) and Z-16 (1 eq) as raw materials, T-8 was obtained under the same conditions as Example 2.

[0332] 1 H NMR(400MHz,acetone-d6)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).

[0333] MS ESI: m / z = 505, [M+H] + .

[0334] Example 10: T-9

[0335] (±)-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

[0336]

[0337] Step 1: Preparation of Z-17

[0338] N-methyl-4-alkynylpyrazole (1.3eq) and intermediate Z-14 (1eq), CuI (0.05eq), PdCl2(PPh3)2 (0.1eq) were 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, concentrated the organic phase, and separated and purified by rapid column chromatography to obtain intermediate Z-17.

[0339] MS-ESI: m / z = 420, [M+H] + .

[0340] Step 2: Preparation of T-9

[0341] Using acid-1 (1.5 eq) and Z-17 (1 eq) as raw materials, T-9 was obtained under the same conditions as in Example 2.

[0342] 1 H NMR(400MHz,acetone-d6)δ8.56(s,1H),7.87(s,1H),7.58(s,1H),7.45(d,J=3.2Hz,1H),7.34-7.24(m,6 H), 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).

[0343] MS ESI: m / z = 505, [M+H] + .

[0344] Example 11: T-10

[0345] (±)-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

[0346]

[0347] Step 1: Preparation of Z-18

[0348] Intermediate Z-18 was obtained by using ethyl iodide and intermediate Z-4 ​​under the same conditions as in Example 1.

[0349] MS-ESI: m / z=230, [M+H]+.

[0350] Step 2: Preparation of T-10

[0351] Using acid-1 (1.5 eq) and Z-18 (1 eq) as raw materials, T-10 was obtained under the same conditions as Example 2.

[0352] 1 H NMR (400MHz, CD3OD) 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).

[0353] MS ESI: m / z = 415, [M + H] + .

[0354] Example 12: T-11

[0355] (±)-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

[0356]

[0357] Step 1: Preparation of Z-19

[0358] Intermediate Z-19 was obtained by reacting intermediate Z-8 with N-bromosuccinimide using the same conditions as in Example 4.

[0359] MS-ESI: m / z = 296, [M+H] + .

[0360] Step 2: Preparation of T-11

[0361] Using acid-1 (1.5 eq) and Z-19 (1 eq) as raw materials, T-11 was obtained under the same conditions as Example 2.

[0362] 1H NMR (400MHz, CD3OD) 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).

[0363] MS ESI: m / z = 481, [M+H] + .

[0364] Example 13: T-12

[0365] (±)-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

[0366]

[0367] 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.

[0368] 1 H NMR(400MHz,acetone-d6)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).

[0369] MS ESI: m / z = 473, [M + H] + .

[0370] Example 14: T-13

[0371] (±)-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

[0372]

[0373] 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.

[0374] 1 H NMR(400MHz,acetone-d6)δ8.55(s,1H),7.63(m,1H),7.45(s,1H),7.38–7.30(m,5 H),7.25(m,2H),5.44(m,1H),4.83(m,1H),4.40(m,1H),4.21(s,2H),3.61(s,3H).

[0375] MS ESI: m / z = 445, [M + H] + .

[0376] Example 15: T-14

[0377] (±)-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

[0378]

[0379] 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.

[0380] 1 H NMR(400MHz, CDCl3)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).

[0381] MS ESI: m / z = 403, [M + H] + .

[0382] Example 16: T-15

[0383] (±)-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

[0384]

[0385] Step 1: Preparation of Z-22

[0386] 1-Methyl-1H-pyrazole-4-boronic acid pinacol ester (1.5eq) and intermediate Z-9 (1eq), Pd(dppf)Cl2 (0.1eq), 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 flash column chromatography to obtain intermediate Z-22.

[0387] Step 2: Preparation of Z-23

[0388] The intermediate Z-22 (1 eq) and trifluoroacetic acid (10 eq) were dissolved in dichloromethane and stirred at room temperature for 3 h. After the organic phase was concentrated, the intermediate Z-23 was directly separated and purified by rapid column chromatography.

[0389] MS ESI: m / z = 296, [M+H] + .

[0390] Step 3: Preparation of T-15

[0391] Using acid-1 (1.5 eq) and Z-23 (1 eq) as raw materials, T-15 was obtained under the same conditions as in Example 2.

[0392] 1 H NMR(400MHz, CDCl3)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).

[0393] MS ESI: m / z = 481, [M+H] + .

[0394] Example 17: T-16

[0395] (±)-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

[0396]

[0397] 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.

[0398] 1 H NMR(400MHz, CDCl3)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).

[0399] MS ESI: m / z = 481, [M+H] + .

[0400] Example 18: T-17

[0401] (±)-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

[0402]

[0403] T-17 was obtained by reacting 3-pyridineboronic acid pinacol ester with intermediate Z-9 using the same conditions as in Example 16.

[0404] 1 H NMR (400MHz, CDCl3) 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).

[0405] MS ESI: m / z = 478, [M+H] + .

[0406] Example 19: T-18

[0407] (±)-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

[0408]

[0409] 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.

[0410] 1 H NMR(400MHz, CDCl3)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).

[0411] MS ESI: m / z = 549, [M+H] + .

[0412] Example 20: Preparation of Intermediate Y-8

[0413]

[0414] Step 1: Preparation of Y-1

[0415] In an ice bath, add 4-nitroindole (4000 mg), NH(CH3)2 (13.58 ml, 2 mol / lin MeOH), HCHO (2.2 ml, 37%), ZnCl2 (5048 mg) and 10 ml methanol to a 100 ml eggplant flask. After stirring at room temperature for 2 h, add NH(CH3)2 (2.46 ml) and HCHO (0.5 ml). After stirring for 4 h, LC-MS showed that the raw material was consumed. Add NaOH solution to adjust the pH to about 13, add EA to dilute, and filter to remove insoluble solids. The filtrate is extracted with EA, and after the sodium sulfate solid is dried, the solvent is spin-dried to obtain a yellow solid, and then PE / EA 10:1 is used for pulping to obtain 4250 mg of a yellow solid.

[0416] MS ESI: m / z = 220, [M+1] + .

[0417] Step 2: Preparation of Y-2

[0418] Add Y-1 (4250 mg), diethyl malonate (2.94 ml), ethyl propiolate (1.96 ml) and anhydrous ether (97 ml) to a 250 ml eggplant-shaped bottle under ice bath. Replace the air in the bottle with N2, stir at room temperature for 3 hours, and then add diethyl malonate (0.59 ml) and ethyl propiolate (1.96 ml). After stirring for 4 hours, TLC shows that the reaction is complete, quench with 1N HCl, and extract with EA. After the organic phase is dried and concentrated with anhydrous sodium sulfate, 5.47 g of yellow solid is obtained by rapid silica gel column chromatography.

[0419] MS ESI: m / z = 335, [M+1] + .

[0420] Step 3: Preparation of Y-3

[0421] Add Y-2 (5470 mg), Pd / C (3530 mg, 5%) and MeOH (78 ml) to a 250 ml eggplant-shaped flask. Replace the air in the reaction flask with hydrogen using a hydrogen balloon, and then stir at room temperature under a hydrogen atmosphere. After about 2 hours, TLC shows that the reaction is complete. Filter through diatomaceous earth, and spin dry the organic phase to obtain 5.04 g of a yellow-brown oil.

[0422] MS ESI: m / z = 305, [M+1] + .

[0423] Step 4: Preparation of Y-4

[0424] Add formic acid (3.1ml) and acetic anhydride (1.9ml) to a 10ml eggplant flask and stir at room temperature for about 20min to prepare formic acetic anhydride. Add Y-3 (4900mg) and dichloromethane (16ml) to a 50ml eggplant flask under ice bath, and then drop the formic acetic anhydride prepared in advance. After stirring at room temperature for 3h, add mixed anhydride prepared from 1ml formic acid and 0.6ml acetic anhydride, continue stirring for 2h, and TLC shows that the reaction is over. The solvent and excess acid are removed by spin drying under vacuum, and the obtained green solid is dissolved in 64ml tetrahydrofuran, and a tetrahydrofuran solution of borane dimethyl sulfide complex (16.2ml, 2mol / l in THF) is 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 4870mg of light green oil by rapid silica gel column chromatography.

[0425] MS ESI: m / z = 319, [M+1] + .

[0426] Step 5: Preparation of Y-5

[0427] Y-4 (2000 mg), TFA (10 ml) and toluene (52 ml) were added to 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.

[0428] MS ESI: m / z = 273, [M+1] + .

[0429] Step 6: Preparation of Y-6

[0430] Y-5 (1225 mg), KOH (1010 mg), water (1.6 ml) and MeOH (10.5 ml) were added to a 50 ml eggplant-shaped bottle. After stirring at room temperature for 2.5 h, the reaction was completed, and the reaction solution was adjusted to acidity with 1N HCl, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain 1.2163 g of a khaki solid.

[0431] MS ESI: m / z = 245, [M+1] + .

[0432] Step 7: Preparation of Y-7

[0433] Add Y-6 (500 mg), DPPA (845.3 mg), DIEA (399.6 mg) and toluene (10 ml) to a 50 ml eggplant-shaped bottle. After replacing the air in the bottle with N2, heat and stir at 85°C for 2 h, then add 1.25 N NaOH (10 ml) solution and stir overnight. The reaction solution is first acidified with hydrochloric acid, washed with EA to remove impurities, then alkalized with NaOH solution, extracted with EA, dried and concentrated with anhydrous Na2SO4 to obtain 274.2 mg of light yellow solid.

[0434] MS ESI: m / z = 216, [M+1] + .

[0435] Step 8: Preparation of Y-8

[0436] Add Y-7 (224 mg), BOC2O (340.7 mg), NEt3 (315.1 mg) and THF (5 ml) to a 25 ml eggplant flask. Stir at room temperature for 6 h, spin dry the solvent, add a little EA to the solid to dissolve it, then add PE to precipitate the product, and filter to obtain 285.7 mg of yellow solid. Use a CHIRALPAK IG column and elute with ethanol / n-hexane = 25% to obtain the first peak of S configuration and the second peak of R configuration.

[0437] MS ESI: m / z = 314, [M-1] - .

[0438] Example 21: T-19

[0439] (±)-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

[0440]

[0441] Add 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) to a 10 ml reaction tube. Replace the gas with nitrogen and stir at room temperature overnight. Quench with saturated NaHCO3 solution, extract with EA, spin dry, and purify by flash column chromatography. The crude product was subjected to preparative HPLC (mobile phase: A: H2O (+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.

[0442] 1 H NMR(400MHz,DMSO-d6)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).

[0443] MS ESI: m / z = 401, [M+1] + .

[0444] Example 22: T-20

[0445] (±)-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

[0446]

[0447] Step 1: Preparation of Y-9

[0448] Add Y-8 (29 mg), K2CO3 (15.2 mg) and DMF (1 ml) to a 10 ml reaction tube. Replace the air with nitrogen and stir at room temperature overnight. After adding MeI and K2CO3 several times, the reaction is complete. Add TFA to quench and spin dry to remove the solvent. Add DCM (2 ml) and TFA (0.4 ml) to the solid, stir overnight to remove BOC, spin dry, and use directly in the next step.

[0449] MS ESI: m / z = 230, [M+1] + .

[0450] Step 2: Preparation of T-20

[0451] Using Y-9 as the starting material and the same conditions as in Example 21, 10 mg of a white solid was obtained.

[0452] 1 H NMR (400MHz, DMSO-d6) δ14.59(s,1H),8.71(m,1H),7.43–7.07(m,8H),6.99(d,J=7.5H z,1H),4.57(m,1H),4.16(s,2H),3.78(s,3H),3.47(s,3H),3.22(m,1H),3.01(m,1H).

[0453] MS ESI: m / z = 415, [M+1] + .

[0454] Example 23: T-21

[0455] (±)-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

[0456]

[0457] Step 1: Preparation of Y-10

[0458] Add Y-8 (29 mg), NaH (4.4 mg, 60%) and THF (1 ml) to a 10 ml reaction tube, stir for a few minutes, then add PhSO2Cl (35.52 mg). Stir for 2 h, then add NaH (10 mg). Stir for 1 h, the reaction is over, wash twice with saturated NaHCO3 solution and NH4Cl solution, dry the organic phase with anhydrous Na2SO4, 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, the reaction is over, spin dry to obtain Y-10.

[0459] MS ESI: m / z = 356, [M+1] + .

[0460] Step 2: Preparation of T-21

[0461] Using Y-10 as the starting material and the same conditions as in Example 21, 15.7 mg of a white solid was obtained.

[0462] 1 H NMR(400MHz,DMSO-d6)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).

[0463] MS ESI: m / z = 541, [M+1] + .

[0464] Example 24: T-22

[0465] (±)-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

[0466]

[0467] Step 1: Preparation of Y-11

[0468] Add Y-8 (29 mg), NaH (7.4 mg, 60%) and DMF (1 ml) to a 10 ml reaction tube, stir for a few minutes, and then add bromomethylcyclopropane (14.9 mg). After stirring for 3 hours, the reaction is completed, and the mixture is washed twice with saturated NH4Cl solution. The organic phase is dried with anhydrous Na2SO4 and spin-dried to obtain 44.5 mg of the intermediate. The intermediate is dissolved in DCM (0.9 ml), and TFA (0.3 ml) is added. After stirring at room temperature for 4 hours, the reaction is completed, and Y-11 is spin-dried to obtain the intermediate, which is directly used in the next step.

[0469] MS ESI: m / z = 270, [M+1] + .

[0470] Step 2: Preparation of T-22

[0471] Using Y-11 as the starting material and the same conditions as in Example 21, 17.8 mg of a light yellow solid was obtained.

[0472] 1 H NMR(400MHz, CDCl3)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).

[0473] MS ESI: m / z = 455, [M+1] + .

[0474] Example 25: T-23

[0475] (±)-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

[0476]

[0477] Step 1: Preparation of Y-12

[0478] Add Y-8 (29 mg), cyclopropylboronic acid (9.5 mg), DMAP (33 mg), Cu(AcO)2 (20 mg) and toluene (1 ml) to a 10 ml reaction tube. Replace the air with nitrogen, stir at 100 °C for 19 h, add cyclopropylboronic acid (15 mg) and Cu(AcO)2 (20 mg), continue heating for 17 h, and the reaction is complete. Wash with saturated NaHCO3 solution, dry and concentrate the organic phase with anhydrous Na2SO4, and obtain 20 mg of the intermediate by rapid silica gel column chromatography. The intermediate is dissolved in DCM (0.9 ml), TFA (0.3 ml) is added, and the reaction is completed after stirring at room temperature for 4 h. Y-12 is spin-dried and used directly in the next step.

[0479] MS ESI: m / z = 256, [M + 1] + .

[0480] Step 2: Preparation of T-23

[0481] Using Y-12 as the starting material, 10.8 mg of a white solid was obtained under the same conditions as in Example 21.

[0482] 1 H NMR (400MHz, CDCl3) 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).

[0483] MS ESI: m / z = 441, [M+1] + .

[0484] Example 26: T-24

[0485] (±)-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

[0486]

[0487] Step 1: Preparation of Y-13

[0488] Add Y-8 (29 mg), phenylboronic acid (13.4 mg), DMAP (33 mg), Cu(AcO)2 (20 mg) and toluene (1 ml) to a 10 ml reaction tube. Replace the air with nitrogen, stir at 100 °C for 6 h, add phenylboronic acid (13.4 mg) and Cu(AcO)2 (20 mg), continue heating for 17 h, and the reaction is complete. Wash with saturated NaHCO3 solution, dry and concentrate the organic phase with anhydrous Na2SO4, and obtain 10 mg of the intermediate by rapid silica gel column chromatography. The intermediate is dissolved in DCM (0.9 ml), TFA (0.3 ml) is added, and the reaction is completed after stirring at room temperature for 4 h. Y-13 is obtained by spin drying and used directly in the next step.

[0489] MS ESI: m / z = 292, [M+1] + .

[0490] Step 2: Preparation of T-24

[0491] Using Y-13 as the starting material and the same conditions as in Example 21, 6.2 mg of a white solid was obtained.

[0492] 1 H NMR (400MHz, CDCl3) δ8.78 (d, J=5.7Hz, 1H), 7.51~7..10 (m, 13H), 6.98 (dd, J=15.8 ,6.4Hz,1H),5.02–4.84(m,1H),4.20(s,2H),3.64(s,3H),3.47(m,1H),3.10m,1H).

[0493] MS ESI: m / z = 477, [M+1] + .

[0494] Example 27: T-25

[0495] (±)-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

[0496]

[0497] Step 1: Preparation of Y-14

[0498] Add Y-8 (15 mg), KOH (5.1 mg) and THF (0.5 ml) to a 10 ml reaction tube, stir at room temperature for a few minutes, and then add BrCH2CN (7.2 mg). After stirring for 2 h, about half of the product was converted into the target product, and KOH and BrCH2CN were added until TLC showed that the reaction was complete. Quench with saturated NH4Cl solution, extract with EA, dry and concentrate the organic phase with anhydrous Na2SO4, and obtain 14 mg of the intermediate by rapid silica gel column chromatography. The intermediate was dissolved in DCM (0.9 ml), TFA (0.3 ml) was added, and after stirring at room temperature for 2 h, the reaction was completed, and Y-14 was spin-dried to obtain, which was directly used in the next step.

[0499] MS ESI: m / z = 255, [M + 1] + .

[0500] Step 2: Preparation of T-25

[0501] Using Y-14 as the starting material and the same conditions as in Example 21, 3.9 mg of a white solid was obtained.

[0502] 1 H NMR(400MHz,acetone-d6)δ13.36(s,1H),8.66(d,J=5.0Hz,1H),7.46–7.20(m,8H),7.11(d,J=7.7 Hz,1H),5.55–5.37(m,2H),4.86–4.62(m,1H),4.20(s,2H),3.60(s,3H),3.41m,1H),3.01(m,1H).

[0503] MS ESI: m / z = 440, [M+1] + .

[0504] Example 28: T-26

[0505] (±)-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

[0506]

[0507] Step 1: Preparation of Y-15

[0508] Add Y-8 (30 mg), 1-fluoro-2-iodoethane (62.6 mg), NaH (14.4 mg, 60%) and THF (1 ml) to a 10 ml reaction tube. Replace the air with nitrogen, stir at room temperature for 13 h, add NaH (20 mg), continue stirring for 4 h, and the reaction is complete. Wash with saturated NH4Cl solution, dry and concentrate the organic phase with anhydrous Na2SO4, and obtain 22.5 mg of the intermediate by rapid silica gel column chromatography. Dissolve the intermediate in DCM (2 ml), add TFA (0.5 ml), stir at room temperature for 2 h, and the reaction is complete. Spin dry to obtain Y-15, which is directly used in the next step.

[0509] MS ESI: m / z = 262, [M+1] + .

[0510] Step 2: Preparation of T-26

[0511] Using Y-15 as the starting material and the same conditions as in Example 21, 8.8 mg of a white solid was obtained.

[0512] 1 H NMR (400MHz, CDCl3) 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).

[0513] MS ESI: m / z = 447, [M+1] + .

[0514] Example 29: T-27

[0515] (±)-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

[0516]

[0517] Step 1: Preparation of Y-16

[0518] Add Y-8 (30 mg), 2-bromo-2-methylpropionitrile (140.6 mg), NaH (16 mg, 60%) and THF (2 ml) to 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 completed. Wash with saturated NH4Cl solution, dry and concentrate the organic phase with anhydrous Na2SO4, and then pass through rapid silica gel column chromatography to obtain 21 mg of the intermediate. The intermediate is dissolved in DCM (2 ml), TFA (0.5 ml) is added, and the reaction is completed after stirring at room temperature for 2 h. Y-16 is spin-dried and used directly in the next step.

[0519] MS ESI: m / z = 283, [M+1] + .

[0520] Step 2: Preparation of T-27

[0521] Using Y-16 as the starting material, 4 mg of a white solid was obtained under the same conditions as in Example 21.

[0522] 1 H NMR (400MHz, CDCl3) 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).

[0523] MS ESI: m / z = 468, [M+1] + .

[0524] Example 30: T-28

[0525] (±)-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

[0526]

[0527] Step 1: Preparation of Y-17

[0528] Add Y-8 (30 mg), 2-bromoethyl methyl ether (36 ul), NaH (15.2 mg, 60%) and THF (1 ml) to 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 hours, and the reaction is completed. Wash with saturated NH4Cl solution, wash with saturated NH4Cl solution, dry and concentrate the organic phase with anhydrous Na2SO4, and then pass through rapid silica gel column chromatography to obtain 13 mg of intermediate. Repeat the reaction under similar conditions to obtain a total of 26 mg of intermediate. Dissolve the intermediate in DCM (2 ml), add TFA (0.5 ml), stir at room temperature for 2 hours, and the reaction is completed. Spin dry to obtain Y-17, which is directly used in the next step.

[0529] MS ESI: m / z = 274, [M+1] + .

[0530] Step 2: Preparation of T-28

[0531] Using Y-17 as the starting material, 5 mg of a white solid was obtained under the same conditions as in Example 21.

[0532] 1 H NMR (400MHz, CDCl3) 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).

[0533] MS ESI: m / z = 459, [M+1] + .

[0534] Example 31: T-29

[0535] (±)-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

[0536]

[0537] Step 1: Preparation of Y-18

[0538] Add Y-8 (63 mg), NaH (32 mg, 60%) and THF (1 ml) to a 10 ml reaction tube, replace the air with nitrogen, stir for a few minutes, add 2-bromoacetic acid methyl ester (306 mg), stir at room temperature overnight, and the reaction is completed. Wash with saturated NH4Cl solution, dry and concentrate the organic phase with anhydrous Na2SO4, and then obtain 51 mg of the intermediate by rapid silica gel column chromatography. The intermediate is dissolved in DCM (2 ml), TFA (0.5 ml) is added, and the reaction is completed after stirring at room temperature for 2 hours. Y-18 is obtained by spin drying and used directly in the next step.

[0539] MS ESI: m / z = 288, [M+1] + .

[0540] Step 2: Preparation of T-29

[0541] Using Y-18 as the starting material, 30 mg of a white solid was obtained under the same conditions as in Example 21.

[0542] 1 H NMR (400MHz, CDCl3) 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),4.8 5(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).

[0543] MS ESI: m / z = 473, [M+1] + .

[0544] Example 32: T-30

[0545] (±)-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

[0546]

[0547] T-29 (8 mg), KOH (4.9 mg), MeOH (0.5 ml), and water (0.1 ml) were added to a 2 ml vial, stirred at room temperature for about 18 h, acidified with diluted HCl, and dried by spin drying. The mixture was subjected to preparative HPLC (mobile phase: A: H2O (+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.

[0548] 1 H NMR(400MHz,DMSO-d6)δ14.49(s,1H),8.68(s,1H),7.40–7.13(m,8H),6.99(d,J=7.2Hz,1H) ,4.95(s,2H),4.69–4.52(m,1H),4.13(s,2H),3.50(s,3H),3.22(m,1H),3.11–2.93(m,1H).

[0549] MS ESI: m / z = 459, [M+1] + .

[0550] Example 33: T-31

[0551] (±)-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

[0552]

[0553] 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 spin-dried. The mixture was subjected to preparative HPLC (mobile phase: A: H2O (+0.1% TFA); B: MeCN; separation conditions: 50% B; flow rate: 18 mL / min; column: Waters Prep MSC18, 19×250mm, 10μm) was purified and freeze-dried to obtain 3 mg of white solid.

[0554] 1H NMR (400MHz, DMSO-d6) 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).

[0555] MS ESI: m / z = 458, [M+1] + .

[0556] Example 34: T-32

[0557] (±)-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

[0558]

[0559] Step 1: Preparation of Y-20

[0560]

[0561] Y-19 (32 mg), THF (1 ml), and HCl (1 ml, 6N) were added to a 10 ml reaction tube and stirred at room temperature overnight. LC-MS showed that the raw material had been completely converted into the product, which was directly spin-dried for the next step.

[0562] MS ESI: m / z = 307, [M+1] + .

[0563] Step 2: Preparation of Y-21

[0564]

[0565] Add Y-7 (18 mg), Y-20 (30 mg), 2-methylpyridine-N-borane (11.1 mg), MeOH (1 ml) and TFA (0.1 ml) to a 10 ml reaction tube, replace the air with nitrogen, stir at room temperature for about 1 day, and the reaction is completed. Quench with saturated NH4Cl solution, extract with EA, dry and concentrate the organic phase with anhydrous Na2SO4, and then chromatograph by rapid silica gel column to obtain 22 mg of the intermediate. The intermediate is dissolved in MeOH (1 ml) and water (0.5 ml), KOH (100 mg) is added, stirred at room temperature overnight, quench the reaction with 1N HCl, extract with EA, and spin dry to obtain 20 mg of solid Y-21.

[0566] MS ESI: m / z = 478, [M+1] + .

[0567] Step 3: Preparation of T-32

[0568] 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. The product was quenched with NH4Cl saturated solution, extracted and concentrated with EA, and then subjected to preparative HPLC (mobile phase: A: H2O (+0.1% TFA); B: MeCN; separation conditions: 50% B; flow rate: 18 mL / min; chromatographic column: Waters PrepMSC18, 19×250mm, 10μm) was purified and freeze-dried to obtain 6 mg of white solid.

[0569] 1 H NMR(400MHz,acetone-d6)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).

[0570] MS ESI: m / z = 460, [M+1] + .

[0571] Example 35: T-33

[0572] (±)-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

[0573]

[0574] Step 1: Preparation of Y-22

[0575] 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. Wash with saturated NH4Cl solution, dry and concentrate the organic phase with anhydrous Na2SO4, and obtain 19.6 mg of the intermediate by rapid silica gel column chromatography. The intermediate is dissolved in DCM (2 ml), TFA (0.5 ml) is added, and after stirring at room temperature for 2 hours, the reaction is terminated, and Y-22 is obtained by spin drying and used directly in the next step.

[0576] MS ESI: m / z = 260, [M+1] + .

[0577] Step 2: Preparation of T-33

[0578] Using Y-22 as the starting material, 2.4 mg of a white solid was obtained under the same conditions as in Example 21.

[0579] 1 H NMR (400MHz, CDCl3) 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).

[0580] MS ESI: m / z = 445, [M+1] + .

[0581] Example 36: T-34

[0582] (±)-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

[0583]

[0584] Step 1: Preparation of Y-23

[0585] 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), K3PO4 (64 mg) and DMSO (1 ml) to a 10 ml reaction tube, replace the air with nitrogen, and stir overnight at 90 ° C. Wash with saturated NH4Cl solution, dry and concentrate the organic phase with anhydrous Na2SO4, and then obtain 25.4 mg of the intermediate by rapid silica gel column chromatography. The intermediate is dissolved in DCM (2 ml), TFA (0.5 ml) is added, and after stirring at room temperature for 2 h, the reaction is completed, and Y-23 is obtained by spin drying and used directly in the next step.

[0586] MS ESI: m / z = 296, [M+1] + .

[0587] Step 2: Preparation of T-34

[0588] Using Y-23 as the starting material, 4 mg of a white solid was obtained under the same conditions as in Example 21.

[0589] 1 H NMR (400MHz, DMSO-d6) 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).

[0590] MS ESI: m / z = 481, [M+1] + .

[0591] Example 37: T-35

[0592] (±)-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

[0593]

[0594] Step 1: Preparation of Y-24

[0595] 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide (29.3mg), KOH (16mg) and DMF (2ml) were added to a 10ml reaction tube, and after stirring at room temperature for a few minutes, Y-8 (30mg) was added. The air was replaced with nitrogen, and after stirring at room temperature for 20h, 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide (29mg) was added. After stirring at room temperature overnight, saturated NH4Cl solution was quenched, EA was extracted, and the organic phase was dried and concentrated with anhydrous Na2SO4, and then 15mg of the intermediate was obtained by rapid silica gel column chromatography. The intermediate was dissolved in DCM (2ml), TFA (0.5ml) was added, and after stirring at room temperature for 2h, the reaction was terminated, and Y-24 was spin-dried to obtain, which was directly used in the next step.

[0596] MS ESI: m / z = 310, [M+1] + .

[0597] Step 2: Preparation of T-35

[0598] Using Y-24 as the starting material and the same conditions as in Example 21, 18 mg of a white solid was obtained.

[0599] 1 H NMR (400MHz, CDCl3) 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).

[0600] MS ESI: m / z = 495, [M+1] + .

[0601] Example 38: T-36

[0602] (±)-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

[0603]

[0604] Step 1: Preparation of Y-25

[0605] Using Y-8 (100 mg) and 5-iodo-1-methyl-1H-pyrazole as raw materials, 22 mg of solid Y-25 was prepared under the same conditions as in the first step of Example 36.

[0606] MS ESI: m / z = 296, [M+1] + .

[0607] Step 2: Preparation of T-36

[0608] Using Y-25 as the starting material, 10 mg of a white solid was obtained under the same conditions as in Example 21.

[0609] 1H NMR (400MHz, CDCl3) 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).

[0610] MS ESI: m / z = 481, [M+1] + .

[0611] Example 39: T-37

[0612] (±)-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

[0613]

[0614] Step 1: Preparation of Y-26

[0615] Using Y-8 (100 mg) and 3-iodo-1-methyl-1H-pyrazole as raw materials, 13 mg of solid Y-26 was prepared under the same conditions as the first step of Example 36.

[0616] MS ESI: m / z = 296, [M+1] + .

[0617] Step 2: Preparation of T-37

[0618] Using Y-26 as the starting material and the same conditions as in Example 21, 7.3 mg of a light yellow solid was obtained.

[0619] 1 H NMR (400MHz, CDCl3) 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).

[0620] MS ESI: m / z = 481, [M+1] + .

[0621] Example 40: T-38

[0622] (±)-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

[0623]

[0624] Step 1: Preparation of Y-27

[0625] Using Y-8 (50 mg) and 4-(2-bromoethyl)morpholine hydrobromide (48 mg) as raw materials, 52 mg of solid Y-27 was prepared under the same conditions as in the first step of Example 37.

[0626] MS ESI: m / z = 329, [M+1] + .

[0627] Step 2: Preparation of T-38

[0628] 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) to a 10 ml reaction tube. Replace the gas with nitrogen and stir at room temperature for 5 h. Quench with saturated NH4Cl solution, extract with EA, spin dry, and purify initially by rapid silica gel column chromatography. Then, perform preparative HPLC (mobile phase: A: H2O (+0.1% TFA); B: MeCN; separation conditions: 60% B; flow rate: 18 mL / min; chromatographic column: Waters PrepMSC18, 19×250mm, 10μm) was purified and freeze-dried to obtain 20mg of white solid.

[0629] 1 H NMR(400MHz, CDCl3)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).

[0630] MS ESI: m / z = 514, [M+1] + .

[0631] Example 41: T-39

[0632] (±)-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

[0633]

[0634] Step 1: Preparation of Y-28

[0635] Add Y-8 (50 mg), DCM (2 ml), pivaloyl chloride (100 ul), DMAP (12.5 mg), triethylamine (144 ul) to a 10 ml reaction tube. Stir at room temperature overnight, then quench with NaHCO3, extract with EA. The organic phase is dried and concentrated with anhydrous Na2SO4, and then 64 mg of oily intermediate is obtained by rapid silica gel column chromatography. Take 24 mg of the intermediate and dissolve it in DCM (2 ml), then add BBr3 (0.12 ml, 1N), stir at room temperature for 5 h, then quench with NaHCO3, extract with EA, and dry and concentrate the organic phase with anhydrous Na2SO4 to obtain Y-28.

[0636] MS ESI: m / z = 300, [M + 1] + .

[0637] Step 2: Preparation of T-39

[0638] Using Y-28 as the starting material, 3 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0639] 1H NMR (400MHz, CDCl3) δ8.70(d,J=6.6Hz,1H),8.36(d,J=8.0Hz,1H),7.56(s1H),7.39(t,J=8.2H z,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).

[0640] MS ESI: m / z = 485, [M+1] + .

[0641] Example 42: T-40

[0642] (±)-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

[0643]

[0644] Step 1: Preparation of Y-29

[0645] 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), K3PO4 (101.9 mg) and toluene (2 ml) to a 10 ml reaction tube, replace the air with nitrogen, and stir at 110 ° C for 21 h. Wash with saturated NH4Cl solution, dry and concentrate the organic phase with anhydrous Na2SO4, and then obtain 13.1 mg of the intermediate by rapid silica gel column chromatography. The intermediate is dissolved in DCM (2 ml), TFA (0.5 ml) is added, and after stirring at room temperature for 2 h, the reaction is completed, and Y-29 is obtained by spin drying and used directly in the next step.

[0646] MS ESI: m / z = 361, [M+1] + .

[0647] Step 2: Preparation of T-40

[0648] Using Y-29 as the starting material, 6 mg of a light yellow solid was obtained under the same conditions as in the second step of Example 40.

[0649] 1H NMR (400MHz, CDCl3) 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).

[0650] MS ESI: m / z = 546, [M+1] + .

[0651] Example 43: T-41

[0652] (±)-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

[0653]

[0654] Step 1: Preparation of Y-30

[0655] 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.

[0656] MS ESI: m / z = 323, [M+1] + .

[0657] Step 2: Preparation of T-41

[0658] Using Y-30 as the starting material, 8 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0659] 1H NMR (400MHz, Acetone-d6) δ8.55(m,1H),8.07–8.03(m,1H),7.61(d,J=8.3Hz,1H),7.49(s,1H),7.35(d,J=8.0Hz,1H),7.31(dd,J=8.3,4.7Hz, 1H),7.28–7.17(m,4H),7.14(m2H),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).

[0660] MS ESI: m / z = 508, [M+1] + .

[0661] Example 44: T-42

[0662] (±)-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

[0663]

[0664] Step 1: Preparation of Y-31

[0665] Using Y-8 (100 mg) and 3-bromo-4-(methoxymethyl)pyridine as raw materials, 100 mg of solid Y-31 was prepared under the same conditions as in the first step of Example 43.

[0666] MS ESI: m / z = 337, [M+1] + .

[0667] Step 2: Preparation of T-42

[0668] Using Y-31 as the starting material, 40 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0669] 1H NMR (400MHz, Acetone-d6) 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),7.1 2(d,J=7.8Hz,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).

[0670] MS ESI: m / z = 522, [M+1] + .

[0671] Example 45: T-43

[0672] (±)-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

[0673]

[0674] Step 1: Preparation of Y-32

[0675] Using Y-8 (50 mg) and 2-bromonicotinoic acid methyl ester as raw materials, 56 mg of solid Y-32 was prepared under the same conditions as in the first step of Example 43.

[0676] MS ESI: m / z = 351, [M+1] + .

[0677] Step 2: Preparation of T-43

[0678] Using Y-32 as the starting material, 30 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0679] 1H 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).

[0680] MS ESI: m / z = 536, [M+1] + .

[0681] Example 46: T-44

[0682] (±)-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

[0683]

[0684] Step 1: Preparation of Y-33

[0685] Using Y-8 (50 mg) and 2-bromo-3-methylpyridine as raw materials, 46.3 mg of solid Y-33 was prepared under the same conditions as in the first step of Example 43.

[0686] MS ESI: m / z = 307, [M+1] + .

[0687] Step 2: Preparation of T-44

[0688] Using Y-33 as the starting material, 52.9 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0689] 1H NMR (400MHz, Acetone-d6) 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).

[0690] MS ESI: m / z = 492, [M+1] + .

[0691] Example 47: T-45

[0692] (±)-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

[0693]

[0694] Step 1: Preparation of S-1

[0695] Add methyl 6-bromo-4-indolecarboxylate (25 g), KOH (22.05 g), water (28 ml) and MeOH (169 ml) to a 500 ml round-bottom flask. Stir at room temperature for 3 h, and the reaction is complete. Use dilute hydrochloric acid to adjust the pH to about 2, and a large amount of solid precipitates. Use a Buchner funnel to filter, and the filter cake is dried in a vacuum oven. The filtrate is extracted with EA, dried over anhydrous Na2SO4, and spin-dried to obtain a total of 23 g of light red solid.

[0696] MS ESI: m / z = 238, [M-1] - .

[0697] Step 2: Preparation of S-2

[0698] 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 to end the reaction. Remove part of the solvent, then add EA, wash with water, dry and concentrate the organic phase with anhydrous Na2SO4, and obtain 3.65 g of khaki solid by rapid silica gel column chromatography.

[0699] MS ESI: m / z = 239, [M+1] + .

[0700] Step 3: Preparation of S-3

[0701] S-2 (3.65 g), dimethylamine (8.4 ml 2N in THF), HCHO (1.36 ml, 37% aqueous solution), ZnCl2 (3122.6 mg) and MeOH (76 ml) were added to a 250 ml eggplant-shaped bottle. The mixture was stirred at room temperature overnight, and NaOH (2N) was added to adjust the pH to alkaline. The mixture was filtered, and the filtrate was extracted with EA, then dried over anhydrous Na2SO4, and 1676 mg of a yellowish brown solid was obtained by spin drying.

[0702] MS ESI: m / z = 296, [M+1] + .

[0703] Step 4: Preparation of S-4

[0704] 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.

[0705] MS ESI: m / z = 384, [M+1] + .

[0706] Step 5: Preparation of S-5

[0707] 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, and NH4Cl saturated solution was added to quench, EA was extracted, and the organic phase was dried and concentrated with anhydrous Na2SO4 and then flash silica gel column chromatography was performed to obtain 330 mg of solid.

[0708] MS ESI: m / z = 370, [M+1] + .

[0709] Step 6: Preparation of S-6

[0710] S-5 (330 mg), zinc powder (1169 mg), AcOH (4 ml) and THF (4 ml) were added to a 10 ml eggplant-shaped bottle. After stirring at room temperature for 12 h, LC-MS showed that the reaction was complete. EA was added to the reaction solution for dilution, then filtered, and the filtrate was washed with a saturated NaHCO3 solution. The organic phase was dried and concentrated with anhydrous Na2SO4 to obtain 120 mg of a solid intermediate. The intermediate was dissolved in THF (4 ml), and then (Boc)2O (85.1 mg) and TEA (54 ul) were added. Stir at room temperature for about 6 h, and the reaction was completed. After the organic phase was concentrated, 130 mg of a solid was obtained by rapid silica gel column chromatography.

[0711] MS ESI: m / z = 440, [M+1] + .

[0712] Step 7: Preparation of S-7

[0713] 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 dried over Na2SO4 and spin-dried to obtain 121 mg of solid.

[0714] MS ESI: m / z = 412, [M+1] + .

[0715] Step 8: Preparation of S-8

[0716] S-7 (125 mg) was dissolved in MeCN (3 ml) under ice bath, then TCFH (102 mg) and NMI (36 ul) were added, and after stirring at room temperature for 2 h, TCFH (10 mg) and NMI (5 ul) were added, and after stirring for 3 h, the reaction was terminated. A saturated solution of NH4Cl was added to quench, and EA was extracted. The organic phase was dried and concentrated with anhydrous Na2SO4, and then flash silica gel column chromatography was performed to obtain 66 mg of a white solid.

[0717] MS ESI: m / z = 392, [M-1] - .

[0718] Step 9: Preparation of S-9

[0719] 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, heated at 110 ° C for 3 days, quenched by adding NH4Cl saturated solution, extracted with EA, and the organic phase was dried and concentrated with anhydrous Na2SO4, and then 53 mg of white solid was obtained by rapid silica gel column chromatography, in which the ratio of raw materials to products was about 1:1. The mixture was dissolved in DCM (2 ml), and then CF3COOH (0.4 ml) was added, stirred at room temperature for about 3 h, the reaction was completed, and 38 mg of the mixture was spin-dried to obtain, which was directly used in the next step.

[0720] MS ESI: m / z = 342, [M+1] + .

[0721] Step 10: Preparation of S-10

[0722] S-9 (38 mg, including bromide), N-methyl-4-alkynylpyrazole (14 mg), Pd(PPh)3Cl2 (8.4 mg), CuI (2.3 mg), NEt3 (1 ml) and DMF (1 ml) were added to a 10 ml reaction tube. The air was replaced with nitrogen and heated at 70 ° C for 2 h to complete the reaction. A saturated solution of NH4Cl was added to quench the reaction, and EA was extracted. The organic phase was dried and concentrated with anhydrous Na2SO4 and then subjected to rapid silica gel column chromatography to obtain 22.4 mg of solid (containing a small amount of bromide).

[0723] MS ESI: m / z = 320, [M+1] + .

[0724] Step 11: Preparation of T-45

[0725] Using S-10 as the starting material, 2 mg of a white solid was obtained under the same conditions as in Example 21.

[0726] 1 H NMR(400MHz,DMSO-d6)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).

[0727] MS ESI: m / z = 505, [M+1] + .

[0728] Example 48: T-46

[0729] (±)-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

[0730]

[0731] Using T-43 (10 mg) as raw material, 3.2 mg of white solid was prepared under the same conditions as in Example 32.

[0732] 1 H NMR (400MHz, Acetone-d6) 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).

[0733] MS ESI: m / z = 522, [M+1] + .

[0734] Example 49: T-47

[0735] (±)-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

[0736]

[0737] Step 1: Preparation of Y-34

[0738] Using Y-8 (30 mg) and 2-bromo-3-(methoxymethoxy)pyridine as raw materials, 28.6 mg of solid Y-34 was prepared under the same conditions as in the first step of Example 43.

[0739] MS ESI: m / z = 309, [M+1] + .

[0740] Step 2: Preparation of T-47

[0741] Using Y-34 as the starting material, 6.9 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0742] 1 H NMR (400MHz, Acetone-d6) 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).

[0743] MS ESI: m / z = 494, [M+1] + .

[0744] Example 50: T-48

[0745] (±)-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

[0746]

[0747] Step 1: Preparation of Y-35

[0748] Y-8 (30 mg) and (3-bromopyridin-4-yl)methanol were used as starting materials to obtain 21 mg of solid Y-35 using the same conditions as the first step of Example 43. This Ullmann reaction requires a longer reaction time.

[0749] MS ESI: m / z = 323, [M+1] + .

[0750] Step 2: Preparation of T-48

[0751] When Y-35 was used as the raw material and the product was prepared under the same conditions as in the second step of Example 40, the amino and hydroxyl groups on Y-35 reacted with triazolecarboxylic acid. Therefore, the product was extracted and the ester was hydrolyzed by lithium hydroxide monohydrate (20 mg), MeOH (2 ml), and water (0.3 ml). Then, it was purified under the same conditions as in the second step of Example 40 to obtain 6.7 mg of a white solid.

[0752] 1H NMR (400MHz, Acetone-d6) 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).

[0753] MS ESI: m / z = 508, [M+1] + .

[0754] Example 51: T-49

[0755] (±)-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

[0756]

[0757] Step 1: Preparation of Y-36

[0758] Y-8 (30 mg) and (2-bromopyridin-3-yl)methanol were used as starting materials to obtain 24 mg of solid Y-36 using the same conditions as the first step of Example 43. The Ullmann reaction also required a longer reaction time.

[0759] MS ESI: m / z = 323, [M+1] + .

[0760] Step 2: Preparation of T-49

[0761] Using Y-36 as the starting material, 5.3 mg of a white solid was obtained under the same conditions as in Example 21.

[0762] 1 H NMR (400MHz, Acetone-d6) 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),7.11(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).

[0763] MS ESI: m / z = 508, [M+1] + .

[0764] Example 52: T-50

[0765] (±)-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

[0766]

[0767] Step 1: Preparation of Y-37

[0768] Using Y-8 (50 mg) and 3-bromopyrazine-2-carboxylic acid methyl ester as raw materials, 58.3 mg of solid Y-37 was prepared under the same conditions as in the first step of Example 43.

[0769] MS ESI: m / z = 352, [M+1] + .

[0770] Step 2: Preparation of T-50

[0771] Using Y-37 as the starting material, 53.6 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0772] 1 H NMR (400MHz, DMSO-d6) 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) ,7.38–7.22(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).

[0773] MS ESI: m / z = 537, [M+1] + .

[0774] Example 53: T-51

[0775] (±)-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

[0776]

[0777] Step 1: Preparation of Y-38

[0778] 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.

[0779] MS ESI: m / z = 352, [M+1] + .

[0780] Step 2: Preparation of T-51

[0781] Using Y-38 as the starting material, 19 mg of a light yellow solid was obtained under the same conditions as in the second step of Example 40.

[0782] 1 H NMR(400MHz,acetone-d6)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).

[0783] MS ESI: m / z = 537, [M+1] + .

[0784] Example 54: T-52

[0785] (±)-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

[0786]

[0787] Step 1: Preparation of Y-39

[0788] Using Y-8 (50 mg) and 2-bromo-3-cyclopropylpyridine as raw materials, 57.6 mg of solid Y-39 was prepared under the same conditions as in the first step of Example 43.

[0789] MS ESI: m / z = 333, [M+1] + .

[0790] Step 2: Preparation of T-52

[0791] Using Y-39 as the starting material, 56 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0792] 1 H NMR (400MHz, acetone-d6) 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,8 H),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).

[0793] MS ESI: m / z = 518, [M+1] + .

[0794] Example 55: T-53

[0795] (±)-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

[0796]

[0797] Step 1: Preparation of Y-40

[0798] Using Y-8 (50 mg) and 2-bromo-3-(difluoromethyl)pyridine as raw materials, 58 mg of solid Y-40 was prepared under the same conditions as in the first step of Example 43.

[0799] MS ESI: m / z = 343, [M+1] + .

[0800] Step 2: Preparation of T-53

[0801] Using Y-40 as the raw material, 80 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0802] 1H NMR(400MHz,acetone-d6)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).

[0803] MS ESI: m / z = 528, [M+1] + .

[0804] Example 56: T-54

[0805] (±)-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

[0806]

[0807] Step 1: Preparation of Y-41

[0808] 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.

[0809] MS ESI: m / z = 325, [M+1] + .

[0810] Step 2: Preparation of T-54

[0811] Using Y-41 as the starting material, 73 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0812] 1 H NMR(400MHz,acetone-d6)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,7 H),7.14(m,1H),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).

[0813] MS ESI: m / z = 510, [M+1] + .

[0814] Example 57: T-55

[0815] (±)-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

[0816]

[0817] Step 1: Preparation of Y-43

[0818] Y-42 (30 mg) and THF (1 ml) were added to a 10 ml reaction tube, and MeMgBr (0.07 ml, 3 M in THF) was added under an ice bath. After stirring at room temperature for 1 h, MeMgBr (0.2 ml, 3 M in THF) was added, and the reaction was terminated after stirring for 2 h. The reaction solution was quenched with a saturated solution of NH4Cl and then extracted with EA. The organic phase was spin-dried to obtain 22 mg of crude product. The crude product was dissolved in DCM (2 ml), and then Me3SiCl was added. After stirring at room temperature for about 1 h, it was quenched with a saturated solution of NH4Cl and then extracted with EA. The organic phase was dried over anhydrous Na2SO4 and spin-dried to obtain 17 mg of Y-43, which was used directly in the next step.

[0819] MS ESI: m / z = 351, [M+1] + .

[0820] Step 2: Preparation of T-55

[0821] Using Y-43 as the starting material, 7 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0822] 1H NMR (400MHz, acetone-d6) 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),4.1 7(s,2H),3.59(m,1H),3.43(s,3H),2.62(m,1H),1.70(s,3H),1.52(s,3H).

[0823] MS ESI: m / z = 536, [M+1] + .

[0824] Example 58: Intermediate Y-45

[0825]

[0826] Y-44 (40 mg), KOH (37.3 mg), MeOH (1 ml) and water (0.2 ml) were added to a 10 ml reaction tube. After stirring at room temperature overnight, a saturated solution of NH4Cl was added to dilute the mixture. The pH was then adjusted to acidic with 2N HCl. The mixture was then extracted with EA and dried to give 58 mg of Y-45.

[0827] MS ESI: m / z = 435, [M-1] - .

[0828] Example 59: T-56

[0829] (±)-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

[0830]

[0831] Step 1: Preparation of Y-46

[0832] Using Y-45 (32 mg) and methylamine hydrochloride as raw materials, 26.4 mg of solid Y-46 was prepared under the same conditions as in the second step of Example 40.

[0833] MS ESI: m / z = 350, [M+1] + .

[0834] Step 2: Preparation of T-56

[0835] 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.

[0836] 1 H NMR (400MHz, acetone-d6) 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,1 H),7.39–7.19(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).

[0837] MS ESI: m / z = 535, [M+1] + .

[0838] Example 60: T-57

[0839] (±)-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

[0840]

[0841] Step 1: Preparation of Y-47

[0842] Using Y-45 (26 mg) and dimethylamine as raw materials, 13.3 mg of solid Y-47 was prepared under the same conditions as in the second step of Example 40.

[0843] MS ESI: m / z = 364, [M+1] + .

[0844] Step 2: Preparation of T-57

[0845] 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.

[0846] 1H NMR (400MHz, DMSO-d6) 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),7.40–7.2 0(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).

[0847] MS ESI: m / z = 549, [M+1] + .

[0848] Example 61: T-58

[0849] (±)-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

[0850]

[0851] Step 1: Preparation of Y-48

[0852] Use Y-8 (50 mg) and 1-(2-bromopyridin-3-yl)ethane-1-ol as raw materials and use the same conditions as the first step of Example 43 to obtain solid Y-48. Since the reaction is not completely purified, the next step is charged according to the theoretical yield.

[0853] MS ESI: m / z = 325, [M+1] + .

[0854] Step 2: Preparation of T-58

[0855] Using Y-48 as the starting material and the same conditions as in Example 21, 10.4 mg of a white solid was obtained.

[0856] 1H NMR(400MHz,acetone-d6)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).

[0857] MS ESI: m / z = 522, [M+1] + .

[0858] Example 62: T-59

[0859] (±)-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

[0860]

[0861] Step 1: Preparation of Y-49

[0862] 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 prepared under the same conditions as in the first step of Example 43.

[0863] MS ESI: m / z = 335, [M+1] + .

[0864] Step 2: Preparation of T-59

[0865] 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.

[0866] 1H NMR (400MHz, DMSO-d6) 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),7.4 7(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).

[0867] MS ESI: m / z = 520, [M+1] + .

[0868] Example 63: T-60

[0869] (±)-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

[0870]

[0871] Step 1: Preparation of Y-50

[0872] Using Y-29 (50 mg) as the starting material, 31.5 mg of solid Y-50 was prepared under the same conditions as in the second step of Example 34.

[0873] MS ESI: m / z = 623, [M+1] + .

[0874] Step 2: Preparation of T-60

[0875] Using Y-50 as the starting material, 20 mg of a white solid was obtained under the same conditions as in the third step of Example 34.

[0876] 1H NMR (400MHz, Acetone-d6) 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),5.44(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).

[0877] MS ESI: m / z = 605, [M+1] + .

[0878] Example 64: T-61

[0879] (±)-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

[0880]

[0881] T-51 (30 mg) and ammonia methanol solution (2 ml, 7N) were added to a 2 ml vial, stirred at 50 °C for about 3 days, and then dried by spin drying. The mixture was subjected to preparative HPLC (mobile phase: A: H2O (+0.1% TFA); B: MeCN; separation conditions: 50% B; flow rate: 18 mL / min; column: Waters Prep MSC18, 19×250 mm, 10 μm) was purified and freeze-dried to obtain 23 mg of white solid.

[0882] 1 H NMR (400MHz, Acetone-d6) 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).

[0883] MS ESI: m / z = 521, [M+1]+ .

[0884] Example 65: T-62

[0885] (±)-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

[0886]

[0887] Step 1: Preparation of Y-51

[0888] Using Y-8 (30 mg) and 2-bromo-3-chloropyridine as raw materials, 25 mg of solid Y-51 was prepared under the same conditions as in the first step of Example 43.

[0889] MS ESI: m / z = 327, [M+1] + .

[0890] Step 2: Preparation of T-62

[0891] Using Y-51 as the starting material, 38 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0892] 1 H NMR(400MHz,acetone-d6)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=4.7Hz,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).

[0893] MS ESI: m / z = 512, [M+1] + .

[0894] Example 66: T-63

[0895] (±)-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

[0896]

[0897] Using Y-29 (23.5 mg) and freshly prepared Y-52 as starting materials, 17 mg of a white solid was obtained using the same conditions as in the second step of Example 40.

[0898] 1 H NMR (400MHz, Acetone-d6) 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,1 H),7.40–7.21(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).

[0899] MS ESI: m / z = 546, [M+1] + .

[0900] Example 67: T-64

[0901] (±)-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

[0902]

[0903] Step 1: Preparation of Y-53

[0904] Using Y-8 (30 mg) and 2-bromo-3-methoxy-6-methylpyridine as raw materials, 31 mg of solid Y-53 was prepared under the same conditions as in the first step of Example 43.

[0905] MS ESI: m / z = 337, [M+1] + .

[0906] Step 2: Preparation of T-64

[0907] Using Y-53 as the starting material, 38 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0908] 1H NMR (400MHz, acetone-d6) 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).

[0909] MS ESI: m / z = 522, [M+1] + .

[0910] Example 68: T-65

[0911] (±)-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

[0912]

[0913] Step 1: Preparation of Y-54

[0914] Using Y-8 (30 mg) and 2-bromo-3-isopropylpyridine as raw materials, 30 mg of solid Y-54 was prepared under the same conditions as in the first step of Example 43.

[0915] MS ESI: m / z = 335, [M+1] + .

[0916] Step 2: Preparation of T-65

[0917] Using Y-54 as the starting material, 41 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0918] 1H NMR(400MHz,acetone-d6)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).

[0919] MS ESI: m / z = 520, [M+1] + .

[0920] Example 69: T-66

[0921] (±)-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

[0922]

[0923] Step 1: Preparation of Y-55

[0924] 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, a saturated solution of NH4Cl was added to quench the mixture, and then extracted with EA. The organic phase was spin-dried and 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 spin-dried to obtain 23.7 mg of solid Y-55.

[0925] MS ESI: m / z = 377, [M+1] + .

[0926] Step 2: Preparation of T-66

[0927] Using Y-55 as the starting material, 16.6 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0928] 1H NMR(400MHz,acetone-d6)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).

[0929] MS ESI: m / z = 562, [M+1] + .

[0930] Example 70: T-67

[0931] (±)-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

[0932]

[0933] Step 1: Preparation of Y-56

[0934] Using Y-8 (30 mg) and 2-bromo-3-ethoxypyridine as raw materials, 26.2 mg of solid Y-56 was prepared under the same conditions as in the first step of Example 43.

[0935] MS ESI: m / z = 337, [M+1] + .

[0936] Step 2: Preparation of T-67

[0937] Using Y-56 as the starting material, 21.8 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0938] 1H NMR (400MHz, acetone-d6) 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).

[0939] MS ESI: m / z = 522, [M+1] + .

[0940] Example 71: T-68

[0941] (±)-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

[0942]

[0943] Step 1: Preparation of Y-57

[0944] Using Y-8 (30 mg) and 2-bromo-3-(methylsulfonyl)pyridine as raw materials, 15.7 mg of solid Y-57 was prepared under the same conditions as in the first step of Example 43.

[0945] MS ESI: m / z = 371, [M+1] + .

[0946] Step 2: Preparation of T-68

[0947] Using Y-57 as the starting material, 21.6 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0948] 1H NMR (400MHz, acetone-d6) 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,6H),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).

[0949] MS ESI: m / z = 556, [M+1] + .

[0950] Example 72: T-69

[0951] (±)-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

[0952]

[0953] Step 1: Preparation of Y-58

[0954] Using Y-8 (30 mg) and 2-bromopyridine as raw materials, 26 mg of solid Y-58 was prepared under the same conditions as in the first step of Example 43.

[0955] MS ESI: m / z = 293, [M+1] + .

[0956] Step 2: Preparation of T-69

[0957] Using Y-58 as the starting material, 30.4 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[0958] 1 H NMR (400MHz, acetone-d6) 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=8.3 Hz,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).

[0959] MS ESI: m / z = 478, [M+1] + .

[0960] Example 73: T-70

[0961] (±)-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

[0962]

[0963] 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.

[0964] 1 H NMR (400MHz, acetone-d6) 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=8.0H z,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).

[0965] MS ESI: m / z = 558, [M+1] + .

[0966] Example 74: Preparation of Intermediate R-7

[0967]

[0968] Step 1: Preparation of R-1

[0969] 4-nitro-indole (11 g) and pyridine (150 ml) were added to a 500 ml reaction bottle, and then pyridinium tribromide was dissolved in pyridine (50 ml) and added to the reaction bottle under ice bath. After stirring at room temperature overnight, the reaction was completed. After removing part of the solvent, water and EA were added to extract the product. The organic phase was subjected to rapid silica gel column chromatography to obtain 15.62 g of yellow solid R-1.

[0970] MS ESI: m / z = 241, [M+1] + .

[0971] Step 2: Preparation of R-2

[0972] R-1 (15.62 g), (Boc)2O (15.5 g), DMAP (0.79 g) and THF (100 ml) were added to a 250 ml reaction bottle. The mixture was stirred at room temperature for 2 h. The reaction was completed. The reaction solution was spin-dried and 21.23 g of yellow solid R-2 was obtained by rapid silica gel column chromatography.

[0973] Step 3: Preparation of R-3

[0974] 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 it to a 500ml reaction bottle containing R-2 (22.72g), Pd(OAc)2 (1.50g) and Sphos (2.74mg). After stirring at 35℃ for 3h, the reaction is completed. Add NH4Cl solution to quench the reaction and extract with EA. The organic phase was spin-dried and purified by flash silica gel column chromatography to obtain 10.21 g of yellow solid R-3.

[0975] MS ESI: m / z = 364, [(M-Boc) + 1] + .

[0976] Step 4: Preparation of R-4

[0977] 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. The mixture was stirred at room temperature overnight under H2 atmosphere, then filtered through diatomaceous earth, dried by spin drying, 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.

[0978] MS ESI: m / z = 424, [M+1] + .

[0979] Step 5: Preparation of R-5

[0980] 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 hours, a saturated solution of NH4Cl was added to dilute, and then the pH was adjusted to acidic with 2N HCl and extracted with EA. The organic phase was dried over anhydrous Na2SO4 and then spin-dried to obtain an intermediate. 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 hours, the reaction was terminated, quenched with a saturated solution of NH4Cl, and extracted with EA. The organic phase was subjected to rapid silica gel column chromatography to obtain 2588.6 mg solid R-5.

[0981] MS ESI: m / z = 400, [M-1] - .

[0982] Step 6: Preparation of R-6

[0983] R-5 (2807 mg) was dissolved in DMF (30 ml), and then Cs2CO3 (2738.4 mg) and MeI (1192.8 mg) were added under ice bath. After stirring at room temperature for 5 h, the reaction was completed. The reaction was quenched with NH4Cl saturated solution and extracted with EA. The organic phase was purified by rapid silica gel column chromatography to obtain 2900 mg of colorless solid R-6.

[0984] MS ESI: m / z = 316, [(M-Boc) + 1] + .

[0985] Step 7: Preparation of R-7

[0986] R-6 (2900mg) was dissolved in DCM (35ml), then TFA (8ml) was added, and after stirring at room temperature for 2h, the reaction solution was spin-dried. The intermediate was dissolved in THF (30ml), then (Boc) O (1600mg) was added, and after stirring at room temperature for 20min, the reaction terminated. The reaction solution was spin-dried, and 1876mg of colorless solid R-7 was obtained by rapid silica gel column chromatography. Using R-7 as a raw material under the same conditions as Example 72, the S enantiomer of this type of structure can be obtained.

[0987] MS ESI: m / z = 314, [M-1] - .

[0988] Example 75: Preparation of Intermediate L-7

[0989]

[0990] Step 1: Preparation of L-1

[0991] 4-nitro-7-azaindole (1000 mg) and pyridine (10 ml) were added to a 50 ml reaction bottle, and then pyridinium tribromide was dissolved in pyridine (5 ml) and added to the reaction bottle under ice bath. After stirring at room temperature for 3 hours, the reaction was completed. After removing part of the solvent, water and EA were added to extract the product. The organic phase was subjected to rapid silica gel column chromatography to obtain 1.09 g of yellow solid L-1.

[0992] MS ESI: m / z = 242, [M+1] + .

[0993] Step 2: Preparation of L-2

[0994] L-1 (1090 mg), (Boc)2O (1800.2 mg), DMAP (55 mg) and THF (10 ml) were added to a 50 ml reaction bottle. After stirring at room temperature overnight, the reaction solution was spin-dried and 1.197 g of yellow solid L-2 was obtained by rapid silica gel column chromatography.

[0995] Step 3: Preparation of L-3

[0996] Zinc powder (2288.3 mg), DMF (8 ml) and 1,2-dibromoethane (0.1 ml) were added to a 50 ml reaction bottle. After stirring at 50 °C for 30 min, heating was stopped, and TMSCl (35 ul) was added after cooling to room temperature. After stirring at room temperature for 30 min, (R)-N-tert-butyloxycarbonyl-3-iodoalanine methyl ester (2533.3 mg) was dissolved in DMF (8 ml) and then added to the reaction solution. After stirring at room temperature for 2 h, the mixture was allowed to stand for 30 min. After the excess zinc powder settled, the supernatant was removed and added to a 50 ml reaction bottle containing L-2 (1197 mg), Pd(OAc)2 (78 mg) and Sphos (144 mg). After stirring at 35 °C for 4 h, the reaction was terminated. NH4Cl solution was added to quench the reaction and EA was extracted. The organic phase was spin-dried and 404 mg of yellow solid L-3 was obtained by rapid silica gel column chromatography.

[0997] MS ESI: m / z = 365, [M+1] + .

[0998] Step 4: Preparation of L-4

[0999] L-3 (404 mg), Pd / C (236.9 mg, 10% active ingredient, 55% water content) and MeOH (5 ml) were added to a 10 ml reaction bottle. The mixture was stirred at room temperature overnight under H2 atmosphere, then filtered through celite and dried by spin drying to obtain L-4, which was used directly in the next step.

[1000] MS ESI: m / z = 335, [M+1] + .

[1001] Step 5: Preparation of L-5

[1002] L-4 was dissolved in MeOH (20ml) and water (0.5ml), and then lithium hydroxide monohydrate (186.5mg) was added. After stirring at room temperature for 3h, NH4Cl saturated solution was added to dilute, and then PH was adjusted to acidity with 2N HCl and extracted with EA. The organic phase was dried over anhydrous Na2SO4 and then spin-dried to obtain an intermediate. The intermediate was dissolved in MeCN (10ml), and then TCFH (467.2mg) and NMI (0.44ml) were added. After stirring at room temperature for 2h, the reaction was terminated, and after quenching with NH4Cl saturated solution, EA was extracted. The organic phase was subjected to rapid silica gel column chromatography to obtain 75mg solid L-5.

[1003] MS ESI: m / z = 303, [M+1] + .

[1004] Step 6: Preparation of L-6

[1005] L-5 (75 mg) was dissolved in THF (5 ml), and then (Boc)2O (266.2 mg) and DMAP (13.5 mg) were added. After stirring at room temperature overnight, a saturated solution of NH4Cl was added to quench the reaction, and EA was extracted. The organic phase was purified by flash silica gel column chromatography to obtain 100 mg of solid L-6.

[1006] MS ESI: m / z = 403, [M+1] + .

[1007] Step 7: Preparation of L-7

[1008] L-6 was dissolved in DMF (2 ml), and then Cs2CO3 (162.2 mg) and MeI (42.4 mg) were added under ice bath. After stirring at room temperature for 1 h, the reaction was completed. The reaction was quenched with NH4Cl saturated solution 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.

[1009] MS ESI: m / z = 417, [M+1] + .

[1010] Example 76: T-71

[1011] (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

[1012]

[1013] Step 1: Preparation of L-8

[1014] L-7 (30 mg) was dissolved in DCM (2 ml), and then TFA (0.5 ml) was added. 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.

[1015] MS ESI: m / z = 217, [M+1] + .

[1016] Step 2: Preparation of T-71

[1017] Using L-8 as the starting material, 43.9 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[1018] 1 H NMR (400MHz, Acetone-d6) 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).

[1019] MS ESI: m / z = 402, [M+1] + .

[1020] Example 77: Preparation of Intermediate S-7

[1021]

[1022] 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.

[1023] Example 78: T-72

[1024] (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

[1025]

[1026] 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.

[1027] 1 H NMR(400MHz,acetone-d6)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).

[1028] MS ESI: m / z = 402, [M+1] + .

[1029] Example 79: T-73

[1030] (±)-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

[1031]

[1032] Step 1: Preparation of Y-60

[1033] 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 deprotecting the protecting group, use 4N HCl dioxane solution instead) to obtain 15.1 mg of solid Y-60.

[1034] MS ESI: m / z = 297, [M+1] + .

[1035] Step 2: Preparation of T-73

[1036] Using Y-60 as the raw material, 10 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[1037] 1H NMR (400MHz, acetone-d6) 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).

[1038] MS ESI: m / z = 482, [M+1] + .

[1039] Example 80: T-74

[1040] (±)-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

[1041]

[1042] Step 1: Preparation of Y-61

[1043] Using Y-8 (30 mg) and 5-iodo-1-methyl-1H-imidazole as raw materials, the same conditions as the first step of Example 43 were used (when deprotecting the protecting group, 4N HCl dioxane solution was used instead) to obtain 18.6 mg of solid Y-61.

[1044] MS ESI: m / z = 296, [M+1] + .

[1045] Step 2: Preparation of T-74

[1046] Using Y-61 as the starting material, 12 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[1047] 1 H NMR(400MHz,acetone-d6)δ8.67(bs,1H),7.69(s,1H),7.40–7.28(m,6H),7.25(m,1H),7.13(m,1H),6.9 6(d,J=8.0Hz,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).

[1048] MS ESI: m / z = 481, [M+1] + .

[1049] Example 81: T-75

[1050] (±)-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

[1051]

[1052] Step 1: Preparation of Y-62

[1053] Using Y-8 (30 mg), 2-chloro-N-methylpyridine-3-sulfonamide and KI (1 eq) as raw materials, 15.8 mg of solid Y-62 was prepared under the same conditions as in the first step of Example 80.

[1054] MS ESI: m / z = 386, [M+1] + .

[1055] Step 2: Preparation of T-75

[1056] Using Y-62 as the starting material, 8 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[1057] 1 H NMR(400MHz,acetone-d6)δ8.83(dd,J=4.7,1.7Hz,1H),8.65(d,J=5.0Hz,1H),8 .61(dd,J=7.9,1.7Hz,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).

[1058] MS ESI: m / z = 571, [M+1] + .

[1059] Example 82: T-76

[1060] (±)-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

[1061]

[1062] Step 1: Preparation of Z-24

[1063] The intermediate Z-8 (1 eq) and chlorosulfonyl isocyanate (1.1 eq) were dissolved in acetonitrile and reacted for 2 h under ice bath conditions. DMF (25 eq) was added and the reaction was continued for 2 h under ice bath conditions. The mixture was extracted with EA, washed with water three times, and the organic phase was concentrated. The intermediate Z-24 was separated and purified by rapid column chromatography.

[1064] Step 2: Preparation of Z-25

[1065] The intermediate Z-24 (1 eq) and trifluoroacetic acid (10 eq) were dissolved in dichloromethane and stirred at room temperature for 3 h. After the organic phase was concentrated, the intermediate Z-25 was directly separated and purified by rapid column chromatography.

[1066] MS ESI: m / z = 241, [M+H] + .

[1067] Step 3: Preparation of T-76

[1068] 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.

[1069] 1 H NMR(400MHz,acetone-d6)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).

[1070] MS ESI: m / z = 426, [M + H] + .

[1071] Example 83: T-77

[1072] (±)-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

[1073]

[1074] T-77 was obtained by reacting 2-trifluoromethylpyridine-4-boronic acid pinacol ester with intermediate Z-9 using the same conditions as Example 16.

[1075] 1 H NMR(400MHz,acetone-d6)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).

[1076] MS ESI: m / z = 546, [M+H] + .

[1077] Example 84: T-78

[1078] 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

[1079]

[1080] 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.

[1081] 1 H NMR(400MHz,acetone-d6)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 ),7.28–7.19(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).

[1082] MS ESI: m / z = 508, [M+H] + .

[1083] Example 85: T-79

[1084] (±)-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

[1085]

[1086] Step 1: Preparation of Z-26

[1087] The intermediate Z-8 (1 eq) and N-bromosuccinimide (1.1 eq) were dissolved in dichloromethane and reacted for 1 h at room temperature. The reaction was quenched with a saturated sodium thiosulfate solution, extracted with EA, washed with water three times, and the organic phase was concentrated. The intermediate Z-26 was separated and purified by rapid column chromatography.

[1088] Step 2: Preparation of Z-27

[1089] The intermediate Z-26 (1 eq) and trifluoroacetic acid (10 eq) were dissolved in dichloromethane and stirred at room temperature for 3 h. After the organic phase was concentrated, the intermediate Z-27 was directly separated and purified by rapid column chromatography.

[1090] MS ESI: m / z = 374, [M+H] + .

[1091] Step 3: Preparation of T-79

[1092] 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).

[1093] 1 H NMR(400MHz,acetone-d6)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).

[1094] MS ESI: m / z = 560, [M + H] + .

[1095] Example 86: T-80

[1096] (±)-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

[1097]

[1098] 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.

[1099] 1 H NMR(400MHz,acetone-d6)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).

[1100] MS ESI: m / z = 521, [M+H] + .

[1101] Example 87: T-81

[1102] 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

[1103]

[1104] 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.

[1105] 1 H NMR(400MHz,acetone-d6)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).

[1106] MS ESI: m / z = 495, [M+H] + .

[1107] Example 88: T-82

[1108] 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

[1109]

[1110] Step 1: Preparation of Z-28

[1111] The intermediate Z-8 (1 eq) and N-bromosuccinimide (1.1 eq) were dissolved in dichloromethane and reacted for 1 h at room temperature. The reaction was quenched with a saturated sodium thiosulfate solution, extracted with EA, washed with water three times, and the organic phase was concentrated. The intermediate Z-28 was separated and purified by rapid column chromatography.

[1112] MS ESI: m / z = 396, [M+H] + .

[1113] Step 2: Preparation of Z-29

[1114] The intermediate Z-28 (1 eq), pinacol borane (2 eq), Pd2(dba)3 (0.02 eq), Xphos (0.02 eq), and triethylamine (3 eq) were dissolved in an ultra-dry 1,4-dioxane solution, and reacted at 110°C under nitrogen protection 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.

[1115] Step 3: Preparation of Z-30

[1116] 2-Bromo-3-trifluoromethylpyridine (1.5 eq) and intermediate Z-29 (1 eq), Pd(dppf)Cl2 (0.1 eq), K3PO4 were dissolved in a mixed solvent of dioxane and water, reacted overnight at 95 °C under argon protection, cooled to room temperature, extracted with EA, washed with water three times, concentrated the organic phase, and separated and purified by flash column chromatography to obtain intermediate Z-30.

[1117] Step 4: Preparation of Z-31

[1118] The intermediate Z-30 (1 eq) and TFA (10 eq) were dissolved in dichloromethane and stirred at room temperature for 3 h. After the organic phase was concentrated, the intermediate Z-31 was directly separated and purified by rapid column chromatography.

[1119] MS ESI: m / z = 361, [M+H] + .

[1120] Step 5: Preparation of T-82

[1121] 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).

[1122] 1 H NMR(400MHz,acetone-d6)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).

[1123] MS ESI: m / z = 546, [M+H] + .

[1124] Example 89: T-83

[1125] (±)-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

[1126]

[1127] 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.

[1128] 1 H NMR(400MHz,acetone-d6)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).

[1129] MS ESI: m / z = 481, [M+H] + .

[1130] Example 90: T-84

[1131] (±)-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

[1132]

[1133] T-84 was obtained by reacting 2-trifluoromethylphenylboronic acid pinacol ester with intermediate Z-9 using the same conditions as in Example 16.

[1134] 1 H NMR (400MHz, acetone-d6) 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).

[1135] MS ESI: m / z = 555, [M + H] + .

[1136] Example 91: T-85

[1137] (±)-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

[1138]

[1139] T-85 was obtained by reacting 2,6-dimethoxyphenylboronic acid pinesol ester with intermediate Z-9 under the same conditions as in Example 16.

[1140] 1H NMR(400MHz,acetone-d6)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).

[1141] MS ESI: m / z = 537, [M+H] + .

[1142] Example 92: T-86

[1143] 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

[1144]

[1145] 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.

[1146] 1 H NMR(400MHz,acetone-d6)δ8.58(s,1H),7.51(s,1H),7.38–7.19(m,8H),4.92–4.84(m,1 H),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).

[1147] MS ESI: m / z = 496, [M+H] + .

[1148] Example 93: T-87

[1149] (±)-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

[1150]

[1151] T-87 was obtained by reacting 2-methoxyphenylboronic acid pinacol ester with intermediate Z-9 using the same conditions as in Example 16.

[1152] 1 H NMR(400MHz,acetone-d6)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,4 H),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).

[1153] MS ESI: m / z = 507, [M+H] + .

[1154] Example 94: T-88

[1155] (±)-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

[1156]

[1157] T-88 was obtained by reacting 4-isoxazole boronic acid pinacol ester with intermediate Z-9 using the same conditions as in Example 16.

[1158] 1 H NMR(400MHz,acetone-d6)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).

[1159] MS ESI: m / z = 468, [M + H] + .

[1160] Example 95: T-89

[1161] (±)-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

[1162]

[1163] 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.

[1164] 1 H NMR(400MHz,acetone-d6)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).

[1165] MS ESI: m / z = 541, [M+H] + .

[1166] Example 96: T-90

[1167] (±)-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

[1168]

[1169] 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.

[1170] 1H NMR(400MHz,acetone-d6)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).

[1171] MS ESI: m / z = 509, [M+H] + .

[1172] Example 97: T-91

[1173] (±)-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

[1174]

[1175] T-90 was obtained by reacting 3-methylthiophene-2-boronate with intermediate Z-9 using the same conditions as in Example 16.

[1176] 1 H NMR (400MHz, DMSO-d6) 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).

[1177] MS ESI: m / z = 497, [M+H] + .

[1178] Example 98: Preparation of Intermediate Z-40

[1179]

[1180] Step 1: Preparation of Z-33

[1181] 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 the reaction was quenched by adding 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 flash column chromatography.

[1182] MS ESI: m / z = 235, [M+H] + .

[1183] Step 2: Preparation of Z-34

[1184] The intermediate Z-33 (1 eq) was dissolved in ultra-dry toluene, and diisobutylaluminum hydride (1.5 eq) was slowly added at -70°C. After stirring for 4 h at -70°C, methanol was added and stirred for 0.5 h to quench the reaction. EA was extracted, 2M sodium hydroxide aqueous solution was added, and the mixture was washed with water three times. The organic phase was concentrated and separated and purified by rapid column chromatography to obtain the intermediate Z-34.

[1185] MS ESI: m / z = 205, [M + H] + .

[1186] Step 3: Preparation of Z-35

[1187] The intermediate Z-34 (1 eq), tetraisopropyl titanate (2.5 eq), and R-(+)-tert-butylsulfenamide (1.2 eq) were dissolved in ultra-dry tetrahydrofuran solution, stirred at room temperature for 6 h, extracted with EA, washed with water three times, the organic phase was concentrated, and separated and purified by rapid column chromatography to obtain the intermediate Z-35.

[1188] MS ESI: m / z = 308, [M+H] + .

[1189] Step 4: Preparation of Z-36

[1190] The intermediate Z-35 (1 eq) was dissolved in ultra-dry DMF solution, trimethylsilyl cyanide (3 eq) was slowly added at -70 °C, and the mixture was cooled to room temperature and stirred for 12 h. The mixture was extracted with EA, washed with water three times, and the organic phase was concentrated. The intermediate Z-36 was separated and purified by rapid column chromatography.

[1191] MS ESI: m / z = 335, [M+H] + .

[1192] Step 5: Preparation of Z-37

[1193] The intermediate Z-36 (1 eq) and iron powder (8 eq) were dissolved in ethanol solution, and an aqueous solution of ammonium chloride (4 eq) was added at room temperature. The mixture was stirred for 4 h at room temperature, filtered through diatomaceous earth, extracted with EA, washed with water three times, and the organic phase was concentrated. The intermediate Z-37 was separated and purified by rapid column chromatography.

[1194] MS ESI: m / z = 305, [M+H] + .

[1195] Step 6: Preparation of Z-38

[1196] The intermediate Z-37 (1 eq) was dissolved in 4N hydrochloric acid methanol solution, stirred at 100°C for 1 h, cooled to room temperature, extracted with EA, washed with water three times, the organic phase was concentrated, and separated and purified by flash column chromatography to obtain the intermediate Z-38.

[1197] MS ESI: m / z = 202, [M + H] + .

[1198] Step 7: Preparation of Z-39

[1199] The intermediate Z-38 (1 eq) was dissolved in dichloromethane, triethylamine (1 eq) and di-tert-butyl dicarbonate (1.2 eq) were slowly added, stirred at room temperature for 3 h, extracted with EA, washed with water three times, the organic phase was concentrated, and the intermediate Z-39 was separated and purified by rapid column chromatography.

[1200] Step 8: Preparation of Z-40

[1201] The intermediate Z-39 (1 eq) was dissolved in ultra-dry DMF, and cesium carbonate (1.5 eq) and iodomethane (1.2 eq) were added. The mixture was stirred for 3 h at room temperature, extracted with EA, washed with water three times, and the organic phase was concentrated. The intermediate Z-40 was separated and purified by rapid column chromatography.

[1202] MS ESI: m / z = 216, [M + H] + .

[1203] Example 99: T-92

[1204] 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

[1205]

[1206] Step 1: Preparation of Z-41

[1207] The intermediate Z-40 (1 eq) and oxalyl chloride (1.1 eq) were dissolved in anhydrous ether, stirred for 2.5 h in an ice bath, quenched with water, and then spin-dried and directly dissolved in a mixed solution of dichloromethane and methanol. Trimethylsilyldiazomethane (2 eq) was added and stirred at room temperature for 3 h. The mixture was extracted with EA, washed with water three times, and the organic phase was concentrated. The intermediate Z-41 was separated and purified by rapid column chromatography.

[1208] Step 2: Preparation of Z-42

[1209] Intermediate Z-41 (1 eq) and TFA (10 eq) were dissolved in dichloromethane and stirred at room temperature for 3 h. After the organic phase was concentrated, intermediate Z-42 was directly separated and purified by rapid column chromatography.

[1210] MS ESI: m / z = 302, [M+H] + .

[1211] Step 3: Preparation of T-92

[1212] 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.

[1213] 1 H NMR (400MHz, acetone-d6) 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).

[1214] MS ESI: m / z = 487, [M+H] + .

[1215] Example 100: T-93

[1216] (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

[1217]

[1218] Step 1: Preparation of Z-43

[1219] The intermediate Z-40 (1 eq) and trifluoroacetic acid (1.5 eq) were dissolved in DMF, stirred at room temperature for 2 h, and the reaction was quenched by adding water. The mixture was extracted with EA, washed with water three times, and the organic phase was concentrated. The intermediate Z-43 was separated and purified by rapid column chromatography.

[1220] Step 2: Preparation of Z-44

[1221] The intermediate Z-43 (1 eq) and trifluoroacetic acid (10 eq) were dissolved in dichloromethane and stirred at room temperature for 3 h. After the organic phase was concentrated, the intermediate Z-44 was directly separated and purified by rapid column chromatography.

[1222] MS ESI: m / z = 312, [M+H] + .

[1223] Step 3: Preparation of T-93

[1224] Using acid-1 (1.5 eq) and Z-44 (1 eq) as raw materials, T-93 was obtained under the same conditions as in Example 2.

[1225] 1 H NMR(400MHz,acetone-d6)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).

[1226] MS ESI: m / z = 497, [M+H] + .

[1227] Example 101: T-94

[1228] (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

[1229]

[1230] 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.

[1231] 1 H NMR(400MHz,acetone-d6)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).

[1232] MS ESI: m / z = 445, [M + H] + .

[1233] Example 102: T-95

[1234] 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

[1235]

[1236] 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.

[1237] 1 H NMR (400MHz, acetone-d6) 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).

[1238] MS ESI: m / z = 459, [M + H] + .

[1239] Example 103: T-96

[1240] (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

[1241]

[1242] 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.

[1243] 1H NMR (400MHz, acetone-d6) 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,1 H),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).

[1244] MS ESI: m / z = 546, [M+1] + .

[1245] Example 104: T-97

[1246] (±)-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

[1247]

[1248] Step 1: Preparation of Y-63

[1249] Using Y-8 (30 mg) and 2-bromo-3-(2,2,2-trifluoroethyl)pyridine as raw materials, 33.9 mg of solid Y-64 was prepared under the same conditions as in the first step of Example 80.

[1250] MS ESI: m / z = 375, [M+1] + .

[1251] Step 2: Preparation of T-97

[1252] Using Y-64 as the starting material, 40 mg of a white solid was obtained under the same conditions as in the second step of Example 40.

[1253] 1H NMR (400MHz, acetone-d6) 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).

[1254] MS ESI: m / z = 560, [M+1] + .

[1255] Activity test:

[1256] 1. Cell activity test (TNFα induced FADD-deficient human leukemia Jurkat cell programmed necrosis (necroptosis) system.

[1257] (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. All cells were cultured in a cell culture incubator at 37°C with 5% CO2. All cells were cryopreserved in complete medium containing 5-10% DMSO. The medium was changed 3-4 times per week.

[1258] (2) Experimental materials: Reagents:

[1259] 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.).

[1260] (3) Experimental consumables:

[1261] 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.

[1262] (4) Experimental plan: The TNFα-induced programmed necrosis system of Jurkat fadd-deficient cells was used to screen compounds with RIPK1 kinase inhibitory activity.

[1263] 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, centrifugation and mixing were required, and the cells were placed in a cell culture incubator at 37℃ with 5% CO2 for 1h. Subsequently, 5μL, 5ng / mL of TNFα was added to stimulate necrosis. After centrifugation and mixing, the cells were placed in a cell culture incubator for a total of 13h (until the cell death rate of the TNF-α group alone reached 65%), and the total volume of each well was 50μL. Then the cell survival rate was detected according to the following steps.

[1264] Remove the Buffer, equilibrate to room temperature before use Buffer Dissolution Substrate, obtained Reagent can be used directly in experiments.

[1265] Add 15 μL of room temperature equilibrated 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).

[1266] Table 1 Results of Jurkat Fadd(- / -) inhibitory activity test

[1267]

[1268]

[1269]

[1270]

[1271] 2. RIPK1 inhibitory activity test

[1272] 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 .

[1273] Table 2 RIPK1 activity inhibition test results

[1274] Example No. <![CDATA[IC 50 (nM)]]> Staurosporine (Kinase Inhibition Standard) 79.8 GSK2982772 (positive control) 11.1 T-16 47.8 T-34 50

[1275] 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, 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 Each is independently hydrogen, 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, substituted C3-C 10 Cycloalkyl, C6-C 10 Aryl, C3-C 10 The substituents of the heteroaryl group are selected from halogen, -C 1-6 Alkyl, -C 3-8 Cycloalkyl, -C 1-6 Haloalkyl, -C 1-6 Alkoxy; or, R a and R b Together with the nitrogen or carbon atom to which they are attached, they 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, 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 Each is independently hydrogen, 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, substituted C3-C 10 Cycloalkyl, C6-C 10 Aryl, C3-C 10 The substituents of the heteroaryl group are selected from halogen, -C 1-6 Alkyl, -C 3-8 Cycloalkyl, -C 1-6 Haloalkyl, -C 1-6 Alkoxy; or, R a and R b Together with the nitrogen or carbon atom to which they are attached, they 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.

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