Compound having kras g12d mutation degradation effect and use thereof

Abstract

Disclosed in the present invention are a compound having a KRASG12D mutation degradation effect and use thereof. The compound of the present invention is a compound represented by formula I or a pharmaceutically acceptable salt thereof or a prodrug thereof. The compound of the present invention has a good inhibitory effect and protein degradation activity against a tumor cell strain with the KRASG12D mutation, exhibiting a good drug development prospect.

Description

With KRAS G12D Compounds with mutagenic degradation effects and their uses

[0001] This application claims priority to Chinese patent applications 2025101269259 (filed January 27, 2025), 2025112665644 (filed September 5, 2025), 2026100860551 (filed January 21, 2026), and 2026100924765 (filed January 22, 2026). The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to a method having KRAS G12D Compounds that exhibit mutagenic degradation and their applications. Background Technology

[0003] The KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) gene belongs to the RAS family and is one of the most common gene mutations in human cancers. It encodes a small GTPase. In human cancers, KRAS gene mutations occur in nearly 90% of pancreatic cancers, approximately 30% to 40% of colon cancers, about 17% of endometrial cancers, and about 15% to 20% of lung cancers (mostly non-small cell lung cancer, NSCLC). It also occurs in other cancer types such as bile duct cancer, cervical cancer, bladder cancer, liver cancer, and breast cancer. In other words, a high proportion of these cancers contain the Kras gene mutation. Most KRAS missense mutations occur at codon 12, resulting in a change from glycine to another amino acid. Depending on the specific mutation present, G12C, G12D, and G12R are the most common Kras mutations found in patients, such as KRAS. G12D and KRAS G12V Mutations in both are found in approximately 90% of pancreatic cancers, while KRAS... G12D It is the most common Kras mutation in colorectal cancer.

[0004] Currently regarding KRAS G12DInhibitors have been reported in some studies. Taking anticancer drugs as an example, traditionally, small molecules inhibit the activity of target proteases by targeting and binding to them, inducing apoptosis in cancer cells. However, target proteins in tumor cells often regain their activity and acquire drug resistance through overexpression or novel mutations of the target proteins. In recent studies, small molecules are used to knock out functional target proteins, rather than simply inhibiting their activity. Protein degradation-targeting chimeras (Protac) are a new method for controlling this degradation pathway. For example, patents WO2022173032A1, WO2024159164A1, WO2024055112A1, and WO2024118960A1 disclose bifunctional degradative molecules targeting Kras-G12D. Some of these compounds are administered intravenously to target Kras-G12D. G12D Significant tumor-suppressing effects were observed in mutant mouse tumor models. However, this was limited by the relatively large molecular weight of the Protac molecule and its relationship with KRAS. G12D Protein-binding fragments typically contain multiple strongly basic nitrogen atoms, making it easier to develop KRAS with appropriate oral absorption exposure that is more readily accepted by patients. G12D Degradative molecules remain a challenge in current research. Therefore, there is an urgent need to develop a class of degradative molecules for KRAS. G12D Mutated tumor cells exhibit significant proliferative inhibitory activity, and Protac molecules, which can be administered orally and have excellent pharmacokinetic effects, can thus enhance treatment, prevention, and KRAS efficacy. G12D Efficacy of drugs for diseases related to gene mutations. Summary of the Invention

[0005] This invention aims to provide a KRAS-based system. G12D Compounds with mutagenic degradation effects and their uses. The compounds of this invention exhibit good inhibitory effects on pancreatic adenocarcinoma cells and protein degradation activity, especially with better pharmacokinetic effects when administered orally.

[0006] This invention provides a compound as shown in Formula I:

[0007] Its pharmaceutically acceptable salt or its prodrug;

[0008] Where -D stands for KRAS G12D Target protein binding group or its prodrug group;

[0009] -H 0 -for-CH2-CR 4 R 5 -CH2-H 01 -H 02 -;

[0010] R 4 and R 5 H, F, C independently 1-6 Alkyl or C substituted with one or more F 1-6 Alkyl, or R 4 and R 5 Together with the C connected to it, they form C 3-6 Cycloalkanes;

[0011] -H 01 - is a 4-6 quinone heterocyclic alkyl group, surrounded by one or more R groups. RH01-1 The substituted 4-6 membered heterocyclic alkylene, 7-12 membered bicyclic or tricyclic heterocyclic alkylene, or alkylene spirocyclic alkylene with one or more R RH01-2 The substituted 7-12-membered bicyclic or tricyclic spirocycloalkyl group; wherein the heteroatoms in the spirocycloalkyl group are independently one or two of N and O, and the number is one, two or three;

[0012] Each R RH01-1 and each R RH01-2 Independently F or C 1-6 alkyl;

[0013] -H 02 - is a connector, -C (=O)-, -CR 6a R 6b -、-O-、-S-、-CR 6a R 6b -O-、-NR 6a R 6b -,-rigid group-CR 6a R 6b -or -O-rigid group-; the -rigid group-CR 6a R 6b The rigid groups in -O- and the rigid groups in -O- can optionally be replaced by one or more F;

[0014] Each R 6a and each R 6b H, F, C independently 1-6 Alkyl or with one or more R R6 Replacement C 1-6 alkyl;

[0015] Each R R6 Independent of deuterium, F or C 1-6 Alkoxy;

[0016] -H 1 -for Mark 1 bit as H 0 Connect, 2 bits or * mark with connect;

[0017] Ring A a and each ring A b Independently, it is a 6-8 membered heterocyclic alkyl group, a 7-11 membered bicyclic spirocyclic heterocyclic alkyl group, or an 8-9 membered bicyclic bridged heterocyclic alkyl group;

[0018] Ring A a In the above, the heteroatoms in the heterocyclic alkyl group, the bicyclic spirocyclic heterocyclic alkyl group, and the bicyclic bridged heterocyclic alkyl group are specifically one or two of N and O, and the number is two or three, and at least two N atoms are present; each ring A b In the above, the heteroatoms in the heterocyclic alkyl group, the bicyclic spirocyclic heterocyclic alkyl group, and the bicyclic bridged heterocyclic alkyl group are specifically one or two of N and O, and the number is one, two, or three, and at least one N is present;

[0019] Each n1 is independently 1, 2, or 3;

[0020] Each R 1 Independent of hydrogen, F, C 1-6 Alkyl, oxo, with one or more R R1 Replacement C 1-6 alkyl;

[0021] Each R R1 For F, C 1-6 Alkoxy or C substituted with one or more F 1-6 Alkoxy; R 2 C 1-6 Alkyl groups or C atoms that are deuterated by one or more deuterated groups 1-6 alkyl;

[0022] n2 is 1, 2, or 3;

[0023] Each R 3 Independently hydrogen, F, Cl, Br, C 1-6 Alkyl, C 1-6 alkoxy, with one or more R R3-1 Replacement C 1-6 Alkyl groups or those with one or more R groups R3-2 Replacement C 1-6 Alkoxy;

[0024] Each R R3-1 and each R R3-2 Independently, it is either F or deuterium.

[0025] This invention provides a compound as shown in Formula I:

[0026] Its pharmaceutically acceptable salt or its prodrug;

[0027] Where -D stands for KRAS G12D Target protein binding group or its prodrug group;

[0028] -H 0 -for-CH2-CR 4 R 5 -CH2-H 01 -H 02 -;

[0029] R 4 and R 5 H, F, C independently 1-6 Alkyl or C substituted with one or more F 1-6 Alkyl, or R 4 and R 5 Together with the C connected to it, they form C 3-6 Cycloalkanes;

[0030] -H 01 - is a 4-6 quinone heterocyclic alkyl group, surrounded by one or more R groups. RH01-1 The substituted 4-6 membered heterocyclic alkylene, 7-12 membered bicyclic spirocyclic alkylene, or alkylene derived from one or more R groups RH01-2 The substituted 7-12 membered bicyclic spirocycloalkyl group; wherein the heteroatoms in the spirocycloalkyl group are independently one or two of N and O, and the number is one, two or three;

[0031] Each R RH01-1 and each R RH01-2 Independently F or C 1-6 alkyl;

[0032] -H 02 - is a connector, -C (=O)-, -CR 6a R 6b -、-O-、-S-、-rigid groups-CR 6a R 6b -or -O-rigid group-; the -rigid group-CR 6a R 6b The rigid groups in -O- and the rigid groups in -O- can optionally be replaced by one or more F;

[0033] Each R 6a and each R 6b H, F, C independently 1-6 Alkyl or with one or more R R6 Replacement C 1-6 alkyl;

[0034] Each R R6 Independent of deuterium, F or C 1-6Alkoxy;

[0035] -H 1 -for Mark 1 bit as H 0 Connect, 2 bits or * mark with connect;

[0036] Ring A a and each ring A b Independently, it is a 6-8 membered heterocyclic alkyl group, a 7-11 membered bicyclic spirocyclic heterocyclic alkyl group, or an 8-9 membered bicyclic bridged heterocyclic alkyl group;

[0037] Ring A a In the above, the heteroatoms in the heterocyclic alkyl group, the bicyclic spirocyclic heterocyclic alkyl group, and the bicyclic bridged heterocyclic alkyl group are specifically one or two of N and O, and the number is two or three, and at least two N atoms are present; each ring A b In the above, the heteroatoms in the heterocyclic alkyl group, the bicyclic spirocyclic heterocyclic alkyl group, and the bicyclic bridged heterocyclic alkyl group are specifically one or two of N and O, and the number is one, two, or three, and at least one N is present;

[0038] Each n1 is independently 1, 2, or 3;

[0039] Each R 1 Independent of hydrogen, F, C 1-6 Alkyl, oxo, with one or more R R1 Replacement C 1-6 alkyl;

[0040] Each R R1 For F, C 1-6 Alkoxy or C substituted with one or more F 1-6 Alkoxy; R 2 C 1-6 Alkyl groups or C atoms that are deuterated by one or more deuterated groups 1-6 alkyl;

[0041] n2 is 1, 2, or 3;

[0042] Each R 3 Independently hydrogen, F, Cl, Br, C 1-6 Alkyl, C 1-6 alkoxy, with one or more R R3-1 Replacement C 1-6 Alkyl groups or those with one or more R groups R3-2 Replacement C 1-6 Alkoxy;

[0043] Each R R3-1 and each R R3-2 Independently defined as F and deuterium.

[0044] The definitions of each group in the compound of the present invention as shown in Formula I can also be as follows, and undefined groups can be defined as in any of the schemes of the present invention.

[0045] In some schemes, each R 1 R 2 Each R 3 R 4 R 5 R 6a R 6b Each R RH01-1 and each R RH01-2 In, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0046] In some schemes, when R 4 and R 5 Together with the C connected to it, they form C 3-6 In the case of cycloalkanes, the C 3-6 Cycloalkanes are cyclopropane, cyclobutane, or cyclopentane.

[0047] In some schemes, -H 0 -in, -(CH2)-CR 4 R 5 -(CH2)- is

[0048] In some schemes, -H 01 - In this context, the 4-6 membered heterocyclic alkyl group and the group with one or more R RH01-1 The substituted 4-6-membered heterocyclic alkyl group is a 5- or 6-membered heterocyclic alkyl group, the heteroatom is N, the number is 1 or 2, and it can also be a piperidinyl group.

[0049] In some schemes, -H 01 - In this context, the 7-12 membered bicyclic spiroheterocyclic alkyl group and the one or more R RH01-2 The 7-12-membered bicyclic spirocycloalkyl group in the substituted 7-12-membered bicyclic spirocycloalkyl group is independently a 6-membered heterocycloalkylspiro4-6-membered cycloalkyl or a 6-membered heterocycloalkylspiro4-6-membered heterocycloalkyl group, the heteroatom being N and / or O, and the number being 1 or 2, and may also be 3-azaspiro[5.5]undecylene, 7-azaspiro[3.5]nonylene or 1-oxa-8-azaspiro[4.5]decylene.

[0050] In some schemes, -H 01 - In this context, the 4-6 membered heterocyclic alkyl group, the one or more R RH01-1The substituted 4-6 membered heterocyclic alkyl group, the 7-12 membered bicyclic spirocyclic alkyl group, and the alkyl group with one or more R RH01-2 In the substituted 7-12 membered bicyclic spiroheterocyclic alkyl group, the 7-12 membered bicyclic spiroheterocyclic alkyl group is independently linked to -CH2- via a heteroatom and to -H via a carbon atom. 02 -connect.

[0051] In some schemes, -H 01 - In this context, the 4-6 membered heterocyclic alkyl group, the one or more R RH01-1 The substituted 4-6 membered heterocyclic alkyl group, the 7-12 membered bicyclic spirocyclic alkyl group, and the alkyl group with one or more R RH01-2 The 7-12 membered bicyclic spiroheterocyclic alkyl group in the substituted 7-12 membered bicyclic spiroheterocyclic alkyl group has an axisymmetric structure, where the axis is the line connecting the two connection sites of the structural segment to the rest of Formula I.

[0052] In some schemes, the term is defined by one or more Rs. RH01-1 The substituted 4-6 membered heterocyclic alkyl group is

[0053] In some schemes, -H 01 - In, the one or more R RH01-2 Substituted 7-12 membered bicyclic spirochetes (The N-terminus is connected to -CH2-, and the carbon-terminus is connected to -H) 02 -connect).

[0054] In some schemes, -H 02 - In, the - rigid group - CR 6a R 6b The rigid groups in -O- and the rigid groups in -O- are independently C 3-6 cycloalkyl, by one or more R RH02-1 Replacement C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, or alkyl grouped with one or more R RH02-2 Substituted 4-6 membered heterocyclic alkyl groups; the 4-6 membered heterocyclic alkyl groups and the groups substituted with one or more R RH02-2 The heteroatoms in the substituted 4-6-membered heterocyclic alkyl groups are independently one or two of N and O, and the number is one, two or three;

[0055] Each R RH02-1 and each R RH02-2 Independently F or C 1-6 alkyl.

[0056] Wherein, the C 3-6 cycloalkyl and the one or more R RH02-1 Replacement C 3-6 C in cycloalkyl 3-6 The cycloalkyl group can be cyclopropyl or cyclobutyl independently.

[0057] Wherein, the 4-6 membered heterocyclic alkyl group and the one or more R RH02-2 The 4-6 membered heterocyclic alkyl group in the substitution can be independently a 4-5 membered heterocyclic alkyl group, with one N heteroatom, and can be a nitrogen-containing heterocyclic butyl group.

[0058] Wherein, the one or more R RH02-2 The substituted 4-6 membered heterocyclic alkyl group can be

[0059] In some schemes, each R 6a and each R 6b In, the one or more R R6 Replacement C 1-6 Alkyl is

[0060] In some schemes, when H 1 for At that time, -H 02 - is -C(=O)- or -O-.

[0061] In some schemes, -H 02 - In, the -CR 6a R 6b -for

[0062] In some schemes, -H 02 In this context, the -O-rigid group is...

[0063] In some schemes, -H 0 - For any of the following structures:

[0064] The 1st bit is connected to 0, and the 2nd bit is connected to H. 1 connect.

[0065] In some schemes, ring A a In this context, the 6-8 membered heterocyclic alkyl group has N heteroatoms, and there are two of them. It can be piperazine, 1,4-diazacycloheptyl, or 1,5-diazacyclooctyl.

[0066] In some schemes, ring A a In this context, the 7-11 member bicyclic spirocyclic heterocyclic alkyl group is a 6-membered heterocyclic alkyl spiro4-6-membered heterocyclic alkyl or a 5-membered heterocyclic alkyl spiro4-membered heterocyclic alkyl group, with heteroatoms being N and / or O, and the number being 2 or 3. It can be 2,7-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.4]octyl, 2,6-diazaspiro[3.3]heptyl, 3,9-diazaspiro[5.5]undecyl, 2-oxo-5,8-diazaspiro[3.5]nonyl or 4,7-diazaspiro[2.5]octyl.

[0067] In some schemes, ring A a In the 8-9 member bicyclic bridged heterocyclic alkyl group, the heteroatom is N, and the number is 2. It can be 3,8-diazabicyclo[3.2.1]octyl or 3,9-diazabicyclo[3.3.1]nonyl.

[0068] In some schemes, ring A b In this context, the 6-8 member heterocyclic alkyl group is piperidinyl.

[0069] In some schemes, ring A b In this context, the 7-11 member bicyclic spirocyclic heterocyclic alkyl group is a 4-6 member heterocyclic alkyl spiro-4-6 member cycloalkyl group, with heteroatoms being N and / or O, and the number being 1, 2 or 3, and can be 7-azaspiro[3.5]nonyl, 3-diazaspiro[5.5]undecyl, 2-azaspiro[3.5]nonane or 7-azaspiro[3.5]nonyl.

[0070] In some schemes, each R 1 Each R R1 Each R 3 and R R6 In, the C 1-6 The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0071] In some schemes, each R 1 In the context, the one or more R R-1 Replacement C 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0072] In some schemes, each R R1 In the context, the C replaced by one or more F 1-6 C in alkoxy 1-6 The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0073] In one of the solutions,

[0074] -H 02 - for connection key, -CR 6a R 6b -or-NR 6a R 6b -;

[0075] -H 1 -for

[0076] In one scheme, -H 02 - is -C(=O)-; H 02 With H 01 or -H 1 The N atom on the - group forms an amide segment. In some schemes, each R... 1 In the context, the one or more R R1 Replacement C 1-6 Alkyl is In some schemes, for (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ),

[0077] In some schemes, for

[0078] In some schemes, for

[0079] In some schemes, for

[0080] In some schemes, R 2 In the context, the C-terminated by one or more deuterium atoms 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0081] In some schemes, R 2 In the context, the C-terminated by one or more deuterium atoms 1-6 The alkyl group is -CD3.

[0082] In some schemes, R 3 In the context, the one or more R R3-1 Replacement C 1-6 alkyl is C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0083] In some schemes, R 3 In the context, the one or more R R3-1 Replacement C 1-6 The alkyl group is -CD3.

[0084] In some schemes, R 3 In the context, the one or more R R3-1 Replacement C 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropoxy, n-butyl, isobutyl, sec-butyl, or tert-butyl;

[0085] In some schemes, R 3 In the context, the one or more R R3-2 Replacement C 1-6 C in alkoxy 1-6 The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0086] In some schemes, R 3 In the context, the one or more R R3-2 Replacement C 1-6 The alkoxy group is -OCD3.

[0087] In some schemes, for

[0088] In some schemes, -D is represented by the following general formula IIa or IIb:

[0089] In equations IIa and IIb, R 7a and R 7b Independently for C 6-10 aryl, 6-10 aryl, with one or more R R7-1 Replacement C 6-10 aryl or aryl group with one or more R groups R7-2The substituted 6-10-membered heteroaryl group; the heteroatoms of the heteroaryl group are independently selected from N, S and O, and the number is 1, 2 or 3;

[0090] Each R R7-1 and each R R7-2 Independently, it can be a halogen, cyano, hydroxyl, amino, oxo group, or C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C substituted with one or more halogens 1-6 Alkyl groups, C atoms substituted with one or more deuterium groups 1- 6-alkyl groups or C groups substituted with one or more halogens 1-6 Alkoxy;

[0091] R 8a and R 8b For H, C 1-6 Alkyl or halogen;

[0092] Ring B a and Ring B b Independently a 7-9 membered bicyclic bridged heterocyclic alkyl group;

[0093] n 3a and n 3b Independently 1, 2, or 3;

[0094] R 9a and R 9b Independently hydrogen, C 1-6 Alkyl, with one or more R R9-1 Replacement C 1-6 Alkyl, C 1-6 alkoxy, with one or more R R9- 2 Replacement C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0095] Each R R9-1 and each R R9-2 Independent of deuterium and C 1-6 Alkyl group or C group replaced by one or more deuterated groups 1-6 Alkoxy;

[0096] R 13a and R 13b Independently hydrogen or -C(=O)R R13 ;

[0097] R R13 C 1-6 Alkyl groups, C atoms substituted with one or more halogens 1-6Alkyl or -O(CHC) 1-6 alkyl)OC(=O)(CHR R13-1 R R13-2 );

[0098] R R13-1 and R R13-2 Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl;

[0099] R 10 H, halogen, C 1-6 Alkyl, C 2-6 alkynyl or C 1-6 Alkoxy;

[0100] R 11 and R 12 H and C independently 1-6 Alkyl, C 1-6 Alkyl groups, C atoms substituted with one or more deuterium groups 1-6 Alkyl groups or C atoms substituted with one or more deuterium atoms 1-6 Alkoxy;

[0101] Y represents O, S, or CH2;

[0102] X a and X b Independently CH, CR 14 Or N;

[0103] R 14 Halogen, C 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 alkyl;

[0104] The heteroatoms in the heterocyclic alkyl group, the heteroaryl group, and the bridged heterocyclic alkyl group are independently selected from 1, 2, or 3 of N, S, and O, and the number of heteroatoms is 1, 2, or 3.

[0105] The heteroatoms in the above-mentioned heterocyclic alkyl, heteroaryl, and bridged heterocyclic alkyl groups are independently selected from N, S, and O, and the number of heteroatoms is 1, 2, or 3.

[0106] Among them, R 7a and R 7b In, the C 6-10 aryl and said being 1 or more R R7-1 Replacement C 6-10 C in aryl 6-10 The aryl group can be phenyl or naphthyl independently.

[0107] Among them, R 7a and R 7b In the context, the 5-10 aryl group and the group with one or more RR7-2 The 6-10 membered heteroaryl group in the substituted heteroaryl group is independently a 6-membered heteroaryl or a 9-membered bicyclic heteroaryl, the heteroatom is N or S, the number is 1 or 2, and it can be pyridyl or benzothiophene.

[0108] Among them, each R R7-1 Each R R7-2 R 8a R 8b R 9a R 9b Each R R9-1 Each R R9-2 R R13 R R13-1 R R13-2 R 10 R 11 R 12 and R 14 In, the C 1-6 The alkyl group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl or ethyl.

[0109] Among them, each R R7-1 Each R R7-2 R 8a R 8b R 10 and R 13 In this context, the halogen can be F, Cl, or Br, for example, F or Cl.

[0110] Among them, each R R7-1 Each R R7-2 R 9a R 9b Each R R9-1 Each R R9-2 R 10 R 11 and R 12 In, the C 1-6 The alkoxy group can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0111] Among them, R R7-1 Each R R7-2 and R 10 In, the C 2-6 The alkynyl group can be ethynyl or propynyl.

[0112] Among them, each R R7-1 and each R R7-2 In, the C 3-6 Cycloalkyl groups can be cyclopropyl groups.

[0113] Among them, each R R7-1 and each RR7-2 In the context, the C substituted with one or more halogens 1-6 Alkyl groups can be -CF3.

[0114] Among them, each R R7-1 and each R R7-2 In the context, the C substituted with one or more deuteriums 1-6 Alkyl groups can be

[0115] Among them, ring B a and Ring B b In this context, the 7-9 member bicyclic bridged heterocyclic alkyl group can be a 7-8 member bicyclic bridged heterocyclic alkyl group, with N heteroatoms, and the number of heteroatoms is 1 or 2. It can also be 3,8-diazabicyclo[3.2.1]octyl or 2,5-diazabicyclo[2.2.1]heptyl.

[0116] Among them, each R R9-1 and each R R9-2 In the context, the C-terminated by one or more deuterium atoms 1-6 C in alkoxy 1-6 The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0117] Among them, each R R9-1 and each R R9-2 In the context, the C-terminated by one or more deuterium atoms 1-6 C in alkoxy 1-6 The alkoxy group can be -OCD3.

[0118] Among them, R R9-3 In the context, the C substituted with one or more halogens 1-6 C in alkyl 1-6 The alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0119] Among them, R R9-3 In the context, the C substituted with one or more halogens 1-6 The alkyl group can be -CF3 or -CHF2.

[0120] Among them, R R13-1 and R R13-2 In, the C 3-6 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclobutyl.

[0121] Among them, R 9a and R 9b In the context, the one or more R R9-1 Replacement C 1-6 Alkyl groups can be

[0122] Among them, R 13a and R 13b In the context, -C(=O)R R13 It can be -C(=O)CF3,

[0123] In some schemes, -D is represented by the following general formulas IIa-1, IIa-2, IIb-1, or IIb-2:

[0124] The definitions of each group in the general formula are the same as those described above.

[0125] In some schemes, general formula IIb-1 is general formula IIb-1a, and general formula IIb-2 is general formula IIb-2a:

[0126] The definitions of each group in the general formula are the same as those described above.

[0127] In some schemes, R 7a and R 7b Independently q1, q2, q3, q4, q5, and q6 are independently 1, 2, 3, or 4; each R R7-1 and each R R7-2 Independent of halogen, C 1-6 Alkyl, C 2-6 alkynyl group, C 3-6 cycloalkyl groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium groups. 1-6 alkyl;

[0128] Preferred

[0129] In some schemes, X a For CR 14 Or N, R 14 Halogen; X is further preferred. a It can be -CCl, -CCF3, or N.

[0130] In some schemes, X b For N, R 11 For H, C 1-6 Alkyl groups or C atoms substituted with one or more deuterium atoms 1-6 Alkyl; more preferably, X b For N, R 11 It can be methyl, ethyl, or -CD3.

[0131] In some schemes, R 8a and R 8b It is independently a halogen, and is further preferably F.

[0132] In some schemes, R 9a and R 9b Independently for hydrogen, In some schemes, R 13a and R 13b Independently for hydrogen,

[0133] In some schemes, -D is any of the following groups:

[0134] In some embodiments, the compound represented by formula I is a compound represented by formula Ia or Ib:

[0135] The definitions of the groups in formulas Ia and Ib are the same as those described above.

[0136] Preferably, in formula Ia, -for

[0137] -H 02 - is a connector, -C (=O)-, -CR 6a R 6b -,-rigid group-CR 6a R 6b -or -O-rigid group-;

[0138] for

[0139] R 3 Hydrogen, F or C 1-6 Alkyl group.

[0140] More preferably, for

[0141] m1, m2, m3, m4, m5, and m6 are independently 1 or 2, and the above substituents -R RH01-2 This indicates that it can replace any one or two rings of the double-spiral ring.

[0142] Preferably, in formula Ib, -for

[0143] for

[0144] Better, for

[0145] In some embodiments, the compound represented by Formula I is a compound represented by Formula I-1a or Ib:

[0146] Among them, -H 0- H 1 -for

[0147] Where 1 is connected to 0, and 2 is connected to... connect;

[0148] R 7a and R 7b Independently

[0149] In some embodiments, the compound represented by Formula I is any of the compounds listed in Table 1.

[0150] Its pharmaceutically unacceptable salt, its prodrug, or its stereoisomer.

[0151] The present invention also provides a pharmaceutical composition comprising the compound shown in Formula I above or a pharmaceutically acceptable salt thereof (in an effective amount), and pharmaceutical excipients.

[0152] The present invention also provides a method for detecting KRAS. G12D A mutation kit comprising the compound as shown in Formula I or a pharmaceutically acceptable salt thereof.

[0153] The present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a compound for the prevention or treatment of KRAS. G12D Application in drugs for mutation-related cancers.

[0154] The KRAS mutation-related cancers may be one or more of the following: pancreatic cancer, lung cancer, small bowel cancer, colorectal cancer, gallbladder cancer, thyroid cancer, cancer, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, esophageal cancer, and blood cancer.

[0155] In structural fragments This refers to the structural segment being connected to the rest of the molecule through this site. For example, It is a monofluoromethyl group.

[0156] The "-" at the end of a group indicates that the group is attached to the rest of the molecule through that site. For example, CH3-C(=O)- refers to an acetyl group.

[0157] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0158] The term "alkyl" refers to an alkyl group having a specified number of carbon atoms (e.g., C40, C50, C6 ... 1-6 Alkyl groups are saturated, linear or branched, and include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0159] The term "alkoxy" refers to the group R. X -O-,R X The definition is the same as the term "alkyl". Alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0160] The term "alkenyl" refers to an alkenyl group having a specified number of carbon atoms (e.g., C36, C46, ​​C56, C6 ... 2-6 An alkenyl, straight-chain or branched, unsaturated monovalent hydrocarbon group having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 2 Double bond. Alkenyl groups include, but are not limited to: vinyl groups, wait.

[0161] The term "alkynyl" refers to a group having a specified number of carbon atoms (e.g., C36, C46, ​​C56, C6 ... 2-6 A straight-chain or branched, unsaturated monovalent hydrocarbon group having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 3 Triple bond. Alkynyl groups include, but are not limited to: ethynyl, wait.

[0162] The term "cycloalkyl" refers to a compound having a specified number of carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C7 ... 3-6 Cyclic, saturated monovalent hydrocarbon groups, which are monocyclic. (Monocyclic)cycloalkyl groups include, but are not limited to: wait.

[0163] The term "(monocyclic)heterocyclic alkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 3-11), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), and is monocyclic. (Monocyclic)heterocyclic alkyl groups are attached to the remainder of the molecule by carbon atoms or heteroatoms. (Monocyclic)heterocyclic alkyl groups include, but are not limited to: wait.

[0164] The term "bridged heterocyclic alkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 3-11), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is polycyclic (e.g., 2 or 3 rings) and shares two or more carbon atoms and / or heteroatoms among the monocyclic rings. Bridged heterocyclic alkyl groups are attached to the remainder of the molecule via a ring having heteroatoms or a ring without heteroatoms; they are attached to the remainder of the molecule via carbon atoms or heteroatoms. Bridged heterocyclic alkyl groups include, but are not limited to: wait.

[0165] The term "spirocyclic heterocyclic alkyl" refers to a cyclic, saturated monovalent group having a specified number of ring atoms (e.g., 3-11), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is polycyclic (e.g., 2 or 3 rings) and shares a carbon atom between the rings. Spirocyclic heterocyclic alkyl groups are attached to the remainder of the molecule via a ring having a heteroatom or a ring without a heteroatom; spirocyclic heterocyclic alkyl groups are attached to the remainder of the molecule via a carbon atom or a heteroatom. Spirocyclic heterocyclic alkyl groups include, but are not limited to: wait.

[0166] The term "heteroaryl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5-10), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, with the monocyclic rings sharing two atoms and one bond, and is aromatic. Heteroaryl groups are attached to the rest of the molecule via carbon atoms or heteroatoms; they can be attached to the rest of the molecule via a ring with or without heteroatoms; or they can be attached to the rest of the molecule via an aromatic ring or a non-aromatic ring. Heteroaryl groups include, but are not limited to: wait.

[0167] The term "pharmaceutical excipients" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and are generally divided into two main categories: excipients and additives. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0168] The term "treatment" refers to eliminating the cause of an illness or relieving symptoms.

[0169] The term "prevention" refers to reducing the risk of developing a disease.

[0170] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, and ammonium salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, sulfate, and methanesulfonate salts. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0171] The term "rigid group" refers to a group that maintains a fixed distance and angle between two connected parts, thereby preserving the stability of the overall structure and a specific conformation. "Rigid groups" include non-aromatic cyclic groups (e.g., cyclic groups containing 3-6 ring atoms), such as "cycloalkyl" or "heterocyclic alkyl" in the terminology.

[0172] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0173] The reagents and raw materials used in this invention are all commercially available.

[0174] The positive and progressive effects of this invention are as follows: the compound of this invention has good inhibitory activity against the proliferation of AsPC-1 cells and protein degradation activity, and in particular, it also has better pharmacokinetic effects. Detailed Implementation

[0175] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the concept and scope of the invention.

[0176] General process

[0177] When the preparation method is not specified, all raw materials and reagents used in this invention are known products that can be synthesized according to methods known in the art, or can be obtained by purchasing commercially available products. None of the commercially available reagents used require further purification.

[0178] Room temperature refers to 20-30℃.

[0179] Unless otherwise specified in the reaction examples, all reactions were carried out under a nitrogen atmosphere. A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon of approximately 1L.

[0180] Hydrogenation reactions are typically carried out under vacuum, filled with hydrogen gas, and repeated three times. A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon of approximately 1L.

[0181] Microwave reaction use Initiator + Microwave Reactor.

[0182] The structure of the compounds of this invention was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) were expressed in terms of 10⁻¹⁰. -6 The unit (ppm) is given. NMR measurements were performed using a BRUKER AVANCE III, 400M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS). The following abbreviations are used for NMR signal multiplicity: s = singlet, brs = broad peak, d = doublet, t = triplet, m = multiplet. Coupling constants are listed in J values ​​and measured in Hz.

[0183] Rapid column chromatography was performed using an Agilent (FS-9200T) automated column press, and pre-packed silica gel columns were used with Sante. Pre-packed column. Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The thickness used for thin-layer chromatography separation and purification of products is 0.4mm to 0.5mm.

[0184] Reversed-phase preparative chromatography was performed using a Waters-3767 reversed-phase preparative chromatograph.

[0185] Preparation column: Waters SunFire, 250*19mm, 5mm

[0186] Alternatively, Xbridge Prep C18 or Gemini C18 21.2*250 5um

[0187] Mobile phase: A: 0.05% ammonia-water solution; B: acetonitrile

[0188] Detection wavelengths: 254nm & 214nm

[0189] Flow rate: 20 ml / min

[0190] LCMS was performed using a Waters ARC HPLC-QDA instrument.

[0191] Chromatographic column: ACQUITY UPLC BEH C18 3.5μm 3.0*50mm

[0192] Ion source: ESI

[0193] Mobile phase: A: 0.05% ammonia-aqueous solution; B: 0.05% ammonia-acetonitrile solution

[0194] Detection wavelengths: 254nm & 214nm

[0195] Run time: 1.5 ml / min / 3.5 min

[0196] HPLC was performed using a Waters W2489 Instrument instrument.

[0197] Column: Xbridge C18, 4.6*50mm

[0198] Mobile phase: A: 0.1% ammonia-water solution; B: acetonitrile

[0199] Detection wavelengths: 254nm & 214nm

[0200] Runtime: 9.0 min

[0201] Supercritical fluid chromatography (SFC) was performed using a Waters SFC 150 instrument.

[0202] Column: DAICL OJ-10 or DAICEL AD-10

[0203] Mobile phase: A: Supercritical CO2; B: 0.05% ammonia-methanol solution

[0204] Detection wavelengths: 254nm & 214nm

[0205] The synthesis method of the intermediate is as follows:

[0206] Intermediate 1

[0207] Intermediate 1 is prepared by the following steps:

[0208] Step A: Int-1b (2.20 g, 11.83 mmol), Int-1a (2 g, 5.91 mmol), Pd-PEPPSI-IHept-Cl (162.48 mg, 177.43 μmol), and cesium carbonate (3.85 g, 11.83 mmol) were dissolved in N,N-dimethylformamide (20 mL) and stirred at 120 °C for 16 hours under nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, quenched with formic acid, and then extracted with water and ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give Int-1c (1.6 g, crude product). ESI-MS (m / z): 462.3 [M+H] + .

[0209] Step B: Int-1c (1.6 g, 3.47 mmol) and N,N'-carbonyldiimidazole (1.12 g, 6.93 mmol) were dissolved in acetonitrile (15 mL), and the reaction mixture was stirred at 70 °C for 4 hours. LC / MS showed that the reaction was complete. The reaction mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined. The crude product obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give Int-1d (1.5 g, overall yield of two steps: 57.18%). ESI-MS (m / z): 444.3 [M+H] + .

[0210] Step C: Dissolve Int-1d (1.5 g, 3.38 mmol) in dichloromethane (15 mL), and slowly add hydrochloric acid-dioxane solution (4.0 M) (10 mL) to the reaction solution. Stir the mixture at room temperature for 2 hours. LC / MS showed that the reaction was complete. Concentrate the reaction solution to obtain Int-1 (1.2 g, crude product, hydrochloride). ESI-MS (m / z): 344.3 [M+H] + .

[0211] Intermediate 2

[0212] Intermediate 2 is prepared by the following steps:

[0213] Step A: At room temperature, Int-2a (20 g, 79.22 mmol) was dissolved in dichloromethane (150 mL). N,N-diisopropylethylamine (30.72 g, 237.66 mmol, 41.40 mL) was added to the reaction solution, and the mixture was cooled to -70 °C with ethanol / dry ice. Int-2b (15.14 g, 71.30 mmol) was dissolved in dichloromethane (100 mL) and slowly added dropwise to the reaction solution. The reaction was carried out at this temperature for about 0.5 hours. LC / MS showed that the reaction was complete. The crude product was obtained by direct silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 10 / 1). The crude product was then slurried with petroleum ether to give a pale yellow solid Int-2c (140 mg, crude product), which required no further purification. ESI-MS (m / z): 429.3 [M+H] + .

[0214] Step B: Under ice bath conditions, Int-2c (27 g, 63.04 mmol) was dissolved in tetrahydrofuran (100 mL) and dichloromethane (100 mL). Cesium carbonate (61.62 g, 189.13 mmol) and triethylenediamine (707.14 mg, 6.30 mmol, 693.27 μL) were added sequentially, followed by Int-2d (143.77 g, 1.41 mol, 135.00 mL). The reaction was carried out at 0 °C for 20 minutes. LC / MS showed the reaction was complete. Water was added to the reaction solution, and a pale yellow solid precipitated. The solid was filtered, the filter cake was washed several times with water, and dried under vacuum to obtain the product Int-2e (21 mg, crude product), which required no further purification. ESI-MS (m / z): 494.9 [M+H] + .

[0215] Step C: Under nitrogen protection, Int-2e (21 g, 36.14 mmol), Int-2f (22.23 g, 43.36 mmol), cataCXium A Pd G3 (5.26 g, 7.23 mmol), potassium phosphate (23.01 g, 108.41 mmol), dioxane (80 mL), and water (17 mL) were added to the reaction flask. The mixture was stirred overnight at 85 °C under nitrogen protection. LC / MS showed the reaction was complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and stirred. The sample was then subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give the brown product Int-2g (30 g, yield 98.35%). ESI-MS (m / z): 614.7 [M+H] + .

[0216] Step D: Dissolve Int-2 g (5 g, 5.92 mmol) in dichloromethane (50 mL), add Dysmartin oxidant (5.02 g, 11.85 mmol) under ice bath conditions, and react at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was washed twice with saturated sodium bicarbonate aqueous solution and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain Int-2h (4.7 g, yield 94.23%). ESI-MS (m / z): 612.6 [M+H] + .

[0217] Step E: Int-2h (4.78 g, 5.68 mmol) was dissolved in tetrahydrofuran (50 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) (11.35 mL) was added under ice bath conditions. The reaction was carried out at room temperature for 0.5 h. LC / MS showed that the reaction was complete. The reaction was quenched with water, extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to silica gel column chromatography (eluent: ethyl acetate / petroleum ether (V / V) = 1 / 2) to give the white product Int-2i (3.2 g, yield 82.21%). ESI-MS (m / z): 625.6 [M+H] + .

[0218] Step F: Int-2i (3 g, 4.37 mmol) was dissolved in THF (45 mL), and 10% palladium on carbon catalyst (1.16 g, 10.94 mmol) was added. The mixture was purged with hydrogen three times and reacted at 40 °C for 5 hours. After cooling to room temperature and filtering through a diatomaceous earth liner, the solution was evaporated to dryness under reduced pressure to obtain the crude product. Purification was performed by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 2 / 1) to obtain the yellow solid product Int-2 (2.7 g, yield 89.47%). ESI-MS (m / z): 629.7 [M+H] + .

[0219] Intermediate 3

[0220] Intermediate 3 is prepared by the following steps:

[0221] Step A: Int-1a (500 mg, 1.48 mmol), Int-3a (1.18 g, 5.91 mmol), cesium carbonate (1.45 g, 4.44 mmol), and Pd-PEPPSI-IHept-Cl (71.92 mg, 73.93 μmol) were dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 110 °C for 4 hours under nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, quenched with formic acid, and extracted twice with ethyl acetate after adding water. The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give the white product Int-3b (250 mg, yield 36.96%). ESI-MS (m / z): 458.5 [M+H] + .

[0222] Step B: Int-3b (250 mg, 546.42 μmol) was dissolved in dichloromethane (5 mL), and then hydrochloric acid-dioxane solution (4.0 M) (5 mL) was added. The reaction was carried out at room temperature for 2 hours. A white solid precipitated. LC / MS showed that the reaction was complete. The reaction solution was concentrated to give crude Int-3 (190 mg, crude product, hydrochloride), which did not require further purification. ESI-MS (m / z): 358.4 [M+H] + .

[0223] Intermediate 4

[0224] Following the synthetic route of intermediate 3, (S)-1-N-Boc-2-methylpiperazine (Int-3a) was replaced with (R)-1-N-Boc-2-methylpiperazine to obtain Int-4 (crude product, hydrochloride). No further purification was required. ESI-MS (m / z): 358.4 [M+H] + .

[0225] Intermediate 5

[0226] Following the synthetic route of intermediate 3, (S)-1-N-Boc-2-methylpiperazine (Int-3a) was replaced with tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate to yield Int-5 (crude, hydrochloride). No further purification was required. ESI-MS (m / z): 370.4 [M+H] + .

[0227] Intermediate 6

[0228] Following the synthetic route of intermediate 3, (S)-1-N-Boc-2-methylpiperazine (Int-3a) was replaced with (2S)-2-(methoxymethyl)-1-piperazine carboxylic acid tert-butyl ester to yield Int-6 (crude product, hydrochloride). No further purification was required. ESI-MS (m / z): 388.4 [M+H] + .

[0229] Intermediate 7

[0230] Following the synthetic route of intermediate 1, N-BOC-piperazine (Int-1a) was replaced with (2R)-2-(methoxymethyl)-1-piperazine carboxylic acid tert-butyl ester to obtain Int-7 (crude product, hydrochloride). No further purification was required. ESI-MS (m / z): 388.3 [M+H] + .

[0231] Intermediate 8

[0232] Intermediate 8 is prepared by the following steps:

[0233] Step A: Int-1a (500 mg, 1.48 mmol), Int-8a (1.18 g, 5.91 mmol), cesium carbonate (1.45 g, 4.44 mmol), and Pd-PEPPSI-IHept-Cl (71.92 mg, 0.074 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, quenched with formic acid, and extracted twice with water and ethyl acetate. The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give the white product Int-8b (250 mg, yield 36.96%). ESI-MS (m / z): 470.3 [M+H] + .

[0234] Step B: Int-8b (250 mg, 0.53 mmol) was dissolved in dichloromethane (2 mL), then trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated to give crude Int-8 (200 mg, crude product, trifluoroacetate). No further purification was required. ESI-MS (m / z): 370.4 [M+H] + .

[0235] Intermediate 9

[0236] Following the synthetic route of intermediate 3, (S)-1-N-Boc-2-methylpiperazine (Int-3a) was replaced with tert-butyl 1,4-diazacycloheptan-1-carboxylate to yield Int-9 (crude, hydrochloride). No further purification was required. ESI-MS (m / z): 358.2 [M+H] + .

[0237] Intermediate 13

[0238] Intermediate 13 is prepared by the following steps:

[0239] Step A: Int-13a (33.6 g, 120.0 mmol) and Int-13b were dissolved in tetrahydrofuran (800 mL). Sodium hydride (7.2 g, 180 mmol, 60% in oil) was added in portions under ice bath conditions. The mixture was brought to room temperature and stirred for approximately 4 hours. LC / MS showed the reaction was complete. The reaction was quenched with aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give Int-13c (56 g, yield: 96.1%). ESI-MS (m / z): 486.2 [M+H] + .

[0240] Step B: At room temperature, Int-13c (52 g, 107.0 mmol) was dissolved in acetonitrile (1000 mL). Triethylamine (25.0 mL, 321.0 mmol) and 1H-benzotriazol-1-yloxytripyrrolyl hexafluorophosphate (111.3 g, 214.00 mmol) were added to the reaction solution. The mixture was heated to 50 °C and reacted for approximately 1 hour. LC / MS showed that the reaction was complete. After cooling to room temperature, the solvent was evaporated under reduced pressure. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to give Int-13d (30 g, yield: 59.9%). ESI-MS (m / z): 468.1 [M+H] + . 1 H NMR (400MHz, CDCl3): δ5.04(dd,J=13.4,2.1Hz,1H),4.49(dd,J=13.3,2.1Hz,1H),4.39(s,1H),4.34–4.21(m,2H),4 .12(dd,J=14.2,7.1Hz,1H),3.18(d,J=11.7Hz,1H),2.60(s,3H),2.05–1.88(m,2H),1.85–1.70(m,2H),1.50(s,9H).19 F NMR (376MHz, CDCl3) δ-140.3.

[0241] Step C: Int-13d (30 g, 64.1 mmol) was dissolved in ethyl acetate (400 mL). Under ice bath conditions, m-chloroperoxybenzoic acid (26.5 g, 160.3 mmol) was added in portions, and the reaction was carried out at this temperature for approximately 1 hour. LC / MS showed the reaction was complete. The mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 2 / 1) to give Int-13e (24.2 g, yield: 75.5%). ESI-MS (m / z): 500.1 [M+H] + .

[0242] Step D: Int-13e (25 g, 50.0 mmol) and Int-13f (25.5 g, 75.0 mmol) were dissolved in tetrahydrofuran (250 mL), and the mixture was cooled to 0 °C in an ice bath. Bistrimethylsilylaminolithium (1.0 M tetrahydrofuran solution) (150.02 mL, 150.0 mmol) was added dropwise to the reaction mixture. After completion, the mixture was stirred at this temperature for approximately 1 hour. LC / MS showed that the reaction was complete. The reaction was quenched by adding ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 2 / 1) to give Int-13g (24 g, yield: 63.1%). ESI-MS (m / z): 760.4 [M+H] + . 1 H NMR (400MHz, CDCl3): δ7.68–7.57(m,4H),7.41–7.27(m,6H),4.97(dd,J=13.4,1.9Hz,1H),4.51–4.43(m,3H),4.25(dd,J=13.3,7.1Hz,2H),4.10 (d,J=7.1Hz,1H),3.72(s,2H),3.16(d,J=12.8Hz,1H),2.02–1.85(m,2H ),1.82–1.69(m,2H),1.02(s,9H),0.66–0.59(m,2H),0.59–0.52(m,2H). 19 F NMR (376MHz, CDCl3): δ-140.6.

[0243] Step E: At room temperature, Int-13 g (25 g, 32.9 mmol) was dissolved in tetrahydrofuran (200 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) (65.8 mL, 65.8 mmol) was added dropwise to the reaction solution. The reaction was carried out at 25 °C for about 2 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was subjected to silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 30 / 1) to give Int-13h (5.9 g, yield: 34.4%). ESI-MS (m / z): 522.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ4.91(dd,J=13.4,1.7Hz,1H),4.64(dt,J=7.9,3.8Hz,2H),4.47(dd,J=13.4,7.4Hz,1H),4.35–4.23(m,4H),4.04(d,J=7.1Hz ,1H),3.42–3.34(m,2H),3.10(d,J=12.6Hz,1H),1.88(d,J=6.0Hz,1H),1. 80–1.63(m,3H),1.44(s,9H),0.56(t,J=4.8Hz,2H),0.52(t,J=4.9Hz,2H).

[0244] Step F: At room temperature, Int-13h (500 mg, 0.96 mmol), Int-13i (414.08 mg, 1.15 mmol), and potassium phosphate (610.01 mg, 2.87 mmol) were dissolved in 5 mL of water and 1 mL of water. CataCXium A Pd G3 (139.52 mg, 0.19 mmol) was added. Nitrogen was purged three times. The reaction mixture was reacted at 85 °C for 16 hours. LC / MS did not show the molecular weight of the product. Thin-layer chromatography (TLC) showed that the starting material reacted completely and new spots were formed. The reaction mixture was concentrated, and the crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 3 / 1) to give Int-13j (540 mg, yield: 78.32%).

[0245] Step G: At room temperature, Int-13j (540 mg, 0.75 mmol) was dissolved in dichloromethane (6 mL), and Dysmartin oxidant (636.41 mg, 1.50 mmol) was added. The reaction was carried out for approximately 2 hours. LC / MS showed that the reaction was complete. Sodium bicarbonate aqueous solution was added dropwise to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was then subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give product Int-13 (400 mg, yield: 74.28%). ESI-MS (m / z): 718.4 [M+H] + .

[0246] Intermediate 14

[0247] Intermediate 14 is prepared by the following steps:

[0248] Step A: At room temperature, Int-2a (1.14 g, 4.53 mmol) was dissolved in dichloromethane (10 mL). N,N-diisopropylethylamine (1.76 g, 13.58 mmol, 2.37 mL) was added to the reaction solution, and the mixture was cooled to -70 °C with ethanol / dry ice. Int-14a (1.0 g, 4.08 mmol) was dissolved in dichloromethane (8 mL) and slowly added dropwise to the reaction solution. The reaction was allowed to proceed at this temperature for approximately 0.5 hours. LC / MS showed that the reaction was complete. The reaction solution was then subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 5 / 1) to give a white solid Int-14b (1.7 g, yield: 81.37%). ESI-MS (m / z): 461.3 [M+H] + .

[0249] Step B: Under ice bath conditions, Int-14b (1.7 g, 3.68 mmol) was dissolved in tetrahydrofuran (10 mL) and dichloromethane (10 mL). Cesium carbonate (3.6 g, 11.05 mmol) and triethylenediamine (41.33 mg, 0.37 mmol, 0.04 mL) were added sequentially, followed by Int-2d (8.28 g, 81.06 mol, 7.77 mL). The reaction was carried out at 0 °C for 20 minutes. LC / MS showed the reaction was complete. Water was added to the reaction solution, and a pale yellow solid precipitated. The solid was filtered, the filter cake was washed several times with water, and dried under vacuum to obtain product Int-14c (600 mg, crude product), which required no further purification. ESI-MS (m / z): 527.4 [M+H] + .

[0250] Step C: Under nitrogen protection, Int-14c (600 mg, 1.14 mmol), Int-2f (700.18 mg, 1.37 mmol), cataCXium A Pd G3 (165.82 mg, 0.23 mmol), potassium phosphate (724.96 mg, 3.42 mmol), dioxane (5 mL), and water (1 mL) were added to the reaction flask. The mixture was stirred overnight at 85 °C under nitrogen protection. LC / MS showed the reaction was complete. The sample was directly stirred and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a brown solid Int-14d (950 mg, yield 95.14%). ESI-MS (m / z): 614.7 [M+H] + .

[0251] Step D: Dissolve Int-14d (950 mg, 1.08 mmol) in dichloromethane (10 mL), add Dys-Martin oxidant (918.73 mg, 11.85 mmol) under ice bath, react at room temperature for one hour, and TLC shows a new spot. Wash the reaction solution twice with saturated sodium bicarbonate aqueous solution, once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate and purify by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain Int-14e (700 mg, yield 73.85%).

[0252] Step E: Int-14e (700 mg, 0.80 mmol) was dissolved in tetrahydrofuran (7 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) (1.2 mL) was added under ice bath conditions. The reaction was carried out at room temperature for 0.5 hours. LC / MS showed that the reaction was complete. The sample was directly stirred and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give the white product Int-14 (500 mg, yield 86.96%). ESI-MS (m / z): 718.6 [M+H] + .

[0253] Intermediate 15

[0254] Intermediate 15 is prepared by the following steps:

[0255] Step A: Int-15a (1.8 g, 5.88 mmol) and Int-15b (1.55 g, 7.05 mmol) were dissolved in tetrahydrofuran (30 mL), and the solution was cooled to -78 °C in an ice bath. Bistrimethylsilylaminolithium (1.0 M tetrahydrofuran solution) (150.02 mL, 150.0 mmol) was slowly added dropwise to the reaction solution. After completion, the reaction was stirred at this temperature for approximately 2 hours. LC / MS showed that the reaction was complete. The reaction was quenched with water. The mixture was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 2 / 1) to give Int-15c (2.2 g, yield: 73.82%). ESI-MS (m / z): 506.2 [M+H] + .

[0256] Step B: At room temperature, Int-15c (2.2 g, 4.34 mmol) was dissolved in ethanol (30 mL) and water (30 mL). Ammonium chloride (1.16 g, 21.72 mmol) and iron powder (1.21 g, 21.72 mmol) were added to the reaction solution. The reaction was carried out at 80 °C for about 2 hours. LC / MS showed that the reaction was complete. The reaction solution was filtered through diatomaceous earth, and the crude product obtained after concentration was subjected to silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 30 / 1) to give Int-15d (1.8 g, yield: 86.97%). ESI-MS (m / z): 476.2 [M+H] + .

[0257] Step C: At room temperature, Int-15d (2.0 g, 4.20 mmol) was dissolved in N,N-dimethylformamide (30 mL), and N,N'-carbonyldiimidazole (3.40 g, 20.99 mmol) was added. The reaction solution was allowed to react at room temperature for approximately 16 hours. LC / MS showed that the reaction was complete. Water and dichloromethane were added to the reaction solution, resulting in the precipitation of a large amount of solid. The mixture was filtered through diatomaceous earth, and the organic phase was collected. The crude product obtained after concentration was subjected to silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 30 / 1) to give Int-15e (1.7 g, yield: 80.60%). ESI-MS (m / z): 502.2 [M+H] + .

[0258] Step D: At room temperature, Int-15e (900 mg, 1.79 mmol) was dissolved in N,N-dimethylformamide (10 mL), cooled to 0°C in an ice bath, and sodium hydride (120.39 mg, 5.02 mmol, 60%) was added in portions. The reaction mixture was allowed to react at this temperature for approximately 30 minutes. Iodoethane (419.13 mg, 2.69 mmol, 0.22 mL) was added dropwise to the reaction mixture. The reaction was allowed to proceed at room temperature for approximately 2 hours. LC / MS showed that the reaction was complete. Water and dichloromethane were added to the reaction mixture, the organic phases were combined, and the crude product obtained after concentration was subjected to silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 30 / 1) to give Int-15f (680 mg, yield: 71.56%). ESI-MS (m / z): 530.2 [M+H] + .

[0259] Step E: Int-15f (500 mg, 0.94 mmol), Int-1b (210.69 mg, 1.13 mmol), sodium tert-butoxide (271.78 mg, 2.83 mmol), and RuPhos Pd G3 (78.84 mg, 0.094 mmol) were dissolved in 1,4-dioxane (7.5 mL), and the mixture was stirred at 90 °C for 16 hours under nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature and quenched with methyl tert-butyl ether, resulting in the precipitation of a large amount of white solid. The mixture was filtered, the filter cake was collected and dried to obtain Int-15 g (200 mg, crude product). ESI-MS (m / z): 546.4 [M-Bn] + .

[0260] Step F: Int-15 g (200 mg, 0.31 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (2.5 mL) and isopropanol (0.5 mL). 10% palladium on carbon catalyst (133.91 mg, 1.26 mmol) was added, and the mixture was purged with hydrogen three times. The mixture was then stirred at 45 °C for 16 hours. LC / MS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, quenched with water, extracted with dichloromethane, and the organic phases were combined, washed with brine, concentrated, and the crude product was subjected to silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give Int-15 h (100 mg, yield: 67.39%). ESI-MS (m / z): 458.4 [M+H] + .

[0261] Step G: Int-15h (100 mg, 0.22 mmol) was dissolved in dichloromethane (1.0 mL). Dioxane hydrochloride (4.0 M) (1.0 mL) was added dropwise to the reaction solution, resulting in the precipitation of a large amount of solid. The reaction was stirred at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was directly concentrated to obtain Int-15 (85 mg, crude product, hydrochloride). ESI-MS (m / z): 358.1 [M+H] + .

[0262] Intermediate 16

[0263] Intermediate 16 is prepared by the following steps:

[0264] Step A: Under nitrogen protection, Int-13h (1.0 g, 1.92 mmol), Int-2f (1.18 g, 2.30 mmol), cataCXium A Pd G3 (279.05 mg, 0.38 mmol), potassium phosphate (1.22 g, 5.75 mmol), dioxane (10 mL), and water (2.5 mL) were added to the reaction flask. The mixture was stirred overnight at 85 °C under nitrogen protection. TLC showed that the reaction was complete and new spots were formed. The sample was directly stirred and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a brown solid Int-16a (1.67 g, yield 99.36%).

[0265] Step B: Int-16a (1.66 g, 1.90 mmol) was dissolved in dichloromethane (16 mL), and Dys-Martin oxidant (1.61 g, 3.81 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for one hour. TLC showed that the reaction was complete and new spots were formed. The reaction solution was washed twice with saturated sodium bicarbonate aqueous solution and once with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain Int-16b (1.66 g, yield 93.59%).

[0266] Step C: Int-16b (1.55 g, 1.78 mmol) was dissolved in tetrahydrofuran (15 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) (3.56 mL) was added under ice bath conditions. The reaction was carried out at room temperature for 0.5 hours. LC / MS showed that the reaction was complete. The sample was directly stirred and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 10) to give the yellow product Int-16 (1.20 g, yield 94.38%). ESI-MS (m / z): 714.4 [M+H] + .

[0267] Intermediate 17

[0268] Intermediate 17 is prepared by the following steps:

[0269] Step A: Compound 17a (23 g, 96.64 mmol) was dissolved in N,N-dimethylformamide (50 mL) in a sealed tube. Then, N,N-diisopropylethylamine (62.45 g, 483.2 mmol) and methylamine hydrochloride (19.57 g, 289.93 mmol) were added. The tube was capped and the mixture was stirred in an oil bath at 80 °C for 6 hours. LC / MS showed the reaction was complete. After cooling, the mixture was diluted with ethyl acetate, washed twice with water, washed with saturated sodium chloride, dried, concentrated, and subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to give an orange oil, 17b (23 g, yield: 95.56%). 1 H NMR (400MHz, CDCl3) δ7.68 (dd, J = 8.2, 3.0Hz, 1H), 7.54 (dd, J = 7.1, 3.1Hz, 1H), 6.05 (s, 1H), 3.00 (d, J = 5.4Hz, 3H).

[0270] Step B: Compound 17b (22 g, 88.34 mmol) was dissolved in ethanol (200 mL), acetic acid (200 mL), and water (100 mL). The solution was cooled to 0 °C, and iron powder (23.6 mg, 422.56 mmol) was added. The reaction was stirred at room temperature for 0.5 hours. LC / MS showed the reaction was complete. The solution was concentrated, and ethyl acetate and water were added. The pH was adjusted to 8-9 with sodium carbonate solution, and the mixture was filtered. The extract was then extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 7 / 3) to give an orange oil, 17c (18.5 g, yield: 95.60%). ESI-MS m / z: 221.0 [M+H] + .

[0271] Step C: Compound 17c (18.5 g, 84.45 mmol) was dissolved in acetonitrile (100 mL), and N,N'-carbonyldiimidazole (27.39 mg, 168.9 mmol) was added. The reaction was stirred at room temperature for 16 hours. LC / MS showed that the reaction was complete. The solid was filtered, washed with acetonitrile, and dried to give a white solid product 17d (18 g, yield: 86.98%). ESI-MS m / z: 245.0 [M+H] + .

[0272] Step D: Compound 17d (10 g, 40.81 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0 °C, and under nitrogen protection, sodium hydride (4.90 g, 122.43 mmol) was added. The reaction was stirred at 0 °C for 0.5 hours, then 17e (23.51 g, 122.43 mmol) was added, and the reaction was stirred at 70 °C for 2 hours. LC / MS showed that the reaction was complete. After cooling to 0 °C, a saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a white solid product 17f (3.5 g, yield: 24.08%). ESI-MS m / z: 356.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),7.26(dd,J=9.0,2.3Hz,1H),7.21(dd,J=9.5,2.3Hz,1H),5.40(dd,J=12.6 ,5.3Hz,1H),3.61(s,3H),2.92–2.80(m,1H),2.80–2.70(m,1H),2.63(dd,J=16.1,2.4Hz,1H),2.08–1.96(m,1H).

[0273] Step E: 17f (1.0 g, 2.81 mmol), Int-1b (1.05 g, 5.62 mmol), Pd-PEPPSI-IHept-Cl (25.71 mg, 0.028 mmol), and cesium carbonate (2.74 g, 8.42 mmol) were dissolved in N,N-dimethylformamide (12 mL) and stirred at 120 °C for 16 hours under nitrogen atmosphere. LC / MS showed that the reaction was complete (product +18, ring-opening product). The reaction solution was cooled to room temperature, quenched with formic acid, and water was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product (600 mg, crude product). The crude product was dissolved in acetonitrile (10 mL) and (2 mL), and N,N'-carbonyldiimidazole (405.8 mg, 2.50 mmol) was added. The mixture was reacted at 70 °C for 2 hours. LC / MS showed the reaction was complete. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined. The crude product was concentrated and purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give 17 g (570 mg, overall yield of two steps: 44.01%). ESI-MS (m / z): 462.3 [M+H] + .

[0274] Step C: Dissolve 17 g (500 mg, 1.08 mmol) in dichloromethane (4 mL). Slowly add hydrochloric acid-dioxane solution (4.0 M) (4 mL) to the reaction solution and stir at room temperature for 2 hours. LC / MS showed that the reaction was complete. Concentrate the reaction solution to give 17 g (360 mg, crude product, hydrochloride). ESI-MS (m / z): 362.2 [M+H] + .

[0275] Intermediate 18

[0276] Intermediate 18 is prepared by the following steps:

[0277] Step A: Compound Int-18a (8 g, 33.60 mmol) was dissolved in N-methylpyrrolidone (100 mL). Potassium carbonate (13.92 g, 100.88 mmol) and methylamine hydrochloride (2.50 g, 36.96 mmol) were added to the reaction solution, and the mixture was stirred in an oil bath at 100 °C for 16 hours. LC / MS showed that the reaction was complete. After cooling, the mixture was diluted with ethyl acetate, washed twice with water, washed with saturated sodium chloride, dried, concentrated, and subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to give an orange oil, Int-18b (8 g, yield: 95.24%). ESI-MS m / z: 251.0 [M+H] + .

[0278] Step B: Compound Int-18b (8 g, 32.12 mmol) was dissolved in methanol (120 mL). Sodium methoxide (3.47 g, 64.25 mmol) was added to the reaction solution, and the mixture was stirred in an oil bath at 70 °C for 6 hours. LC / MS showed that the reaction was complete. After cooling, the mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to give Int-18c (7.5 g, yield: 89.39%). ESI-MS m / z: 263.0 [M+H] + .

[0279] Step C: Compound Int-18c (7.5 g, 28.73 mmol) was dissolved in ethanol (80 mL) and water (15 mL). Iron powder (4.81 g, 86.18 mmol) and ammonium chloride (4.61 g, 86.18 mmol) were added, and the reaction was stirred at 60 °C for 5 hours. LC / MS showed the reaction was complete. After cooling to room temperature, the mixture was concentrated, and after adding ethyl acetate and water, it was filtered, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 3 / 1) to give Int-18d (3.4 g, yield: 51.22%). ESI-MS m / z: 233.0 [M+H] + .

[0280] Step D: Compound Int-18d (3.4 g, 14.71 mmol) was dissolved in acetonitrile (50 mL), and N,N'-carbonyldiimidazole (7.16 g, 44.14 mmol) was added. The reaction was stirred at 80 °C for 16 hours. LC / MS showed that the reaction was complete. The solution was concentrated, water was added, and the mixture was filtered to obtain a solid product. After drying, product Int-18e (3.5 g, crude product) was obtained. ESI-MS m / z: 259.0 [M+H] + .

[0281] Step E: Compound Int-18e (800 mg, 3.11 mmol) was dissolved in tetrahydrofuran (10 mL). After cooling to 0 °C and under nitrogen protection, sodium tert-butoxide (747.64 mg, 7.78 mmol) was added, and the reaction was stirred at 0 °C for 0.5 hours. Then, Int-17e (1.20 g, 6.22 mmol) was added, and the reaction was stirred at 70 °C for 4 hours. LC / MS showed that the reaction was complete. After cooling to 0 °C, a saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-18f (600 mg, yield: 52.17%). ESI-MS m / z: 370.1 [M+H] + .

[0282] Step F: Int-18f (600 mg, 1.63 mmol), Int-1b (607.04 mg, 3.26 mmol), Pd-PEPPSI-IHept-Cl (74.56 mg, 0.081 mmol), and sodium tert-butoxide (1.59 g, 16.57 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at 120 °C for 16 hours under nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, quenched with formic acid, and then extracted with water and ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give Int-18g (500 mg, yield: 64.79%). ESI-MS (m / z): 474.3 [M+H] + .

[0283] Step G: Dissolve Int-18 g (500 mg, 1.06 mmol) in dichloromethane (2 mL), and slowly add (1 mL) dropwise to the reaction solution. Stir the mixture at room temperature for 1 hour. LC / MS showed that the reaction was complete. Concentrate the reaction solution to obtain Int-18 (280 mg, crude product, trifluoroacetate). ESI-MS (m / z): 374.3 [M+H] + .

[0284] Intermediate 19

[0285] Intermediate 19 is prepared by the following steps:

[0286] Step A: Int-19a (14.5 g, 50.11 mmol) was dissolved in tetrahydrofuran (150 mL). Sodium hydride (8.02 g, 200.43 mmol, 60% in oil) was added in portions under ice bath conditions, and the reaction was allowed to proceed for approximately 1 hour at this temperature. Int-13a (14.04 g, 120.0 mmol) was added in portions to the reaction solution. The mixture was brought to room temperature and stirred for approximately 1 hour. LC / MS showed the reaction was complete. The reaction was quenched with an aqueous solution of ammonium chloride. The mixture was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-19b (14 g, yield: 52.42%). 1H NMR (400MHz, DMSO-d6): δ4.25-4.10(m,3H),3.78(d,J=8.2Hz,1H),3.55(d,J=9.0Hz,1H),3.23 (s,1H),2.84-2.68(m,2H),2.55(s,3H),1.93-1.79(m,3H),1.64(d,J=7.4Hz,1H),1.34(s,9H).

[0287] Step B: At room temperature, Int-19b (14 g, 26.26 mmol) was dissolved in chloroform (140 mL). N,N-diisopropylethylamine (22.87 mL, 131.32 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (13.37 g, 52.53 mmol) were added to the reaction solution. The mixture was heated to 65 °C and reacted for approximately 1 hour. LC / MS showed that the reaction was complete. After cooling to room temperature, the solvent was evaporated under reduced pressure. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 3 / 1) to give Int-19c (10 g, yield: 73.93%). 1 H NMR (400MHz, DMSO-d6): δ5.11(d,J=13.2Hz,1H),4.68-4.59(m,1H),4.56-4.47(m,1H),4.30(d,J=5.6Hz,1H),4.09(d,J=7.2Hz,1H), 3.92(d,J=9.6Hz,1H),3.65(d,J=9.4Hz,1H),3.04(d,J=13.4Hz,1H),2.53(s,3H),1.96-1.82(m,2H),1.80-1.63(m,2H),1.45(s,9H).

[0288] Step C: Int-19c (12 g, 23.30 mmol) was dissolved in dichloromethane (120 mL). Under ice bath conditions, m-chloroperoxybenzoic acid (14.19 g, 69.90 mmol) was added in portions, and the reaction was carried out at this temperature for about 2 hours. LC / MS showed that the reaction was complete. The mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 2 / 1) to give Int-19d (9 g, yield: 70.61%). 1H NMR (400MHz, DMSO-d6): δ5.08(d,J=13.4Hz,1H),4.78-4.71(m,1H),4.62-4.57(m,1H),4.42-4.34(m,1H),4.21(d,J=7.4Hz,1H),3. 93(d,J=9.6Hz,1H),3.68(d,J=9.4Hz,1H),3.39(s,3H),3.15(d,J=13.4Hz,1H),2.02-1.93(m,1H),1.91-1.63(m,3H),1.45(s,9H).

[0289] Step D: Int-19d (7.3 g, 13.35 mmol) and Int-2d (2.73 g, 26.69 mmol) were dissolved in tetrahydrofuran (80 mL), cooled to 0 °C in an ice bath, and bis(trimethylsilylaminolithium) (1.0 M tetrahydrofuran solution) (53.38 mL) was added dropwise to the reaction solution. After completion, the reaction was stirred at this temperature for about 1 hour. LC / MS showed that the reaction was complete. The reaction was quenched by adding ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 2 / 1) to give Int-19e (2.28 g, yield: 30.02%). ESI-MS (m / z): 569.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6): δ5.01(d,J=13.2Hz,1H),4.69-4.59(m,2H),4.53-4.48(m,1H),4.35-4.24(m,3H),4.05(d,J=6.8Hz,1H),3.94(d ,J=9.4Hz,1H),3.64(d,J=9.4Hz,1H),3.40-3.38(m,2H),3.04(d,J=13.4Hz,1H),1.99-1.63(m,4H),1.45(s,9H),0.54(d,J=8.7Hz,4H).

[0290] Step E: At room temperature, Int-19e (1.33 g, 2.34 mmol), Int-2f (1.0 g, 1.95 mmol), and potassium phosphate (1.24 g, 5.85 mmol) were dissolved in 10 mL of water and 2.5 mL of cataCXium A Pd G3 (284.18 mg, 0.39 mmol). Nitrogen was purged three times. The reaction mixture was reacted at 85 °C for 16 hours. LC / MS did not show the molecular weight of the product. TLC on a thin-layer plate showed that the starting material had reacted completely and new spots were formed. The reaction mixture was concentrated, and the crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-19f (1.68 g, yield: 93.68%).

[0291] Step F: At room temperature, Int-19f (1.68 g, 1.83 mmol) was dissolved in dichloromethane (17 mL), and Dys-Martin oxidant (1.55 g, 3.66 mmol) was added. The reaction was carried out for about 3 hours. TLC showed that the reaction was complete. Sodium bicarbonate aqueous solution was added dropwise to the reaction solution, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated and subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 5 / 1) to give product Int-19g (1.5 g, yield: 89.48%).

[0292] Step G: Dissolve 1.5 g (1.64 mmol) of Int-19 in 15 mL of tetrahydrofuran, and add 3.56 mL of tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) under ice bath conditions. React at room temperature for 0.5 h. LC / MS showed the reaction was complete. The sample was directly mixed and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 10) to give the yellow product Int-19 (1.22 g, yield 98.05%). ESI-MS (m / z): 761.4 [M+H] + .

[0293] Intermediate 20

[0294] Intermediate 20 is prepared by the following steps:

[0295] Step A: Under ice bath conditions, Int-2c (4.6 g, 10.74 mmol) was dissolved in tetrahydrofuran (20 mL) and dichloromethane (20 mL). Cesium carbonate (10.5 g, 32.22 mmol) and triethylenediamine (120.48 mg, 1.07 mmol, 0.12 mL) were added sequentially, followed by Int-20a (21.29 g, 236.29 mmol, 20 mL). The reaction was carried out at 0 °C for 20 minutes. LC / MS showed the reaction was complete. Water was added to the reaction solution, and a pale yellow solid precipitated. The solid was filtered, the filter cake was washed several times with water, and dried under vacuum to obtain product Int-20b (5.1 g, crude product), which required no further purification. ESI-MS (m / z): 482.3 [M+H] + .

[0296] Step B: Under nitrogen protection, Int-20b (3.1 g, 6.43 mmol), Int-2f (3.96 g, 7.72 mmol), cataCXium A Pd G3 (0.94 g, 1.29 mmol), potassium phosphate (4.10 g, 19.30 mmol), dioxane (15 mL), and water (3 mL) were added to the reaction flask. The mixture was stirred overnight at 85 °C under nitrogen protection. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and stirred. Silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) was performed to give the brown product Int-20c (4.0 g, yield: 74.74%). ESI-MS (m / z): 832.5 [M+H] + .

[0297] Step C: Dissolve Int-20c (2g, 2.40mmol) in dichloromethane (20mL), add Dysmart oxidant (2.04g, 4.81mmol) under ice bath, react at room temperature for 1 hour, and LC / MS shows that the reaction is complete. Wash the reaction solution twice with saturated sodium bicarbonate aqueous solution, once with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate and purify by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain Int-20 (1.6g, yield: 80.19%).

[0298] Intermediate 21

[0299] Following the synthetic route of intermediate 3, (S)-1-N-Boc-2-methylpiperazine (Int-3a) was replaced with 1-Boc-2,2-dimethylpiperazine to obtain Int-21 (crude product, hydrochloride). No further purification was required. ESI-MS (m / z): 372.1 [M+H] + .

[0300] Intermediate 22

[0301] Intermediate 22 is prepared by the following steps:

[0302] Step A: Under ice bath conditions, Int-2c (2 g, 4.67 mmol) was dissolved in tetrahydrofuran (10 mL) and dichloromethane (10 mL). Cesium carbonate (4.56 g, 14.01 mmol) and triethylenediamine (52.38 mg, 0.47 mmol, 0.05 mL) were added sequentially, followed by Int-22a (10.36 g, 99.47 mmol, 10 mL). The reaction was carried out at 0 °C for 20 minutes. LC / MS showed the reaction was complete. Water was added to the reaction solution, and a pale yellow solid precipitated. The solid was filtered, the filter cake was washed several times with water, and dried under vacuum to obtain product Int-22b (1.85 g, crude product), which required no further purification. ESI-MS (m / z): 496.3 [M+H] + .

[0303] Step B: Under nitrogen protection, Int-22b (1.85 g, 3.72 mmol), Int-2f (2.29 g, 4.47 mmol), cataCXium A Pd G3 (0.54 g, 0.74 mmol), potassium phosphate (2.37 g, 11.17 mmol), dioxane (20 mL), and water (4 mL) were added to the reaction flask. Under nitrogen protection, the mixture was stirred overnight at 85 °C. TLC showed a new reaction point. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. After drying the organic phase with anhydrous sodium sulfate, the sample was mixed and subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give the brown product Int-22c (1.3 g, yield: 41.26%).

[0304] Step C: Int-22c (1 g, 1.18 mmol) was dissolved in dichloromethane (15 mL), and Dysmart oxidant (1 g, 2.36 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 1 hour. TLC showed that the reaction was complete and new spots were formed. The reaction solution was washed twice with saturated sodium bicarbonate aqueous solution, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain Int-22d (980 mg, yield: 98.23%).

[0305] Step D: Int-22d (500 mg, 0.59 mmol) was dissolved in tetrahydrofuran (7.5 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) (1.18 mL) was added under ice bath conditions. The reaction was carried out at room temperature for 0.5 hours. LC / MS showed that the reaction was complete. The sample was directly stirred and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give the yellow product Int-22 (330 mg, yield: 81.00%). ESI-MS (m / z): 688.4 [M+H] + .

[0306] Intermediate 23

[0307] Intermediate 23 is prepared by the following steps:

[0308] Step A: Under ice bath conditions, Int-2c (2 g, 4.67 mmol) was dissolved in tetrahydrofuran (10 mL) and dichloromethane (10 mL). Cesium carbonate (4.56 g, 14.01 mmol) and triethylenediamine (52.38 mg, 0.47 mmol, 0.05 mL) were added sequentially, followed by Int-23a (11.55 g, 99.47 mmol, 10 mL). The reaction was carried out at 0 °C for 20 minutes. LC / MS showed the reaction was complete. Water was added to the reaction solution, and a pale yellow solid precipitated. The solid was filtered, the filter cake was washed several times with water, and dried under vacuum to obtain product Int-23b (1.12 g, crude product), which required no further purification. ESI-MS (m / z): 508.3 [M+H] + .

[0309] Step B: Under nitrogen protection, Int-23b (671.41 mg, 1.32 mmol), Int-2f (812.91 mg, 1.59 mmol), cataCXium A Pd G3 (192.51 mg, 0.26 mmol), potassium phosphate (841.69 mg, 3.97 mmol), dioxane (10 mL), and water (2 mL) were added to the reaction flask. Under nitrogen protection, the mixture was stirred overnight at 85 °C. TLC showed a new reaction point. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and then mixed. Silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) yielded the brown product Int-23c (670 mg, yield: 59.07%).

[0310] Step C: Int-23c (650 mg, 0.76 mmol) was dissolved in dichloromethane (10 mL), and Dysmart oxidant (642.56 mg, 1.51 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 1 hour. TLC showed that the reaction was complete and new spots were formed. The reaction solution was washed twice with saturated sodium bicarbonate aqueous solution, once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain Int-23d (630 mg, yield: 97.15%).

[0311] Step D: Int-23d (500 mg, 0.58 mmol) was dissolved in tetrahydrofuran (7.5 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) (1.18 mL) was added under ice bath conditions. The reaction was carried out at room temperature for 0.5 hours. LC / MS showed that the reaction was complete. The sample was directly stirred and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give the yellow product Int-23 (350 mg, yield: 85.64%). ESI-MS (m / z): 700.4 [M+H] + .

[0312] Intermediate 24

[0313] Intermediate 24 is prepared by the following steps:

[0314] Step A: Under nitrogen atmosphere, Int-2f (23 g, 44.88 mmol) was dissolved in N,N-dimethylformamide (115 mL), and cesium fluoride (102.25 g, 673.13 mmol) was added. The reaction was carried out at 25 °C for 60 hours. LC / MS showed that the reaction was complete. Water and ethyl acetate were added to the reaction solution, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 4) to give the pale yellow solid product Int-24a (14.9 g, yield: 91.35%). 1 H NMR (400MHz, CDCl3) δ7.72 (dd, J=5.8, 9.0Hz, 1H), 7.49 (d, J=2.4Hz, 1H), 7.41 (d, J= 2.4Hz,1H),7.26-7.21(m,1H),5.29(s,2H),3.69(s,1H),3.51(s,3H),1.45(s,12H).

[0315] Step B: Under nitrogen protection, Int-24a (7.1 g, 19.88 mmol) was dissolved in acetonitrile (90 mL), and potassium carbonate (8.24 g, 59.63 mmol) and D2O (80 mL) were added separately. The reaction was carried out at 25 °C for 24 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was washed with ethyl acetate. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was then subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 4) to give the brown product Int-24b (6.1 g, yield: 82.93%). 1 H NMR (400MHz, CDCl3) δ7.77 (dd, J=5.8, 9.0Hz, 1H), 7.54 (d, J=2.4Hz, 1H), 7.46 (d,J=2.6Hz,1H),7.33-7.29(m,1H),5.33(s,2H),3.56(s,3H),1.50(s,12H).

[0316] Step C: Under argon atmosphere, Pd / C (1.82 g, 1.71 mmol) was dissolved in deuterated methanol (20 mL). A solution of Int-24b (6.1 g, 17.08 mmol) dissolved in deuterated methanol (20 mL) was added to the suspension. The mixture was purged three times with deuterium (30 Psi.) and reacted at room temperature for 1 hour. LC-MS showed the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product, which was then subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 20 / 1) to give a white solid product Int-24 (3.39 g, yield: 51.04%). ESI-MS (m / z): 366.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.58 (dd, J=5.8, 9.0Hz, 1H), 7.42-7.37 (m, 2H), 7.21 (t, J=9.2Hz, 1H), 5.28 (s, 2H), 3.51 (s, 3H), 1.45 (s, 12H).

[0317] Intermediate 25

[0318] Intermediate 25 is prepared by the following steps:

[0319] Step A: Int-13a (1.25 g, 4.45 mmol) and Int-25a (950 mg, 3.71 mmol) were dissolved in tetrahydrofuran (15 mL). Sodium hydride (592.90 mg, 14.82 mmol, 60% in oil) was added in portions under ice bath conditions. The mixture was brought to room temperature and stirred for approximately 4 hours. LC / MS showed the reaction was complete. The reaction was quenched with aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product, Int-25b (2.5 g, crude), required no further purification. ESI-MS (m / z): 500.2 [M+H] + .

[0320] Step B: At room temperature, Int-25b (2.5 g, 5.0 mmol, crude product) was dissolved in dichloromethane (30 mL). N,N-diisopropylethylamine (13.06 mL, 75.0 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (5.09 g, 20.0 mmol) were added to the reaction solution. The reaction was allowed to proceed for approximately 16 hours at room temperature. LC / MS showed the reaction was complete. After cooling to room temperature, the solvent was evaporated under reduced pressure. The crude product was then subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 2 / 1) to give Int-25c (1.8 g, yield: 74.69%). ESI-MS (m / z): 482.2 [M+H] + .

[0321] Step C: Int-25c (1.8 g, 3.73 mmol) was dissolved in ethyl acetate (30 mL). Under ice bath conditions, m-chloroperoxybenzoic acid (1.93 g, 11.2 mmol) was added in portions, and the reaction was carried out at this temperature for approximately 1 hour. LC / MS showed the reaction was complete. The mixture was quenched with water, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-25d (1.4 g, yield: 72.94%). ESI-MS (m / z): 514.2 [M+H] + .

[0322] Step D: Int-25d (1.4 g, 2.72 mmol) and Int-13f (884.14 mg, 4.09 mmol) were dissolved in tetrahydrofuran (15 mL), cooled to 0 °C in an ice bath, and bis(trimethylsilylaminolithium) (1.0 M tetrahydrofuran solution) (8.17 mL, 8.17 mmol) was added dropwise to the reaction solution. After completion, the reaction was stirred at this temperature for about 1 hour. TLC showed that the reaction was complete. The reaction was quenched by adding ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 4 / 1) to give Int-25e (1.5 g, yield: 71.11%).

[0323] Step E: At room temperature, Int-25e (1.5 g, 1.94 mmol) was dissolved in tetrahydrofuran (15 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) (5.81 mL, 5.81 mmol) was added dropwise to the reaction solution. The reaction was carried out at 25 °C for about 2 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 3) to give Int-25f (860 mg, yield: 82.83%). ESI-MS (m / z): 536.3 [M+H] + .

[0324] Step F: At room temperature, Int-25f (200 mg, 0.37 mmol) was dissolved in dichloromethane (3 mL), and Dysmartin oxidant (316.53 mg, 0.75 mmol) was added. The reaction was allowed to proceed for approximately 2 hours. LC / MS showed the reaction was complete. Sodium bicarbonate aqueous solution was added dropwise to the reaction mixture, followed by two extractions with dichloromethane. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product Int-25 (180 mg, crude product). No further purification was required. ESI-MS (m / z): 534.3 [M+H] + .

[0325] Intermediate 26

[0326] Intermediate 26 is prepared by the following steps:

[0327] Step A: Under nitrogen protection, Int-2e (300 mg, 0.61 mmol), Int-26a (255.2 mg, 0.73 mmol), cataCXium A Pd G3 (88.46 mg, 0.12 mmol), potassium phosphate (386.76 mg, 1.82 mmol), dioxane (2.5 mL), and water (0.5 mL) were added to the reaction flask. The mixture was stirred overnight at 85 °C under nitrogen protection. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 2) to give the brown solid product Int-26b (350 mg, yield 84.54%). ESI-MS (m / z): 682.4 [M+H] + .

[0328] Step B: Int-26b (350 mg, 0.51 mmol) was dissolved in dichloromethane (4 mL), and Dysmartin oxidant (435.53 mg, 1.03 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 2 hours. LC / MS showed that the reaction was complete. The reaction solution was washed twice with saturated sodium bicarbonate aqueous solution and once with saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain Int-26 (300 mg, yield: 85.97%). ESI-MS (m / z): 680.1 [M+H] + .

[0329] Intermediate 27

[0330] Using the synthetic route of intermediate 1, N-BOC-piperazine (Int-1a) was replaced with (2S,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester.

[0331] Int-27 (crude, hydrochloride) was obtained. No further purification was required. ESI-MS (m / z): 372.4 [M+H] + .

[0332] Intermediate 28

[0333] Following the synthetic route of intermediate 1, N-BOC-piperazine (Int-1a) was replaced with (S)-1-Boc-2-ethylpiperazine to obtain Int-28 (crude, hydrochloride). No further purification was required. ESI-MS (m / z): 372.3 [M+H] + .

[0334] Intermediate 29

[0335] Following the synthetic route of intermediate 1, N-BOC-piperazine (Int-1a) was replaced with (R)-1-Boc-2-ethylpiperazine to obtain Int-29 (crude, hydrochloride). No further purification was required. ESI-MS (m / z): 372.3 [M+H] + .

[0336] Intermediate 30

[0337] Intermediate 30 is prepared by the following steps:

[0338] Step A: Int-30a (230 mg, 0.71 mmol), Int-1a (239.71 mg, 0.71 mmol), Pd-PEPPSI-IHept-Cl (68.96 mg, 0.071 mmol), and cesium carbonate (692.90 mg, 2.13 mmol) were dissolved in N,N-dimethylformamide (3 mL), and stirred at 100 °C for 16 hours under nitrogen atmosphere. LC / MS showed the product as a +18 ring-opening product. The reaction solution was cooled to room temperature, quenched with formic acid, and water was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was dissolved in acetonitrile (3 mL), and N,N'-carbonyldiimidazole (574.72 mg, 3.54 mmol) was added. LC / MS showed the reaction was complete. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined. The crude product obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give Int-30b (180 mg, overall yield of two steps: 43.65%). ESI-MS (m / z): 582.5 [M+H] + .

[0339] Step B: Int-30b (180 mg, 0.31 mmol) was dissolved in dichloromethane (2 mL). Hydrochloric acid-dioxane solution (4.0 M) (1 mL) was slowly added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction solution was concentrated to obtain Int-30 (160 mg, crude product, hydrochloride). ESI-MS (m / z): 482.4 [M+H] + .

[0340] Intermediate 31

[0341] Intermediate 31 is prepared by the following steps:

[0342] Step A: Int-31a (450 mg, 1.26 mmol), Int-1a (424.50 mg, 1.26 mmol), Pd-PEPPSI-IHept-Cl (122.11 mg, 0.13 mmol), and cesium carbonate (1.23 g, 3.77 mmol) were dissolved in N,N-dimethylformamide (5 mL), and stirred at 100 °C for 16 hours under nitrogen atmosphere. LC / MS showed the product as a +18 ring-opening product. The reaction solution was cooled to room temperature, quenched with formic acid, and water was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was dissolved in acetonitrile (5 mL), and N,N'-carbonyldiimidazole (1.02 g, 6.28 mmol) was added. LC / MS showed the reaction was complete. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined. The crude product obtained by concentration was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give Int-31b (250 mg, overall yield of two steps: 32.34%). ESI-MS (m / z): 616.5 [M+H] + .

[0343] Step B: Int-31b (180 mg, 0.31 mmol) was dissolved in tetrahydrofuran (2 mL). 10% palladium on carbon (1 mL) was added to the reaction solution, and the mixture was purged with hydrogen three times. The mixture was stirred at room temperature for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was filtered and concentrated to obtain Int-31 (90 mg, crude product). ESI-MS (m / z): 482.4 [M+H] + .

[0344] Intermediate 32

[0345] Intermediate 32 is prepared by the following steps:

[0346] Step A: Int-32a (950.6 mg, 4.44 mmol), Int-1a (500 mg, 1.48 mmol), Pd-PEPPSI-IHept-Cl (71.9 mg, 0.074 mmol), cesium carbonate (1.45 g, 4.44 mmol), and N,N-dimethylformamide (3 mL) were added sequentially to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 90 °C and stirred for 16 hours under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, quenched with formic acid, and then water was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to obtain Int-32b (400 mg, yield: 57.37%). ESI-MS (m / z): 472.4 [M+H] + .

[0347] Step B: Dissolve Int-32b (280 mg, 0.59 mmol) in dichloromethane (2 mL), and slowly add hydrochloric acid-dioxane solution (4.0 M, 1 mL) to the reaction solution. Stir the mixture at room temperature for 2 hours. LC / MS showed that the reaction was complete. Concentrate the reaction solution to obtain Int-32 (220 mg, hydrochloride).

[0348] Intermediate 33

[0349] Intermediate 33 is prepared by the following steps:

[0350] Step A: At room temperature, Int-33a (340 mg, 1.05 mmol), Int-1a (295.3 mg, 0.87 mmol), Pd-PEPPSI-IHept-Cl (84.95 mg, 0.087 mmol), cesium carbonate (853.57 mg, 2.62 mmol), and N,N-dimethylformamide (5 mL) were added to a reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 100 °C and stirred for 16 hours under a nitrogen atmosphere. LC / MS showed the product as a +18 ring-opening product. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was dissolved in acetonitrile (5 mL), and N,N'-carbonyldiimidazole (707.99 mg, 4.37 mmol) was added. The mixture was heated to 70 °C and reacted for 5 hours. LC / MS showed the reaction was complete. The reaction solution was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phases were combined. The crude product obtained by concentration was purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give Int-33b (150 mg, overall yield of two-step conversion: 29.53%). ESI-MS (m / z): 582.5 [M+H] + .

[0351] Step B: At room temperature, Int-33b (150 mg, 0.26 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.3 mL) was added. The mixture was stirred for 2 hours, and LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain Int-33 (120 mg, trifluoroacetate). ESI-MS (m / z): 482.4 [M+H] + .

[0352] Intermediate 34

[0353] Intermediate 34 is prepared by the following steps:

[0354] Step A: In a reaction flask, Int-1a (500 mg, 1.48 mmol), Int-34a (821.79 mg, 4.44 mmol), Pd-PEPPSI-IHept-Cl (143.83 mg, 0.15 mmol), cesium carbonate (1.45 mg, 4.44 mmol), and N,N-dimethylformamide (10 mL) were added sequentially. After purging the reaction system with nitrogen, the mixture was heated to 100 °C and stirred for 16 hours under a nitrogen atmosphere. LC / MS showed the formation of a ring-opening product with the target molecular weight of +18. The reaction solution was cooled to room temperature, and formic acid (1 mL) and water (20 mL) were added sequentially. The mixture was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product (1 g, brown oil) was dissolved in acetonitrile (5 mL), and N,N'-carbonyldiimidazole (1.20 g, 7.39 mmol) was added. The mixture was heated to 70 °C and reacted for 16 hours. LC / MS showed that the ring-opening byproduct had been completely converted to the target molecule. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0 to 30%) to give Int-34b (630 mg, overall yield of two-step conversion: 78.47%). ESI-MS (m / z): 443.3 [M+H] + .

[0355] Step B: Int-34b (200 mg, 0.45 mmol) was dissolved in dichloromethane (2 mL), and hydrochloric acid-dioxane solution (4.0 M, 1 mL) was added under ice bath cooling. The mixture was then allowed to react at room temperature for 16 hours, and LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain Int-34c (200 mg), which was used directly in the next step. ESI-MS (m / z): 387.2 [M+H] + .

[0356] Step C: Int-34c (200 mg) and Int-34d (94.01 mg, 0.37 mmol) were dissolved in N,N-dimethylformamide (2 mL), and triethylamine (169.98 mg, 1.68 mmol, 0.23 mL) and HATU (127.75 mg, 0.34 mmol) were added. The reaction was carried out at room temperature for 2 hours, and LC / MS showed that the reaction was complete. The reaction solution was directly purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain Int-34e (110 mg, two-step reaction yield: 39.14%). ESI-MS (m / z): 623.5 [M+H] + .

[0357] Step D: Int-34e (110 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL), and a hydrochloric acid-dioxane solution (4.0 M, 0.5 mL) was added under ice bath cooling. The mixture was then heated to room temperature and reacted for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated to give Int-34 (90 mg, hydrochloride, yield: 91.13%). ESI-MS (m / z): 523.5 [M+H) + .

[0358] Intermediate 35

[0359] Intermediate 35 is prepared by the following steps:

[0360] Step A: Int-10 (210 mg, 0.23 mmol, hydrochloride) and Int-35a (53.74 mg, 0.23 mmol) were dissolved in N,N-dimethylformamide (2 mL), followed by the sequential addition of triethylamine (118.59 mg, 1.17 mmol, 0.16 mL) and HATU (89.12 mg, 0.23 mmol). The reaction mixture was stirred at 25 °C for 2 hours, and LC / MS showed complete reaction. The reaction solution was purified directly by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain Int-35b (140 mg, yield: 95.91%). ESI-MS (m / z): 623.5 [M+H] + .

[0361] Step B: Int-35b (140 mg, 0.22 mmol) was dissolved in dichloromethane (2 mL), and a hydrochloric acid-dioxane solution (4.0 M, 0.7 mL) was added under ice bath cooling. The mixture was then heated to room temperature and reacted for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated to give Int-35 (120 mg, hydrochloride, yield 89.46%). ESI-MS (m / z): 523.4 [M+H] + .

[0362] Intermediate 36

[0363] Intermediate 36 is prepared by the following steps:

[0364] Step A: Dissolve 1a (9 g, 37.61 mmol) and p-toluenesulfonyl hydrazine (7 g, 37.61 mmol) in ethanol (100 mL), and stir at 80 °C for 2 hours. LC / MS showed the reaction was complete. Cool the reaction solution to 0 °C, filter, wash the filter cake with cold ethanol and dry to obtain Int-36a (15 g), which was used directly in the next step. ESI-MS (m / z): 408.2 [M+H] + .

[0365] Step B: Int-36a (15 g), pyridine-4-boronic acid (9.05 g, 73.61 mmol), and cesium carbonate (35.98 g, 110.42 mmol) were dispersed in 1,4-dioxane (100 mL). The reaction mixture was heated to 110 °C and stirred for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated. The residue was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 5 / 1) to give a white solid product Int-36b (1.4 g, yield 10.78%). ESI-MS (m / z): 303.3 [M+H] + .

[0366] Step C: Int-36b (1.4 g, 4.63 mmol) was dissolved in methanol (30 mL), and 10% palladium on carbon (492.67 mg), acetic acid (278 mg, 4.63 mmol), and platinum dioxide (315.38 mg, 1.39 mmol) were added. The reaction system was purged with hydrogen and reacted at 30 °C for 48 hours under a hydrogen atmosphere (50 psi). LC / MS showed that the reaction was complete. The reaction solution was filtered, the filtrate was concentrated, the residue was alkalized with 2N sodium hydroxide aqueous solution, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain Int-36c (720 mg), which was directly used in the next step of the reaction. ESI-MS (m / z): 309.3 [M+H] + .

[0367] Step D: Int-36c (100 mg, 0.32 mmol), Int-1a (131.55 mg, 0.36 mmol), cesium carbonate (316.89 mg, 0.97 mmol), Pd-PEPPSI-IHept-Cl (29.66 mg, 0.032 mmol), and N,N-dimethylformamide (2 mL) were added sequentially to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 130 °C under nitrogen atmosphere and stirred for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give the white product Int-36d (70 mg, yield 38.17%). ESI-MS (m / z): 566.5 [M+H] + .

[0368] Step E: Int-36d (70 mg, 0.12 mmol) was dissolved in dichloromethane (1 mL), and hydrochloric acid-dioxane solution (4.0 M, 1 mL) was added under ice bath cooling. The mixture was then allowed to return to room temperature and reacted for 1 hour. A white solid precipitated, and LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain Int-36 (80 mg, hydrochloride), which required no further purification. ESI-MS (m / z): 466.4 [M+H] + .

[0369] Intermediate 37

[0370] Intermediate 37 is prepared by the following steps:

[0371] Step A: Int-37a (950.6 mg, 4.44 mmol), Int-1a (500 mg, 1.48 mmol), PEPPSI-IHept-Cl (71.9 mg, 0.074 mmol), cesium carbonate (1.45 g, 4.44 mmol), and N,N-dimethylformamide (3 mL) were added sequentially to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 90 °C and stirred for 16 hours under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, and formic acid (1 mL) and water (20 mL) were added sequentially. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative thin-layer chromatography (developing solvent: dichloromethane / methanol (V / V) = 20 / 1) to obtain Int-37b (180 mg, yield: 25.82%). ESI-MS (m / z): 472.4 [M+H] + .

[0372] Step B: Dissolve Int-37b (180 mg, 0.38 mmol) in dichloromethane (2 mL), add hydrochloric acid-dioxane solution (4.0 M, 1 mL) under ice bath cooling, and then allow the mixture to return to room temperature for 1 hour. LC / MS showed that the reaction was complete. Concentrate the reaction solution to obtain Int-37 (140 mg, hydrochloride).

[0373] Intermediate 38

[0374] Intermediate 38 is prepared by the following steps:

[0375] Step A: Int-38a (300 mg, 0.93 mmol), Int-1a (471.9 mg, 1.40 mmol), cesium carbonate (909.3 mg, 2.79 mmol), PEPPSI-I Hept-Cl (85.1 mg, 0.093 mmol), and N,N-dimethylformamide (6 mL) were added sequentially to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 100 °C and stirred for 16 hours under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give the white product Int-38b (130 mg, yield: 24.10%).

[0376] Step B: Int-38b (100 mg, 0.17 mmol) was dissolved in dichloromethane (1 mL), and hydrochloric acid-dioxane solution (4.0 M, 1 mL) was added under ice bath cooling. The mixture was then allowed to return to room temperature and reacted for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain Int-38 (80 mg, hydrochloride). ESI-MS (m / z): 480.4 [M+H] + .

[0377] Intermediate 39

[0378] Intermediate 39 is prepared by the following steps:

[0379] Step A: Int-39a (5 g, 17.85 mmol) was dissolved in N,N-dimethylformamide (50 mL), cooled to 0 °C in an ice bath, and sodium methoxide-methanol solution (5.4 M, 21.49 mL, 116.03 mmol) was added dropwise to the reaction solution. The mixture was then allowed to return to room temperature for 2 hours, and LC / MS showed complete reaction. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 10 / 1) to give Int-39b (4.2 g, yield: 85.35%). ESI-MS (m / z): 276.0 [M+H] + .

[0380] Step B: Int-39b (2 g, 7.25 mmol) was dissolved in acetonitrile (30 mL), and N,N-diisopropylethylamine (3.75 g, 29.02 mmol, 5.05 mL) was added. Phosphorus oxychloride (2.22 g, 1.35 mL, 14.51 mmol) was slowly added dropwise under ice bath cooling. The mixture was then heated to 80 °C and reacted for 2 hours. LC / MS showed the reaction was complete. The reaction solution was cooled to room temperature, quenched with ice water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 10 / 1) to give Int-39c (1.7 g, yield: 79.67%). ESI-MS (m / z): 295.4 [M+H] + .

[0381] Step C: Int-39c (1.3 g, 4.42 mmol) was dissolved in acetonitrile (15 mL), and N,N-diisopropylethylamine (2.86 g, 22.10 mmol, 3.85 mL) was added. The mixture was cooled to -70 °C using an ethanol / dry ice bath, and a dichloromethane solution (10 mL) of Int-2b (1.03 g, 4.86 mmol) was slowly added dropwise. The reaction was allowed to proceed at this temperature for 0.5 hours, and LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 7 / 1) to give a yellow solid Int-39d (1.9 g, 91.35%). ESI-MS (m / z): 470.3 [M+H] + .

[0382] Step D: Int-39d (1.9 g, 4.04 mmol) was dissolved in dichloromethane (21 mL). Under ice bath cooling, m-chloroperoxybenzoic acid (1.74 g, purity: 85%) was added in portions. The mixture was then allowed to return to room temperature for 1 hour. LC / MS showed the reaction was complete. The reaction solution was diluted with water, extracted with dichloromethane, and the combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-39e (1.9 g, yield: 92.43%). ESI-MS (m / z): 502.2 [M+H] + .

[0383] Step E: Int-39e (1.9 g, 3.79 mmol) and Int-13f (1.68 mg, 4.92 mmol) were dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0 °C in an ice bath, and LiHMDS (1.0 M tetrahydrofuran solution, 11.36 mL, 11.36 mmol) was slowly added dropwise to the reaction solution. The reaction was then carried out at 0 °C for 1 hour, and TLC showed that the reaction was complete. The reaction was quenched by adding saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 5 / 1) to give Int-39f (2.4 g, yield: 83.17%).

[0384] Step F: Int-39f (2.4 g, 3.15 mmol) was dissolved in tetrahydrofuran (22 mL). Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 7.87 mL, 7.87 mmol) was added dropwise to the reaction solution at room temperature. The reaction was continued for 1 hour, and LC / MS showed complete reaction. Sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-39g (1.1 g, yield: 66.69%). ESI-MS (m / z): 524.3 [M+H] + .

[0385] Step G: Int-39 g (200 mg, 0.38 mmol), Int-2f (234.8 mg, 0.46 mmol), cataCXium A Pd G3 (55.6 mg, 0.076 mmol), potassium phosphate (243.1 mg, 1.15 mmol), dioxane (3 mL), and water (0.6 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 85 °C under nitrogen atmosphere and stirred overnight. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a white solid Int-39h (270 mg, yield: 70.39%). ESI-MS (m / z): 503.3 [M+2H] 2+ / 2.

[0386] Step H: Int-39h (270 mg, 0.27 mmol) was dissolved in dichloromethane (5 mL), and Dysmart oxidant (227.9 mg, 0.54 mmol) was added under ice bath conditions. The reaction was then carried out at room temperature for 6 hours, and LC / MS showed that the reaction was complete. Saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-39i (250 mg, yield: 92.78%).

[0387] Step I: Int-39i (250 mg, 0.25 mmol) was dissolved in tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) (0.5 mL) was added under ice bath conditions. The reaction was then carried out at room temperature for 0.5 hours, and LC / MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate / petroleum ether (V / V) = 1 / 1) to give Int-39 (102 mg, yield: 48.33%). ESI-MS (m / z): 846.9 [M+H] + .

[0388] Intermediate 40

[0389] Intermediate 40 is prepared by the following steps:

[0390] Step A: Int-40a (900 mg, 3.42 mmol, hydrochloride) and Int-40b (920 mg, 3.42 mmol, hydrochloride) were dissolved in ethanol (50 mL), and sodium bicarbonate (1.44 g, 17.12 mmol) was added. The reaction mixture was heated to 90 °C and reacted for 6 hours. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a colorless oily substance, Int-40c (904 mg, yield: 68.46%). ESI-MS (m / z): 386.4 [M+H] + .

[0391] Step B: Int-40c (904 mg, 2.34 mmol) was dissolved in methanol (9 mL), and 10% Pd / C (374.3 mg) was added. The reaction system was purged with hydrogen gas, and the reaction was carried out at room temperature for 6 hours under a hydrogen atmosphere. LC-MS showed that the reaction was complete. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give a colorless oily substance, Int-40d (350 mg, yield: 51.53%). ESI-MS (m / z): 296.3 [M+H] + .

[0392] Step C: Int-40d (350 mg, 1.18 mmol), Int-1a (267.1 mg, 0.79 mmol), cesium carbonate (772.03 mg, 2.37 mmol), PEPPSI-I Hept-Cl (76.83 mg, 0.079 mmol), and N,N-dimethylformamide (3 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was subjected to silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 20 / 1) to give a white solid Int-40e (60 mg, yield: 13.75%). ESI-MS (m / z): 553.5 [M+H] + .

[0393] Step D: Dissolve Int-40e (60 mg, 0.11 mol) in dichloromethane (1 mL), cool to 0°C in an ice bath, add hydrochloric acid-dioxane solution (4.0 M, 1 mL), and then raise the temperature to room temperature and react for 1 hour. LC-MS showed that the reaction was complete. Concentrate the reaction solution to obtain a white solid Int-40 (62 mg, hydrochloride). ESI-MS (m / z): 453.4 [M+H] + .

[0394] Intermediate 41

[0395] Intermediate 41 is prepared by the following steps:

[0396] Step A: Int-1a (0.78 g, 2.31 mmol), Int-41a (1.03 g, 3.46 mmol), PEPPSI-I Hept-Cl (224.38 mg, 0.23 mmol), cesium carbonate (2.25 g, 6.92 mmol), and N,N-dimethylformamide (8 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 24 hours. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 2) to give a white solid Int-41b (300 mg, yield: 23.49%). ESI-MS (m / z): 554.4 [M+H] + .

[0397] Step B: Int-41b (300 mg, 0.54 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was slowly added under ice bath cooling. The reaction was then carried out at room temperature for 2 hours, and LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain a brown solid, Int-41 (300 mg, trifluoroacetate). ESI-MS (m / z): 454.4 [M+H] + .

[0398] Intermediate 42

[0399] Intermediate 42 is prepared by the following steps:

[0400] Step A: Int-25f (200.76 mg, 0.37 mmol), Int-2f (230.36 mg, 0.45 mmol), cataCXium A Pd G3 (54.55 mg, 0.075 mmol), potassium phosphate (238.52 mg, 1.12 mmol), dioxane (2 mL), and water (0.4 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 85 °C under nitrogen atmosphere and reacted overnight. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a brown oily substance, Int-42a (320 mg, yield: 96.42%). ESI-MS (m / z): 886.9 [M+H] + .

[0401] Step B: Int-42a (320 mg, 0.36 mmol) was dissolved in dichloromethane (5 mL), and Dysmartin oxidant (306.34 mg, 0.72 mmol) was added under ice bath conditions. The mixture was heated to room temperature and reacted for 5 hours. LC / MS showed that the reaction was complete. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 2 / 1) to give a yellow solid Int-42b (285 mg, yield: 89.27%). ESI-MS (m / z): 885.5 [M+H] + .

[0402] Step C: Int-42b (285 mg, 0.32 mmol) was dissolved in tetrahydrofuran (3 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 645 μL) was added at room temperature. The mixture was stirred for 1 hour, and LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a yellow solid Int-42 (220 mg, yield: 93.78%). ESI-MS (m / z): 728.4 [M+H] 2+ .

[0403] Intermediate 43

[0404] Intermediate 43 is prepared by the following steps:

[0405] Step A: Int-1a (996.3 mg, 2.95 mmol), Int-43a (835 mg, 2.95 mmol), PEPPSI-I Hept-Cl (286.6 mg, 0.29 mmol), cesium carbonate (2.88 g, 8.84 mmol), and N,N-dimethylformamide (9 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 10 / 1) to give a yellow solid Int-43b (470 mg, yield: 29.51%). ESI-MS (m / z): 541.5 [M+H] + .

[0406] Step B: Int-43b (470 mg, 0.87 mmol) was dissolved in dichloromethane (2 mL). Under ice bath cooling, hydrochloric acid-dioxane solution (4.0 M, 2 mL) was added, and the mixture was allowed to return to room temperature for 1 hour. LC / MS showed the reaction was complete. The reaction solution was concentrated to give a white solid Int-43 (370 mg, hydrochloride). ESI-MS (m / z): 441.4 [M+H] + .

[0407] Intermediate 44

[0408] Intermediate 44 is prepared by the following steps:

[0409] Step A: Int-1a (437.43 mg, 1.29 mmol), Int-44a (600 mg, 1.55 mmol), PEPPSI-IHept-Cl (125.84 mg, 129.36 μmol), cesium carbonate (1.26 g, 3.88 mmol), and N,N-dimethylformamide (10 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain a white solid, Int-44b (173 mg, yield: 20.77%). ESI-MS (m / z): 644.5 [M+H] + .

[0410] Step B: Int-44b (173 mg, 268.73 μmol) was dissolved in tetrahydrofuran (3 mL), and 10% palladium on carbon (285.98 mg) was added. After purging the reaction system with hydrogen, the reaction was carried out at room temperature for 16 hours under a hydrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with tetrahydrofuran, and the filtrate was concentrated to give a yellow solid Int-44 (120 mg, yield: 81.94%). ESI-MS (m / z): 510.4 [M+H] + .

[0411] Intermediate 45

[0412] Intermediate 45 is prepared by the following steps:

[0413] Step A: Int-1a (782.34 mg, 2.31 mmol), Int-45a (500 mg, 3.15 mmol), PEPPSI-IHept-Cl (187.55 mg, 0.19 mmol), cesium carbonate (1.88 g, 5.78 mmol), and N,N-dimethylformamide (6 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by preparative thin-layer chromatography (developing solvent: dichloromethane / methanol (V / V) = 20 / 1) to give a pale yellow solid Int-45b (344 mg, yield: 35.72%). ESI-MS (m / z): 417.3 [M+H] + .

[0414] Step B: Int-45b (344 mg, 0.83 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added under ice bath cooling. The reaction was then carried out at room temperature for 1 hour, and LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain a yellow solid, Int-45c (300 mg), which was used directly in the next step of the reaction. ESI-MS (m / z): 371.3 [M+H] + .

[0415] Step C: Int-45c (150 mg) and Int-45d (137.47 mg, 0.61 mmol) were dissolved in N,N-dimethylformamide (2 mL), and acetic acid (0.1 mL) and sodium triacetoxyborohydride (171.66 mg, 0.81 mmol) were added sequentially at room temperature. The reaction mixture was allowed to react at room temperature for 2 hours, and LC / MS showed that the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by preparative thin-layer chromatography (developing solvent: dichloromethane / methanol (V / V) = 20 / 1) to give Int-45e (120 mg, yield: 51.03%). ESI-MS (m / z): 581.5 [M+H] + .

[0416] Step D: Int-45e (120 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added under ice bath cooling. The reaction was then carried out at room temperature for 1 hour, and LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain a brown solid, Int-41 (120 mg, trifluoroacetate), which was used directly in the next step of the reaction. ESI-MS (m / z): 481.4 [M+H] + .

[0417] Intermediate 46

[0418] Intermediate 46 is prepared by the following steps:

[0419] Step A: At room temperature, Int-10 (0.24 g, hydrochloride) and Int-46a (137.43 mg, 0.51 mmol) were dissolved in N,N-dimethylformamide (2.5 mL), followed by the sequential addition of triethylamine (154.90 mg, 1.53 mmol, 213 μL) and HATU (194.01 mg, 0.51 mmol). The reaction mixture was stirred for 2 hours, and LC / MS showed that the reaction was complete. The reaction solution was purified directly by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid Int-46b (230 mg, yield: 68.01%). ESI-MS (m / z): 563.5 [M+H-100] + .

[0420] Step B: Int-46b (0.23 g, 0.35 mmol) was dissolved in dichloromethane (2 mL). Under ice bath cooling, 1.5 mL of hydrochloric acid-dioxane solution (4.0 M) was added. The mixture was heated to room temperature and stirred for 1 hour. LC / MS showed the reaction was complete. The reaction solution was concentrated to give a white solid Int-46 (120 mg, hydrochloride). ESI-MS (m / z): 563.5 [M+H] + .

[0421] Intermediate 47

[0422] Intermediate 47 is prepared by the following steps:

[0423] Step A: At room temperature, Int-10 (239.32 mg, 0.47 mmol, hydrochloride) and 43a (0.15 g, 0.50 mmol) were dissolved in N,N-dimethylformamide (3 mL), followed by the addition of triethylamine (135.54 mg, 1.34 mmol, 186.69 μL) and HATU (169.76 mg, 0.45 mmol). The reaction mixture was stirred at room temperature for 3 hours, and LC / MS showed that the reaction was complete. The reaction solution was purified directly by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid Int-47a (200 mg, yield: 64.84%). ESI-MS (m / z): 691.5 [M+H] + .

[0424] Step B: Int-47b (0.23 g, 0.35 mmol) was dissolved in dichloromethane (2 mL), and hydrochloric acid-dioxane solution (4.0 M, 2 mL) was added under ice bath cooling. The mixture was then allowed to react at room temperature for 2 hours, and LC / MS showed that the reaction was complete. The reaction solution was concentrated to give a white solid Int-47 (180 mg, hydrochloride). ESI-MS (m / z): 591.5 [M+H] + .

[0425] Intermediate 48

[0426] Intermediate 48 is prepared by the following steps:

[0427] Step A: Int-48a (600 mg, 1.77 mmol), Int-1a (499.52 mg, 1.48 mmol), PEPPSI-IHept-Cl (143.70 mg, 0.147 mmol), cesium carbonate (1.44 g, 4.43 mmol), and N,N-dimethylformamide (8 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 16 hours. LC / MS showed the formation of a ring-opening product with a molecular weight of +18. The reaction solution was cooled to room temperature, and formic acid (1 mL) and water (20 mL) were added sequentially. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was dissolved in acetonitrile (3 mL), and N,N'-carbonyldiimidazole (462.34 mg, 2.85 mmol) was added. The mixture was heated to 70 °C and reacted for 12 hours. LC / MS showed that the reaction was complete. The reaction solution was purified directly by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid Int-48b (270 mg, overall yield of two steps: 30.68%). ESI-MS (m / z): 596.5 [M+H] + .

[0428] Step B: Int-48b (270 mg, 0.45 mmol) was dissolved in dichloromethane (3 mL), and hydrochloric acid-dioxane solution (4.0 M, 1 mL) was added under ice bath cooling. The mixture was then allowed to react at room temperature for 1 hour, and LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain a creamy white solid, Int-48 (240 mg, hydrochloride). ESI-MS (m / z): 496.3 [M+H] + .

[0429] Intermediate 49

[0430] Intermediate 49 is prepared by the following steps:

[0431] Step A: Int-49a (1 g, 3.19 mmol) was dissolved in dichloromethane (15 mL), and N,N-diisopropylethylamine (2.06 g, 15.93 mmol, 2.77 mL) was added. The mixture was cooled to -70 °C using an ethanol / dry ice bath. A dichloromethane solution (10 mL) of Int-2b (743.9 mg, 3.50 mmol) was slowly added dropwise to the reaction mixture. The reaction mixture was then stirred at -70 °C for 2 hours. LC / MS showed that the reaction was complete. The reaction mixture was filtered through a silica gel column, eluted with dichloromethane, and the crude product was collected and slurried with petroleum ether to give a pale yellow solid, Int-49b (1.5 g, yield: 96.15%). ESI-MS (m / z): 491.2 [M+H] + .

[0432] Step B: Int-49b (1.5 g, 3.06 mmol) was dissolved in N,N-dimethylformamide (10 mL), and cesium carbonate (2.99 g, 9.19 mmol) and DABCO (34.36 mg, 0.31 mmol) were added. Under ice bath cooling, a dry THF solution (10 mL) of Int-2d (6.66 g, 65.24 mmol, 6.26 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 30 min, and TLC showed complete reaction. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a white solid Int-49c (507 mg, yield: 29.80%). ESI-MS (m / z): 556.3 [M+H] + .

[0433] Step C: Int-49c (388 mg, 0.70 mmol), Int-2f (429.66 mg, 0.84 mmol), cataCXium APd G3 (101.75 mg, 0.14 mmol), cesium carbonate (682.84 mg, 2.10 mmol), dioxane (6 mL), and water (1.2 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 120 °C and stirred for 2 hours under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give the pale yellow product Int-49d (405 mg, yield: 67.33%).

[0434] Step D: Int-49d (380 mg, 0.44 mmol) was dissolved in dichloromethane (6 mL), and Dysmart oxidant (382.24 mg, 0.90 mmol) was added under ice bath cooling. The mixture was then heated to room temperature and reacted for 6 hours. LC / MS showed that the reaction was complete. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give a pale yellow solid, Int-49e (380 mg), which was used directly in the next step of the reaction.

[0435] Step E: Int-49e (380 mg) was dissolved in tetrahydrofuran (6 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 885 μL) was added under ice bath conditions. The mixture was then heated to room temperature and reacted for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (V / V) = 1 / 2) to give the white product Int-49 (302 mg, two-step reaction yield: 97.15%). ESI-MS (m / z): 703.4 [M+H] + .

[0436] Intermediate 50

[0437] Intermediate 50 is prepared by the following steps:

[0438] Step A: Int-2e (1 g, 2.02 mmol), Int-50a (700.87 mg, 2.02 mmol), cataCXium A Pd G3 (294.76 mg, 0.40 mmol), potassium phosphate (1.29 g, 6.07 mmol), dioxane (15 mL), and water (3 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 85 °C and stirred for 6 hours under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% to 100%) to give a white solid Int-50b (1 g, yield: 72.88%).

[0439] Step B: Int-50b (1 g, 1.48 mmol) was dissolved in tetrahydrofuran (16 mL), and Dysmartin oxidant (938.73 mg, 2.21 mmol) was added under ice bath conditions. The reaction was then brought to room temperature and allowed to proceed for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid Int-50 (700 mg, yield: 70.21%). ESI-MS (m / z): 676.3 [M+H] + .

[0440] Intermediate 51

[0441] Intermediate 51 is prepared by the following steps:

[0442] Step A: Int-1a (1 g, 2.96 mmol), Int-51a (1.27 g, 5.91 mmol), PEPPSI-IHept-Cl (81.24 mg, 0.89 mmol), cesium carbonate (1.93 g, 5.91 mmol), and dioxane (15 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid Int-51b (500 mg, yield: 35.86%). ESI-MS (m / z): 472.2 [M+H] + .

[0443] Step B: Int-51b (0.3 mg, 0.64 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added under ice bath cooling. The mixture was then allowed to return to room temperature and reacted for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain a white solid, Int-51 (0.3 g, trifluoroacetate), which was used directly in the next step of the reaction. ESI-MS (m / z): 372.2 [M+H] + .

[0444] Intermediate 52

[0445] Intermediate 52 is prepared by the following steps:

[0446] Step A: Int-1a (400 mg, 1.18 mmol), Int-52a (635.0 mg, 2.37 mmol), PEPPSI-I Hept-Cl (115.1 mg, 0.12 mmol), cesium carbonate (1.16 g, 3.55 mmol), and N,N-dimethylformamide (4 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 100 °C for 24 hours under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 3 / 1) to give a white solid Int-52b (160 mg, yield: 25.73%). ESI-MS (m / z): 526.4 [M+H] + .

[0447] Step B: Int-52b (160 mg, 0.30 mmol) was dissolved in dichloromethane (1 mL), and hydrochloric acid-dioxane solution (4.0 M, 0.8 mL) was added under ice bath cooling. The mixture was then heated to room temperature and stirred for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain a creamy white solid, Int-52c (150 mg, hydrochloride). ESI-MS (m / z): 426.3 [M+H] + .

[0448] Step C: Int-52c (150 mg, hydrochloride) and Int-35a (74.4 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), followed by the addition of triethylamine (164.3 mg, 1.62 mmol, 0.23 mL) and HATU (123.5 mg, 0.32 mmol). The mixture was stirred at 25 °C for 2 hours, and LC / MS showed complete reaction. The reaction solution was diluted with ethyl acetate and washed successively with saturated ammonium chloride, water, and saturated brine. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give a white solid Int-52d (160 mg, yield: 77.39%). ESI-MS (m / z): 537.4 [M+H-100] + .

[0449] Step D: Int-52d (160 mg, 0.25 mmol) was dissolved in dichloromethane (2 mL), and a hydrochloric acid-dioxane solution (4.0 M, 0.6 mL) was added under ice bath cooling. The mixture was then heated to room temperature and stirred for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated to give a white solid Int-52 (140 mg, hydrochloride). ESI-MS (m / z): 537.4 [M+H] + .

[0450] Intermediate 53

[0451] Intermediate 53 is prepared by the following steps:

[0452] Step A: Int-25f (400 mg, 0.75 mmol), Int-13i (403.24 mg, 1.12 mmol), potassium phosphate (475.24 mg, 2.24 mmol), cataCXium A Pd G3 (108.7 mg, 0.15 mmol), dioxane (5 mL), and water (1 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 85 °C under a nitrogen atmosphere and reacted for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was subjected to preparative thin-layer chromatography (developing solvent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to obtain Int-53a (520 mg, yield: 94.96%). ESI-MS (m / z): 734.4 [M+H] + .

[0453] Step B: Int-53a (520 mg, 0.71 mmol) was dissolved in dichloromethane (7 mL), and Dysmartin oxidant (601.13 mg, 1.42 mmol) was added. The reaction was carried out at room temperature for about 5 hours, and LC / MS showed that the reaction was complete. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 16% to 50%) to give the product Int-53 (487 mg, yield: 93.91%). ESI-MS (m / z): 732.4 [M+H] + .

[0454] Intermediate 54

[0455] Intermediate 54 is prepared by the following steps:

[0456] Step A: Int-2e (600 mg, 1.21 mmol), Int-54a (498.85 mg, 1.46 mmol), cataCXium A Pd G3 (176.92 mg, 0.24 mmol), potassium phosphate (773.52 mg, 3.64 mmol), dioxane (5 mL), and water (1 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 85 °C under nitrogen atmosphere and stirred overnight. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a brown oily product Int-54b (500 mg, yield: 55.77%). ESI-MS (m / z): 674.5 [M+H] + .

[0457] Step B: Int-54b (500 mg, 0.74 mmol) was dissolved in dichloromethane (5 mL), and Dysmartin oxidant (629.50 mg, 1.48 mmol) was added under ice bath conditions. The reaction was then brought to room temperature for 4 hours, and LC / MS showed that the reaction was complete. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-54 (450 mg, yield: 90.27%). ESI-MS (m / z): 672.4 [M+H] + .

[0458] Intermediate 55

[0459] Intermediate 55 is prepared by the following steps:

[0460] Step A: Int-11 (150 mg) and 43a (79.4 mg, 0.27 mmol) were dissolved in N,N-dimethylformamide (2 mL). Triethylamine (81.10 mg, 0.80 mmol, 0.11 mL) and HATU (101.6 mg, 0.27 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour, and LC / MS showed that the reaction was complete. The reaction solution was purified directly by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid Int-55a (120 mg, yield: 61.80%). ESI-MS (m / z): 727.4 [M+H] + .

[0461] Step B: Int-55a (120 mg, 0.16 mmol) was dissolved in dichloromethane (2 mL), and a hydrochloric acid-dioxane solution (4.0 M, 0.24 mL) was added under ice bath cooling. The mixture was then heated to room temperature and stirred for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated to give a white solid Int-55 (100 mg, hydrochloride). ESI-MS (m / z): 627.4 [M+H] + .

[0462] Intermediate 56

[0463] Intermediate 56 is prepared by the following steps:

[0464] Step A: Int-34c (250 mg, 0.58 mmol) and Int-56a (178.1 mg, 0.61 mmol) were dissolved in N,N-dimethylformamide (3 mL). Triethylamine (177.4 mg, 1.75 mmol, 0.24 mL) and HATU (222.1 mg, 0.58 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours, and LC / MS showed that the reaction was complete. The reaction solution was directly purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain Int-56b (200 mg, yield: 51.97%). ESI-MS (m / z): 659.3 [M+H] + .

[0465] Step B: Int-56b (200 mg, 0.30 mmol) was dissolved in dichloromethane (2 mL). Under ice bath cooling, a hydrochloric acid-dioxane solution (4.0 M, 1 mL) was added, and the mixture was then stirred at room temperature for 1 hour. LC / MS showed the reaction was complete. The reaction solution was concentrated to obtain Int-56 (150 mg, hydrochloride). ESI-MS (m / z): 559.3 [M+H] + .

[0466] Intermediate 57

[0467] Intermediate 57 is prepared by the following steps:

[0468] Step A: Int-1a (400 mg, 1.18 mmol), Int-57a (668.1 mg, 2.37 mmol), PEPPSI-I Hept-Cl (115.1 mg, 0.12 mmol), cesium carbonate (1.16 g, 3.55 mmol), and N,N-dimethylformamide (4 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 100 °C and stirred for 24 hours under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 2) to give Int-57b (100 mg, yield: 15.67%). ESI-MS (m / z): 540.5 [M+H] + .

[0469] Step B: Int-57b (100 mg, 0.18 mmol) was dissolved in dichloromethane (1 mL). Under ice bath cooling, 0.5 mL of hydrochloric acid-dioxane solution (4.0 M) was added, and the mixture was stirred at room temperature for 1 hour. LC / MS showed the reaction was complete. The reaction solution was concentrated to obtain Int-57c (85 mg, hydrochloride). ESI-MS (m / z): 440.3 [M+H] + .

[0470] Step C: Int-57c (85 mg) and Int-35a (40.9 mg, 0.18 mmol) were dissolved in N,N-dimethylformamide (1 mL), followed by the addition of triethylamine (90.4 mg, 0.89 mmol, 0.12 mL) and HATU (67.9 mg, 0.18 mmol). The reaction mixture was stirred at room temperature for 2 hours, and LC / MS showed complete reaction. The reaction solution was diluted with ethyl acetate and washed successively with saturated ammonium chloride, water, and saturated brine. The organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give Int-57d (100 mg, yield: 86.05%). ESI-MS (m / z): 551.5 [M+H-100] + .

[0471] Step D: Int-57d (100 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL). Under ice bath cooling, 0.4 mL of hydrochloric acid-dioxane solution (4.0 M) was added, and the mixture was stirred at room temperature for 1 hour. LC / MS showed the reaction was complete. The reaction solution was concentrated to obtain Int-57 (90 mg, hydrochloride). ESI-MS (m / z): 551.5 [M+H]+ .

[0472] Intermediate 58

[0473] Intermediate 58 is prepared by the following steps:

[0474] Step A: At room temperature, Int-1 (150 mg) and Int-46a (106.36 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (2 mL), followed by the addition of triethylamine (199.80 mg, 1.97 mmol, 0.28 mL) and HATU (150.15 mg, 0.39 mmol). The reaction mixture was stirred at room temperature for 2 hours, and LC / MS showed complete reaction. The reaction solution was diluted with ethyl acetate and washed successively with saturated ammonium chloride, water, and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography (eluent: dichloromethane / methanol (V / V) = 15 / 1) to give Int-58a (160 mg, yield: 68.13%). ESI-MS (m / z): 495.4 [M-100+H] + .

[0475] Step B: Int-58a (160 mg, 0.27 mmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (4.0 M, 1 mL) was added under ice bath cooling. The mixture was then allowed to react at room temperature for 1 hour, and LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain Int-58 (140 mg hydrochloride). ESI-MS (m / z): 495.4 [M+H] + .

[0476] Intermediate 59

[0477] Intermediate 59 is prepared by the following steps:

[0478] Step A: Int-59a (1 g, 2.95 mmol), Int-1a (832.5 mg, 2.46 mmol), PEPPSI-IHept-Cl (239.5 mg, 0.25 mmol), cesium carbonate (2.4 g, 7.39 mmol), and N,N-dimethylformamide (10 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 100 °C and stirred for 16 hours under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water (50 mL), and the pH was adjusted to 5 with acetic acid. The solution was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain Int-59b (300 mg, yield: 16.03%). ESI-MS (m / z): 614.3 [M+H] + .

[0479] Step B: Int-59b (300 mg, 0.39 mmol) and N,N'-carbonyldiimidazole (224.0 mg, 1.38 mmol) were dissolved in a mixed solution of acetonitrile (3 mL) and N,N-dimethylformamide (3 mL). The reaction solution was heated to 70 °C and stirred for 5 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain Int-59c (200 mg, yield: 85.06%). ESI-MS (m / z): 596.4 [M+H] + .

[0480] Step C: Int-59c (200 mg, 0.34 mmol) was dissolved in dichloromethane (2 mL), and a hydrochloric acid-dioxane solution (4.0 M, 1 mL) was added under ice bath cooling. The mixture was then heated to room temperature and stirred for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain Int-59 (170 mg, hydrochloride). ESI-MS (m / z): 496.2 [M+H] + .

[0481] Intermediate 60

[0482] Intermediate 60 is prepared by the following steps:

[0483] Step A: Int-25f (1.3 g, 2.43 mmol), Int-60a (1.47 g, 3.64 mmol), PdCl2(PPh3)2 (173.6 mg, 0.24 mmol), cesium carbonate (2.4 g, 7.28 mmol), and 1,4-dioxane (13 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 90 °C and stirred for 3 hours under a nitrogen atmosphere. TLC showed that the starting materials reacted completely. The reaction solution was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-60b (1.8 g, yield: 93.72%). 1 H NMR(500MHz, CDCl3)δ7.96(s,1H),7.62–7.53(m,1H),7.13–7.06(m,1H),5.44– 5.36(m,1H),4.67–4.59(m,1H),4.39–4.34(m,2H),3.54–3.49(m,5H),3.41–3. 35(m,1H),3.20–3.11(m,1H),1.98–1.90(m,2H),1.72–1.65(m,4H),1.56–1.48 (m,12H),1.25–1.24(m,1H),0.91(s,6H),0.71–0.65(m,2H),0.64–0.59(m,2H).

[0484] Step B: Int-60b (1.8 g, 2.27 mmol) was dissolved in dichloromethane (20 mL), and Dysmartin oxidant (1.9 g, 4.55 mmol) was added under ice bath conditions. The reaction was then brought to room temperature and reacted for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was diluted with saturated sodium carbonate aqueous solution, extracted three times with dichloromethane, and the organic phases were combined, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give Int-60 (1.35 g, yield: 75.19%). ESI-MS (m / z): 790.3 [M+H] + .

[0485] Intermediate 62

[0486] Intermediate 62 is prepared by the following steps:

[0487] Step A: Int-2e (350 mg, 0.71 mmol), Int-62a (287.9 ​​mg, 0.85 mmol), cataCXium APd G3 (51.6 mg, 0.071 mmol), potassium phosphate (450 mg, 2.13 mmol), dioxane (10 mL), and water (2 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was stirred overnight at 85 °C. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated by filtration. The crude product was purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid Int-62b (290 mg, yield: 61.07%). ESI-MS (m / z): 670.3 [M+H] + .

[0488] Step B: Int-62b (290 mg, 0.43 mmol) was dissolved in dichloromethane (5 mL), and Dysmartin oxidant (367.1 mg, 0.87 mmol) was added under ice bath conditions. The reaction was allowed to proceed overnight at room temperature, and LC / MS showed that the reaction was complete. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give a white solid Int-62 (240 mg, yield: 83.01%). ESI-MS (m / z): 668.3 [M+H] + .

[0489] Intermediate 64

[0490] Intermediate 64 is prepared by the following steps:

[0491] Step A: At room temperature, Int-2i (600 mg, 0.87 mmol) and Int-64a (120.9 mg, 1.05 mmol) were dissolved in N,N-dimethylformamide (10 mL). Acetic acid (78.8 mg, 1.31 mmol) was added dropwise to the reaction solution, and the mixture was stirred for about 1 hour. Then, sodium triacetoxyborohydride (556.3 mg, 2.62 mmol) was added in portions. The reaction was allowed to proceed for 16 hours at room temperature, and LC / MS showed that the reaction was complete. The reaction was quenched with water, and the mixture was extracted with dichloromethane / methanol (V / V) = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0–50%) to give a yellow solid Int-64b (550 mg, yield: 80.08%), ESI-MS (m / z): 785.4 [M+H]. + .

[0492] Step B: Int-64b (500 mg, 0.64 mmol) was dissolved in dichloromethane (10 mL), and Dysmartin oxidant (540.4 mg, 1.27 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 6 hours, and LC / MS showed that the reaction was complete. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, a yellow solid Int-64 (240 mg, used directly in the next step) was obtained. ESI-MS (m / z): 783.4 [M+H] + .

[0493] Intermediate 71

[0494] Intermediate 71 is prepared by the following steps:

[0495] Step A: At room temperature, Int-51 (300 mg, 0.62 mmol) and 1a (147.9 mg, 0.62 mmol) were dissolved in tetrahydrofuran (6 mL). Sodium triacetoxyborohydride (164.6 mg, 0.78 mmol) was added to the reaction solution, and the reaction was carried out at 55 °C for 4 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography (mobile phase: acetonitrile / 0.1% formic acid aqueous solution) to give a white solid Int-71a (270 mg, yield: 73.46%), ESI-MS (m / z): 595.4 [M+H]. + .

[0496] Step B: Int-71a (270 mg, 0.45 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added under ice bath cooling. The mixture was then allowed to react at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain a yellow oily Int-71 (270 mg, trifluoroacetate, used directly in the next step). ESI-MS (m / z): 495.3 [M+H] + .

[0497] Intermediate 72

[0498] Intermediate 72 is prepared by the following steps:

[0499] Step A: Int-1a (1.46 g, 4.30 mmol), Int-72a (1.0 g, 4.30 mmol), cesium carbonate (2.81 g, 8.61 mmol), and Pd-PEPPSI-IHept-Cl (118.2 mg, 0.13 mmol) were dispersed in 1,4-dioxane (15 mL). After purging the reaction system with nitrogen, the mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. LC / MS showed that the reaction was essentially complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by reversed-phase column chromatography (mobile phase: acetonitrile / 0.1% formic acid aqueous solution) to give the white product Int-72b (600 mg, yield: 26.37%). ESI-MS (m / z): 490.2 [M+H] + .

[0500] Step B: Int-72b (600 mg, 0.89 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added under ice bath cooling. The reaction was carried out at room temperature for 1 hour, and LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain a yellow oily Int-72c (450 mg, trifluoroacetate), which was used directly in the next step of the reaction. ESI-MS (m / z): 390.2 [M+H] + .

[0501] Step C: At room temperature, Int-72c (450 mg, 0.89 mmol) and 1a (213.9 mg, 0.89 mmol) were dissolved in tetrahydrofuran (6 mL), and sodium triacetoxyborohydride (377.3 mg, 1.78 mmol) was added. The reaction was carried out at 55 °C for 4 hours, and LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography (mobile phase: acetonitrile / 0.1% formic acid aqueous solution) to give a white solid Int-72d (400 mg, yield: 73.35%), ESI-MS (m / z): 613.4 [M+H]. + .

[0502] Step D: Int-72d (290 mg, 0.47 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added under ice bath cooling. The mixture was then allowed to react at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain a yellow oily Int-72 (290 mg, trifluoroacetate, used directly in the next step). ESI-MS (m / z): 495.3 [M+H] + .

[0503] Intermediate 73

[0504] Intermediate 73 is prepared by the following steps:

[0505] Step A: Int-1a (817 mg, 2.42 mmol), Int-73a (900 mg, 2.90 mmol), cesium carbonate (2.36 g, 7.25 mmol), and Pd-PEPPSI-IHept-Cl (235 mg, 0.24 mmol) were dispersed in N,N-dimethylformamide (10 mL). After purging the reaction system with nitrogen, the mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. LC / MS showed that the reaction was essentially complete. The reaction solution was cooled to room temperature, diluted with 10% formic acid aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by reversed-phase column chromatography (mobile phase: acetonitrile / 0.1% formic acid aqueous solution) to give the white product Int-73b (210 mg, yield: 15.31%). ESI-MS (m / z): 568.3 [M+H] + .

[0506] Step B: Int-73b (210 mg, 0.37 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added under ice bath cooling. The mixture was then allowed to react at room temperature for 1 hour, and LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain a brown solid Int-73 (215 mg, trifluoroacetate, used directly in the next step). ESI-MS (m / z): 468.23 [M+H] + .

[0507] Intermediate 75

[0508] Intermediate 75 is prepared by the following steps:

[0509] Step A: Int-1a (600 mg, 1.77 mmol), Int-75a (452.5 mg, 1.42 mmol), cesium carbonate (1.73 g, 5.32 mmol), and Pd-PEPPSI-IHept-Cl (162.4 mg, 0.18 mmol) were dispersed in 1,4-dioxane (10 mL). After purging the reaction system with nitrogen, the mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. LC / MS showed that the reaction was essentially complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by reversed-phase column chromatography (mobile phase: acetonitrile / 0.1% formic acid aqueous solution) to give the white product Int-75b (310 mg, yield: 29.33%). ESI-MS (m / z): 596.3 [M+H] + .

[0510] Step B: Int-75b (240 mg, 0.40 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added under ice bath cooling. The mixture was then allowed to react at room temperature for 1 hour, and LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain a brown solid, Int-75 (240 mg, trifluoroacetate, used directly in the next step). ESI-MS (m / z): 496.3 [M+H] + .

[0511] Intermediate 91

[0512] Intermediate 91 is prepared by the following steps:

[0513] Step A: At room temperature, Int-2a (6.0 g, 23.77 mmol) was dissolved in dichloromethane (50 mL), and N,N-diisopropylethylamine (9.21 g, 71.3 mmol, 12.4 mL) was added. The mixture was cooled to -70 °C using an ethanol / dry ice bath. Int-91a (4.84 g, 21.39 mmol) was dissolved in dichloromethane (50 mL) and slowly added dropwise to the reaction mixture. The reaction was carried out at -70 °C for approximately 0.5 hours, and LC / MS showed that the reaction was complete. The reaction mixture was directly purified by silica gel short column chromatography (eluent: dichloromethane) to obtain a yellow solid crude Int-91b (9.36 g), which was used directly in the next step. ESI-MS (m / z): 442.1 [M+H] + .

[0514] Step B: Under ice bath conditions, Int-91b (7.0 g, 15.83 mmol) was dissolved in tetrahydrofuran (50 mL) and N,N-dimethylformamide (50 mL). Cesium carbonate (15.5 g, 47.48 mmol), triethylenediamine (177.5 mg, 1.58 mmol), and Int-2d (53.25 g, 521.4 mol, 50 mL) were added sequentially. The reaction was carried out at 0 °C for 30 minutes, and LC / MS showed complete reaction. The reaction solution was diluted with water, and a pale yellow solid precipitated. The precipitate was filtered, washed with water, and dried to obtain a pale yellow solid, Int-91c (7.7 g), which required no further purification. ESI-MS (m / z): 508.2 [M+H] + .

[0515] Step C: Int-91c (2.53 g, 4.62 mmol), Int-2f (2.84 g, 5.54 mmol), cataCXium A Pd G3 (672.7 mg, 0.92 mmol), potassium phosphate (2.94 g, 13.85 mmol), dioxane (40 mL), and water (8 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was stirred overnight at 85 °C under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated by filtration. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to give a yellow solid Int-91d (3.5 g, yield: 88.32%).

[0516] Step D: Int-91d (3g, 3.5mmol) was dissolved in tetrahydrofuran (60mL), and tetrabutylammonium fluoride (1.0M tetrahydrofuran solution, 4.2mL) was added under ice bath conditions. The mixture was then heated to room temperature and reacted for 0.5 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 0–50%) to obtain the yellow product Int-91e (2g).

[0517] Step E: Int-91e (2g) was separated by a chiral column using an SFC (Waters SFC 200); column: Daicel CHIRALPAK IH, 250*30mm, 10μm; mobile phase: CO2 / MeOH; flow rate: 80g / min; wavelength: 214nm; column temperature: 30℃. The first eluted fraction was Int-91e-P1, followed by Int-91e-P2.

[0518] Int-91e-P1: 760 mg; Chiral analysis column retention time: 2.3 min (Daicel CHIRALPAK IH, 250*4.6 mm, 5 μm; Mobile phase: CO2 / MeOH; Flow rate: 3.0 g / min; Wavelength: 214 nm; Column temperature: 30℃); ee value: 100%. ESI-MS (m / z): 702.53 [M+H] + .

[0519] Int-91e-P2: 860 mg; Chiral analysis column retention time: 3.1 min (Daicel CHIRALPAK IH, 250*4.6 mm, 5 μm; Mobile phase: CO2 / MeOH; Flow rate: 3.0 g / min; Wavelength: 214 nm; Column temperature: 30℃); ee value: 98.2%. ESI-MS (m / z): 702.58 [M+H] + .

[0520] The structures corresponding to Int-91e-P1 and Int-91e-P2 are assumed absolute configurations. The two enantiomers undergo subsequent reactions separately.

[0521] Step F: Int-91e-P1 (760 mg, 1.08 mmol) was dissolved in dichloromethane (8 mL), and Dysmartin oxidant (918.7 mg, 2.17 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 2 hours. TLC showed that the starting material disappeared and a new spot appeared. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 1) to give a yellow solid Int-91 (720 mg, yield: 95.01%). ESI-MS (m / z): 700.3 [M+H] + .

[0522] Intermediate 92

[0523] Intermediate 92 is prepared by the following steps:

[0524] Step A: Int-91e-P2 (760 mg, 1.08 mmol) was dissolved in dichloromethane (8 mL), and Dysmartin oxidant (918.7 mg, 2.17 mmol) was added under ice bath conditions. The reaction was carried out at room temperature for 2 hours. TLC showed that the starting material disappeared and a new spot appeared. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether = 0–50%) to give a yellow solid Int-92 (700 mg, yield: 92.37%). ESI-MS (m / z): 700.3 [M+H] + .

[0525] Intermediate 96

[0526] Intermediate 96 is prepared by the following steps:

[0527] Step A: Int-2e (1.31 g, 2.64 mmol), Int-96a (1.5 g, 2.64 mmol), cataCXium A Pd G3 (192.5 mg, 0.26 mmol), potassium phosphate (1.68 g, 7.93 mmol), dioxane (15 mL), and water (3 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was stirred overnight at 85 °C under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by reversed-phase column chromatography (mobile phase: acetonitrile / 0.1% formic acid aqueous solution) to give a pale yellow solid product Int-96b (2.0 g, yield 84.17%).

[0528] Step B: Int-96b (2.0 g, 2.22 mmol) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (1.0 M THF solution, 4.45 mL) was added under ice bath conditions. The reaction was carried out at room temperature for 2 hours, and LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography (mobile phase: acetonitrile / 0.1% formic acid aqueous solution) to give the pale yellow product Int-96c (1.5 g, yield: 65.68%). ESI-MS (m / z): 743.3 [M+H] + .

[0529] Step C: Int-96c (1.5 g, 1.46 mmol) was dissolved in tetrahydrofuran (20 mL), and Dysmartin oxidant (1.24 g, 2.92 mmol) was added under ice bath conditions. The reaction was brought to room temperature and carried out for 5 hours. LC / MS showed that the reaction was complete. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by reversed-phase column chromatography (mobile phase: acetonitrile / 0.1% formic acid aqueous solution) to give Int-96 (1.0 g, yield: 77.01%). ESI-MS (m / z): 741.3 [M+H] + .

[0530] Intermediate 97

[0531] Intermediate 97 is prepared by the following steps:

[0532] Step A: Int-25f (1.42 g, 2.64 mmol), Int-96a (1.5 g, 2.64 mmol), cataCXium A Pd G3 (192.5 mg, 0.26 mmol), potassium phosphate (1.68 g, 7.93 mmol), dioxane (15 mL), and water (3 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was stirred overnight at 85 °C under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by reversed-phase column chromatography (mobile phase: acetonitrile / 0.1% formic acid aqueous solution) to give a pale yellow solid product Int-97a (2.1 g, yield: 84.43%).

[0533] Step B: Int-97a (2.0 g, 2.12 mmol) was dissolved in tetrahydrofuran (20 mL), and tetrabutylammonium fluoride (1.0 M THF solution, 4.25 mL) was added under ice bath conditions. The reaction was carried out at room temperature for 2 hours, and LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by reversed-phase column chromatography (mobile phase: acetonitrile / 0.1% formic acid aqueous solution) to give a pale yellow solid Int-97b (1.52 g, yield: 80.68%). ESI-MS (m / z): 786.3 [M+H] + .

[0534] Step C: Int-97b (1.52 g, 1.71 mmol) was added to tetrahydrofuran (20 mL) with Dysmartin oxidant (1.45 g, 3.43 mmol) under ice bath conditions. The reaction was carried out at room temperature for 5 hours, and LC / MS showed that the reaction was complete. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reversed-phase column chromatography (mobile phase: acetonitrile / 0.1% formic acid aqueous solution) to give a pale yellow solid Int-97 (1.0 g, yield: 74.51%). ESI-MS (m / z): 783.3 [M+H] + .

[0535] Intermediate 99

[0536] Intermediate 99 is prepared by the following steps:

[0537] Step A: At room temperature, Int-2a (1.08 g, 4.28 mmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (1.66 g, 12.85 mmol, 2.24 mL) was added. The mixture was cooled to -70 °C using an ethanol / dry ice bath. Int-99a (1.0 g, 3.86 mmol) was dissolved in dichloromethane (5 mL) and slowly added dropwise to the reaction mixture. The reaction was carried out at -70 °C for approximately 0.5 hours, and LC / MS showed that the reaction was complete. The reaction mixture was purified directly by silica gel short column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 5 / 1) to give a yellow solid Int-99b (700 mg, yield: 34.37%). ESI-MS (m / z): 475.1 [M+H] + .

[0538] Step B: Under ice bath conditions, Int-99b (700 mg, 1.47 mmol) was dissolved in tetrahydrofuran (10 mL). Cesium carbonate (1.44 g, 4.42 mmol), triethylenediamine (16.5 mg, 0.15 mmol), and Int-2d (4.26 g, 41.71 mol, 4 mL) were added sequentially. The reaction was carried out at 0 °C for 1 hour, and LC / MS showed complete reaction. The reaction solution was diluted with water, and a pale yellow solid precipitated. The solution was filtered, the filter cake was washed several times with water, and dried under vacuum to obtain the crude product. This crude product was then purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (V / V) = 0–50%) to obtain the yellow solid Int-99c (710 mg, yield: 89.12%). ESI-MS (m / z): 541.2 [M+H] + .

[0539] Step C: Int-99c (710 mg, 1.31 mmol), Int-2f (1.01 g, 1.97 mmol), cataCXium A Pd G3 (191.1 mg, 0.26 mmol), potassium phosphate (835.7 mg, 3.94 mmol), dioxane (15 mL), and water (4 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was stirred overnight at 85 °C under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to give a yellow solid Int-99d (822 mg, yield: 70.29%).

[0540] Step D: Int-99d (800 mg, 0.90 mmol) was dissolved in dichloromethane (11 mL), and Dys-Martin oxidant (761.5 mg, 1.8 mmol) was added under ice bath conditions. The reaction was brought to room temperature and reacted for 2 hours. TLC showed that the starting material disappeared and new spots formed. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether (V / V) = 0–50%) to give a yellow solid Int-99e (680 mg, yield: 85.19%).

[0541] Step E: Int-99e (680 mg, 0.76 mmol) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.9 mL) was added under ice bath conditions. The mixture was then heated to room temperature and reacted for 0.5 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to give the yellow product Int-99 (500 mg, yield: 89.22%). ESI-MS (m / z): 733.3 [M+H] + .

[0542] Intermediate 101

[0543] Intermediate 101 is prepared by the following steps:

[0544] Step A: Int-101a (8.5 g, 32.79 mmol) was dissolved in tetrahydrofuran (100 mL). Sodium hydride (5.24 g, 131.09 mmol, 60% in oil) was added in portions under ice bath conditions. The mixture was then brought to room temperature and stirred for approximately 1 hour. The reaction solution was cooled again under ice bath conditions. Int-13a (11.02 g, 39.33 mmol) was added in portions. The mixture was brought to room temperature and stirred for approximately 2 hours. LC / MS showed that the reaction was complete. The reaction was quenched with water, resulting in the formation of a large amount of white solid. The solid was filtered, the filter cake was washed with water, and dried in an oven to obtain a white solid, Int-101b (20 g), which required no further purification. ESI-MS (m / z): 503.1 [M+H] + .

[0545] Step B: At room temperature, Int-101b (20 g, 24.53 mmol) was dissolved in dichloromethane (200 mL), and N,N-diisopropylethylamine (64.1 mL, 367.93 mmol) and PyBOP (25 g, 98.11 mmol) were added sequentially. The reaction was carried out at room temperature for approximately 16 hours, and LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–40%) to give a yellow solid Int-101c (11.3 g, yield: 94.99%). ESI-MS (m / z): 485.1 [M+H] + .

[0546] Step C: Int-101c (11.3 g, 23.3 mmol) was dissolved in ethyl acetate (100 mL). Under ice bath conditions, m-chloroperoxybenzoic acid (12.1 g, 69.9 mmol) was added in portions. The mixture was allowed to react at room temperature for approximately 1 hour, and LC / MS showed complete reaction. The reaction was quenched with water, extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to give a pale yellow solid, Int-101d (12.0 g, yield: 93.38%). ESI-MS (m / z): 517.1 [M+H] + .

[0547] Step D: Under nitrogen protection, Int-101d (12.0 g, 21.67 mmol) and Int-13f (8.86 g, 26.01 mmol) were dissolved in dry tetrahydrofuran (160 mL) and cooled in an ice bath. Bistrimethylsilylaminolithium (1.0 M tetrahydrofuran solution, 65 mL, 65.02 mmol) was added dropwise to the reaction solution, and the mixture was stirred in an ice bath for approximately 1 hour. TLC showed that the reaction was complete. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–27%) to give an off-white solid Int-101e (13.3 g, yield: 78.93%). 1H NMR(500MHz,Chloroform-d)δ7.65-7.61(m,4H),7.39-7.35(m,2H),7.33-7.29 (m,4H),5.30-5.24(m,1H),4.48-4.30(m,3H),4.27-4.16(m,1H),4.08-3.95(m, 1H),3.76-3.70(m,2H),3.49(s,2H),3.19-2.99(m,1H),2.03-1.83(m,3H),1.5 2(s,9H),1.29-1.24(m,2H),1.02(s,9H),0.68-0.59(m,2H),0.58-0.53(m,2H).

[0548] Step E: At room temperature, Int-101e (12.3 g, 15.82 mmol) was dissolved in tetrahydrofuran (120 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 19 mL, 18.99 mmol) was added. The reaction was carried out at room temperature for approximately 16 hours, and LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–70%) to give Int-101f (6.8 g, yield: 79.74%). ESI-MS (m / z): 539.2 [M+H] + .

[0549] Step F: Int-101f (500 mg, 0.93 mmol), Int-60a (562.5 mg, 1.39 mmol), XPhos Pd G2 (146 mg, 0.19 mmol), potassium phosphate (1.77 g, 8.35 mmol), and tetrahydrofuran (6 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was heated to 65 °C and stirred for 2 hours under a nitrogen atmosphere. TLC showed that the starting materials reacted completely. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 0–50%) to give a yellow solid Int-101 g (710 mg, yield: 81.66%). ESI-MS (m / z): 795.3 [M+H] + .

[0550] Step G: At room temperature, Int-101 g (710 mg, 0.76 mmol) was dissolved in dichloromethane (8 mL), and Dysmartin oxidant (642.6 mg, 1.52 mmol) was added. The reaction was carried out at room temperature for about 2 hours, and LC / MS showed that the reaction was complete. Sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 0–40%) to give a yellow solid Int-101 (590 mg, yield: 98.23%). ESI-MS (m / z): 793.3 [M+H] + .

[0551] Intermediate 102

[0552] Intermediate 102 is prepared by the following steps:

[0553] Step A: Int-101f (500 mg, 0.93 mmol), Int-2f (713.2 mg, 1.39 mmol), cataCXium APd G3 (135.1 mg, 0.19 mmol), potassium phosphate (590.7 mg, 2.78 mmol), dioxane (5 mL), and water (1 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was stirred overnight at 85 °C under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 0–50%) to give a yellow solid Int-102a (750 mg, yield 73.66%). ESI-MS (m / z): 889.5 [M+H] + .

[0554] Step B: Int-102a (750 mg, 0.68 mmol) was dissolved in tetrahydrofuran (8 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.8 mL) was added under ice bath conditions. The mixture was then heated to room temperature and reacted for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to give the yellow product Int-102b (499 mg, yield 99.66%). ESI-MS (m / z): 733.3 [M+H] + .

[0555] Step C: Int-102b (499 mg, 0.68 mmol) was dissolved in dichloromethane (6 mL), and Dys-Martin oxidant (577.7 mg, 1.36 mmol) was added under ice bath conditions. The reaction was brought to room temperature and reacted for 2 hours. TLC showed that the starting material disappeared and new spots formed. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 0–40%) to give a yellow solid Int-102 (490 mg, yield 98.47%). ESI-MS (m / z): 731.3 [M+H] + .

[0556] Intermediate 103

[0557] Intermediate 103 is prepared by the following steps:

[0558] Step A: Int-101f (500 mg, 0.93 mmol), Int-96a (631.8 mg, 1.11 mmol), cataCXium A Pd G3 (67.6 mg, 0.09 mmol), potassium phosphate (590.7 mg, 2.78 mmol), dioxane (5 mL), and water (1 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was stirred overnight at 85 °C under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 0–50%) to give a yellow solid Int-103a (820 mg, yield: 93.62%). ESI-MS (m / z): 944.5 [M+H] + .

[0559] Step B: Int-103a (820 mg, 0.87 mmol) was dissolved in tetrahydrofuran (9 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 1 mL) was added under ice bath conditions. The mixture was then reacted at room temperature for 1 hour, and LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to give the yellow product Int-103b (630 mg, yield: 92.07%). ESI-MS (m / z): 788.4 [M+H] + .

[0560] Step C: Int-103b (630 mg, 0.8 mmol) was dissolved in dichloromethane (7 mL), and Dysmartin oxidant (678.3 mg, 1.6 mmol) was added under ice bath conditions. The reaction was brought to room temperature and reacted for 2 hours. TLC showed that the starting material disappeared and new spots formed. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 0–40%) to give a yellow solid Int-103 (547 mg, yield: 87.05%). ESI-MS (m / z): 787.3 [M+H] + .

[0561] Intermediate 106

[0562] Intermediate 106 is prepared by the following steps:

[0563] Step A: At room temperature, Int-106a (550 mg, 1.95 mmol) was dissolved in dichloromethane (6 mL), and N,N-diisopropylethylamine (754.9 mg, 5.84 mmol, 1 mL) was added. The mixture was cooled to -70 °C using an ethanol / dry ice bath. Int-99a (505 mg, 1.95 mmol) was dissolved in dichloromethane (5 mL) and slowly added dropwise to the reaction solution. The reaction was carried out at -70 °C for approximately 0.5 hours, and LC / MS showed that the reaction was complete. The reaction solution was purified directly by silica gel short column chromatography (eluent: dichloromethane) to obtain a yellow solid, Int-106b (960 mg), which was used directly in the next step. ESI-MS (m / z): 505.1 [M+H] + .

[0564] Step B: Under ice bath conditions, Int-106b (900 mg, 1.78 mmol) was dissolved in tetrahydrofuran (10 mL) and N,N-dimethylformamide (10 mL), followed by the sequential addition of cesium carbonate (1.74 g, 5.34 mmol), triethylenediamine (20 mg, 0.18 mmol), and Int-2d (4 g, 39.18 mol, 3.8 mL). The reaction was carried out at 0 °C for 1 hour, and LC / MS showed complete reaction. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–70%) to give a pale yellow solid, Int-106c (870 mg, yield: 85.55%). ESI-MS (m / z): 571.3 [M+H] + .

[0565] Step C: Int-106c (870 mg, 1.52 mmol), Int-2f (937 mg, 1.83 mmol), cataCXium APd G3 (221.9 mg, 0.3 mmol), potassium phosphate (970 mg, 4.57 mmol), dioxane (9 mL), and water (3 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the mixture was stirred overnight at 85 °C under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to give a pale yellow solid Int-106d (1.21 g, yield: 86.22%). 1 HNMR (500MHz, CDCl3) δ7.77(dd,J=9.0,5.6Hz,1H),7.49(s,1H),7.39(m,1H),7.29(t,J=8.7Hz,1H),7.26(s,2H),5.32-5.29(m,2H),5 .03-4.94(m,1H),4.74-4.64(m,1H),4.52-4.43(m,1H),4.41-4.36(m,1H),4.15-4.10(m,1H),4.07-4.02(m,2H),4.02-3.98(m,2H),3 .98-3.87(m,3H),3.82-3.74(m,1H),3.74-3.68(m,2H),3.46-3.39(m,1H),3.29-3.22(m,1H),3.19-3.06(m,2H),2.50-2.39(m,1H),2 .05-2.04(m,2H),1.62-1.54(m,1H),1.51-1.48(m,9H),1.26-1.25(m,3H),0.89-0.86(m,18H),0.77-0.67(m,2H),0.65-0.55(m,7H).

[0566] Step D: Int-106d (1.21 g, 1.31 mmol) was dissolved in dichloromethane (15 mL), and Dys-Martin oxidant (1.11 g, 2.63 mmol) was added under ice bath conditions. The reaction was brought to room temperature and carried out for 6 hours. TLC showed that the starting material disappeared and new spots were formed. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to give a yellow solid Int-106e (800 mg, yield: 66.26%). 1H NMR(500MHz,DMSO-d6)δ8.91(d,J=4.2Hz,1H),8.13-8.07(m,1H),7.75-7.71(m,1H),7.58-7.54(m,1H),7.4 4-7.40(m,1H),5.40-5.35(m,2H),4.63-4.57(m,1H),4.54-4.47(m,2H),4.34-4.24(m,2H),3.97-3.88(m,4 H),3.68-3.56(m,2H),3.42-3.36(m,1H),3.34-3.31(m,3H),3.22-2.99(m,2H),2.33-2.20(m,1H),1.97-1. 79(m,3H),1.47-1.41(m,9H),1.39-1.33(m,2H),1.32-1.25(m,2H),0.86-0.78(m,18H),0.58-0.52(m,3H).

[0567] Step E: Int-106e (800 mg, 0.87 mmol) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 1 mL) was added under ice bath conditions. The mixture was then heated to room temperature and reacted for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to give the pale yellow product Int-106 (500 mg, yield: 89.22%). ESI-MS (m / z): 763.4 [M+H] + .

[0568] Intermediates 107-P1 and 107-P2

[0569] Intermediates 107-P1 and 107-P2 were prepared by the following steps:

[0570] Step A: Int-107a (21.3 g, 66.7 mmol) was dissolved in a mixed solvent of tetrahydrofuran (200 mL) and water (50 mL). Lithium hydroxide monohydrate (11.3 g, 67 mmol) was added to the reaction solution. After nitrogen purging, the reaction was stirred at 70 °C for 3 hours. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid Int-107b (18.2 g, yield: 85.8%). ESI-MS (m / z): 301.9 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ7.91-8.06 (m, 1H).

[0571] Step B: Int-107b (18.2 g, 57.3 mmol) and thionyl chloride (69.5 g, 572.5 mmol) were added to a reaction flask and stirred at 80 °C for 3 hours. The reaction was cooled to room temperature, and the thionyl chloride was removed by concentration under reduced pressure. The residue was dissolved in toluene, and the toluene was removed by concentration and distillation to obtain crude acyl chloride. The crude product was dissolved in acetone (200 mL), and cooled to below 5 °C in an ice-water bath. Ammonium thiocyanate (4.71 g, 61.25 mmol) was dissolved in acetone (50 mL) and slowly added dropwise to the reaction system, followed by stirring at room temperature for 2 hours. Water was added dropwise to the reaction solution, and a large amount of dark yellow solid precipitated out. The solid was filtered. The filter cake was dissolved in a 2 mol / L sodium hydroxide aqueous solution (9.54 g, 229 mmol), and iodomethane (4.36 mL, 68.7 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the pH of the filtrate was adjusted to approximately 3 with 2 mol / L dilute hydrochloric acid, resulting in the precipitation of a white solid. This was filtered again, and the filter cake was washed with water and dried to obtain a white solid, Int-107c (19.5 g, 51.9 mmol, yield: 90.6%). ESI-MS (m / z): 357.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ2.61(s,3H)8.10(s,1H)13.22(br s,1H).

[0572] Step C: Int-107c (19.5 g, 51.9 mmol) was dissolved in ultra-dry acetonitrile (500 mL), and Int-2b (16.9 g, 77.8 mmol), BOP (35.1 g, 77.8 mmol), and diisopropylethylamine (20.3 g, 155.6 mmol) were added. After nitrogen purging, the reaction was stirred at 50 °C for 8 hours, and LC / MS showed that the reaction was complete. The reaction solution was rapidly cooled to below 10 °C in an ice-water bath, the reaction was quenched with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was obtained. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–20%) to give a white solid Int-107d (28.0 g, yield: 94.9%). ESI-MS (m / z): 551.7 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ1.46(s,10H),1.57-1.63(m,2H),1.74-1.81(m,2H),2.54-2.58(m,4H),3.60(br d,J=12.26Hz,2H),4.20-4.27(m,2H),4.36-4.44(m,2H),8.05-8.09(m,1H).

[0573] Step D: Int-107d (7.18 g, 12.6 mmol) was dissolved in 1,4-dioxane (250 mL), and Int-60a (5.16 g, 12.6 mmol), cesium carbonate (18.3 g, 56.0 mmol), and bis(diphenylphosphine ether)palladium(II) dichloride (3.97 g, 5.43 mmol) were added. After nitrogen purging, the mixture was stirred at 100 °C for 18 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to obtain Int-107e (3.80 g).

[0574] Step E: Int-107e (3.80 g) was chirally separated by SFC (column: ChiralPak IG, 250×30 mm ID, 5 μm, column temperature: 35℃, flow rate: 80 mL / min, detection: 210 nm, mobile phase: EtOH [0.1% NH3 (7 M in MeOH)], gradient: 20%). The first eluted component was Int-107-P1 (1.70 g, two-step yield: 17.7%), followed by Int-107-P2 (1.69 g, two-step yield: 17.5%), both of which were yellow solids.

[0575] Int-107-P1: Chiral column elution time: 1.422 min (IG-3, 100*4.6 mm, 3 μm; mobile phase: EtOH (0.1% DEA); flow rate: 3.0 mL / min; wavelength: 214 nm; column temperature: 40 °C); ee value: 100%. ESI-MS (m / z): 762.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ1.44-1.48(m,9H),1.50(s,9H),1.57-1.63(m,2H),1.74-1.87(m,2H),2.54-2.59(m,3H),3.62(br d,J=12.13Hz,1H),3.70-3.81(m,1H),4.28(br s,2H),4.36(br d,J=11.76Hz,1H),4.43-4.53(m,1H),7.37-7.49(m,2H),8.14(s,1H),11.70-11.88( m,1H),11.76(s,1H),11.73-11.79(m,1H),11.74-11.75(m,1H),11.78-11.79(m,1H).

[0576] Int-107-P2: Chiral column elution time: 1.904 min (IG-3, 100*4.6 mm, 3 μm; mobile phase: EtOH (0.1% DEA); flow rate: 3.0 mL / min; wavelength: 214 nm; column temperature: 40 °C), ee value: 100%. ESI-MS (m / z): 763.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ1.47(s,9H),1.50(s,9H),1.60(br d,J=8.63Hz,2H),1.81(br d,J=1.88Hz,2H),2.56(s,3H),3.62(br d,J=12.51Hz,1H),3.75(br d,J=11.38Hz,1H),4.28(br s,2H),4.36(br d,J=12.13Hz,1H),4.48(br d,J=11.63Hz,1H),7.36-7.48(m,2H),8.14(s,1H),11.76(s,1H).

[0577] The structures corresponding to Int-107-P1 and Int-107-P2 are assumed absolute configurations. The two enantiomers undergo subsequent reactions separately.

[0578] Intermediate 108

[0579] Intermediate 108 is prepared by the following steps:

[0580] Step A: Int-25f (500.2 mg, 0.93 mmol), Int-108a (500 mg, 1.4 mmol), cataCXium A Pd G3 (135.9 mg, 0.19 mmol), potassium phosphate (594.3 mg, 2.8 mmol), dioxane (5 mL), and water (1 mL) were added to the reaction flask. After purging the reaction system with nitrogen, the reaction was carried out overnight at 85 °C under a nitrogen atmosphere. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to give a brown solid Int-108b (590 mg, yield: 86.62%). ESI-MS (m / z): 731.3 [M+H] + .

[0581] Step B: Int-108b (590 mg, 0.81 mmol) was dissolved in dichloromethane (6 mL), and Dysmartin oxidant (684.9 mg, 1.61 mmol) was added under ice bath conditions. The mixture was heated to room temperature and reacted for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was diluted with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–40%) to give a brown solid Int-108 (490 mg, yield: 83.28%). ESI-MS (m / z): 729.3 [M+H] + .

[0582] Intermediate 109

[0583] Intermediate 109 is prepared by the following steps:

[0584] Step A: Int-107-P1 (500 mg, 0.66 mmol) was dissolved in ethyl acetate (10 mL). Under ice bath conditions, m-chloroperoxybenzoic acid (339.3 mg, 1.97 mmol) was added in portions, and the reaction was carried out at room temperature for approximately 1 hour. LC / MS showed the reaction was complete. The mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to give a pale yellow solid, Int-109a (501 mg, yield: 96.17%). ESI-MS (m / z): 795.3 [M+H] + .

[0585] Step B: Int-109a (501 mg, 0.63 mmol) and Int-13f (258.1 mg, 0.76 mmol) were dissolved in tetrahydrofuran (5 mL), cooled to 0°C in an ice bath, and bis(trimethylsilylaminolithium) (1.0 M tetrahydrofuran solution) (0.7 mL, 0.63 mmol) was added dropwise to the reaction solution. After completion, the reaction was stirred at this temperature for about 1 hour. TLC showed that the reaction was complete. The reaction was quenched by adding ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–27%) to give a yellow solid Int-109b (528 mg, yield: 79.22%).

[0586] Step C: At room temperature, Int-109b (528 mg, 0.5 mmol) was dissolved in tetrahydrofuran (6 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) (0.75 mL, 0.75 mmol) was added dropwise to the reaction solution. The reaction was carried out at 25 °C for approximately 16 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was subjected to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–70%) to give Int-109c (275 mg, yield: 67.28%). ESI-MS (m / z): 817.3 [M+H] + .

[0587] Step D: At room temperature, Int-109c (275 mg, 0.34 mmol) was dissolved in dichloromethane (3 mL), and Dys-Martin oxidant (214 mg, 0.51 mmol) was added. The reaction was carried out for about 1 hour under these conditions. LC / MS showed that the reaction was complete. Sodium bicarbonate aqueous solution was added dropwise to the reaction solution, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration of the filtrate was purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 0–40%) to obtain a yellow solid Int-109 (220 mg, yield 80.2%).

[0588] Intermediate 110

[0589] Intermediate 110 is prepared by the following steps:

[0590] Step A: Int-107-P2 (600 mg, 0.79 mmol) was dissolved in ethyl acetate (10 mL). Under ice bath conditions, m-chloroperoxybenzoic acid (407.2 mg, 2.36 mmol) was added in portions, and the reaction was carried out at room temperature for approximately 1 hour. LC / MS showed the reaction was complete. The mixture was quenched with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to give a pale yellow solid, Int-110a (582 mg, yield: 93.09%). ESI-MS (m / z): 795.4 [M+H] + .

[0591] Step B: Int-110a (582 mg, 0.73 mmol) and Int-13f (300 mg, 0.88 mmol) were dissolved in tetrahydrofuran (6 mL), cooled to 0°C in an ice bath, and bis(trimethylsilylaminolithium) (1.0 M tetrahydrofuran solution) (0.75 mL, 0.73 mmol) was added dropwise to the reaction solution. After completion, the reaction was stirred at this temperature for about 1 hour. TLC showed that the reaction was complete. The reaction was quenched by adding ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–30%) to give a yellow solid Int-110b (630 mg, yield: 81.53%).

[0592] Step C: At room temperature, Int-110b (630 mg, 0.6 mmol) was dissolved in tetrahydrofuran (7 mL), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) (0.9 mL, 0.9 mmol) was added dropwise to the reaction solution. The reaction was carried out at 25 °C for approximately 16 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was subjected to silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–70%) to give Int-110c (360 mg, yield: 73.82%). ESI-MS (m / z): 817.3 [M+H] + .

[0593] Step D: At room temperature, Int-110c (360 mg, 0.44 mmol) was dissolved in dichloromethane (4 mL), and Dys-Martin oxidant (280.4 mg, 0.66 mmol) was added. The reaction was carried out for about 1 hour under these conditions. LC / MS showed that the reaction was complete. Sodium bicarbonate aqueous solution was added dropwise to the reaction solution, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration of the filtrate was purified by silica gel column chromatography (eluent: ethyl acetate / dichloromethane = 0–40%) to obtain a yellow solid Int-110 (245 mg, yield 68.22%).

[0594] Intermediates 111-P1 and 111-P2

[0595] Intermediates 111-P1 and 111-P2 are prepared by the following steps:

[0596] Step A: Int-49d (5.60 g, 6.31 mmol) was dissolved in ultradry N,N-dimethylformamide (40 mL), and cesium fluoride (9.68 g, 63.1 mmol) was added. After purging with nitrogen, the reaction mixture was stirred at 50 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to obtain Int-111a (3.40 g).

[0597] Step B: Int-111a (3.40 g) was chirally separated by SFC (chiral column: ChiralPak IG, 100 × 4.6 mm ID, 3 μm, column temperature: 40 °C, flow rate: 3 mL / min, detection: 214 nm, mobile phase: EtOH (0.1% DEA), gradient: 40%). The first eluted fraction was Int-111-P1 (1.47 g, two-step yield: 33.1%), and the second eluted fraction was Int-111-P2 (1.57 g, two-step yield: 35.3%), both of which were yellow solids.

[0598] Int-111-P1: Chiral column elution time: 1.554 min (IG-3, 100*4.6 mm, 3 μm; mobile phase: EtOH (0.1% DEA); flow rate: 3.0 mL / min; wavelength: 214 nm; column temperature: 40 °C); ee value: 100%. ESI-MS (m / z): 705.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ0.48-0.56(m,4H),1.46(s,9H),1.71-1.89(m,4H) ,3.39(t,J=5.50Hz,2H),3.45(s,3H),3.47-3.60(m,2H),4.03(s,1H),4.22 -4.35(m,6H),4.61(t,J=5.75Hz,1H),5.37(s,2H),7.38(d,J=2.50Hz,1H) ,7.55-7.63(m,2H),7.76(d,J=2.50Hz,1H),8.11(dd,J=9.19,5.94Hz,1H).

[0599] Int-111-P2: Chiral column elution time: 2.048 min (IG-3, 100*4.6 mm, 3 μm; mobile phase: EtOH (0.1% DEA); flow rate: 3.0 mL / min; wavelength: 214 nm; column temperature: 40 °C); ee value: 100%. ESI-MS (m / z): 705.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ0.48-0.57(m,4H),1.46(s,9H),1.71-1.89(m,4H),3 .39(d,J=4.75Hz,2H),3.44(s,3H),3.47-3.61(m,2H),4.03(s,1H),4.22-4. 35(m,6H),4.55-4.55(m,1H),4.62(s,1H),5.37(s,2H),7.38(d,J=2.50Hz,1 H),7.54-7.64(m,2H),7.76(d,J=2.63Hz,1H),8.11(dd,J=9.19,5.94Hz,1H).

[0600] The structures corresponding to Int-111-P1 and Int-111-P2 are assumed absolute configurations. The two enantiomers undergo subsequent reactions separately.

[0601] Intermediate 112

[0602] Intermediate 112 is prepared by the following steps:

[0603] Step A: Int-112a (1.4 g, 2.76 mmol) was dissolved in dichloromethane (5 mL). Under ice bath cooling, hydrochloric acid-dioxane solution (4.0 M, 5 mL) was added, and the mixture was then allowed to react at room temperature for 1 hour. LC / MS showed the reaction was complete. The reaction solution was concentrated to obtain a white solid, Int-112b (1.2 g, crude product, hydrochloride). ESI-MS (m / z): 408.1 [M+H] + .

[0604] Step B: At room temperature, Int-112b (350 mg, 0.79 mmol) and 1a (377.4 mg, 1.58 mmol) were dissolved in N-methylpyrrolidone (5 mL), and sodium triacetoxyborohydride (501.4 mg, 2.37 mmol) was added to the reaction solution. The reaction was carried out at 55 °C for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was purified by reversed-phase column chromatography (mobile phase: acetonitrile / 0.1% formic acid aqueous solution) to obtain a white solid Int-112c (300 mg, yield 60.32%), ESI-MS (m / z): 631.3 [M+H]. + .

[0605] Step C: Int-112c (300 mg, 0.48 mmol) was dissolved in dichloromethane (3 mL). Under ice bath cooling, hydrochloric acid-dioxane solution (4.0 M, 3 mL) was added, and the mixture was then allowed to react at room temperature for 1 hour. LC / MS showed the reaction was complete. The reaction solution was concentrated to give a white solid Int-112 (260 mg, crude product, hydrochloride). ESI-MS (m / z): 531.3 [M+H] + .

[0606] Intermediates 113-P1 and 113-P2

[0607] Intermediates 113-P1 and 113-P2 were prepared by the following steps:

[0608] Step A: Int-49c (12.3 g, 20 mmol), Int-96a (14.8 g, 26.0 mmol), and cataCXium A Pd G3 (2.97 g, 4.00 mmol) were dissolved in tetrahydrofuran (100 mL). A potassium phosphate aqueous solution (53.3 mL, 80.0 mmol, 1.5 mol / L) was added. After purging the reaction system with nitrogen, the mixture was stirred at 75 °C for 30 minutes under a nitrogen atmosphere. LC / MS showed the reaction was complete. The reaction solution was cooled to room temperature, the reaction was quenched with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to give a yellow solid Int-113a (4.10 g, yield: 21.2%). ESI-MS (m / z): 916.7 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ0.44-0.55(m,7H),0.75-0.79(m,9H),0.82-0.87(m,9H),1.45(s,9H) ,1.50(s,9H),1.61-1.73(m,1H),1.82-2.01(m,3H),3.16-3.21(m,1H),3.34-3.39(m,2H),3.4 3-3.48(m,1H),3.58-3.65(m,1H),3.91-3.98(m,1H),4.14-4.19(m,1H),4.24-4.33(m,3H),4 .53-4.63(m,1H),7.50-7.67(m,3H),8.05-8.12(m,1H),8.23-8.27(m,1H),9.79-9.87(m,1H).

[0609] Step B: Under nitrogen protection, Int-113a (4.00 g, 4.15 mmol) was dissolved in ultradry N,N-dimethylformamide (50 mL), and cesium fluoride (6.36 g, 41.5 mmol) was added. The reaction mixture was stirred at 50 °C for 2 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0–50%) to obtain Int-113b (3.10 g).

[0610] Step C: Int-113b (3.10 g) was chirally separated by SFC (chiral column: ChiralPak IC, 250 × 30 mm ID, 5 μm, column temperature: 35 °C, flow rate: 100 mL / min; detection: 214 nm; mobile phase: methanol [0.1% NH3 (7 M in MeOH)]; gradient: 35%). The first eluted fraction was Int-113-P1 (1.36 g, two-step yield: 43.1%), and the second eluted fraction was Int-113-P2 (1.39 g, two-step yield: 44.1%), both of which were yellow solids.

[0611] Int-113-P1: Chiral column elution time: 1.523 min (IG-3, 100*4.6 mm, 3 μm; mobile phase: MeOH (0.1% DEA); flow rate: 3.0 mL / min; wavelength: 214 nm; column temperature: 40 °C), ee value: 100%. ESI-MS (m / z): 760.4 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ0.46-0.58(m,4H),1.46(s,9H),1.50(s,9H),1.7 5-1.90(m,4H),3.36-3.40(m,2H),3.43-3.65(m,2H),4.02(s,1H),4.20-4 .42(m,6H),4.62(t,J=5.69Hz,1H),7.53(t,J=9.01Hz,1H),7.59-7.67(m ,2H),8.08(dd,J=9.19,5.94Hz,1H),8.27(d,J=1.63Hz,1H),9.83(s,1H).

[0612] Int-113-P2: Chiral column elution time: 1.974 min (IG-3, 100*4.6 mm, 3 μm; mobile phase: MeOH (0.1% DEA); flow rate: 3.0 mL / min; wavelength: 214 nm; column temperature: 40 °C), ee value: 100%. ESI-MS (m / z): 760.4 [M+H] + ; 1H NMR(400MHz, DMSO-d6)δ0.47-0.57(m,4H),1.46(s,9H),1.50(s,9H),1.71-1.89(m,4H),3.35-3.43(m,2H),3.44-3.64(m,2H),4.00-4.04(m ,1H),4.21-4.43(m,6H),4.58-4.65(m,1H),7.50-7.57(m,1H),7.59- 7.68(m,2H),8.05-8.12(m,1H),8.24-8.30(m,1H),9.80-9.87(m,1H).

[0613] The structures corresponding to Int-113-P1 and Int-113-P2 are assumed absolute configurations. The two enantiomers undergo subsequent reactions separately.

[0614] The synthesis method of the compounds in the embodiments of this invention is as follows:

[0615] Example 1

[0616] 3-(4-(4-(7-((1-(((4-((3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0617] Example 1 was prepared by the following steps:

[0618] Step A: At room temperature, 1a (69.69 mg, 0.29 mmol) and Int-1 (0.1 g, 0.29 mmol) were dissolved in N,N-dimethylformamide (2 mL), and a catalytic equivalent of acetic acid (3 drops) was added. The reaction was carried out at room temperature for about 1 hour. Sodium triacetoxyborohydride (123.44 mg, 0.58 mmol) was added, and the mixture was stirred at 60 °C for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was cooled to room temperature and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain 1b (110 mg, yield: 66.65%). ESI-MS (m / z): 567.5 [M+H] + .

[0619] Step B: Dissolve 1b (110 mg, 0.19 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (1 mL) and stir at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction solution was concentrated to give 1c (90 mg, crude product, trifluoroacetate). No further purification was required. ESI-MS (m / z): 467.4 [M+H] + .

[0620] Step C: Int-2 (73.92 mg, 0.11 mmol) and 1c (50 mg, 0.11 mmol, trifluoroacetate) were dissolved in N,N-dimethylformamide (1 mL), and a catalytic equivalent of acetic acid (3 drops) was added. The reaction was carried out at room temperature for about 1 hour. Sodium triacetoxyborohydride (22.71 mg, 0.11 mmol) was added, and the reaction was stirred at 60 °C for 5 hours. LC / MS monitoring showed product formation. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain 1d (50 mg, yield: 40.92%). ESI-MS (m / z): 571.0 [M+2H] 2+ / 2.

[0621] Step D: Dissolve 1 d (45 g, 0.039 mmol) in dichloromethane (1 mL), then add trifluoroacetic acid (0.5 mL) and stir at room temperature for 1 hour. LC / MS monitoring showed product formation. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 1 (11 mg, yield: 27.42%). ESI-MS (m / z): 499.0 [M+2H] 2+ / 2; 1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.94(s,1H),9.08(s,1H),7.76(dd,J=9.1,6 .0Hz,1H),7.37-7.31(m,2H),7.01(d,J=2.5Hz,1H),6.98(t,J=7.9Hz,1H),6.92(d, J=7.5Hz,1H),6.88(d,J=7.7Hz,1H),5.35(dd,J=12.7,5.4Hz,1H),4.45–4.38(m,2H ),4.33(d,J=10.8Hz,1H),4.26(d,J=10.8Hz,1H),3.63-3.58(m,4H),3.57–3.52(m, 2H),3.02-2.94(m,2H),2.90-2.77(m,5H),2.73–2.66(m,2H),2.65–2.61(m,1H),2 .61-2.58(m,1H),2.40–2.31(m,3H),2.29-2.22(m,3H),2.18–2.10(m,2H),2.02–1. 95(m,2H),1.90-1.84(m,2H),1.69–1.58(m,4H),1.52-1.45(m,4H),1.43-1.38(m,2 H),1.25-1.22(m,1H),0.72(t,J=7.4Hz,3H),0.65-0.61(m,2H),0.41-0.37(m,2H).

[0622] Example 2

[0623] 3-(4-(4-((1-((1-((((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0624] Example 2 was prepared by the following steps:

[0625] Step A: Dissolve 2a (37.27 mg, 0.17 mmol) and Int-1 (60 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL), then add sodium triacetoxyborohydride (55.55 mg, 0.26 mmol), and stir at room temperature for 1 hour. LC / MS showed the reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 2b (94 mg, crude). ESI-MS (m / z): 541.4 [M+H] + .

[0626] Step B: Dissolve 2b (94 mg, 0.17 mmol, crude product) in dichloromethane (1 mL), then slowly add trifluoroacetic acid (0.5 mL) dropwise, and stir at room temperature for 1 hour. LC / MS showed the reaction was complete. Concentrate the reaction solution to give 2c (70 mg, crude product, trifluoroacetate). No further purification is required. ESI-MS (m / z): 441.4 [M+H] + .

[0627] Step C: Dissolve 2c (70 mg, 0.16 mmol, trifluoroacetate) and Int-2 (109.60 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL), then add sodium triacetoxyborohydride (50.51 mg, 0.24 mmol), and stir at 60 °C for 5 hours. LC / MS showed the reaction was complete. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phases were combined, concentrated under reduced pressure, and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to obtain 2d (50 mg, yield: 28.24%). ESI-MS (m / z): 558.1 [M+2H] 2+ / 2.

[0628] Step D: Compound 2 (50 mg, 0.045 mmol) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give compound 2 (10 mg, yield: 22.51%). ESI-MS (m / z): 486.0 [M+2H] 2+ / 2; 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),9.97(s,1H),9.09(s,1H),7.76(dd,J=9.1,6.0Hz,1H),7.37-731(m,2H),7.02(d,J=2.5Hz,1H),6.97(q,J= 8.0Hz,1H),6.89(dd,J=17.1,8.1Hz,2H),5.35(dd,J=12.7,5.3Hz,1H),4.42(d,J=11.9Hz,2H),4.33(d,J=10.9Hz,1H),4.27(d,J=10.7Hz,1H),3 .64–3.54(m,6H),3.01–2.87(m,5H),2.85-2.76(m,3H),2.73–2.57(m,3 H),2.38-2.24(m,4H),2.16-2.10(m,3H),2.02–1.96(m,1H),1.86-1.80( m,2H),1.69–1.59(m,5H),1.51-1.43(m,2H),1.28-1.21(m,2H),1.10-0 .97(m,3H),0.73(t,J=7.4Hz,3H),0.66-0.61(m,2H),0.42-0.36(m,2H).

[0629] Example 3

[0630] 3-(4-(4-(3-((1-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecane-9-yl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0631] Example 3 was prepared by the following steps:

[0632] Step A: Dissolve Int-1 (250 mg, 0.73 mmol) in N,N-dimethylformamide (3 mL), add triethylamine (221.02 mg, 2.18 mmol, 0.30 mL), and stir for about 10 minutes. Add 3a (233.59 mg, 0.87 mmol) to the reaction solution, add catalytic equivalent acetic acid (3 drops), and stir for about 1 hour. Add sodium triacetoxyborohydride (462.91 mg, 2.18 mmol) in portions. React at 60 °C for 2 hours. LC / MS showed the reaction was complete. Quench the reaction with water and extract with ethyl acetate. Combine the organic phases, dry to anhydrous sodium sulfate, filter and concentrate. Purify the residue by silica gel column chromatography (dichloromethane / methanol (V / V) = 20 / 1) to give 3b (250 mg, yield: 57.74%). ESI-MS (m / z): 595.5 [M+H] + .

[0633] Step B: Dissolve 3b (250 mg, 0.42 mmol) in dichloromethane (2 mL), then slowly add dropwise 2 mL of hydrochloric acid-dioxane solution (4.0 M). Stir the mixture at room temperature for 1 hour. LC / MS showed the reaction was complete. Concentrate the reaction solution to give 3c (60 mg, crude product, hydrochloride). No further purification was required. ESI-MS (m / z): 495.5 [M+H] + .

[0634] Step C: Dissolve 3c (50 mg, 0.10 mmol, hydrochloride) and Int-2 (69.72 mg, 0.10 mmol) in N,N-dimethylformamide (2 mL). Add sodium triacetoxyborohydride (32.14 mg, 0.15 mmol) to the reaction solution and stir at 60 °C for 5 hours. LC / MS showed that the reaction was complete. Cool the reaction solution to room temperature and purify by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia solution) to obtain 3d (49 mg, yield: 38.95%). ESI-MS (m / z): 585.1 [M+2H] 2+ / 2.

[0635] Step D: Compound 3 (49 mg, 0.043 mmol) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give compound 3 (12 mg, yield: 26.83%). ESI-MS (m / z): 513.0 [M+2H] 2+ / 2. 1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.96(s,1H),9.08(s,1H),7.76(dd,J =9.1,6.0Hz,1H),7.37-7.31(m,2H),7.01(d,J=2.5Hz,1H),6.97(t,J=7.9H z,1H),6.93-6.86(m,2H),5.35(dd,J=12.6,5.4Hz,1H),4.45–4.38(m,2H), 4.32(d,J=10.9Hz,1H),4.26(d,J=10.8Hz,1H),3.63-3.58(m,4H),3.57-3. 52(m,2H),3.03-2.94(m,2H),2.92-2.82(m,4H),2.74–2.65(m,2H),2.66–2 .57(m,2H),2.39–2.30(m,5H),2.29–2.19(m,3H),2.17–2.11(m,1H),2.01– 1.96(m,1H),1.68–1.56(m,7H),1.42-1.31(m,4H),1.27-1.20(m,5H),1.05 –0.97(m,2H),0.73(t,J=7.4Hz,3H),0.66-0.60(m,2H),0.42-0.37(m,2H).

[0636] Example 4

[0637] 3-(4-(4-(8-((1-((((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-1-oxa-8-azaspiro[4.5]decane-3-yl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0638] Example 4 was prepared by the following steps:

[0639] Step A: At room temperature, Int-1 (100 mg, 0.29 mmol, hydrochloride) and 4a (111.53 mg, 0.44 mmol) were dissolved in tetrahydrofuran (2 mL). Sodium triacetoxyborohydride (92.58 mg, 0.44 mmol) was added to the reaction solution, and the reaction was stirred at 50 °C for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 4b (120 mg, yield: 70.72%). ESI-MS (m / z): 583.5 [M+H] + .

[0640] Step B: Dissolve 4b (70 mg, 0.12 mmol) in dichloromethane (2 mL), then add trifluoroacetic acid (1 mL) and stir at room temperature for 1 hour. LC / MS showed the reaction was complete. Concentrate the reaction solution to give 4c (57 mg, crude product, trifluoroacetate). No further purification was required. ESI-MS (m / z): 483.4 [M+H] + .

[0641] Step C: Int-2 (71.47 mg, 0.10 mmol) and 4c (50 mg, 0.10 mmol, trifluoroacetate) were dissolved in tetrahydrofuran (2 mL). Sodium triacetoxyborohydride (32.94 mg, 0.15 mmol) was added to the reaction solution, and the mixture was stirred at 50 °C for 4 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 4d (60 mg, yield: 50.08%). ESI-MS (m / z): 579.0 [M+2H] 2+ / 2.

[0642] Step D: Compound 4 (45 mg, 0.039 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give compound 4 (12 mg, yield: 29.86%). ESI-MS (m / z): 507.0 [M+2H] 2+ / 2; 1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.96(s,1H),9.08(s,1H),7.76(dd,J=9.1,6.0Hz,1H),7.39–7.31(m,2H),7.04–6.95(m,2H),6.93-6.87(m ,2H),5.35(dd,J=12.6,5.4Hz,1H),4.45–4.38(m,2H),4.35-4.26(m,2H ),3.92–3.87(m,1H),3.61(s,3H),3.59–3.50(m,4H),2.99-2.92(m,3H), 2.90–2.81(m,3H),2.74–2.66(m,2H),2.65-2.62(m,1H),2.61-2.58(m, 1H),2.45–2.35(m,4H),2.35–2.23(m,5H),2.18-2.12(m,1H),2.02–1.89 (m,3H),1.69-1.61(m,3H),1.60-1.53(m,3H),1.51-1.43(m,3H),1.25-1 .22(m,1H),0.72(t,J=7.4Hz,3H),0.65-0.61(m,2H),0.42-0.37(m,2H).

[0643] Example 5

[0644] 3-(4-(4-(7-((1-((((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0645] Example 5 was prepared by the following steps:

[0646] Step A: Dissolve 1c (70 mg, 0.15 mmol, trifluoroacetate) and Int-2i (102.88 mg, 0.15 mmol) in tetrahydrofuran (3 mL), stir at room temperature for 0.5 h, then add sodium triacetoxyborohydride (95.39 mg, 0.45 mmol) in portions, and stir the reaction mixture at 50 °C for 2 h. LC / MS showed that the reaction was complete. The reaction mixture was concentrated and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 5a (80 mg, yield: 46.93%). ESI-MS (m / z): 569.0 [M+2H] 2+ / 2.

[0647] Step B: 5a (70 mg, 0.062 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added dropwise to the reaction solution. The mixture was stirred at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give compound 5 (34 mg, yield: 55.63%). ESI-MS (m / z): 497.0 [M+2H] 2+ / 2; 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),10.18(s,1H),9.02(s,1H),7.97(dd,J =9.2,6.0Hz,1H),7.46(t,J=9.0Hz,1H),7.39(d,J=2.5Hz,1H),7.17(d,J=2.4 Hz,1H),6.98(t,J=7.9Hz,1H),6.92(d,J=7.6Hz,1H),6.88(d,J=7.8Hz,1H), 5.34(dd,J=12.7,5.4Hz,1H),4.48(d,J=11.4Hz,1H),4.32–4.23(m,3H),3.93 (s,1H),3.66–3.58(m,4H),3.56-3.52(m,3H),3.04–2.90(m,3H),2.88-2.75 (m,5H),2.74–2.66(m,2H),2.65–2.61(m,1H),2.60-2.57(m,1H),2.38–2.35( m,1H),2.33-2.20(m,5H),2.02–1.96(m,2H),1.91-1.84(m,2H),1.66(s,4H) ,1.56–1.46(m,4H),1.45-1.40(m,2H),0.65-0.60(m,2H),0.42-0.37(s,2H).

[0648] Example 6

[0649] 3-(4-((S)-4-(7-((1-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)-3-methylpiperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0650] Example 6 was prepared by the following steps:

[0651] Step A: At room temperature, Int-3 (190 mg, 0.53 mmol, hydrochloride) and 1a (127.22 mg, 0.53 mmol) were dissolved in N,N-dimethylformamide (3 mL). Under ice bath conditions, catalytic equivalent acetic acid (3 drops) was added dropwise, followed by the addition of sodium triacetoxyborohydride (225.34 mg, 1.06 mmol) in portions. The reaction was carried out at room temperature for 2 hours. LC / MS showed that the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 15 / 1) to give 6a (170 mg, yield: 55.07%), ESI-MS (m / z): 581.7 [M+H]. + .

[0652] Step B: Dissolve 6a (170 mg, 0.29 mmol) in dichloromethane (3 mL), and add hydrochloric acid-dioxane solution (4.0 M) (3 mL) dropwise to the reaction solution. React at room temperature for 2 hours. A white solid precipitates. LC / MS shows the reaction is complete. Concentrate the reaction solution to obtain 6b (156 mg, crude product, hydrochloride), which requires no further purification. ESI-MS (m / z): 481.6 [M+H] + .

[0653] Step C: At room temperature, 6b (70.00 mg, 0.14 mmol, hydrochloride) and Int-2 (140.07 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (3 mL). Under ice bath conditions, catalytic equivalent acetic acid (3 drops) was added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (114.77 mg, 0.54 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC / MS showed that the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 6c (130 mg, yield: 83.19%), ESI-MS (m / z): 579.2 [M+2H]. 2+ / 2.

[0654] Step D: Dissolve 6c (50 mg, 0.043 mmol) in dichloromethane (2 mL), and add hydrochloric acid-dioxane solution (4.0 M) (2 mL) dropwise to the reaction solution. React at room temperature for 2 hours. A pale yellow solid is produced. LC / MS shows that the reaction is complete. The reaction solution is concentrated, and the residue is purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 6 (37.3 mg, yield: 36.96%, formate). ESI-MS (m / z): 506.6 [M+2H] 2+ / 2; 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),9.09(s,1H),8.20(s,2H),7.76(dd,J=9. 1,6.0Hz,1H),7.34(dd,J=15.6,6.1Hz,2H),7.01(d,J=2.5Hz,1H),6.98(t,J=7 .9Hz,1H),6.89(dd,J=13.0,8.0Hz,2H),5.35(dd,J=12.7,5.1Hz,1H),4.44(d, J=12.4Hz,2H),4.30(dd,J=32.3,10.8Hz,2H),3.67–3.58(m,7H),3.18–3.07(m ,2H),3.07–2.93(m,3H),2.93–2.74(m,4H),2.73–2.66(m,1H),2.62–2.55(m,1 H),2.36–2.31(m,2H),2.30–2.23(m,3H),2.21–2.06(m,3H),2.05–1.95(m,2H) ,1.92–1.79(m,2H),1.74–1.63(m,4H),1.58–1.47(m,3H),1.45–1.36(m,2H),1 .08–0.93(m,3H),0.72(t,J=7.4Hz,3H),0.67–0.60(m,2H),0.45–0.37(m,2H).

[0655] Example 7

[0656] 3-(4-((S)-4-(7-((1-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)-3-methylpiperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0657] Example 7 was prepared by the following steps:

[0658] Step A: At room temperature, 6b (70.00 mg, 0.14 mmol, hydrochloride) and Int-2i (139.25 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (2 mL). Under ice bath conditions, catalytic equivalent acetic acid (3 drops) was added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (114.77 mg, 0.54 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC / MS showed that the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 7a (50 mg, yield: 30.87%), ESI-MS (m / z): 576.1 [M+H]. + .

[0659] Step B: 7a (50 mg, 0.043 mmol) was dissolved in formic acid (2 mL) and reacted at room temperature for 1 hour. LC / MS showed the reaction was complete. The reaction solution was concentrated to give the crude product, which was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 7 (35.6 mg, yield: 77.84%, formate). ESI-MS (m / z): 504.0 [M+2H] 2+ / 2; 1H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.05(s,1H),8.18(s,1H),7.98(dd,J=9.2,6. 0Hz,1H),7.47(t,J=9.0Hz,1H),7.40(d,J=2.5Hz,1H),7.18(d,J=2.4Hz,1H),6.98( t,J=7.9Hz,1H),6.93–6.85(m,2H),5.35(dd,J=12.7,5.3Hz,1H),4.55(d,J=12.3Hz ,1H),4.36(d,J=12.0Hz,1H),4.31–4.24(m,2H),3.97–3.93(m,1H),3.82–3.76(m,2 H),3.76–3.69(m,2H),3.69–3.63(m,2H),3.61(s,3H),3.22–3.08(m,2H),3.05–2.9 6(m,2H),2.94–2.75(m,4H),2.74–2.66(m,1H),2.62–2.55(m,1H),2.35–2.25(m,3H ),2.17–2.08(m,1H),2.04–1.94(m,2H),1.90–1.84(m,1H),1.77(s,3H),1.61–1.51 (m,3H),1.50–1.34(m,3H),1.13–0.87(m,4H),0.70–0.62(m,2H),0.47–0.40(m,2H).

[0660] Example 8

[0661] 3-(4-((R)-4-(7-((1-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)-3-methylpiperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0662] Example 8 was prepared by the following steps:

[0663] Step A: At room temperature, Int-4 (190 mg, 0.53 mmol) and 1a (127.22 mg, 0.53 mmol) were dissolved in N,N-dimethylformamide (3 mL). Under ice bath conditions, catalytic equivalent acetic acid (3 drops) was added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (225.34 mg, 1.06 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC / MS showed that the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 15 / 1) to give 8a (100 mg, yield: 32.29%), ESI-MS (m / z): 581.7 [M+H]. + .

[0664] Step B: Dissolve 8a (100 mg, 0.17 mmol) in dichloromethane (3 mL), and add hydrochloric acid-dioxane solution (4.0 M) (3 mL) dropwise to the reaction solution. React at room temperature for 2 hours. A white solid is produced. LC / MS shows that the reaction is complete. Concentrate the reaction solution to give crude product 8b (80 mg, crude product, hydrochloride), which requires no further purification. ESI-MS (m / z): 481.6 [M+H] + .

[0665] Step C: At room temperature, 8b (40 mg, 0.077 mmol, hydrochloride) and Int-2 (80.04 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (3 mL). Under ice bath conditions, catalytic equivalent acetic acid (3 drops) was added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (114.77 mg, 0.54 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC / MS showed that the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 8c (70 mg, yield: 78.39%), ESI-MS (m / z): 579.2 [M+2H]. 2+ / 2.

[0666] Step D: Dissolve compound 8 (30 mg, 0.026 mmol) in dichloromethane (2 mL), and add hydrochloric acid-dioxane solution (4.0 M) (2 mL) dropwise to the reaction solution. React at room temperature for 2 hours. A pale yellow solid is produced. LC / MS shows that the reaction is complete. The reaction solution is concentrated, and the residue is purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 8 (19.2 mg, yield: 73.13%, formate). ESI-MS (m / z): 506.6 [M+2H] 2+ / 2; 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.08(s,1H),8.26(s,2H),7.76(dd,J=9 .2,6.0Hz,1H),7.34(dd,J=15.7,6.1Hz,2H),7.01(d,J=2.5Hz,1H),6.97(t,J= 8.0Hz,1H),6.89(dd,J=13.5,7.9Hz,2H),5.35(dd,J=13.1,5.3Hz,1H),4.47– 4.39(m,2H),4.30(dd,J=32.5,10.8Hz,2H),3.65–3.56(m,7H),3.18–3.09(m,2 H),3.07–2.95(m,3H),2.92–2.74(m,4H),2.73–2.65(m,1H),2.62–2.54(m,1H ),2.35–2.30(m,2H),2.28–2.25(m,2H),2.18–2.10(m,2H),2.02–1.94(m,2H), 1.90–1.80(m,2H),1.75–1.59(m,5H),1.56–1.47(m,3H),1.42–1.36(m,2H),1 .05–0.96(m,3H),0.72(t,J=7.4Hz,3H),0.66–0.59(m,2H),0.44–0.36(m,2H).

[0667] Example 9

[0668] 3-(4-((R)-4-(7-((1-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)-3-methylpiperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0669] Example 9 was prepared by the following steps:

[0670] Step A: At room temperature, 8b (40 mg, 0.077 mmol, hydrochloride) and Int-2i (79.57 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (3 mL). Under ice bath conditions, catalytic equivalent acetic acid (3 drops) was added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (65.58 mg, 0.31 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC / MS showed that the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 9a (20 mg, yield: 22.47%), ESI-MS (m / z): 579.2 [M+H]. + .

[0671] Step B: 9a (20 mg, 0.017 mmol) was dissolved in formic acid (4 mL), and the reaction was carried out at room temperature for 2 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 9 (7.0 mg, yield: 38.26%, formate). ESI-MS (m / z): 504.0 [M+2H] 2+ / 2; 1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),10.19(s,1H),9.03(s,1H),8.19(s,1H), 7.98(dd,J=9.2,6.0Hz,1H),7.47(t,J=9.0Hz,1H),7.39(d,J=2.5Hz,1H),7.17 (d,J=2.4Hz,1H),7.01–6.95(m,1H),6.94–6.85(m,2H),5.35(d,J=8.1Hz,1H), 4.50(d,J=11.5Hz,1H),4.36–4.21(m,3H),3.97–3.92(m,1H),3.69–3.62(m,2H ),3.61(s,3H),3.59–3.52(m,2H),3.08–2.96(m,3H),2.93–2.75(m,4H),2.73– 2.66(m,1H),2.63–2.56(m,1H),2.32–2.22(m,4H),2.12–2.06(m,1H),2.02–1. 95(m,2H),1.91–1.82(m,2H),1.69(s,3H),1.67–1.62(m,1H),1.60–1.50(m,3H ),1.48–1.38(m,3H),1.09–0.94(m,4H),0.70–0.61(m,2H),0.44–0.37(m,2H).

[0672] Example 10

[0673] 3-(4-((S)-4-(7-((1-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)-3-(methoxymethyl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0674] Example 10 was prepared by the following steps:

[0675] Step A: At room temperature, Int-6 (100 mg, 0.26 mmol) and 1a (185.30 mg, 0.77 mmol) were dissolved in N,N-dimethylformamide (3 mL). Under ice bath conditions, catalytic equivalent acetic acid (3 drops) was added dropwise to the reaction solution, followed by the addition of sodium triacetoxyborohydride (218.82 mg, 1.03 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC / MS showed that the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 15 / 1) to give 10a (100 mg, yield 63.44%), ESI-MS (m / z): 611.7 [M+H]. + .

[0676] Step B: Dissolve 10a (100 mg, 0.16 mmol) in dichloromethane (3 mL), and add hydrochloric acid-dioxane solution (4.0 M) (3 mL) dropwise to the reaction solution. React at room temperature for 2 hours. A white solid is produced. LC / MS shows that the reaction is complete. Concentrate the reaction solution to give crude product 10b (90 mg, crude product, hydrochloride), which requires no further purification. ESI-MS (m / z): 511.6 [M+H] + .

[0677] Step C: At room temperature, 10b (40 mg, 0.073 mmol, hydrochloride) and Int-2 (80.04 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (3 mL). Acetic acid (3 drops) was added dropwise to the reaction solution under ice bath conditions, followed by the addition of sodium triacetoxyborohydride (114.77 mg, 0.54 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC / MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 10c (30 mg, yield: 34.64%), ESI-MS (m / z): 592.7 [M+2H]. 2+ / 2.

[0678] Step D: Dissolve 10c (30 mg, 0.025 mmol) in dichloromethane (2 mL), and add hydrochloric acid-dioxane solution (4.0 M) (2 mL) dropwise to the reaction solution. React at room temperature for 2 hours. A pale yellow solid is produced. LC / MS shows that the reaction is complete. The reaction solution is concentrated to give a crude product, which is purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 10 (21.6 mg, yield: 78.51%, formate). ESI-MS (m / z): 522.2 [M+2H] 2+ / 2; 1 H NMR(500MHz,DMSO-d6)δ11.10(s,1H),9.09(s,1H),8.23(s,2H),7.76(dd,J=9.1,6 .0Hz,1H),7.36(d,J=9.4Hz,1H),7.33(d,J=2.6Hz,1H),7.02(d,J=2.6Hz,1H),7.0 0–6.96(m,1H),6.89(d,J=6.9Hz,1H),5.35(dd,J=11.9,4.8Hz,1H),4.43(d,J=12. 0Hz,2H),4.30(dd,J=35.6,10.9Hz,2H),3.69–3.61(m,5H),3.59(s,3H),3.21(s,3H ),3.06–2.95(m,4H),2.91–2.84(m,2H),2.75–2.66(m,2H),2.61–2.57(m,1H),2.5 4–2.52(m,1H),2.35–2.32(m,1H),2.30–2.23(m,3H),2.19–2.11(m,2H),2.05–1.9 6(m,2H),1.94–1.84(m,2H),1.75–1.60(m,5H),1.58–1.48(m,3H),1.43–1.36(m,2 H),1.32–1.18(m,3H),0.73(t,J=7.4Hz,3H),0.66–0.61(m,2H),0.43–0.37(m,2H).

[0679] Example 11

[0680] 3-(4-((S)-4-(7-((1-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)-3-(methoxymethyl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0681] Example 11 was prepared by the following steps:

[0682] Step A: At room temperature, 10b (60 mg, 0.11 mmol, hydrochloride) and Int-2i (112.81 mg, 0.16 mmol) were dissolved in N,N-dimethylformamide (3 mL). Acetic acid (3 drops) was added dropwise to the reaction solution under ice bath conditions, followed by the addition of sodium triacetoxyborohydride (92.98 mg, 0.44 mmol) in portions. The reaction was allowed to proceed for 2 hours at room temperature. LC / MS showed complete reaction. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 11a (40 mg, yield: 30.90%), ESI-MS (m / z): 591.9 [M+2H]. 2+ / 2.

[0683] Step B: 11a (40 mg, 0.034 mmol) was dissolved in dichloromethane (2 mL), and hydrochloric acid-dioxane solution (4.0 M) (2 mL) was added dropwise to the reaction solution. The reaction was carried out at room temperature for 2 hours. A pale yellow solid was produced. LC / MS showed that the reaction was complete. The reaction solution was concentrated to obtain a crude product, which was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 11 (21.3 mg, yield: 58.08%, formate). ESI-MS (m / z): 519.0 [M+2H] 2+ / 2; 1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),9.04(s,1H),8.22(s,1H),7.98(dd,J=9.2, 5.9Hz,1H),7.47(t,J=9.0Hz,1H),7.39(d,J=2.5Hz,1H),7.17(d,J=2.4Hz,1H),7. 00–6.83(m,3H),5.35(dd,J=12.5,5.1Hz,1H),4.51(d,J=11.8Hz,1H),4.31(d,J= 11.9Hz,1H),4.25(d,J=11.5Hz,2H),3.94(d,J=0.7Hz,1H),3.75–3.66(m,2H),3.6 6–3.61(m,3H),3.61–3.55(m,4H),3.53–3.41(m,4H),3.35–3.25(m,2H),3.21(s, 3H),3.13–3.06(m,1H),3.06–2.95(m,3H),2.94–2.82(m,2H),2.72–2.66(m,1H),2 .34–2.20(m,4H),2.17–2.05(m,1H),2.02–1.96(m,1H),1.94–1.82(m,2H),1.70(s ,3H),1.60–1.49(m,3H),1.46–1.31(m,3H),0.68–0.60(m,2H),0.45–0.36(m,2H).

[0684] Example 12

[0685] 3-(4-((R)-4-(7-((1-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)-3-(methoxymethyl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0686] Example 12 was prepared by the following steps:

[0687] Step A: At room temperature, Int-7 (130 mg, 0.34 mmol, hydrochloride) and 1a (120.45 mg, 0.50 mmol) were dissolved in N,N-dimethylformamide (2 mL). A catalytic equivalent of acetic acid (3 drops) was added dropwise to the reaction solution, and the mixture was stirred for approximately 1 hour. Sodium triacetoxyborohydride (213.35 mg, 1.01 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 16 hours. LC / MS showed the reaction was complete. The reaction was quenched with water, and extraction was performed using dichloromethane / methanol (V / V) = 10 / 1. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 12a (39 mg, yield 19.03%), ESI-MS (m / z): 611.5 [M+H]. + .

[0688] Step B: Dissolve 12a (39 mg, 0.064 mmol) in dichloromethane (3 mL), and add hydrochloric acid-dioxane solution (4.0 M) (3 mL) dropwise to the reaction solution. React at room temperature for 2 hours. A pale yellow solid is produced. LC / MS shows that the reaction is complete. Concentrate the reaction solution to give crude product 12b (45 mg, crude product, hydrochloride), which requires no further purification. ESI-MS (m / z): 511.6 [M+H] + .

[0689] Step C: Dissolve 12b (45 mg, 0.088 mmol, hydrochloride) and Int-2 (60.79 mg, 0.088 mmol) in N,N-dimethylformamide (1 mL). Add catalytically equivalent acetic acid (3 drops) dropwise to the reaction solution and react at room temperature for about 1 hour. Add sodium triacetoxyborohydride (114.77 mg, 0.54 mmol) in portions. React at room temperature for 16 hours. LC / MS showed that the reaction was complete. Quench the reaction with water and extract with dichloromethane / methanol (V / V) = 10 / 1. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate. The resulting residue is purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 12c (38 mg, yield: 36.41%), ESI-MS (m / z): 593.1 [M+2H]. 2+ / 2.

[0690] Step D: Compound 12 (38 mg, 0.032 mmol) was dissolved in dichloromethane (2 mL). Hydrochloric acid-dioxane solution (4.0 M) (2 mL) was added dropwise to the reaction solution, and the reaction was carried out at room temperature for 1 hour. A pale yellow solid precipitated. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 12 (16.5 mg, yield: 50.04%). ESI-MS (m / z): 521.42 [M+2H] 2+ / 2; 1 H NMR(500MHz,DMSO-d6)δ11.10(s,1H),9.09(s,1H),8.20(s,1H),7.76(dd,J=9.2,6.0Hz,1H),7.40–7.29(m,2H),7.05– 6.85(m,4H),5.35(dd,J=12.7,5.5Hz,1H),4.43(d,J=12.3Hz,2H),4.34–4.24(m,2H),3.68–3.55(m,9H),3.50–3.47(m, 1H),3.23–3.18(m,5H),3.07–2.82(m,6H),2.72–2.66(m,1H),2.62–2.54(m,2H),2.34–2.21(m,5H),2.19–2.08(m,2H) ,2.02–1.84(m,3H),1.71–1.59(m,5H),1.56–1.35(m,6H),0.72(t,J=7.4Hz,3H),0.67–0.59(m,2H),0.44–0.34(m,2H).

[0691] Example 13

[0692] 3-(4-(4-(7-((1-((((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)-4,7-diazaspiro[2.5]octane-7-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0693] Example 13 was prepared by the following steps:

[0694] Step A: At room temperature, Int-5 (150 mg, 0.41 mmol, hydrochloride) and 1a (291.51 mg, 1.22 mmol) were dissolved in N,N-dimethylformamide (3 mL), and a catalytic equivalent of acetic acid (3 drops) was added. The mixture was stirred for about 1 hour. Sodium triacetoxyborohydride (344.23 mg, 1.62 mmol) was added in portions. The reaction was continued at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 15 / 1) to give a white solid 13a (170 mg, yield: 70.63%), ESI-MS (m / z): 593.7 [M+H]. + .

[0695] Step B: Dissolve 13a (169 mg, 0.28 mmol) in dichloromethane (3 mL), then add hydrochloric acid-dioxane solution (4.0 M) (3 mL) and react at room temperature for 2 hours. A white solid is produced. LC / MS shows the reaction is complete. Concentrate the reaction solution to give crude product 13b (140 mg, crude product, hydrochloride), no further purification required. ESI-MS (m / z): 493.5 [M+H] + .

[0696] Step C: At room temperature, 13b (40 mg, 0.076 mmol, hydrochloride) and Int-2 (80.04 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (3 mL), and a catalytic equivalent of acetic acid (3 drops) was added. The mixture was stirred for approximately 1 hour. Sodium triacetoxyborohydride (114.77 mg, 0.54 mmol) was added in portions. The reaction was continued at room temperature for 16 hours. LC / MS showed complete reaction. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 13c (30 mg, yield: 34.02%), ESI-MS (m / z): 584.2 [M+2H]. 2+ .

[0697] Step D: 13c (20 mg, 0.017 mmol) was dissolved in dichloromethane (2 mL), and then dioxane hydrochloride solution (4.0 M) (2 mL) was added. The reaction was carried out at room temperature for 1 hour. A pale yellow solid was produced. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 13 (14.1 mg, yield: 76.98%, formate). ESI-MS (m / z): 512.2 [M+2H] 2+ / 2; 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.08(s,1H),8.26(s,2H),7.76(dd,J =9.1,6.1Hz,1H),7.34(dd,J=15.3,6.0Hz,2H),7.05–7.00(m,2H),6.98(t,J =7.9Hz,1H),6.88(d,J=7.1Hz,1H),5.34(dd,J=11.4,4.5Hz,1H),4.46–4.40 (m,2H),4.30(dd,J=28.3,10.7Hz,2H),3.67(s,3H),3.65–3.57(m,6H),2.91 –2.79(m,4H),2.75–2.65(m,3H),2.61–2.56(m,1H),2.35–2.31(m,1H),2.31 –2.22(m,4H),2.19–2.10(m,2H),2.03–1.89(m,5H),1.74–1.59(m,5H),1.58 –1.51(m,2H),1.48–1.42(m,2H),1.40–1.34(m,2H),1.24-1.20(m,2iH),0.7 2(t,J=7.4Hz,3H),0.68–0.61(m,2H),0.50–0.42(m,3H),0.40–0.34(m,2H).

[0698] Example 14

[0699] 3-(4-(4-(7-((1-((((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)-4,7-diazaspiro[2.5]octan-7-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0700] Example 14 was prepared by the following steps:

[0701] Step A: At room temperature, 13b (60 mg, 0.11 mmol, hydrochloride) and Int-2i (116.65 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (2 mL). A catalytic equivalent of acetic acid (3 drops) was added dropwise to the reaction solution, and the mixture was stirred for approximately 1 hour. Sodium triacetoxyborohydride (96.14 mg, 0.45 mmol) was added in portions. The reaction was continued at room temperature for 16 hours. LC / MS showed the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution, resulting in the precipitation of a large amount of white solid. The mixture was filtered, the filter cake was washed with water and dried, and the residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 14a (40 mg, yield: 30.35%), ESI-MS (m / z): 582.1 [M+2H]. 2+ / 2.

[0702] Step B: 14a (20 mg, 0.017 mmol) was dissolved in formic acid (2 mL) and reacted at room temperature for 3 hours. LC / MS showed the reaction was complete. The reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 14 (27.6 mg, yield: 60.29%, formate). ESI-MS (m / z): 510.0 [M+2H] 2+ / 2; 1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),9.03(s,1H),8.20(s,1H),7.97(dd,J=9.2,5.9Hz ,1H),7.46(t,J=9.0Hz,1H),7.39(d,J=2.5Hz,1H),7.17(d,J=2.4Hz,1H),7.02(d,J=7. 7Hz,1H),6.97(t,J=7.9Hz,1H),6.88(d,J=7.5Hz,1H),5.34(dd,J=12.6,5.2Hz,1H),4. 51(d,J=11.9Hz,1H),4.34–4.18(m,3H),3.97–3.89(m,1H),3.74–3.69(m,1H),3.69–3. 66(m,3H),3.66–3.61(m,2H),3.59–3.52(m,2H),3.52–3.48(m,1H),3.48–3.44(m,1H), 3.27–3.07(m,3H),2.99–2.79(m,4H),2.73–2.66(m,1H),2.63–2.55(m,1H),2.33–2.19 (m,4H),2.03–1.88(m,4H),1.88–1.75(m,1H),1.70(s,3H),1.62–1.52(m,2H),1.50–1. 34(m,4H),0.94–0.69(m,2H),0.68–0.59(m,2H),0.55–0.43(m,2H),0.42–0.37(m,2H).

[0703] Example 15

[0704] 3-(4-(8-(7-((1-((((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0705] Example 15 was prepared by the following steps:

[0706] Step A: At room temperature, Int-8 (200 mg, 0.54 mmol, trifluoroacetate) and 1a (194.34 mg, 0.81 mmol) were dissolved in N,N-dimethylformamide (2 mL). A catalytic equivalent of acetic acid (3 drops) was added dropwise to the reaction solution, and the mixture was stirred for approximately 1 hour. Sodium triacetoxyborohydride (344.23 mg, 1.62 mmol) was added in portions. The reaction was continued at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 20 / 1) to give 15a (182 mg, yield: 56.72%), ESI-MS (m / z): 593.5 [M+H]. + .

[0707] Step B: Dissolve 15a (169 mg, 0.28 mmol) in dichloromethane (2 mL), and add trifluoroacetic acid (2 mL) dropwise to the reaction solution. React at room temperature for 1 hour. LC / MS showed that the reaction was complete. Concentrate the reaction solution to give crude product 15b (150 mg, crude product, trifluoroacetate), which requires no further purification. ESI-MS (m / z): 493.1 [M+H] + .

[0708] Step C: At room temperature, dissolve 15b (75 mg, 0.15 mmol, trifluoroacetate) in N,N-dimethylformamide (2 mL). Add N,N-diisopropylethylamine (98.39 mg, 0.76 mmol, 0.36 mL) dropwise to the reaction solution and stir for about 5 minutes. Add Int-2 (105.01 mg, 0.15 mmol) to the reaction solution, and add catalytically equivalent acetic acid (3 drops) dropwise. Stir for about 1 hour. Add sodium triacetoxyborohydride (129.07 mg, 0.61 mmol) in portions. The reaction was carried out at room temperature for 16 hours. LC / MS showed that the reaction was complete. The reaction was quenched by adding saturated sodium bicarbonate solution, resulting in the precipitation of a large amount of white solid. The solid was filtered, the filter cake was washed with water and dried, and the residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 15c (60 mg, yield: 38.55%), ESI-MS (m / z): 584.0 [M+2H]. 2+ / 2.

[0709] Step D: Compound 15 (30 mg, 0.026 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added dropwise to the reaction solution. The reaction was carried out at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 15 (27.48 mg, yield: 65.51%, formate). ESI-MS (m / z): 512.0 [M+2H] 2+ / 2; 1 H NMR (500MHz, DMSO-d6) δ11.11(s,1H),9.98(s,1H),9.14(s,1H),8.14(s,1H),7.78(dd,J=9.1,6.0Hz,1H),7.35(dd,J=15.3,6.0Hz,2H),7.26–7 .17(m,1H),7.12(d,J=8.2Hz,1H),7.02(dd,J=14.4,5.3Hz,2H),6.95(d,J=7.3Hz,1H),5.40–5.34(m,1H),4.59–4.53(m,2H),4.31(dd,J=28.1, 11.0Hz,3H),4.01–3.85(m,3H),3.76(dd,J=28.3,12.9Hz,2H),3.69(s, 3H),3.54–3.44(m,2H),3.22–3.11(m,3H),2.93–2.83(m,3H),2.74–2.6 6(m,1H),2.18–2.10(m,2H),2.06–1.92(m,7H),1.89–1.78(m,5H),1.76 –1.65(m,3H),1.63–1.48(m,5H),0.75–0.65(m,5H),0.52–0.43(m,2H).

[0710] Example 16

[0711] 3-(4-(4-(7-((1-((((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)-1,4-diazoylheptane-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0712] Example 16 was prepared by the following steps:

[0713] Step A: At room temperature, Int-9 (130 mg, 0.36 mmol, hydrochloride) and 1a (130.57 mg, 0.55 mmol) were dissolved in N,N-dimethylformamide (2 mL), and catalytically equivalent acetic acid (3 drops) was added. The mixture was stirred for about 1 hour. Sodium triacetoxyborohydride (231.27 mg, 1.09 mmol) was added in portions. The reaction was continued at room temperature for 2 hours. LC / MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give a white solid 16a (115 mg, yield: 54.44%), ESI-MS (m / z): 581.5 [M+H]. + .

[0714] Step B: Dissolve 16a (115 mg, 0.20 mmol) in dichloromethane (2 mL), then add hydrochloric acid-dioxane solution (4.0 M) (1 mL) and react at room temperature for 1 hour. A pale yellow solid is produced. LC / MS shows the reaction is complete. Concentrate the reaction solution to give crude product 16b (123 mg, crude product, hydrochloride), no further purification required. ESI-MS (m / z): 481.5 [M+H] + .

[0715] Step C: At room temperature, 16b (80 mg, 0.17 mmol, hydrochloride) and Int-2 (114.81 mg, 0.17 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and catalytically equivalent acetic acid (3 drops) was added. The mixture was stirred for approximately 1 hour. Sodium triacetoxyborohydride (105.84 mg, 0.50 mmol) was added in portions. The reaction was continued at room temperature for 16 hours. LC / MS showed complete reaction. The reaction was quenched with water, and extracted with dichloromethane / methanol (V / V) = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 16c (90 mg, yield: 46.84%), ESI-MS (m / z): 578.1 [M+2H]. 2+ / 2.

[0716] Step D: Compound 16 (90 mg, 0.078 mmol) was dissolved in dichloromethane (1 mL), and then 0.5 mL of dioxane hydrochloride solution (4.0 M) was added. The reaction was carried out at room temperature for 1 hour. A pale yellow solid was produced. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 16 (46.2 mg, yield: 58.66%). ESI-MS (m / z): 506.2 [M+2H] 2+ / 2; 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.10(s,1H),8.19–8.18(m,2H),7.76(dd,J=9.1,6.0Hz,1H),7.39–7.29(m,2H),7.01(d,J=2.6Hz, 1H),7.00–6.92(m,2H),6.87(d,J=7.0Hz,1H),5.35(dd,J=12.7,5.4Hz,1H),4.46(d,J=12.3Hz,2H),4.35–4.24(m,2H),3.72–3.59(m,9H ),3.17–3.09(m,5H),3.02–2.96(m,1H),2.92–2.84(m,1H),2.73–2.66(m,1H),2.63–2.55(m,3H),2.39–2.26(m,6H),2.18–2.10(m,1H), 2.02–1.96(m,1H),1.94–1.83(m,4H),1.76–1.65(m,4H),1.54–1.39(m,6H),0.72(t,J=7.4Hz,3H),0.67–0.61(m,2H),0.44–0.37(m,2H).

[0717] Example 17

[0718] 3-(4-(4-(7-((1-((((5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaza-6,9-methylenenaphtho[1,8-ab]heptadene-12-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0719] Example 17 was prepared by the following steps:

[0720] Step A: At room temperature, dissolve 1c (30 mg, 0.060 mmol, trifluoroacetate) in N,N-dimethylformamide (1 mL), add N,N-diisopropylethylamine (7.17 mg, 0.060 mmol, 0.01 mL), and stir for about 10 minutes. Add Int-13 (47.09 mg, 0.066 mmol) to the reaction solution, add catalytic equivalent acetic acid (3 drops), and stir for about 1 hour. Add sodium triacetoxyborohydride (63.20 mg, 0.30 mmol) in portions. React at 60 °C for 1 hour. LC / MS showed that the reaction was complete. Quench the reaction with water, and extract with dichloromethane / methanol (V / V) = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 17a (35 mg, yield: 93.57%), ESI-MS (m / z): 585.1 [M+2H]. 2+ / 2.

[0721] Step B: 17a (35 mg, 0.030 mmol) was dissolved in formic acid (2 mL) and reacted at room temperature for 1 hour. LC / MS showed the reaction was complete. The reaction solution was concentrated, and the residue was purified by reversed-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 17 (17 mg, yield: 28.03%, formate). ESI-MS (m / z): 513.5 [M+2H] 2+ / 2; 1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),10.09–9.80(m,1H),8.18(s,1H),7.77–7.72( m,1H),7.36–7.32(m,1H),7.32–7.29(m,1H),7.08–7.00(m,1H),7.00–6.94(m,1H),6 .94–6.91(m,1H),6.90–6.85(m,1H),5.34(dd,J=11.9,5.8Hz,1H),4.82(d,J=14.6Hz ,1H),4.59–4.49(m,1H),4.40–4.30(m,2H),4.30–4.22(m,1H),4.03–3.97(m,1H),3. 63–3.61(m,1H),3.60(s,3H),3.55–3.51(m,3H),3.12–3.07(m,3H),3.01–2.96(m,2H ),2.87–2.79(m,4H),2.73–2.68(m,2H),2.34–2.31(m,2H),2.29–2.24(m,3H),2.03– 1.95(m,3H),1.90–1.86(m,2H),1.74–1.64(m,4H),1.52–1.46(m,4H),1.44–1.40(m, 2H),0.85(t,J=7.3Hz,2H),0.81–0.70(m,3H),0.65–0.61(m,2H),0.42–0.37(m,2H).

[0722] Example 18

[0723] 3-(4-(4-(7-((1-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)-6-fluoro-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0724] Example 18 was prepared by the following steps:

[0725] Step A: At room temperature, Int-17 (150 mg, 0.41 mmol, hydrochloride) and 1a (119.20 mg, 0.50 mmol) were dissolved in tetrahydrofuran (2 mL), and sodium triacetoxyborohydride (131.96 mg, 0.66 mmol) was added to the reaction solution. The reaction was carried out at 50 °C for 16 hours. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 18a (160 mg, yield: 65.93%), ESI-MS (m / z): 585.5 [M+H]. + .

[0726] Step B: Dissolve 18a (140 mg, 0.24 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (1 mL) dropwise to the reaction solution, and react at room temperature for 1 hour. LC / MS showed that the reaction was complete. Concentrate the reaction solution to give crude product 18b (110 mg, crude product, trifluoroacetate), which requires no further purification. ESI-MS (m / z): 485.5 [M+H] + .

[0727] Step C: At room temperature, 18b (60 mg, 0.12 mmol, trifluoroacetate) and Int-2i (84.91 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). A catalytic equivalent of acetic acid (3 drops) was added dropwise to the reaction solution, and the mixture was stirred for approximately 1 hour. Sodium triacetoxyborohydride (39.36 mg, 0.19 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 16 hours. LC / MS showed the reaction was complete. The reaction was quenched with water, and extraction was performed using dichloromethane / methanol (V / V) = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 18c (72 mg, yield: 50.38%), ESI-MS (m / z): 578.1 [M+2H]. 2+ / 2.

[0728] Step D: Compound 18 (54 mg, 0.047 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added dropwise to the reaction solution. The reaction was carried out at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give compound 18 (15 mg, yield: 31.42%). ESI-MS (m / z): 506.0 [M+2H] 2+ / 2; 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),10.17(s,1H),9.03(s,1H),7.97(dd,J=9.2,5.9Hz,1H),7.46(t,J=9.0Hz,1H),7.39(d,J=2.5Hz,1H),7.17(d ,J=2.4Hz,1H),6.93–6.87(m,1H),6.77(dd,J=11.7,2.2Hz,1H),5.33(dd, J=12.7,5.2Hz,1H),4.49(d,J=11.7Hz,1H),4.33–4.20(m,3H),3.93(s,1H ),3.65(d,J=11.7Hz,1H),3.61–3.53(m,5H),3.39(s,2H),3.03–2.78(m, 6H),2.76-2.66(m,3H),2.65–2.61(m,1H),2.60-2.57(m,1H),2.37-2.20( m,6H),2.03–1.94(m,2H),1.92-1.84(m,2H),1.68(s,3H),1.56–1.46(m,4 H),1.45-1.40(m,2H),1.23(s,1H),0.66-0.60(m,2H),0.42-0.38(m,2H).

[0729] Example 19

[0730] 3-(4-(4-(7-((1-((((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)piperazin-1-yl)-6-fluoro-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0731] Example 19 was prepared by the following steps:

[0732] Step A: At room temperature, 18b (60 mg, 0.12 mmol, trifluoroacetate) and Int-2 (85.41 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). A catalytic equivalent of acetic acid (3 drops) was added dropwise to the reaction solution, and the mixture was stirred for approximately 1 hour. Sodium triacetoxyborohydride (39.36 mg, 0.19 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 16 hours. LC / MS showed the reaction was complete. The reaction was quenched with water, and the mixture was extracted with dichloromethane / methanol (V / V) = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 19a (59 mg, yield: 41.14%), ESI-MS (m / z): 580.1 [M+2H]. 2+ / 2.

[0733] Step B: 19a (52 mg, 0.045 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added dropwise to the reaction solution. The reaction was carried out at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give compound 19 (24 mg, yield: 52.19%). ESI-MS (m / z): 508.0 [M+2H] 2+ / 2; 1H NMR(500MHz,DMSO-d6)δ11.10(s,1H),9.96(s,1H),9.08(s,1H),7.76(dd,J=9.1 ,6.0Hz,1H),7.36(d,J=9.4Hz,1H),7.33(d,J=2.7Hz,1H),7.01(d,J=2.5Hz,1H), 6.90(dd,J=8.7,2.0Hz,1H),6.76(dd,J=11.7,2.3Hz,1H),5.33(dd,J=12.5,5.5 Hz,1H),4.46–4.38(m,2H),4.33(d,J=10.8Hz,1H),4.26(d,J=10.8Hz,1H),3.65– 3.52(m,6H),3.03-2.91(m,2H),2.89–2.80(m,3H),2.76–2.66(m,3H),2.66–2.6 1(m,1H),2.60-2.57(m,1H),2.40–2.31(m,3H),2.30-2.22(m,3H),2.18-2.11(m, 2H),2.02–1.95(m,2H),1.91-1.84(m,2H),1.71–1.58(m,4H),1.53-1.45(m,4H) ,1.43-1.37(m,2H),0.72(t,J=7.4Hz,3H),0.66-0.60(m,2H),0.41-0.36(m,2H).

[0734] Example 20

[0735] 1-(butoxy)ethyl 3-(2-((1-((2-(4-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazin-1-yl)-7-azaspiro[3.5]nonane-7-yl)methyl)cyclopropyl)methoxy)-7-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid ester

[0736] Example 20 was prepared by the following steps:

[0737] Step A: Compound 1 (50 mg, 0.05 mmol) and 20a (17.9 mg, 0.06 mmol) were dissolved in tetrahydrofuran (1 mL). Triethylamine (12.7 mg, 0.125 mmol, 0.017 mL) and 4-dimethylaminopyridine (1.23 mg, 0.01 mmol) were added dropwise to the reaction solution. The reaction solution was stirred at 25 °C for 1 hour. LC / MS showed that the reaction was complete. The crude product obtained after removing the solvent under reduced pressure was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 20 (18 mg, yield 29.28%, formate). ESI-MS (m / z): 385.8 [M+3H] 3+ / 3; 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.10(s,1H),8.23(s,1H),8.05(t,J=3.1Hz,1H),7.5 6(t,J=9.3Hz,1H),7.44(dd,J=10.8,2.4Hz,1H),6.98(t,J=7.9Hz,1H),6.92(d,J=7.9Hz,1H ),6.89(t,J=6.8Hz,1H),6.74(dt,J=9.2,4.6Hz,1H),5.35(dd,J=12.8,5.4Hz,1H),4.48-4. 38(m,2H),4.33(d,J=10.9Hz,1H),4.27(d,J=10.7Hz,1H),3.65–3.55(m,8H),3.02-2.93(m, 3H),2.92–2.76(m,5H),2.74–2.66(m,2H),2.65–2.62(m,1H),2.61-2.56(m,1H),2.48-2.4 1(m,5H),2.38-2.34(m,1H),2.31-2.21(m,5H),2.05–1.95(m,3H),1.91-1.85(m,2H),1.70– 1.59(m,4H),1.54(d,J=5.2Hz,2H),1.51-1.46(m,3H),1.43-1.37(m,2H),1.10(s,1H),1.09 (d,J=2.2Hz,2H),1.08(s,1H),0.76(t,J=7.4Hz,3H),0.65-0.61(m,2H),0.42-0.38(m,2H).

[0738] Example 22

[0739] 3-(4-(4-(3-((1-(((4-((1R,5S)-1-(ethyl-d5)-3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecane-9-yl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0740] Example 22 was prepared by the following steps:

[0741] Step A: At room temperature, dissolve 3c (44.33 mg, 0.083 mmol, hydrochloride) in N,N-dimethylformamide (2 mL). Add triethylamine (21.12 mg, 0.21 mmol, 0.03 mL) dropwise to the reaction solution and stir for about 10 minutes. Add Int-14 (50 mg, 0.070 mmol) to the reaction solution, and add catalytically equivalent acetic acid (3 drops) dropwise. Stir for about 1 hour. Add sodium triacetoxyborohydride (44.23 mg, 0.21 mmol) in portions. React at 60 °C for 2 hours. LC / MS showed that the reaction was complete. Quench the reaction with water and extract with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 22a (50 mg, yield: 60.03%), ESI-MS (m / z): 599.6 [M+2H]. 2+ / 2.

[0742] Step B: 22a (50 mg, 0.042 mmol) was dissolved in dichloromethane (1 mL), and hydrochloric acid-dioxane solution (4.0 M) (1 mL) was added dropwise to the reaction solution. The reaction was carried out at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 22 (20 mg, yield: 43.57%, formate). ESI-MS (m / z): 527.5 [M+2H] 2+ / 2. 1H NMR (500MHz, DMSO-d6) δ11.10(s,1H),9.05(d,J=2.8Hz,1H),8.23(s,1H),7.98(dd,J=9.2,5.9Hz,1H),7.49–7.44(m,1H),7.39(d,J=2.6H z,1H),7.19–7.17(m,1H),7.00–6.95(m,1H),6.93–6.86(m,2H),5.35(dd,J=12.8,5.4Hz,1H),4.60–4.45(m,2H),4.41–4.23(m,4H),3.95 –3.89(m,1H),3.61(s,3H),3.02–2.96(m,2H),2.92–2.79(m,5H),2.71–2.66(m,1H),2.65–2.58(m,2H),2.43–2.34(m,6H),2.30–2.20(m, 2H),2.02–1.96(m,1H),1.79–1.56(m,8H),1.45–1.32(m,5H),1.29–1 .25(m,2H),1.07–0.98(m,2H),0.68–0.61(m,2H),0.46–0.39(m,2H).

[0743] Example 23

[0744] 3-(4-(4-((7-((1-((((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)methyl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0745] Example 23 was prepared by the following steps:

[0746] Step A: Int-1 (100 mg, 0.29 mmol, hydrochloride) and 23a (73.78 mg, 0.29 mmol) were dissolved in tetrahydrofuran (3 mL), and sodium triacetoxyborohydride (92.58 mg, 0.44 mmol) was added in portions. The mixture was stirred at room temperature for 2 hours. LC / MS showed that the reaction was complete. After concentrating the reaction solution, the crude product was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 23b (90 mg, yield: 53.22%). ESI-MS (m / z): 581.5 [M+H]+ .

[0747] Step B: Dissolve 23b (80 mg, 0.14 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (0.5 mL) dropwise to the reaction solution, and stir at room temperature for 1 hour. LC / MS showed that the reaction was complete. Concentrate the reaction solution to obtain 23c (60 mg, crude product, trifluoroacetate). ESI-MS (m / z): 481.4 [M+H] + .

[0748] Step C: 23c (70 mg, 0.15 mmol, trifluoroacetate) and Int-2i (99.88 mg, 0.15 mmol) were dissolved in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 0.5 h. Then, sodium triacetoxyborohydride (92.61 mg, 0.44 mmol) was added in portions, and the mixture was stirred at 50 °C for 2 h. LC / MS showed that the reaction was complete. The reaction solution was concentrated and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 23d (70 mg, yield: 41.78%). ESI-MS (m / z): 576.1 [M+2H] 2+ / 2.

[0749] Step D: Compound 23 (30 mg, 0.026 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added dropwise to the reaction solution. The mixture was stirred at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give compound 23 (12 mg, yield: 44.82%). ESI-MS (m / z): 504.0 [M+2H] 2+ / 2; 1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),10.16(s,1H),9.02(s,1H),7.97(dd,J= 9.2,6.0Hz,1H),7.46(t,J=9.0Hz,1H),7.39(d,J=2.5Hz,1H),7.17(d,J=2.4Hz ,1H),6.97(t,J=7.9Hz,1H),6.91(d,J=7.6Hz,1H),6.87(d,J=7.7Hz,1H),5.34 (dd,J=12.8,5.4Hz,1H),4.48(d,J=11.1Hz,1H),4.31–4.22(m,3H),3.93(s,1H ),3.66–3.59(m,3H),3.57-3.52(m,2H),3.41-3.36(m,3H),3.01–2.75(m,7H), 2.74–2.66(m,2H),2.65–2.61(m,1H),2.60-2.58(m,1H),2.43–2.34(m,4H),2. 29-2.19(m,5H),2.02–1.96(m,1H),1.89-1.81(m,2H),1.66(s,3H),1.53(s,2H ),1.44-1.39(m,2H),1.38-1.32(m,2H),0.65-0.60(m,2H),0.42-0.36(m,2H).

[0750] Example 24

[0751] 3-(4-(4-((7-((1-((((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)methyl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0752] Example 24 was prepared by the following steps:

[0753] Step A: Dissolve 23d (50 mg, 0.043 mmol) in a mixed solvent of tetrahydrofuran (3 mL) and ethyl acetate (3 mL), add 10% palladium on carbon catalyst (10 mg, 0.043 mmol), purge with hydrogen three times, and stir at room temperature for 16 hours. LC / MS showed the reaction was complete. Filter the reaction solution through diatomaceous earth, concentrate the filtrate to obtain 24a (50 mg, crude product). ESI-MS (m / z): 578.1 [M+2H] 2+ / 2.

[0754] Step B: 24a (50 mg, 0.043 mmol, crude product) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was added dropwise to the reaction solution. The mixture was stirred at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give compound 24 (15 mg, yield: 34.28%). ESI-MS (m / z): 506.0 [M+2H] 2+ / 2; 1 H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.95(s,1H),9.08(s,1H),7.76(dd,J=9.1,6.0Hz,1H),7.34(dd,J=15.7,6.0Hz,2H),7.02–6.95(m,2H), 6.89(dd,J=19.2,7.7Hz,2H),5.34(dd,J=12.8,5.3Hz,1H),4.44-4.38(m,2H),4.32(d,J=10.8Hz,1H),4.26(d,J=10.8Hz,1H),3.63-3.58(m,4H ),3.56-3.51(m,2H),2.99–2.74(m,8H),2.74–2.57(m,4H),2.41-2.35( m,4H),2.27-2.21(m,4H),2.16–2.11(m,2H),2.03–1.95(m,2H),1.87-1 .81(m,2H),1.68–1.57(m,4H),1.50(s,2H),1.41-1.31(m,4H),1.25-1. 22(m,1H),0.72(t,J=7.4Hz,3H),0.64-0.60(m,2H),0.40-0.36(m,2H).

[0755] Example 25

[0756] 3-(4-(4-((7-((1-((((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonane-2-yl)methyl)-1,4-diazoylheptane-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0757] Example 25 was prepared by the following steps:

[0758] Step A: At room temperature, Int-9 (200 mg, 0.56 mmol, hydrochloride) and 23a (212.65 mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (2 mL). A catalytic equivalent of acetic acid (3 drops) was added dropwise to the reaction solution, and the mixture was stirred for approximately 1 hour. Sodium triacetoxyborohydride (355.80 mg, 1.68 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 16 hours. LC / MS showed the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane / methanol (V / V) = 10 / 1. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 25a (120 mg, yield: 36.06%), ESI-MS (m / z): 595.5 [M+H]. + .

[0759] Step B: Dissolve 25a (120 mg, 0.20 mmol) in dichloromethane (2 mL), and add hydrochloric acid-dioxane solution (4.0 M) (1 mL) dropwise to the reaction solution. React at room temperature for 1 hour. A pale yellow solid is produced. LC / MS shows that the reaction is complete. Concentrate the reaction solution to give crude product 25b (90 mg, crude product, hydrochloride), which requires no further purification. ESI-MS (m / z): 495.4 [M+H] + .

[0760] Step C: At room temperature, 25b (90 mg, 0.17 mmol, hydrochloride) and Int-2 (128.58 mg, 0.19 mmol) were dissolved in N,N-dimethylformamide (2 mL). A catalytic equivalent of acetic acid (3 drops) was added dropwise to the reaction solution, and the mixture was stirred for approximately 1 hour. Sodium triacetoxyborohydride (107.75 mg, 0.51 mmol) was added in portions. The reaction was continued at room temperature for 4 hours. LC / MS showed the reaction was complete. The reaction was quenched with water, and extracted with dichloromethane / methanol (V / V) = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 25c (64 mg, yield: 32.32%), ESI-MS (m / z): 585.1 [M+2H]. 2+ / 2.

[0761] Step D: Compound 25 (64 mg, 0.055 mmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (4.0 M) (1 mL) was added dropwise to the reaction solution. The reaction was carried out at room temperature for 1 hour. A pale yellow solid was produced. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 25 (20.8 mg, yield: 37.07%). ESI-MS (m / z): 513.0 [M+2H] 2+ / 2; 1H NMR (500MHz, DMSO-d6) δ11.09(s,1H),9.09(s,1H),8.19(d,J=1.2Hz,2H),7.76(dd,J=9.1,6.0Hz,1H),7.37–7.29(m,2H),7.01(d,J=2.6Hz,1H),6 .99–6.92(m,2H),6.86(d,J=6.7Hz,1H),5.34(dd,J=12.6,5.5Hz,1H),4. 44(d,J=12.2Hz,2H),4.35–4.22(m,2H),3.66–3.58(m,8H),3.15–3.06(m, 5H),2.93–2.84(m,1H),2.77–2.65(m,5H),2.62–2.53(m,2H),2.45–2.37 (m,3H),2.35–2.32(m,1H),2.29–2.21(m,4H),2.17–2.12(m,1H),2.01–1 .95(m,1H),1.87–1.80(m,4H),1.71–1.61(m,4H),1.55–1.48(m,2H),1.4 2–1.32(m,4H),0.72(t,J=7.4Hz,3H),0.63(d,J=4.7Hz,2H),0.40(s,2H).

[0762] Example 26

[0763] 3-(4-(4-(1-(1-((1-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)piperidin-4-yl)ethyl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0764] Example 26 was prepared by the following steps:

[0765] Step A: Int-1 (100 mg, 0.29 mmol, hydrochloride) and 26a (132.39 mg, 0.58 mmol) were dissolved in dimethyl sulfoxide (2 mL). Tetraisopropyl titanate (331.08 mg, 1.46 mmol, 0.35 mL) was added dropwise to the reaction solution. The reaction solution was stirred at 25 °C for 16 hours. Sodium cyanoborohydride (91.5 mg, 1.46 mmol) was added to the reaction solution in portions. The reaction solution was stirred at 25 °C for 2 hours. LC / MS showed that the reaction was complete. Water and a dichloromethane / methanol (V / V) ratio of 10 / 1 were added to the reaction solution, resulting in the formation of a large amount of solid. After filtration through diatomaceous earth, the organic phase was collected, washed with saturated brine, combined, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give product 26b (120 mg, yield: 74.29%). ESI-MS (m / z): 555.5 [M+H] + .

[0766] Step B: Dissolve 26b (120 mg, 0.22 mmol) in dichloromethane (2 mL), and add hydrochloric acid-dioxane solution (4.0 M) (1 mL) dropwise to the reaction solution. React at room temperature for 1 hour. A pale yellow solid is produced. LC / MS shows that the reaction is complete. Concentrate the reaction solution to give crude product 26c (95 mg, crude product, hydrochloride), which requires no further purification. ESI-MS (m / z): 455.4 [M+H] + .

[0767] Step C: At room temperature, 26C (50 mg, 0.11 mmol, hydrochloride) and Int-2 (75.87 mg, 0.11 mmol) were dissolved in dimethyl sulfoxide (2 mL). Tetraisopropyl titanate (125.05 mg, 0.44 mmol, 0.13 mL) was added dropwise to the reaction solution, and the mixture was stirred at 25 °C for approximately 16 hours. Sodium cyanoborohydride (34.56 mg, 0.55 mmol) was added in portions. The reaction was continued to be stirred for 2 hours. LC / MS showed that the reaction was complete. The reaction was quenched with water, and a large amount of solid was produced. The mixture was filtered through diatomaceous earth and washed with dichloromethane / methanol (V / V) = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 26d (61 mg, yield: 49.15%), ESI-MS (m / z): 565.0 [M+2H]. 2+ / 2.

[0768] Step D: Compound 26 (61 mg, 0.054 mmol) was dissolved in dichloromethane (1 mL), and dioxane hydrochloride solution (4.0 M) (1 mL) was added dropwise to the reaction solution. The reaction was carried out at room temperature for 1 hour. A pale yellow solid was produced. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give compound 26 (29.1 mg, yield: 53.81%). ESI-MS (m / z): 493.0 [M+2H] 2+ / 2; 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),9.09(d,J=1.7Hz,1H),8.21(d,J=4.4Hz ,1H),7.76(dd,J=9.0,6.0Hz,1H),7.38–7.30(m,2H),7.01(d,J=2.6Hz,1H),6. 97(td,J=8.0,1.9Hz,1H),6.92–6.85(m,2H),5.35(dd,J=12.8,5.4Hz,1H),4.4 4(d,J=12.3Hz,2H),4.34(dd,J=11.0,3.1Hz,1H),4.27(d,J=10.9Hz,1H),3.71 –3.55(m,8H),3.08–2.79(m,7H),2.78–2.66(m,3H),2.63–2.52(m,2H),2.44–2 .37(m,1H),2.36–2.23(m,3H),2.23–2.09(m,2H),2.01–1.96(m,1H),1.94–1.8 8(m,1H),1.86–1.78(m,2H),1.71–1.57(m,5H),1.32–1.22(m,1H),1.11–0.97( m,2H),0.92–0.86(m,3H),0.73(td,3H),0.68–0.61(m,2H),0.44–0.36(m,2H).

[0769] Example 27

[0770] 3-(4-(4-((3-((1-((((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecane-9-yl)methyl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0771] Example 27 was prepared by the following steps:

[0772] Step A: At room temperature, Int-1 (130 mg, 0.38 mmol, hydrochloride) and 27a (106.53 mg, 0.38 mmol) were dissolved in N,N-dimethylformamide (2 mL). A catalytic equivalent of acetic acid (3 drops) was added dropwise to the reaction solution, and the mixture was stirred for approximately 1 hour. Sodium triacetoxyborohydride (120.36 mg, 0.57 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 16 hours. LC / MS showed the reaction was complete. The reaction was quenched with water, and the mixture was extracted with dichloromethane / methanol (V / V) = 10 / 1. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 27b (140 mg, yield: 60.74%), ESI-MS (m / z): 609.6 [M+H]. + .

[0773] Step B: Dissolve 27b (130 mg, 0.21 mmol) in dichloromethane (2 mL), and add trifluoroacetic acid (1 mL) dropwise to the reaction solution. React at room temperature for 1 hour. LC / MS showed that the reaction was complete. Concentrate the reaction solution to obtain crude product 27c (90 mg, crude product, trifluoroacetate), which requires no further purification. ESI-MS (m / z): 509.5 [M+H] + .

[0774] Step C: At room temperature, 27c (90 mg, 0.18 mmol, trifluoroacetate) and Int-2i (121.33 mg, 0.18 mmol) were dissolved in N,N-dimethylformamide (2 mL). A catalytic equivalent of acetic acid (3 drops) was added dropwise to the reaction solution, and the mixture was stirred for approximately 1 hour. Sodium triacetoxyborohydride (75.00 mg, 0.35 mmol) was added in portions. The reaction was continued at room temperature for 16 hours. LC / MS showed complete reaction. The reaction was quenched with water, and extracted with dichloromethane / methanol (V / V) = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 27d (140 mg, yield: 67.15%), ESI-MS (m / z): 590.1 [M+2H]. 2+ / 2.

[0775] Step D: Compound 27 (60 mg, 0.051 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (4.0 M) (1 mL) was added dropwise to the reaction solution. The reaction was carried out at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give compound 27 (24 mg, yield: 44.66%). ESI-MS (m / z): 518.0 [M+2H] 2+ / 2; 1 H NMR (500MHz, DMSO-d6) δ11.10(s,1H),10.17(s,1H),9.03(s,1H),7.98(dd,J=9. 3,5.9Hz,1H),7.47(t,J=9.0Hz,1H),7.39(d,J=2.5Hz,1H),7.16(d,J=2.4Hz,1H ),6.98(t,J=7.9Hz,1H),6.92(d,J=7.6Hz,1H),6.88(d,J=7.8Hz,1H),5.35(dd, J=12.8,5.3Hz,1H),4.49(d,J=11.1Hz,1H),4.27(d,J=17.5Hz,3H),3.94(s,1H), 3.64(d,J=12.2Hz,1H),3.61(s,2H),3.58-3.52(m,3H),3.40-3.35(m,3H),3.01 -2.93(m,2H),2.91-2.78(m,4H),2.72–2.66(m,1H),2.65–2.61(m,1H),2.39–2.2 5(m,6H),2.19-2.14(m,3H),2.02–1.96(m,1H),1.67(s,3H),1.60-1.50(m,4H), 1.45-1.37(m,3H),1.29-1.21(m,7H),1.03-0.96(m,3H),0.65-0.60(m,2H),0.42 -0.38(m,2H).

[0776] Example 28

[0777] 3-(4-(4-((3-((1-((((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)-3-azaspiro[5.5]undecane-9-yl)methyl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0778] Example 28 was prepared by the following steps:

[0779] Step A: At room temperature, 27c (70 mg, 0.14 mmol, trifluoroacetate) and Int-2 (94.92 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (2 mL). A catalytic equivalent of acetic acid (3 drops) was added dropwise to the reaction solution, and the mixture was stirred for approximately 1 hour. Sodium triacetoxyborohydride (43.75 mg, 0.21 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 16 hours. LC / MS showed the reaction was complete. The reaction was quenched with water, and the mixture was extracted with dichloromethane / methanol (V / V) = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 28a (65 mg, yield: 39.95%), ESI-MS (m / z): 592.1 [M+2H]. 2+ / 2.

[0780] Step B: 28a (58 mg, 0.049 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (4.0 M) (1 mL) was added dropwise to the reaction solution. The reaction was carried out at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give compound 28 (27 mg, yield: 52.49%). ESI-MS (m / z): 520.0 [M+2H] 2+ / 2; 1H NMR(500MHz,DMSO-d6)δ11.09(s,1H),9.97(s,1H),9.08(s,1H),7.76(dd,J=9.1,6 .0Hz,1H),7.35(t,J=7.0Hz,1H),7.33(d,J=2.7Hz,1H),7.01(d,J=2.5Hz,1H),6.9 7(d,J=7.9Hz,1H),6.90(dd,J=21.3,7.6Hz,2H),5.34(dd,J=12.7,5.4Hz,1H),4.4 2(d,J=12.6Hz,2H),4.33(d,J=10.8Hz,1H),4.26(d,J=10.8Hz,1H),3.64–3.53(m,7 H),3.03–2.75(m,8H),2.71-2.66(m,1H),2.66–2.62(m,1H),2.61-2.57(m,1H),2. 41–2.31(m,5H),2.30-2.24(m,2H),2.19–2.09(m,4H),2.05–1.95(m,2H),1.70–1.6 0(m,4H),1.58-1.49(m,4H),1.48-1.42(m,1H),1.41-1.36(m,2H),1.27-1.20(m,3 H), 1.04-0.95 (m, 4H), 0.73 (t, J = 7.4Hz, 3H), 0.65-0.61 (m, 2H), 0.42-0.38 (m, 2H).

[0781] Example 29

[0782] 3-(4-(4-(3-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)piperidin-4-yl)oxo)cyclobutyl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0783] Example 29 was prepared by the following steps:

[0784] Step A: Int-2i (350 mg, 0.51 mmol) and 29a (174.80 mg, 1.02 mmol) were dissolved in tetrahydrofuran (2 mL), followed by the addition of sodium triacetoxyborohydride (162.27 mg, 0.77 mmol). The reaction mixture was stirred at 50 °C for approximately 4 hours. LC / MS showed that the reaction was complete. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined. The crude product was concentrated under reduced pressure and purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% formic acid system) to give 29b (250 mg, yield: 58.24%). ESI-MS (m / z): 841.5 [M+H] + .

[0785] Step B: At room temperature, 29b (250 mg, 0.30 mmol) was dissolved in tetrahydrofuran (4 mL), and Dysmartin oxidant (189.13 mg, 0.45 mmol) was added. The reaction was carried out for approximately 5 hours. LC / MS showed that the reaction was complete. Sodium bicarbonate aqueous solution was added dropwise to the reaction mixture, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was then subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate (V / V) = 1 / 1) to give product 29c (230 mg, yield: 92.22%). ESI-MS (m / z): 839.4 [M+H] + .

[0786] Step C: At room temperature, 29c (150 mg, 0.18 mmol) and Int-1 (61.40 mg, 0.18 mmol, hydrochloride) were dissolved in N,N-dimethylformamide (2 mL). A catalytic equivalent of acetic acid (3 drops) was added dropwise to the reaction solution, and the mixture was stirred for approximately 1 hour. Sodium triacetoxyborohydride (56.84 mg, 0.27 mmol) was added in portions. The reaction was allowed to proceed at room temperature for 16 hours. LC / MS showed the reaction was complete. The reaction was quenched with water, and the mixture was extracted with dichloromethane / methanol (V / V) = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (V / V) = 10 / 1) to give 29d (120 mg, yield: 57.54%), ESI-MS (m / z): 584.0 [M+2H]. 2+ / 2.

[0787] Step D: Compound 29 (60 mg, 0.051 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added dropwise to the reaction solution. The reaction was carried out at room temperature for 1 hour. LC / MS showed that the reaction was complete. The reaction solution was concentrated, and the residue was purified by reverse-phase column chromatography (mobile phase A: acetonitrile; mobile phase B: 0.1% ammonia system) to give compound 29 (14 mg, yield: 26.09%). ESI-MS (m / z): 512.0 [M+2H] 2+ / 2; 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),10.16(s,1H),9.03(d,J=7.9Hz,1H),7.97(dd,J= 9.2,6.0Hz,1H),7.46(t,J=9.0Hz,1H),7.39(d,J=2.5Hz,1H),7.17(d,J=2.4Hz,1H),6. 98(t,J=7.9Hz,1H),6.91(d,J=8.0Hz,1H),6.88(d,J=7.8Hz,1H),5.35(dd,J=12.7,5.3 Hz,1H),4.48(d,J=10.8Hz,1H),4.31-4.24(m,2H),3.93(s,1H),3.79–3.73(m,1H),3.6 4(d,J=11.3Hz,1H),3.60(s,3H),3.57-3.52(m,3H),3.04-2.93(m,3H),2.92-2.84(m,3 H),2.83-2.71(m,5H),2.69(dd,J=12.9,4.6Hz,1H),2.65-2.61(m,1H),2.61-2.58(m,1 H),2.41-2.34(m,3H),2.33-2.30(m,1H),2.28-2.26(m,2H),2.05-1.95(m,4H),1.77-1 .71(m,2H),1.69-1.62(m,5H),1.39-1.31(m,2H),0.65-0.60(m,2H),0.41-0.37(m,2H).

[0788] Example 30

[0789] 3-(4-(4-(3-((1-((1-(((4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-7-(8-ethyl-7-fluoro-3-hydroxynaphth-1-yl)-8-fluoropyridino[4,3-d]pyrimidin-2-yl)oxo)methyl)cyclopropyl)methyl)piperidin-4-yl)oxo)cyclobutyl)piperazin-1-yl)-3-methyl-2-carbonyl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0790] Example 30 was prepared by the following steps:

[0791] Step A: Dissolve 29d (50 mg, 0.043 mmol) in a mixed solvent of tetrahydrofuran (2 mL) and ethyl acetate (2 mL), add 10% palladium on carbon catalyst (9.12 mg, 0.086 mmol), purge with hydrogen three times, and stir at room temperature for 16 hours. LC / MS showed the reaction was complete. Filter the reaction solution through diatomaceous earth, concentrate the filtrate to give 30a (39 mg, crude product). ESI-MS (m / z): 586.1 [M+2H] 2+ / 2.

[0792] Step B: Dissolve 30a (50 mg, 0.043 mmol, crude product) in dichlorom...

Claims

1. A compound as shown in Formula I: Its pharmaceutically acceptable salt or its prodrug; in, -D is for KRAS G12D Target protein binding group or its prodrug group; -H 0 -for-CH2-CR 4 R 5 -CH2-H 01 -H 02 -; R 4 and R 5 H, F, C independently 1-6 Alkyl or C substituted with one or more F 1-6 Alkyl, or R 4 and R 5 Together with the C connected to it, they form C 3-6 Cycloalkanes; -H 01 - is a 4-6 quinone heterocyclic alkyl group, surrounded by one or more R groups. RH01-1 The substituted 4-6 membered heterocyclic alkylene, 7-12 membered bicyclic or tricyclic heterocyclic alkylene, or alkylene spirocyclic alkylene with one or more R RH01-2 The substituted 7-12 membered bicyclic or tricyclic spirocycloalkyl group; wherein the heteroatoms in the spirocycloalkyl group are independently one or two of N and O, and the number is one, two or three; Each R RH01-1 and each R RH01-2 Independently F or C 1-6 alkyl; -H 02 - is a connector, -C (=O)-, -CR 6a R 6b -、-O-、-S-、-CR 6a R 6b -O-、-NR 6a R 6b -,-rigid group-CR 6a R 6b -or -O-rigid group-; the -rigid group-CR 6a R 6b The rigid groups in -O- and the rigid groups in -O- can optionally be replaced by one or more F; Each R 6a and each R 6b H, F, C independently 1-6 Alkyl or with one or more R R6 Replacement C 1-6 alkyl; Each R R6 Independent of deuterium, F or C 1-6 Alkoxy; -H 1 -for Mark 1 bit as H 0 Connect, 2 bits or * mark with connect; Ring A a and each ring A b Independently, it is a 6-8 membered heterocyclic alkyl group, a 7-11 membered bicyclic spirocyclic heterocyclic alkyl group, or an 8-9 membered bicyclic bridged heterocyclic alkyl group; Ring A a In the above, the heteroatoms in the heterocyclic alkyl group, the bicyclic spirocyclic heterocyclic alkyl group, and the bicyclic bridged heterocyclic alkyl group are specifically one or two of N and O, and the number is two or three, and at least two N atoms are present; each ring A b In the above, the heteroatoms in the heterocyclic alkyl group, the bicyclic spirocyclic heterocyclic alkyl group, and the bicyclic bridged heterocyclic alkyl group are specifically one or two of N and O, and the number is one, two, or three, and at least one N is present; Each n1 is independently 1, 2, or 3; Each R 1 Independent of hydrogen, F, C 1-6 Alkyl, oxo, with one or more R R1 Replacement C 1-6 alkyl; Each R R1 For F, C 1-6 Alkoxy or C substituted with one or more F 1-6 Alkoxy; R 2 C 1-6 Alkyl groups or C atoms that are deuterated by one or more deuterated groups 1-6 alkyl; n2 is 1, 2, or 3; Each R 3 Independently hydrogen, F, Cl, Br, C 1-6 Alkyl, C 1-6 alkoxy, with one or more R R3-1 Replacement C 1-6 Alkyl groups or those with one or more R groups R3-2 Replacement C 1-6 Alkoxy; Each R R3-1 and each R R3-2 Independently, it is either F or deuterium.

2. The compound of formula I as claimed in claim 1, characterized in that, It meets one or more of the following conditions: (1) Each R 1 R 2 Each R 3 R 4 R 5 R 6a R 6b Each R RH01-1 and each R RH01-2 In, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (2) When R 4 and R 5 Together with the C connected to it, they form C 3-6 In the case of cycloalkanes, the C 3-6 The cycloalkane is cyclopropane, cyclobutane, or cyclopentane; (3)-H 01 - In this context, the 4-6 membered heterocyclic alkyl group and the group with one or more R RH01-1 The 4-6 membered heterocyclic alkyl group in the substituted heterocyclic alkyl group is independently a 5- or 6-membered heterocyclic alkyl group, the heteroatom is N, the number is 1 or 2, and it may also be a piperidinyl group; (4)-H 01 - In this context, the 7-12 membered bicyclic spiroheterocyclic alkyl group and the one or more R RH01-2 The 7-12-membered bicyclic spirocycloalkyl group in the substituted 7-12-membered bicyclic spirocycloalkyl group is independently a 6-membered heterocycloalkylspiro4-6-membered cycloalkyl or a 6-membered heterocycloalkylspiro4-6-membered heterocycloalkyl, the heteroatom being N and / or O, and the number being 1 or 2, and may also be 3-azaspiro[5.5]undecylene, 7-azaspiro[3.5]nonylene or 1-oxa-8-azaspiro[4.5]decylene; (5)-H 01 - In this context, the 4-6 membered heterocyclic alkyl group, the one or more R RH01-1 The substituted 4-6 membered heterocyclic alkyl group, the 7-12 membered bicyclic spirocyclic alkyl group, and the alkyl group with one or more R RH01-2 In the substituted 7-12 membered bicyclic spiroheterocyclic alkyl group, the 7-12 membered bicyclic spiroheterocyclic alkyl group is independently linked to -CH2- via a heteroatom and to -H via a carbon atom. 02 -connect; (6)-H 01 - In this context, the 4-6 membered heterocyclic alkyl group, the one or more R RH01-1 The substituted 4-6 membered heterocyclic alkyl group, the 7-12 membered bicyclic spirocyclic alkyl group, and the alkyl group with one or more R RH01-2 The 7-12-membered bicyclic spiroheterocyclic alkyl group in the substituted 7-12-membered bicyclic spiroheterocyclic alkyl group has an axisymmetric structure, wherein the axis is the line connecting the two connection sites of the structural segment to the rest of Formula I. (7)-H 02 - In, the - rigid group - CR 6a R 6b The rigid groups in -O- and the rigid groups in -O- are independently C 3- 6-cycloalkyl group, with one or more R RH02-1 Replacement C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, or alkyl grouped with one or more R RH02-2 Substituted 4-6 membered heterocyclic alkyl groups; the 4-6 membered heterocyclic alkyl groups and the groups substituted with one or more R RH02-2 The heteroatoms in the substituted 4-6-membered heterocyclic alkyl groups are independently one or two of N and O, and the number is one, two or three; Each R RH02-1 and each R RH02-2 Independently F or C 1-6 alkyl; (8) Ring A a In this context, the 6-8 membered heterocyclic alkyl group has N heteroatom, and there are two of them. It can be piperazine, 1,4-diazacycloheptyl, or 1,5-diazacyclooctyl. (9) Ring A a In this context, the 7-11 member bicyclic spirocyclic heterocyclic alkyl group is a 6-membered heterocyclic alkyl spiro-4-6-membered heterocyclic alkyl group or a 5-membered heterocyclic alkyl spiro-4-membered heterocyclic alkyl group, with heteroatoms being N and / or O, and the number being 2 or 3. It can be 2,7-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.4]octyl, 2,6-diazaspiro[3.3]heptyl, 3,9-diazaspiro[5.5]undecyl, 2-oxo-5,8-diazaspiro[3.5]nonyl or 4,7-diazaspiro[2.5]octyl; (10) Ring A a In the 8-9 member bicyclic bridged heterocyclic alkyl group, the heteroatom is N, and the number is 2, which can be 3,8-diazabicyclo[3.2.1]octyl or 3,9-diazabicyclo[3.3.1]nonyl; (11) Ring A b In this context, the 6-8 membered heterocyclic alkyl group is a piperidinyl group; (12) Ring A b In this context, the 7-11 member bicyclic spirocyclic heterocyclic alkyl group is a 4-6 member heterocyclic alkyl spiro-4-6 member cycloalkyl group, with heteroatoms being N and / or O, and the number being 1, 2 or 3, and can be 7-azaspiro[3.5]nonyl, 3-diazaspiro[5.5]undecyl, 2-azaspiro[3.5]nonane or 7-azaspiro[3.5]nonyl; (13) Each R 1 Each R R1 Each R 3 and R R6 In the middle, the C 1-6 The alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; (14) Each R 1 In the context, the one or more R R1 Replacement C 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (15) Each R R1 In the context, the C replaced by one or more F 1-6 C in alkoxy 1-6 The alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; (16)R 2 In the context, the C-terminated by one or more deuterium atoms 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (17)R 3 In the context, the one or more R R3-1 Replacement C 1-6 C in alkyl 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropoxy, n-butyl, isobutyl, sec-butyl, or tert-butyl; (18)R 3 In the context, the one or more R R3-2 Replacement C 1-6 C in alkoxy 1-6 The alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; (19) When -H 1 -for At that time, -H 02 - is -C(=O)- or -O-.

3. The compound of formula I as described in claim 2, characterized in that, It meets one or more of the following conditions: (1)-H 01 - In, the one or more R RH01-1 The substituted 4-6 membered heterocyclic alkyl group is (2)-H 01 - In, the one or more R RH01-2 The substituted 7-12 membered bicyclic spirocyclic alkyl group is (3) In the rigid group, the C 3-6 cycloalkyl and the one or more R RH02-1 Replacement C 3-6 C in cycloalkyl 3- The cycloalkyl group of 6 is independently cyclopropyl or cyclobutyl; (4) Among the rigid groups, the 4-6 membered heterocyclic alkyl group and the group with one or more R RH02-2 The 4-6-membered heterocyclic alkyl group in the substituted heterocyclic alkyl group is independently a 4-5-membered heterocyclic alkyl group, the heteroatom is N, the number is 1, and it can be a nitrogen-heterocyclic butyl group; (5) Each R 6a and each R 6b In, the one or more R R6 Replacement C 1-6 Alkyl is (6) Each R 1 In the context, the one or more R R1 Replacement C 1-6 Alkyl is (6)R 2 In the context, the C-terminated by one or more deuterium atoms 1-6 The alkyl group is -CD3; (7)R 3 In the context, the one or more R R3-2 Replacement C 1-6 The alkoxy group is -OCD3.

4. The compound of formula I as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions: (1)-H 0 - For any of the following structures: The 1st bit is connected to 0, and the 2nd bit is connected to H. 1 connect; (2) (3) for (4) for (5) for (6) for 5. The compound of formula I as described in any one of claims 1-4, characterized in that, -D represents the following general formula IIa or IIb: In equations IIa and IIb, R 7a and R 7b Independently for C 6-10 aryl, 6-10 aryl, with one or more R R7-1 Replacement C 6- 10 aryl or aryl group with one or more R groups R7-2 The substituted 6-10-membered heteroaryl group; the heteroatoms of the heteroaryl group are independently selected from N, S and O, and the number is 1, 2 or 3; Each R R7-1 and each R R7-2 Independently, it can be a halogen, cyano, hydroxyl, amino, oxo group, or C group. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, C substituted with one or more halogens 1-6 Alkyl groups, C atoms substituted with one or more deuterium groups 1- 6-alkyl groups or C groups substituted with one or more halogens 1-6 Alkoxy; R 8a and R 8b For H, C 1-6 Alkyl or halogen; Ring B a and Ring B b Independently a 7-9 membered bicyclic bridged heterocyclic alkyl group; n 3a and n 3b Independently 1, 2, or 3; R 9a and R 9b Independently hydrogen, C 1-6 Alkyl, with one or more R R9-1 Replacement C 1-6 Alkyl, C 1-6 alkoxy, with one or more R R9-2 Replacement C 1-6 Alkoxy or C 3-6 cycloalkyl; Each R R9-1 and each R R9-2 Independent of deuterium and C 1-6 Alkyl group or C group replaced by one or more deuterated groups 1-6 Alkoxy; R 13a and R 13b Independently hydrogen or -C(=O)R R13 ; R R13 C 1-6 Alkyl groups, C atoms substituted with one or more halogens 1-6 Alkyl or -O(CHC) 1-6 alkyl)OC(=O)(CHR R13-1 R R13-2 ); R R13-1 and R R13-2 Independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; R 10 H, halogen, C 1-6 Alkyl, C 2-6 alkynyl or C 1-6 Alkoxy; R 11 and R 12 Independently for H and C 1-6 Alkyl, C 1-6 Alkyl groups, C atoms substituted with one or more deuterium groups 1-6 Alkyl groups or C atoms substituted with one or more deuterium atoms. 1-6 Alkoxy; Y represents O, S, or CH2; X a and X b Independently CH, CR 14 Or N; R 14 Halogen, C 1-6 Alkyl groups or C atoms substituted with one or more halogens 1-6 alkyl; The heteroatoms in the heterocyclic alkyl group, the heteroaryl group, and the bridged heterocyclic alkyl group are independently selected from 1, 2, or 3 of N, S, and O, and the number of heteroatoms is 1, 2, or 3.

6. The compound of formula I as described in claim 5, characterized in that, It meets one or more of the following conditions: (1) Each R R7-1 Each R R7-2 R 8a R 8b R 9a R 9b Each R R9-1 Each R R9-2 R R13 R R13-1 R R13-2 R 10 R 11 R 12 and R 14 In the middle, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl or ethyl; (2) Each R R7-1 Each R R7-2 R 8a R 8b R 10 and R 13 In this context, the halogen is F, Cl, or Br, for example, F or Cl; (3) Each R R7-1 Each R R7-2 R 9a R 9b Each R R9-1 Each R R9-2 R 10 R 11 and R 12 In the middle, the C 1-6 The alkoxy group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (4) Each R R7-1 Each R R7-2 and R 10 In the middle, the C 2-6 The alkynyl group is either ethynyl or propynyl; (5) Ring B a and Ring B b In this context, the 7-9 member bicyclic bridged heterocyclic alkyl group is a 7-8 member bicyclic bridged heterocyclic alkyl group with N heteroatoms and two heteroatoms. It can also be 3,8-diazabicyclo[3.2.1]octyl or 2,5-diazabicyclo[2.2.1]heptyl. (6)R R13-1 and R R13-2 In the middle, the C 3-6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclobutyl.

7. The compound of formula I as described in claim 6, characterized in that, It meets one or more of the following conditions: (1) Each R R7-1 and each R R7-2 In the context, the C substituted with one or more halogens 1-6 The alkyl group is -CF3; (2) Each R R7-1 and each R R7-2 In the context, the C substituted with one or more deuteriums 1-6 Alkyl is (3) Each R R9-1 and each R R9-2 In the context, the C-terminated by one or more deuterium atoms 1-6 C in alkoxy 1-6 The alkoxy group is -OCD3; (4)R R9-3 In the context, the C substituted with one or more halogens 1-6 The alkyl group is -CF3 or -CHF2; (5)R 9a and R 9b In the context, the one or more R R9-1 Replacement C 1-6 Alkyl is (5)R 13a and R 13b In the context, -C(=O)R R13 -C(=O)CF3, 8. The compound of formula I as described in claim 5, characterized in that, -D represents the following general formulas: IIa-1, IIa-2, IIb-1, IIb-2, IIb-1a, or IIb-2a:

9. The compound of formula I as claimed in claim 8, characterized in that, It meets one or more of the following conditions: (1)R 7a and R 7b Independently q1, q2, q3, q4, q5, and q6 are independently 1, 2, 3, or 4; each R R7-1 and each R R7-2 Independent of halogen, C 1-6 Alkyl, C 2-6 alkynyl group, C 3- 6-cycloalkyl, C substituted with one or more halogens 1-6 Alkyl groups, or C groups substituted with one or more deuterium groups. 1-6 alkyl; Preferred (2)X a For CR 14 Or N, R 14 Halogen; X is further preferred. a -CCl, -CCF3, or N; (3)X b For N, R 11 For H, C 1-6 Alkyl groups or C atoms substituted with one or more deuterium atoms. 1-6 Alkyl; more preferably, X b For N, R 11 It can be methyl, ethyl, -CD3 or -CD2CD3; (4)R 8a and R 8b It is independently a halogen, and more preferably F; (5)R 9a and R 9b Independently for hydrogen, (6)R 13a and R 13b Independently for hydrogen, 10. The compound of formula I as described in claim 5, characterized in that, -D can be any of the following groups:

11. The compound of formula I as described in any one of claims 1-4, characterized in that, The compound represented by Formula I is a compound represented by Formula Ia or Ib: Equation Ia is preferably defined as follows: -for -H 02 - is a connector, -C (=O)-, -CR 6a R 6b -,-rigid group-CR 6a R 6b -or -O-rigid group-; for R 3 Hydrogen, F or C 1-6 Alkoxy; More preferably, for m1, m2, m3, m4, m5, and m6 are independently 1 or 2, and the above substituents -R RH01-2 This indicates that it can replace any one or two rings of the double-spiral ring; Formula Ib is preferably defined as follows: -for for More preferably, for 12. The compound of formula I as claimed in claim 1, characterized in that, The compound shown in Formula I is a compound shown in Formula I-1a or Ib: Among them, -H 0 -H 1 -for R 7 a and R 7 b independently for 13. The compound of formula I as described in any one of claims 1-4, characterized in that, The compound shown in Formula I is a compound with the following formula: t is 0, 1, 2 or 3; the definitions of the other groups are as described in any one of claims 1-12.

14. The compound of formula I as claimed in claim 1, characterized in that, The compound represented by Formula I is any one of the compounds in Table 1 below: Table 1 Its pharmaceutically unacceptable salt, its prodrug, or its stereoisomer.

15. A pharmaceutical composition, characterized in that, It includes compounds as shown in Formula I as described in any one of claims 1-14, or pharmaceutically acceptable salts thereof, and pharmaceutical excipients.

16. A method for detecting KRAS G12D The mutation kit is characterized by, It includes compounds as shown in Formula I as described in any one of claims 1-14, or pharmaceutically acceptable salts thereof.

17. A compound of Formula I as described in any one of claims 1-14, or a pharmaceutically acceptable salt thereof, in the preparation of a compound for the prevention or treatment of KRAS. G12D Applications in drugs for mutation-related cancers; The KRAS G12D Mutation-related cancers can be one or more of the following: pancreatic cancer, lung cancer, small bowel cancer, colorectal cancer, gallbladder cancer, thyroid cancer, thyroid cancer, bile duct cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, prostate cancer, esophageal cancer, and blood cancer.

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