Macrocyclic compounds and use thereof

Abstract

Provided are macrocyclic compounds and a use thereof. Specifically, the present invention relates to compounds represented by general formulas (2) and (3), and the use of the compounds as RAS inhibitors in the preparation of antitumor drugs.

Description

Macrocyclic compounds and their applications

[0001] This application claims priority to Chinese patent applications 202411580715.9 (filed November 7, 2024), 202411655810.0 (filed November 19, 2024), 202510257442.2 (filed March 5, 2025), 202510565752.0 (filed April 30, 2025), 202510971742.7 (filed July 15, 2025), and 202511409667.1 (filed September 29, 2025). The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of medicinal chemistry, and more specifically, relates to a class of macrocyclic compounds, their preparation methods, and their application in the preparation of drugs for treating or preventing cancer. Background Technology

[0003] Overactivation of Ras family proteins is a significant contributing factor to the development and progression of various cancers. Targeting and inhibiting Ras protein activity is an important approach in cancer treatment.

[0004] Ras protein exists in two forms: bound to GDP and bound to GTP. When bound to GDP, it remains in an inactive, quiescent state. Upon binding to GTP, Ras protein is activated, recruiting various signal transduction proteins and promoting the phosphorylation of downstream signaling molecules such as ERK and S6, thus activating the Ras signaling pathway and regulating cell growth, survival, migration, and differentiation. Ras protein's own GTPase activity can hydrolyze GTP back to GDP. The interaction between GTPase-activating proteins (GAPs) and Ras significantly promotes Ras GTPase activity, thereby preventing overactivation of the Ras protein.

[0005] Mutations in the K-Ras, H-Ras, and N-Ras proteins of the Ras protein family lead to overactivation of Ras proteins in tumors and are among the most common gene mutations in tumors. Compared to wild-type Ras proteins, these mutations result in more active Ras proteins that stably bind to GTP and remain continuously activated. Mutations in the K-Ras protein are the most common, accounting for 85% of all Ras mutations, while N-Ras (12%) and H-Ras (3%) are relatively rare. K-Ras mutations are extremely prevalent in various cancers, including pancreatic cancer (95%), colorectal cancer (45%), lung cancer (25%), and ovarian cancer (9%). K-Ras mutation sites are mainly concentrated at the G12 position, including mutations in G12D / V / C / A / S / R. Besides tumors, abnormal activation of the Ras protein is also involved in non-tumor diseases, including diabetes and neurodegenerative diseases. Therefore, small molecule compounds targeting the Ras protein can benefit a large number of cancer patients carrying specific gene mutations and non-cancer patients with over-activation of the Ras pathway.

[0006] Forty years since Ras mutations were discovered in tumors, although our understanding of the pathogenic mechanism of the Ras pathway has deepened and the development of G12C-targeted inhibitors has brought hope to some patients, there are still no effective Ras-targeting therapies available clinically for the large number of patients carrying non-G12C Ras protein mutations and those with overactivated Ras pathways. Therefore, developing highly active small-molecule inhibitors targeting mutant Ras proteins is of significant clinical importance.

[0007] Research on Pan RAS inhibitors targeting multiple G12 mutations is still limited, with only a few compounds having entered clinical trials. Revolution Medicines, Inc. recently disclosed a class of macrocyclic compounds that can form a ternary complex with the molecular chaperone proteins CypA and RAS(on) in vivo, blocking the binding of RAS to downstream RAF, thereby inhibiting the RAS-RAF-MEK-ERK signaling pathway and achieving an anti-tumor effect. A representative compound, RMC-6236, achieved very good survival and disease control effects in a Phase I clinical trial for PDAC. There is an urgent need to design and optimize this type of compound, researching and discovering compounds with good activity and excellent pharmacokinetic properties. Summary of the Invention

[0008] This invention provides a compound as shown in general formula (2) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0009] In general formula (2):

[0010] Ring D is (C5-C14) heterocyclic alkyl, (C6-C14) aryl, or (5-14) heteroaryl;

[0011] X1 and X2 are each independently N or CR d ;

[0012] X3 is CR 10 or NR 10 X4 is either C or N, and X3 and X4 are not both N at the same time;

[0013] Indicates a single or double bond, and when X3 or X4 is N, the bond connected to it is... Represented as a single bond;

[0014] R 7 For -OR a -NR a R b (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace;

[0015] R 8 Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, or -OR. a -NR a R b -C(O)R a -CO2R a -S(O) p R a -S(O) p NR a R b -CONR a R b -C(=NR) a )-NR b R c -NR a COR b -NR a CONR b R c -NR a CO2Rb -NR a S(O) p NR b R c -NR a S(O) p R b (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace;

[0016] R 9 -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a -NR a R b -C(O)R a -CO2R a -S(O) p R a -S(O) p NR a R b -CONR a R b -C(=NR) a )-NR b R c -NR a COR b -NR a CONR b R c -NR a CO2R b -NR a S(O) p NR b R c -NR a S(O) p R b(C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace;

[0017] R 10 The radical is -H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently optionally surrounded by 1, 2, 3, or 4 R radicals. d replace;

[0018] R 11 -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a -NR a R b -C(O)R a -CO2R a -S(O) p R a -S(O) p NR a R b -CONR a R b -C(=NR) a )-NR b R c -NR a COR b -NR a CONR b R c -NR a CO2R b -NR a S(O) p NR b Rc -NR a S(O) p R b (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace;

[0019] R a R b and R c Each of the following is independently H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C 1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3 or 4 Rs. e replace;

[0020] Or R a and R b R b and R c Or R a and R c Together with one or more atoms to which they are attached, they form (3-12-membered) heterocyclic alkyl groups, wherein the (3-12-membered) heterocyclic alkyl groups may optionally be composed of 1, 2, 3 or 4 R atoms. e replace;

[0021] R d Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, or -OR. e (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C1-C8)alkylene-(C3-C14)alkylene-(C2-C8)alkylene-(C2-C8)heteroaryl, 8) Alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3 or 4 Rs. e replace;

[0022] Or when 2 R d When attached to the same atom, an oxo group can be formed or a (C3-C8) cycloalkyl or (3-8) heterocycloalkyl group can be formed with the attached atom. The (C3-C8) cycloalkyl or (3-8) heterocycloalkyl group can each be independently and optionally bound by 1, 2, 3, or 4 R groups. e replace;

[0023] R e Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, or -OR. f -NR f R g -C(O)R f -CO2R f -S(O) p R f -S(O) p NR f R g -CONR f R g -C(=NR) f )-NR f R h -NR f COR g -NRf CONR g R h -NR f CO2R g -NR f S(O) p NR g R h -NR f S(O) p R g (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl;

[0024] R f R g and R h Each can be independently H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl;

[0025] n and p are integers of 0, 1, 2, 3, and 4, respectively.

[0026] In another preferred embodiment, in the general formula (2), R 7 It is (C3-C6) cycloalkyl, preferably cyclopropyl, wherein the cyclopropyl group is substituted with 1, 2, 3, or 4 H, D, methyl, halomethyl, or deutermethyl groups; R 7 More preferably

[0027] In another preferred embodiment, in the general formula (2), R 7 It is a (C7-C9)cycloalkyl or (7-9) heterocycloalkyl, wherein the (C7-C9)cycloalkyl or (7-9) heterocycloalkyl may be substituted with 1, 2, 3 or 4 H, D, hydroxyl, methyl, halomethyl or deuterated methyl.

[0028] In another preferred embodiment, in the general formula (2), X1 and X2 are each independently N or CR. d R d X1 is -H, -D, or halogen; X1 is preferably CH, CF, or N, and X2 is preferably CH.

[0029] In another preferred embodiment, in the general formula (1), the structural unit for Preferred

[0030] In another preferred embodiment, in the general formula (2), R 9 -H, -D, halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl; R 9 Preferably, it is -H, -D, halogen, methyl, or -CF3.

[0031] In another preferred embodiment, in the general formula (2), R 10 The alkyl group is -H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl, or (3-6-membered)heterocyclic alkyl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl, or (3-6-membered)heterocyclic alkyl group may each be independently optionally surrounded by 1, 2, 3, or 4 R groups. d replace.

[0032] In another preferred embodiment, in the general formula (2), R 10 for

[0033] In another preferred embodiment, in the general formula (2), R 8 -H, -D, halogen, hydroxyl, amino, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl; R 8 Preferably, it is -H, -D, halogen, methyl, hydroxyl, or amino.

[0034] In another preferred embodiment, in the general formula (2), ring D is The asterisk (*) indicates that it is connected to an aromatic ring.

[0035] In another preferred embodiment, in the general formula (2), R 11For -NR a R b -C(O)R a (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C3)alkenyl, (C2-C33)alkynyl, (C5-C6)cycloalkyl, (4-10-membered)heterocyclic alkyl, (C6-C10)aryl, or (5-6-membered)heteroaryl, wherein the (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C3)alkenyl, (C2-C33)alkynyl, (C5-C6)cycloalkyl, (4-10-membered)heterocyclic alkyl, (C6-C10)aryl, or (5-6-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace.

[0036] In another preferred embodiment, the general formula (2) has the structure shown in general formula 2(a):

[0037] In general formula 2(a), R 7 It is a (C7-C9)cycloalkyl or (7-9-membered) heterocycloalkyl, wherein the (C7-C9)cycloalkyl or (7-9-membered) heterocycloalkyl may be substituted with 1, 2, 3 or 4 H, D, hydroxyl, methyl, halomethyl, or deuterated methyl; R 10 for R 17 -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR f -C(O)R f -CO2R f (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl, (3-6-membered)heterocyclic alkyl, phenyl, (5-14-membered)heteroaryl, -(C1-C3)alkylene-(C3-C6)cycloalkyl, -(C1-C3)alkylene-(3-6-membered)heterocyclic alkyl, -(C1-C3)alkylene-(C6-C10)aryl, -(C1-C3)alkylene-(5-14-membered)heteroaryl; R f The radicals are H, hydroxyl, amino, methylamino, dimethylamino, (C1-C6)alkyl, (C1-C8)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl, (3-9-membered)heterocyclic alkyl, phenyl, (5-14-membered)heteroaryl, -(C1-C3)alkylene-(C3-C6)cycloalkyl, -(C1-C3)alkylene-(3-6-membered)heterocyclic alkyl, -(C1-C3)alkylene-(C6-C10)aryl, and -(C1-3)alkylene-(5-14-membered)heteroaryl.

[0038] In another preferred embodiment, the compound of general formula (2) has one of the following structures:

[0039] A compound of general formula (3) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0040] In general formula (3):

[0041] Ring E is Where * indicates that it is connected to the carbon atom of the ester group;

[0042] Ring F is (C6-C14)aryl or (5-14)heteroaryl;

[0043] Ring G is (C5-C14) heterocyclic alkyl, (C6-C14) aryl, or (5-14) heteroaryl;

[0044] X1 and X2 are each independently N or CR d ;

[0045] X3 is CR 3 or NR 3 X4 is either C or N, and X3 and X4 are not both N at the same time;

[0046] Indicates a single or double bond, and when X3 or X4 is N, the bond connected to it is... Represented as a single bond;

[0047] R 12 For -OR a -NR a R b(C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace;

[0048] R 3 The radical is -H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently optionally surrounded by 1, 2, 3, or 4 R radicals. d replace;

[0049] R 13 -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a -NR a R b -C(O)R a -CO2R a -S(O) p R a -S(O) p NR a R b -CONR a R b -C(=NR) a )-NR b R c -NR a COR b -NR a CONR b R c -NR a CO2R b -NR a S(O) p NR b Rc -NR a S(O) p R b -POR a R b -PSR a R b -N(=S(O)R a R b ), -BR a R b -(C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently optionally surrounded by 1, 2, 3, or 4 Rs. d replace;

[0050] Or R 13 and R 3 The atoms to which it is attached constitute a 6-10 membered heterocyclic alkyl group, each of which may be independently and optionally bound by 1, 2, 3 or 4 R atoms. d replace;

[0051] R 15 Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, carbonyl, or -OR. a -NR a R b -C(O)R a -CO2R a -S(O) p R a -S(O) p NR a R b -CONR a R b -C(=NR) a )-NR b R c -NR a COR b -NR a CONR b R c -NR a CO2R b -NR a S(O)p NR b R c -NR a S(O) p R b (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace;

[0052] R 16 Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, or -OR. a -NR a R b -C(O)R a -CO2R a -S(O) p R a -S(O) p NR a R b -CONR a R b -C(=NR) a )-NR b R c -NR a COR b -NR a CONR b R c -NR a CO2R b -NR a S(O) p NR b R c -NR a S(O) p R b -POR a R b -PSR a R b -N(=S(O)R a R b ), -BR a R b(C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace;

[0053] R 14 Each is an independent structural unit Where Y1 is S or O, and Y2 is O or NR. c ;

[0054] R a R b and R c Each of the following is independently H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C 1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3 or 4 Rs. e replace;

[0055] Or R a and R b R b and R c Or R a and R cTogether with one or more atoms to which they are attached, they form (3-12-membered) heterocyclic alkyl groups, wherein the (3-12-membered) heterocyclic alkyl groups may optionally be composed of 1, 2, 3 or 4 R atoms. e replace;

[0056] R d Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, or -OR. e (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C1-C8)alkylene-(C3-C14)alkylene-(C2-C8)alkylene-(C2-C8)heteroaryl, 8) Alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3 or 4 Rs. e replace;

[0057] Or when 2 R d When attached to the same atom, an oxo group can be formed or a (C3-C8) cycloalkyl or (3-8) heterocycloalkyl group can be formed with the attached atom. The (C3-C8) cycloalkyl or (3-8) heterocycloalkyl group can each be independently and optionally bound by 1, 2, 3, or 4 R groups. e replace;

[0058] R e Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, or -OR. f -NR f R g -C(O)R f -CO2R f -S(O) p R f -S(O) p NR f R g -CONR f R g-C(=NR) f )-NR f R h -NR f COR g -NR f CONR g R h -NR f CO2R g -NR f S(O) p NR g R h -NR f S(O) p R g (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl;

[0059] R f R g and R h Each can be independently H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl;

[0060] n and p are integers of 0, 1, 2, and 3 respectively.

[0061] In another preferred embodiment, in the general formula (2), R 12 It is a (C7-C9)cycloalkyl or (7-9) heterocycloalkyl, wherein the (C7-C9)cycloalkyl or (7-9) heterocycloalkyl may be substituted with 1, 2, 3 or 4 H, D, hydroxyl, methyl, halomethyl or deuterated methyl.

[0062] In another preferred embodiment, in the general formula (3), R 12It is (C3-C6) cycloalkyl, preferably cyclopropyl, wherein the cyclopropyl group is substituted with 1, 2, 3, or 4 H, D, methyl, halomethyl, or deutermethyl groups; R 12 More preferably

[0063] In another preferred embodiment, in the general formula (3), X1 and X2 are each independently N or CR. d R d X1 is -H, -D, or halogen; X1 is preferably CH, CF, or N, and X2 is preferably CH.

[0064] In another preferred embodiment, wherein the structural unit is described in general formula (3). for Preferred

[0065] In another preferred embodiment, in the general formula (3), ring G is a benzene ring or a 6-membered heteroaromatic ring; ring G is preferably a benzene ring or a pyridine ring.

[0066] In another preferred embodiment, in the general formula (3), R 15 Each of the following groups is independently -H, -D, halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C5)cycloalkyl, (3-5-membered)heterocyclic alkyl, (C6-C10)aryl, or (5-10-membered)heteroaryl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C5)cycloalkyl, (3-5-membered)heterocyclic alkyl, (C6-C10)aryl, or (5-10-membered)heteroaryl groups may be independently and optionally surrounded by 1, 2, 3, or 4 R groups. d Replace; R 15 Preferably, it is -H, -D, halogen, or (C1-C3) alkyl.

[0067] In another preferred embodiment, wherein the structural unit is described in general formula (3). for Where * indicates that it is connected to the carbon atom of the ester group;

[0068] In another preferred embodiment, in the general formula (3), R 13 -H, -D, halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl; R 13 Preferably, it is -H, -D, halogen, methyl, or -CF3.

[0069] In another preferred embodiment, in the general formula (3), R 3 for

[0070] In another preferred embodiment, in the general formula (3), R 13 and R 3 The atoms to which it is attached constitute a 6-10 membered heterocyclic alkyl group, each of which may be independently and optionally bound by 1, 2, 3 or 4 R atoms. d replace;

[0071] In another preferred embodiment, in the general formula (3), R 16 -H, -D, halogen, hydroxyl, amino, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl; R 16 Preferably, it is -H, -D, halogen, methyl, hydroxyl, or amino.

[0072] In another preferred embodiment, in the general formula (3), the ring F is The asterisk (*) indicates that it is connected to an aromatic ring.

[0073] In another preferred embodiment, in the general formula (3), R 14 Each is an independent structural unit Where Y1 is S or O, and Y2 is O or NR. c ;R a R b and R c Each of the following is independently H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C 1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3 or 4 Rs.e Replace; or R a and R b R b and R c Or R a and R c Together with one or more atoms to which they are attached, they form (3-12-membered) heterocyclic alkyl groups, wherein the (3-12-membered) heterocyclic alkyl groups may optionally be composed of 1, 2, 3 or 4 R atoms. e Replace; R 14 Preferred R 14 More preferably

[0074] In another preferred embodiment, wherein the compound of the general formula (3) has one of the following structures:

[0075] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a diluent and / or an excipient, and a compound of the general formula of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

[0076] Another object of the present invention is to provide the use of the compounds of the general formula of the present invention, or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical compositions thereof, in the preparation of medicaments for the treatment, regulation or prevention of diseases related to RAS protein kinase.

[0077] Another object of the present invention is to provide a method for treating, modulating or preventing diseases associated with RAS protein kinase, comprising administering to a subject a therapeutically effective amount of a compound of the general formula of the present invention, or any isomer thereof, crystal form thereof, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof.

[0078] It should be understood that the foregoing general description of the invention and the following detailed description are exemplary and illustrative, and are intended to provide further explanation of the claimed invention.

[0079] Compound Synthesis

[0080] The preparation method of the compound of general formula (1) of the present invention is described in detail below, but these specific methods do not constitute any limitation on the present invention.

[0081] The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with the methods described herein. Furthermore, the solvents, temperatures, and other reaction conditions mentioned herein can be varied. Starting materials used in the synthesis of the compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds with different substituents can be synthesized using known techniques and starting materials, including those discovered in March, ADVANCED ORGANIC CHEMISTRY 4. th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd The method described in Ed. (Wiley 1999) can be used to prepare compounds by employing appropriate reagents and by introducing different groups into the molecular formulas provided herein.

[0082] On the one hand, the compounds described herein are prepared according to methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to those explained below. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0083] Further forms of the compound

[0084] "Pharmaceutical acceptable" here means that a substance, such as a carrier or diluent, will not destroy the biological activity or properties of a compound and is relatively non-toxic. For example, when given to an individual, a substance will not cause unwanted biological effects or interact with any of its components in a harmful manner.

[0085] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the administered organism and does not diminish the compound's biological activity and properties. In some specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of a general formula with an acid or base, wherein said acid or base includes, but is not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use 1. st Acids and bases in Ed. (Wiley, 2002).

[0086] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. A hydrate is formed when the solvent is water, or an alcohol is formed when the solvent is ethanol. Solvates of compounds of general formula (1) are readily prepared or formed according to the methods described herein. For example, hydrates of compounds of general formula (1) are readily prepared by recrystallization from a mixture of water and organic solvents, including but not limited to tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, the compounds mentioned herein can exist in both solvated and non-solvated forms. In summary, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form.

[0087] In other specific embodiments, compounds of general formula (1) are prepared in various forms, including but not limited to amorphous, pulverized, and nano-particle forms. Furthermore, compounds of general formula (1) include crystalline forms and can also be polymorphic. Polymorphs comprise different lattice arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability, and solubility. Different factors such as recrystallization solvents, crystallization rates, and storage temperatures may cause a single crystal form to dominate.

[0088] In another aspect, compounds of general formula (1) may possess a chiral center and / or axial chirality, and thus appear as racemates, racemic mixtures, single enantiomers, diastereomers, and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds, are included within the scope of this invention. This invention means including all such isomeric forms of these compounds.

[0089] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Oxygen-18 ( 18 O), Iodine-125 ( 125 I) and C-14 14C). For example, deuterium can be used to replace hydrogen atoms to form deuterated compounds. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs generally have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0090] Unless otherwise specified, any atom in the compounds described in this invention refers to its stable-state isotope. Unless otherwise specified, when a site on the molecular structure is chosen as "H" or "hydrogen", that site should be understood as having a natural abundance of hydrogen isotopes. Similarly, unless otherwise specified, when a site is chosen as "D" or "deuterium", that site should be understood as having a deuterium isotope abundance of at least 3000 times its natural abundance (the natural abundance of deuterium isotopes is 0.015%).

[0091] More preferably, the deuterium abundance at each deuteration site of the deuterated compound in this invention is at least 3500 times its natural abundance (52.2% deuterium enrichment). More preferably, at least 4500 times (67.5% deuterium enrichment). More preferably, at least 5000 times (75% deuterium enrichment). More preferably, at least 6000 times (90% deuterium enrichment). More preferably, at least 6333 times (95% deuterium enrichment). More preferably, at least 6466.7 times (97% deuterium enrichment). More preferably, at least 6600 times (99% deuterium enrichment). More preferably, at least 6633.3 times (99.5% deuterium enrichment).

[0092] the term

[0093] Unless otherwise specified, the terms used in this application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, unless otherwise clearly indicated, the singular form "a" includes the plural meaning. Unless otherwise specified, substituents (such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.) in this application are optionally substituted, i.e., they can be substituted or unsubstituted. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are used. In this application, unless otherwise specified, "or" or "and" refers to "and / or".

[0094] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 6 carbon atoms. Lower alkyl groups containing 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, and tert-butyl. Lower alkyl groups containing 1 to 3 carbon atoms are more preferred, such as methyl, ethyl, propyl, and 2-propyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, etc. i Pr, n Pr, i Bu、 n Bu or t Bu.

[0095] Unless otherwise specified, "alkylene" means a divalent alkyl group as defined above. Examples of alkylene include, but are not limited to, methylene and ethylene.

[0096] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight-chain or branched groups with 1 to 14 carbon atoms. Lower alkenyl groups containing 1 to 4 carbon atoms are preferred, such as vinyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl. Lower alkenyl groups containing 1 to 2 carbon atoms are more preferred.

[0097] Unless otherwise specified, “alkenyl” refers to a divalent alkenyl group as defined above.

[0098] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight-chain and branched groups with 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms are preferred, such as ethynyl, 1-propynyl, or 1-butynyl. Lower alkynyl groups containing 1 to 2 carbon atoms are more preferred.

[0099] Unless otherwise specified, “ethynyl” means a divalent ethynyl group as defined above.

[0100] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), preferably containing 3-14 ring carbon atoms (C14-C24). 3-14 A non-aromatic hydrocarbon ring system (cycloalkyl). In some embodiments, the cycloalkyl group has 3-10 ring carbon atoms (C60-C70). 3-10 (Cycloalkyl). In some embodiments, the cycloalkyl group has 3-8 cyclic carbon atoms (C60-C85). 3-8 (Cycloalkyl). In some embodiments, the cycloalkyl group has 3-7 cyclic carbon atoms (C60-C75). 3-7 (Cycloalkyl). In some embodiments, the cycloalkyl group has 3-6 cyclic carbon atoms (C66-C66). 3-6(Cycloalkyl). In some embodiments, the cycloalkyl group has 4-6 cyclic carbon atoms (C66-C66). 4-6 (Cycloalkyl). In some embodiments, the cycloalkyl group has 5-6 cyclic carbon atoms (C66-C66). 5-6 (Cycloalkyl). In some embodiments, the cycloalkyl group has 5-10 cyclic carbon atoms (C10-C20). 5-10 Cycloalkyl groups. A partially unsaturated cycloalkyl group may be referred to as a "cycloalkenyl" if the carbide ring contains at least one double bond, or as a "cycloynyl" if the carbide ring contains at least one triple bond. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic. In some embodiments, the cycloalkyl group is either monocyclic or bicyclic. In some embodiments, the cycloalkyl group is tricyclic. The cycloforming carbon atom of the cycloalkyl group may optionally be oxidized to form an oxo or thio group. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, the cycloalkyl group contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl group contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, the cycloalkyl group may be fused with aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl groups. In some embodiments, the cycloalkyl group may be fused with aryl, cycloalkyl, and heterocyclic alkyl groups. In some embodiments, the cycloalkyl group may be fused with aryl and heterocyclic alkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norcamphenyl, norpinel, norcarel, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and so on.

[0101] Unless otherwise specified, “cycloalkylene” means a divalent cycloalkyl group as defined above.

[0102] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule via an ether oxygen atom. Representative alkoxy groups are those having 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, particularly those substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, etc. i- PrO, n- PrO, i- BuO、 n- BuO or t- BuO.

[0103] Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, which can be monocyclic or polycyclic, such as a monocyclic aryl ring fused with one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrene.

[0104] Unless otherwise specified, "aryloxy group" refers to an aryl group bonded to the rest of the molecule via an ether oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy groups.

[0105] Unless otherwise specified, "arylene" refers to a divalent aryl group as defined above. Examples of arylene groups include, but are not limited to, 1,4-phenylene, 1,3-phenylene, 1,2-phenylene, naphthylene, and phenanthrene.

[0106] Unless otherwise specified, "heteroaryl" refers to a substituted or unsubstituted aromatic group containing one or more heteroatoms, the heteroatoms being independently selected from O, N, or S. The number of heteroatoms is preferably 1, 2, 3, or 4, preferably a 5-14-membered aromatic group containing 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen; more preferably a 5-9-membered aromatic group containing 1-2 heteroatoms optionally selected from oxygen, sulfur, or nitrogen; and even more preferably a 5-6-membered aromatic group containing 1-3 heteroatoms optionally selected from oxygen, sulfur, or nitrogen. The heteroaryl group can be monocyclic or polycyclic. A monocyclic heteroaryl group is preferably a 5-6-membered aromatic group containing 1-3 heteroatoms optionally selected from oxygen, nitrogen, or sulfur. More preferably a 5-6-membered aromatic group containing 1-2 heteroatoms optionally selected from oxygen, nitrogen, or sulfur. Even more preferably a 5-6-membered aromatic group containing 1 heteroatom optionally selected from oxygen, nitrogen, or sulfur. In some embodiments, the monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocyclic alkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, furanyl, thiopheneyl, isoxazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isothiazolyl, pyrroleyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiaphenyl, benzooxazolyl, benzopyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridyl, 1H-pyrrolo[2,3-c]pyridyl, 1H-pyrrolo[3,2-c]pyridyl, and 1H-pyrrolo[2,3-b]pyridyl.

[0107] Unless otherwise specified, “hybrid aryl” refers to a divalent heteroaryl group as defined above.

[0108] Unless otherwise specified, "heterocyclic alkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenyl groups as part of a ring structure, having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and selenium, preferably containing 1-4 heteroatoms selected from oxygen, sulfur, or nitrogen, and more preferably containing 1-2 heteroatoms selected from oxygen, sulfur, or nitrogen. In some embodiments, the heterocyclic alkyl is a 5-14 membered non-aromatic ring containing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, or sulfur (5-14 membered heterocyclic alkyl). In some embodiments, the heterocyclic alkyl is a 3-9 membered non-aromatic ring containing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, or sulfur (3-9 membered heterocyclic alkyl). In some embodiments, the heterocyclic alkyl group is a 5-8 membered non-aromatic ring containing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, or sulfur (5-8 membered heterocyclic alkyl group). In some embodiments, the heterocyclic alkyl group is a 5-6 membered non-aromatic ring containing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, or sulfur (5-6 membered heterocyclic alkyl group). In some embodiments, the 5-6 membered heterocyclic alkyl group contains 1-3 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic alkyl group contains 1-2 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic alkyl group contains 1 cyclic heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl group is a 10-13 membered non-aromatic ring containing a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, or sulfur (10-13 membered heterocyclic alkyl group). In some embodiments, the 10-13 membered heterocyclic alkyl group contains 1-3 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 10-13 membered heterocyclic alkyl group contains 1-2 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 10-13 membered heterocyclic alkyl group contains 1 cyclic heteroatom independently selected from nitrogen, oxygen, and sulfur. If the heterocyclic alkyl group contains at least one double bond, then the partially unsaturated heterocyclic alkyl group may be referred to as a "heterocyclic alkenyl group," or if the heterocyclic alkyl group contains at least one triple bond, then the partially unsaturated heterocyclic alkyl group may be referred to as a "heterocyclic ynyl group." Heterocyclic alkyl groups may include monocyclic, bicyclic, spirocyclic, or polycyclic (e.g., having two fused or bridging rings) ring systems. In some embodiments, the heterocyclic alkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The cyclic carbon atoms and heteroatoms of the heterocyclic alkyl group may optionally be oxidized to form oxo or thio groups or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O)2, N-oxides, etc.), or the nitrogen atom may be quaternized. The heterocyclic alkyl group may be linked via cyclic carbon atoms or cyclic heteroatoms. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds.In some embodiments, the heterocyclic alkyl group contains 0 to 2 double bonds. The definition of heterocyclic alkyl also includes portions of an aromatic ring (also called partially unsaturated heterocycles) having one or more aromatic rings fused to (i.e., sharing bonds with) the heterocyclic alkyl ring, such as benzo[a] derivatives of piperidine, morpholine, aziridine, or tetrahydrothiophene, and pyrido[a] derivatives of piperidine, morpholine, aziridine, or tetrahydrothiophene. Heterocyclic alkyl groups containing fused aromatic rings can be linked via any cyclizing atom, including the cyclizing atom of the fused aromatic ring. Examples of heterocyclic alkyl groups include, but are not limited to, azirrobutyl, azirroheptyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxoperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolamine, 4,5,6,7-tetrahydrothiazo[5,4-c]pyridinyl, and 4,5,6,7-tetrahydro-1H-imidazolium. [4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolyl, butyrolactam, valproic acid, imidazolinone, hydantoin, dioxolane, phthalimide, pyrimidin-2,4(1H,3H)-diketoyl, 1,4-dioxane, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide, thiomorpholin-S,S-oxide, piperazine, pyranyl, pyridinone, 3-pyrrololinyl, thiaranyl, pyranone, tetrahydrothiophene, 2-azaspiro[3.3]heptyl, indololinyl.

[0109] Unless otherwise specified, “heterocyclic alkylene” means a divalent heterocyclic alkylene as defined above.

[0110] Unless otherwise specified, "halogen" (or halogenated group) means fluorine, chlorine, bromine or iodine. The term "halogenated" (or "halogen substituted") appearing before the group name indicates that the group is partially or completely halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.

[0111] Unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on a specified atom or group are substituted by one or more substituents other than hydrogen atoms, without exceeding the normal valence of the specified atom. For example, one or more hydrogen atoms of alkyl, alkylene, alkenyl, alkynyl, hydroxyl, or amino groups may be substituted by one or more substituents. The substituents mentioned include, but are not limited to, alkyl, alkenyl, alkynyl, acyl, amino, amide, amidyl, aryl, azide, carbamoyl, carboxyl, carboxylic acid ester, cyano, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazyl, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. The definition of "substituted" does not include similar indeterminate structures obtained by defining substituents having further substituents attached to infinity (e.g., a substituted aryl group having a substituted alkyl group itself substituted by a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.). Unless otherwise specified, the maximum number of successive substitutions in the compounds described herein is three. For example, the successive substitution of a substituted aryl group by two other substituted aryl groups is limited to ((substituted aryl) substituted aryl) substituted aryl. Similarly, the above definition does not include disallowed substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such disallowed substitution patterns are well known to those skilled in the art. Whenever used to modify a chemical group, “substituted” may describe other chemical groups as defined herein. For example, the term “substituted aryl” includes, but is not limited to, “alkylaryl.” Unless otherwise specified, if a group is described as optionally substituted, any substituted elements of that group are themselves unsubstituted.

[0112] "Optional" or "optionally" means that the event or condition described below may, but is not required, occur, and the description includes both the scenario in which the event or condition occurs and the scenario in which the event or condition does not occur.

[0113] Unless otherwise specified, "acyl" means -C(=O)-R, where R is selected from optionally substituted alkyl, alkenyl, ynyl, cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl or heterocycloalkyl.

[0114] Unless otherwise specified, the word “comprising”, or variations thereof such as “including” or “containing”, may be understood to mean including the stated element or integer, or a group of elements or integers, but does not exclude any other element or integer, or a group of elements or integers.

[0115] The substituent "-O-CH2-O-" indicates that the two oxygen atoms in the substituent are connected to two adjacent carbon atoms of a heterocyclic alkyl, aryl, or heteroaryl group. For example:

[0116] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a single bond.

[0117] When one of the variables is selected as a chemical bond, it means that the two groups connected are directly linked. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0118] The term "membered ring" includes any ring structure. The term "membered" refers to the number of skeleton atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thioranyl are six-membered rings, while cyclopentyl, pyrroleyl, furanyl, and thiophenyl are five-membered rings.

[0119] The term "fragment" refers to a specific part or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to a molecule.

[0120] The term "isomer" refers to any tautomer, stereoisomer, transisomer, isotopic isomer, enantiomer, or diastereomer of any compound of the present invention. The compounds of the present invention may have one or more chiral centers or double bonds, and thus exist in stereoisomeric form, such as double-bonded isomers (i.e., E / Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). Therefore, the compounds of the present invention encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms, as well as mixtures of enantiomers and stereoisomers, such as racemates. The enantiomers and stereoisomers of the compounds of this invention can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high-performance liquid chromatography, and by crystallizing the compounds as chiral salt complexes or by crystallizing the compounds in chiral solvents. The enantiomers and stereoisomers can also be obtained by well-known asymmetric synthetic methods using stereoisomerically pure or enantiomerically pure intermediates, reagents, and catalysts.

[0121] The term "isotope isomers" refers to different molecules that are identical in structure except for their isotopes.

[0122] The term "restricted transisomer" refers to a conformational stereoisomer that arises when rotation around a single bond within a molecule is prevented or significantly slowed by spatial interactions with other parts of the molecule, and when the substituents at the ends of the single bond are asymmetrical; that is, a restricted transisomer does not require a stereocenter. When the rotational barrier around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, the separation of individual isomers is permissible (LaPlante et al., J.Med.Chem. 2011, 54, 20, 7005), preferably by chiral resolution.

[0123] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be linked to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds being connected, resulting in a group with a corresponding valence. For example, "pyridyl" indicates... "Oxazolyl" indicates

[0124] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key

[0125] Unless otherwise stated, use Indicates a single bond or a double bond.

[0126] Specific pharmaceutical and medical terms

[0127] The term “acceptable,” as used herein, means that a prescription component or active ingredient does not have an excessively harmful effect on health for general therapeutic purposes.

[0128] The terms “treatment,” “treatment process,” or “therapy” as used herein include alleviating, suppressing, or improving symptoms or conditions of a disease; suppressing the development of complications; improving or preventing underlying metabolic syndromes; suppressing the development of a disease or symptom, such as controlling the progression of a disease or condition; reducing a disease or symptom; alleviating a disease or symptom; reducing complications arising from a disease or symptom; or preventing or treating signs arising from a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, may improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether administered regularly or intermittently, continuously or intermittently, it may be attributable to or related to the administration.

[0129] "Active ingredient" refers to the compound represented by general formula (1), and pharmaceutically acceptable inorganic or organic salts of compounds of general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality), and thus appear as racemates, racemic mixtures, single enantiomers, diastereomers, and single diastereomers. The asymmetric centers that may exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention means including all such isomeric forms of these compounds.

[0130] The terms “compound,” “composition,” “agent,” or “medicine or medicament” may be used interchangeably here, and all refer to a compound or composition that, when applied to an individual (human or animal), can induce a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0131] The term “administered, administering, or administration” here refers to the direct application of the compound or composition described herein, or the application of a prodrug, derivative, or analog of the active compound.

[0132] While the numerical ranges and parameters used to define the broader scope of this invention are approximate values, the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any value inevitably contains standard deviations due to individual test methods. Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "approximately" may mean that the actual value falls within the acceptable standard error of the mean, as determined by those skilled in the art. Except for experimental examples, or unless explicitly stated otherwise, it is understood that all ranges, quantities, values, and percentages used herein (e.g., to describe material usage, duration, temperature, operating conditions, quantity ratios, and others similar) are modified with "approximately". Therefore, unless otherwise stated, the numerical parameters disclosed in this specification and the accompanying claims are approximate values ​​and are subject to change as needed. At a minimum, these numerical parameters should be understood as the indicated significant digits and values ​​obtained using general rounding.

[0133] Unless otherwise defined in this specification, scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art. Furthermore, unless conflicting with the context, singular nouns used herein include their plural forms, and vice versa.

[0134] Therapeutic uses

[0135] This invention provides methods for treating diseases using compounds or pharmaceutical compositions of the general formula of this invention, including but not limited to conditions involving RAS (e.g., cancer).

[0136] In some embodiments, a method for treating cancer is provided, the method comprising administering to an individual in need an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of the general structural formula. In some embodiments, the cancer is mediated by the renal arterial system (RAS). In other embodiments, the cancer is a hematologic malignancy and a solid tumor, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial carcinoma, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all metastatic cancers.

[0137] route of administration

[0138] The compounds of this invention and their pharmaceutically acceptable salts can be formulated into various preparations, comprising, within a safe and effective range, the compounds of this invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective range of the compound is determined based on the age, condition, and duration of treatment of the patient.

[0139] "Pharmaceutically acceptable excipients or carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0140] When applying the compounds of this invention, they can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0141] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0142] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0143] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0144] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0145] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0146] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0147] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0148] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the compound of this invention is applied to the mammal (such as a human) requiring treatment, wherein the dose administered is a pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.

[0149] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features. Detailed Implementation

[0150] The following description will elaborate on the specific aspects, characteristics, and advantages of the aforementioned compounds, methods, and pharmaceutical compositions, making the content of this invention readily apparent. It should be understood that the detailed descriptions and examples described below are specific embodiments and are for reference only. After reading this description, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by this application.

[0151] In all embodiments, 1 H-NMR was recorded using a Varian Mercury 400 NMR spectrometer, and chemical shifts are expressed as δ (ppm). Unless otherwise specified, the silica gel used for separation was 200-300 mesh, and all eluent ratios were by volume.

[0152] The following abbreviations are used in this invention: ACN represents acetonitrile; (Boc)₂O represents ditert-butyl dicarbonate; B₂(OH)₄ represents tetrahydroxydiboron; B₂pin₂ represents dipinanolyldiboron; CDCl₃ represents deuterated chloroform; Cs₂CO₃ represents cesium carbonate; CuI represents cuprous iodide; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; Diox represents 1,4-dioxane; DMF represents N,N-dimethylformamide; DMAP represents 4-(dimethylamino)pyridine; DMSO represents dimethyl sulfoxide; EA represents ethyl acetate; EtOH represents anhydrous ethanol; EDCI represents 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; Et₃SiH represents... Table 1: Triethylsilane; Flash represents rapid medium-pressure preparative chromatography; Hexane represents n-hexane; Heptane represents n-heptane; HBpin represents pinacol borane; HCl represents hydrochloric acid; HATU represents 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; HPLC represents high-performance liquid chromatography; hr represents hours; HOBt represents 1-hydroxybenzotriazole; [Ir(COD)(OMe)]2 represents (1,5-cyclooctadiene)methoxyiridium(I) dimer; K2CO3 represents potassium carbonate; K3PO4 represents potassium phosphate; KOAc represents potassium acetate; KOH represents potassium hydroxide; KOPiv represents potassium tert-pentanol; LC-MS represents... Mass spectrometry; LiOH represents lithium hydroxide; LDA represents lithium diisopropylamino; LiBH4 represents lithium borohydride; MeOH represents methanol; mL represents milliliters; min represents minutes; NaH represents sodium hydride; NaHCO3 represents sodium bicarbonate; NBS represents N-bromosuccinimide; NIS represents N-iodosuccinimide; NMR represents nuclear magnetic resonance; NMM represents N-methylmorpholine; NMI represents N-methylimidazolium; PE represents petroleum ether; Pre-TLC indicates thin-layer chromatography; Pd / C represents palladium on carbon; Pd(OH)2 represents palladium hydroxide; Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium(0); Pd(dp pf)Cl2 represents 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride; Pd(dtbpf)Cl2 represents 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride; PdCl2 represents palladium dichloride; Pd(PPh3)2Cl2 represents bis(triphenylphosphino) palladium dichloride; POCl3 represents phosphorus oxychloride; PPh3 represents triphenylphosphine; Py represents pyridine; SOCl2 represents thionyl chloride; TBAF represents tetrabutylammonium fluoride; TBDPSCl represents tert-butyldiphenylchlorosilane; TBSCl represents tert-butyldimethylchlorosilane; TFA represents trifluoroacetic acid; TLC represents thin-layer chromatography; TEA represents triethylamine; THF represents tetrahydrofuran; Tol represents toluene;XantPhos represents 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene; XPhos represents 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl; XPhos-Pd-G3 represents methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); 2-MeTHF represents dimethyltetrahydrofuran.

[0153] Preparation Example 1: Synthesis of IntA1, IntA1-S, and IntA1-R:

[0154] Synthesize IntA1-2:

[0155] IntA1-1 (15 g, 105.52 mmol), n-heptane (300 mL), and tert-butyl hydrazide carboxylate (13.95 g, 105.52 mmol) were added to a 500 mL single-necked flask, and the mixture was heated to 70 °C and stirred for 12 h. After the reaction was confirmed to be complete by LC-MS, the mixture was cooled to room temperature, water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound IntA1-2.

[0156] LC-MS: m / z = 201[M-56+1] + .

[0157] Synthesize IntA1-3:

[0158] Borane dimethyl sulfide (1M, 390mL) was added to a 500mL three-necked flask. After argon protection, the mixture was cooled to 0℃, and then a THF solution of IntA1-2 (10g, 39mmol) in 15mL was added dropwise. After the addition was complete, the mixture was stirred at 0℃ for 0.5h, and then the reaction was continued at room temperature for 1h. After the reaction was confirmed to be complete by LC-MS, the reaction was quenched by slow dropwise addition of methanol under ice bath conditions. The system was concentrated and purified by column chromatography to obtain compound IntA1-3.

[0159] LC-MS: m / z = 203[M-56+1] + .

[0160] Synthesis of IntA1-4:

[0161] IntA1-3 (3 g, 11.61 mmol) and THF (60 mL) were added to a 250 mL single-necked flask and stirred until dissolved. Then, di-tert-butyl dicarbonate (3.8 g, 17.42 mmol), TEA (3.52 g, 34.83 mmol), and 4-dimethylaminopyridine (142 mg, 1.16 mmol) were added sequentially, and the mixture was reacted at room temperature for 1 h. After the reaction was confirmed to be complete by LC-MS, water was added, and the mixture was extracted twice with EA. The organic phases were combined, washed with saturated sodium chloride, concentrated, and purified by column chromatography to obtain compound IntA1-4.

[0162] LC-MS: m / z = 359 [M+1] + .

[0163] Synthesize IntA1-5:

[0164] IntA1-4 (1 g, 2.79 mmol) and THF (20 mL) were added to a 100 mL three-necked flask. After argon protection, the mixture was cooled to -70 °C, and lithium bis(trimethylsilyl)amino (8.37 mL, 1 M) was added dropwise. After half an hour of reaction, trimethylchlorosilane (909 mg, 8.37 mmol) was added dropwise, and the reaction was continued at -70 °C for 1 hour. Then, NBS (1.99 g, 11.16 mmol) was added, and the mixture was slowly heated to room temperature for another 1 hour. After the reaction was confirmed to be complete by LC-MS, saturated sodium chloride was added, and the mixture was extracted twice with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound IntA1-5.

[0165] LC-MS: m / z = 353[M-100-56+1] + .

[0166] Synthesizing IntA1-6:

[0167] IntA1-5 (510 mg, 1 mmol) and THF (20 mL) were added to a 100 mL single-necked flask, followed by citric acid monohydrate (630 mg, 3 mmol). The mixture was reacted at room temperature for 1 h. After the reaction was confirmed to be complete by LC-MS, saturated sodium chloride was added, and the mixture was extracted twice with EA. The organic phases were combined, concentrated, and subjected to column chromatography to obtain compound IntA1-6.

[0168] LC-MS: m / z = 281[M-100-56+1] + .

[0169] Synthesize IntA1-7:

[0170] IntA1-6 (219 mg, 0.5 mmol), ACN (10 mL), and cesium carbonate (652 mg, 2 mmol) were added to a 100 mL single-necked flask and heated to 60 °C for 12 h. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered, the filter cake was washed with ACN, the filtrate was concentrated, and column chromatography was performed to obtain compound IntA1-7. This compound was resolved by SFC to obtain two fractions, labeled IntA1-7S and IntA1-7R, respectively.

[0171] LC-MS: m / z = 201[M-100-56+1] + .

[0172] Synthesize IntA1:

[0173] IntA1-7 (100 mg, 0.28 mmol), DCM (5 mL), and HCl / dioxane (4 M, 10 mL) were added to a 50 mL single-necked flask, and the mixture was heated to 40 °C for 1 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated to obtain the hydrochloride salt of compound IntA1.

[0174] LC-MS: m / z = 157 [M+1] + .

[0175] IntA1-S and IntA1-R were prepared using the same method as IntA1 described above.

[0176] Preparation Example 2: Synthesis of IntA2:

[0177] Synthesize IntA2-1:

[0178] Trimethyl phosphonoacetate (124 g, 0.681 mol) and THF (2 L, ultra-dry) were added to a 3 L three-necked flask. After purging with argon, the mixture was cooled to -10 °C in an ice-salt bath. Then, NaH (34 g, 60%, 0.851 mol) was added slowly in portions. After the addition was complete, the mixture was stirred at 0–5 °C for 1 h. Then, a THF (200 mL) solution of 100 g, 0.567 mol of 3-(benzyloxy)-1-cyclobutanone was slowly added dropwise under ice bath. After the addition was complete, the system was allowed to rise naturally to room temperature, and the reaction was stirred under argon protection for 2 h. After the reaction was completed, the mixture was cooled again in an ice bath and then quenched dropwise with saturated ammonium chloride solution (500 mL). Add EA (1L) and water (2L), stir, separate the layers, extract the aqueous phase with EA (500mL), combine the organic phases, wash twice with saturated sodium chloride solution (1L*2), concentrate, and purify the residue by column chromatography (PE:EA = 40:0 to 40:1 to 30:1). Obtain a colorless oily product (88.3g, yield: 67.1%).

[0179] LC-MS: m / z = 233[M+1] + .

[0180] Synthesize IntA2-2:

[0181] Add the above compound IntA2-1 (88.3 g, 0.381 mol), MeOH (1.5 L), and... to a 3 L single-necked flask.

[0182] 10% Pd / C (8.8 g, wet: 55%) was purged with hydrogen three times, and then reacted vigorously with a hydrogen bag at room temperature for 20 h. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filter cake was washed with anhydrous methanol. The filtrate was concentrated to dryness to give a colorless oily product (52.5 g, yield: 95.9%).

[0183] LC-MS: m / z = 145 [M+1] + .

[0184] Synthesize IntA2-3:

[0185] Add the above-mentioned compound IntA2-2 (52.5 g, 0.364 mol), DCM (600 mL), imidazole (37.1 g, 0.547 mol), and DMAP (8.9 g, 0.072 mol) to a 3 L three-necked flask. Cool the mixture to 0–5 °C in an ice bath under argon protection, and then slowly add a DCM solution of TBSCl (82.4 g, 0.547 mol) in 200 mL. After the addition is complete, stir the mixture at room temperature for 20 h. After the reaction is complete as detected by LC-MS, add water (1 L), stir, separate the liquids, and wash the organic phase successively with 10% citric acid solution (500 mL) and saturated sodium chloride solution (500 mL). Dry the mixture with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain the crude product.

[0186] Synthesize IntA2-4:

[0187] The above-mentioned compound IntA2-3 (crude product, 0.364 mol), THF (300 mL), MeOH (300 mL), water (100 mL), and lithium hydroxide monohydrate (30.6 g, 0.728 mol) were added to a 3 L three-necked flask. The mixture was stirred at room temperature for 4 h under argon protection. After the reaction was completed as detected by LC-MS, the mixture was concentrated to about 1 / 3 of its original volume, diluted with water (500 mL), and washed twice with EA (200 mL * 2). The aqueous phase was then adjusted to pH 4-5 with 2N HCl in an ice bath, extracted twice with EA (300 mL * 2), and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a pale yellow oily product (86.4 g, yield: 97.1%).

[0188] LC-MS: m / z = 243 [M-1] - .

[0189] Synthesize IntA2-5:

[0190] The above-mentioned compounds IntA2-4 (86.4 g, 0.354 mol), DCM (1 L), (S)-4-benzyl-2-azolidinone (69.0 g, 0.389 mol), TEA (107.3 g, 1.062 mol), and DMAP (4.32 g, 0.035 mol) were added to a 2 L single-necked flask. After argon purging protection, the mixture was cooled to 0–5 °C in an ice bath. Then, 2-chloro-1-methylpyridine iodide (135.7 g, 0.531 mol) was slowly added in portions. After the addition was complete, the mixture was stirred at room temperature for 20 h. After the reaction was detected by LC-MS, water (500 mL) was added to the mixture, stirred, and separated. The aqueous phase was extracted with DCM (200 mL), and the combined organic phases were washed with saturated sodium chloride solution (500 mL), concentrated, and the residue was purified by column chromatography (PE:EA = 20:0 to 20:1 to 10:1) to give a white solid product (143 g, yield: 100%).

[0191] LC-MS: m / z = 404.3 [M+1] + .

[0192] Synthesize IntA2-6:

[0193] Add the above compound IntA2-5 (143 g, 0.354 mol) and THF (700 mL) to a 2 L single-necked flask. After dissolving by stirring at room temperature, add 2N HCl (531 mL, 1.062 mol). Stir the mixture at room temperature for 2 h. After the reaction is complete as detected by LC-MS, add EA (300 mL), stir, separate the phases, and extract the aqueous phase with EA (200 mL * 2). Combine the organic phases and wash successively with saturated sodium chloride solution (500 mL), saturated sodium bicarbonate solution (500 mL), and saturated sodium chloride solution (500 mL). Dry with anhydrous sodium sulfate, filter, and concentrate to dryness to give a brown oily product (100 g, yield: 97.7%).

[0194] LC-MS: m / z = 290.3 [M+1] + .

[0195] Synthesize IntA2-7:

[0196] The above-mentioned compounds IntA2-6 (85.3 g, 0.295 mol), DCM (1.28 L), imidazole (30.1 g, 0.443 mol), and PPh3 (116 g, 0.443 mol) were added to a 2 L single-necked flask. The mixture was cooled to 0–5 °C in an ice bath, and then iodine (112.5 g, 0.443 mol) was added in portions at room temperature. After the addition was complete, the mixture was heated to 30–40 °C and stirred for 20 h. After the reaction was completed by LC-MS stirring, the mixture was cooled, filtered, and the filter cake was washed with a small amount of PE. The filtrate was concentrated, and the residue was purified by column chromatography (PE:EA = 4:0 to 4:1) to give an off-white solid product (108 g, yield: 91.7%).

[0197] LC-MS: m / z = 400.2 [M+1] + .

[0198] Synthesize IntA2-8:

[0199] The above-mentioned compound IntA2-7 (66.5 g, 0.167 mol) and THF (800 mL, ultra-dry) were added to a 1 L three-necked flask. Under argon protection, the mixture was cooled to -70–-80 °C, and then kept at -65 °C with dropwise addition of LDA (208 mL, 2 M in THF, 0.416 mol). After the addition was complete, the mixture was kept at -65–-70 °C with stirring for 2 h. The temperature was then lowered again to -70–-80 °C, and di-tert-butyl azodicarbonate (46 g, 0.20 mol) was added dropwise, controlled below -65 °C. After the addition was complete, the mixture was kept at this temperature for 2 h. Then, N,N-dimethylpropenylurea (124 g, 0.97 mol) was added dropwise at -65–-70 °C. After the addition was complete, the mixture was allowed to rise naturally to room temperature with stirring for 4 h. LC-MS analysis showed that most of the intermediates were unclosed ring-closed. The mixture was then further heated to 60 °C with stirring for 8 h. After the intermediate disappeared as detected by LC-MS, the system was cooled to room temperature, and then water (400 mL) and lithium hydroxide monohydrate (14.4 g, 0.343 mol) were added. The mixture was stirred at room temperature for 2 h. After the reaction was completed as detected by LC-MS, EA (400 mL) was added, the mixture was stirred, and the liquid was separated. The organic phase was extracted with water (400 mL), and the combined aqueous phases were washed with EA (300 mL * 3). The combined aqueous phases were adjusted to pH 4–5 with 2N HCl, and then extracted with EA (200 mL * 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown oily impurity product (44 g, yield: 77.0%).

[0200] LC-MS: m / z = 341.2 [M-1] — .

[0201] Synthesize IntA2-9:

[0202] The above-mentioned compound IntA2-8 (44 g, impurity, 0.129 mol), DMF (400 mL), K2CO3 (53.3 g, 0.386 mol), and benzyl bromide (22 g, 0.129 mol) were added to a 1 L single-necked flask. The mixture was stirred at room temperature for 20 h. After the reaction was completed as detected by LC-MS, water (400 mL) and EA (200 mL) were added to the mixture, stirred, and separated. The aqueous phase was extracted again with EA (200 mL). The combined organic phases were washed with saturated sodium chloride solution, concentrated, and the residue was purified by column chromatography (PE:EA = 20:0 to 20:1 to 10:1) to give a brown oily product (19.5 g, yield: 34.9%, chiral HPLC analysis showed that the isomer ratio was 81%:19%).

[0203] LC-MS: m / z = 433.3 [M+1] + .

[0204] Synthesize IntA2:

[0205] The above-mentioned compound IntA2-9 (19.07 g, 44.1 mmol), DCM (100 mL), and TFA (57 mL) were added to a 250 mL single-necked flask, and the mixture was stirred at room temperature for 4 h. After the reaction was completed as detected by LC-MS, the mixture was concentrated, and the residue was flash purified (0.1% TFA / ACN system), lyophilized, and a pale yellow gelatinous product (15.6 g, TFA salt, yield: 100%) was obtained.

[0206] LC-MS: m / z = 233.2 [M+1] + .

[0207] Preparation Example 3: Synthesis of IntB1:

[0208] Synthesize IntB1-1:

[0209] 5-Fluoro-3-bromo-2-cyanopyridine (25 g, 124.38 mmol), THF (275 mL), TEA (12.59 g, 124.38 mmol), and 1-methylpiperazine (18.69 g, 186.57 mmol) were added to a 500 mL single-necked flask, and the mixture was heated to 60 °C and stirred for 8 h. After the reaction was confirmed to be complete by LC-MS, the mixture was concentrated and extracted three times with water (150 mL), saturated sodium bicarbonate solution (50 mL), and EA (100 mL * 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was then slurried with PE (100 mL) and filtered to obtain a solid compound IntB1-1 (34.9 g, Y: 99%).

[0210] LC-MS: m / z = 281[M+1] + .

[0211] Synthesize IntB1-2:

[0212] IntB1-1 (20.7 g, 73.62 mmol) and anhydrous THF (350 mL) were added to a 1 L three-necked flask. After argon protection, the mixture was cooled to -5 to 0 °C, and methyl magnesium bromide (3 M, 98 mL) was added dropwise. After the addition was complete, the mixture was reacted at 0 °C for 0.5 h, and then at room temperature for 2 h. After the reaction was confirmed to be complete by LC-MS, saturated ammonium chloride (200 mL) was added to quench the reaction, followed by the addition of saturated sodium chloride (100 mL). The mixture was extracted three times with EA (200 mL * 3), the organic phases were combined, washed with saturated sodium chloride, concentrated, and purified by column chromatography to obtain compound IntB1-2 (17.58 g, Y: 80%).

[0213] LC-MS: m / z = 298 [M+1] + .

[0214] Synthesize IntB1-3:

[0215] Formic acid (21.15 g, 459.45 mmol) was added to a 500 mL three-necked flask. After argon protection, the mixture was cooled to 0 °C, and TEA (239 g, 2.362 mol) was added dropwise. Then, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (877 mg, 1.378 mmol) was added, and the mixture was heated to 40 °C and stirred for 15 minutes. The mixture was then cooled to room temperature, and IntB1-2 (27.4 g, 91.89 mmol) was added in portions. The mixture was then heated to 50 °C and reacted overnight. After the reaction was confirmed to be complete by LC-MS, the reaction solution was directly concentrated, and the crude product was purified by column chromatography to obtain compound IntB1-3 (27.3 g, Y: 98%, ee%: 93.7%).

[0216] LC-MS: m / z = 300[M+1] + .

[0217] Synthesis of IntB1-4:

[0218] IntB1-3 (20.7 g, 68.95 mmol) and DMF (210 mL) were added to a 500 mL three-necked flask. After argon protection, the mixture was cooled to 0 °C, and NaH (3.31 g, 82.74 mmol, 60%) was added in portions. The reaction was carried out at 0 °C for 1 h. Then, iodomethane (10.77 g, 75.85 mmol) was added dropwise, and the reaction was continued at 0 °C for 2 h. After the reaction was confirmed to be complete by LC-MS, saturated ammonium chloride (100 mL) was added dropwise to quench the reaction mixture, followed by the addition of saturated sodium chloride (200 mL). The mixture was extracted four times with EA (300 mL * 4), the organic phases were combined, concentrated, and the crude product was purified by rapid column chromatography to obtain compound IntB1-4 (15.354 g, Y: 70%).

[0219] LC-MS: m / z = 314[M+1] + .

[0220] Synthesize IntB1-5:

[0221] IntB1-4 (7.264 g, 23.12 mmol) and neopentyl glycol diboronate (13.05 g, 57.79 mmol) were added to a 250 mL single-necked flask and dissolved in Dioxane (150 mL). Then, potassium acetate (5.67 g, 57.79 mmol) and Pd(dppf)Cl2 (1.691 g, 2.31 mmol) were added. After three purgings with argon gas, the mixture was heated to 90 °C and reacted overnight. After LC-MS analysis to confirm the reaction was complete, the reaction solution was filtered, and the filtrate was directly concentrated to obtain the crude compound IntB1-5 (24.95 g).

[0222] LC-MS: m / z = 348 [M+1] + .

[0223] Synthesize IntB1-6:

[0224] IntB1-5 (crude product 24.95 g, 23.12 mmol) and IntC2 (17.94 g, 27.74 mmol) were added to a 500 mL single-necked flask and dissolved in Dioxane (200 mL) / H2O (40 mL). Then, potassium carbonate (9.59 g, 69.36 mmol) and Pd(dppf)Cl2 (1.691 g, 2.31 mmol) were added. After three purgings with argon gas, the mixture was heated to 70 °C and reacted overnight. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by column chromatography to obtain compound IntB1-6 (20.6 g, Y: 118%).

[0225] LC-MS: m / z = 753 [M+1] + .

[0226] Synthesize IntB1-7:

[0227] IntB1-6 (crude product 20.6 g, 23.12 mmol) and THF (400 mL) were added to a 1 L single-necked flask. After argon protection, the mixture was cooled to 0 °C, and NaH (4.624 g, 115.6 mmol) was added in portions. The mixture was stirred at 0 °C for 0.5 h, and then iodoethane (5.41 g, 34.68 mmol) was added dropwise. The reaction was continued at 0 °C for 1 h, and then iodoethane (4.33 g, 27.74 mmol) was added. The mixture was allowed to react naturally overnight in an ice bath. After the reaction was confirmed to be complete by LC-MS, ice water (50 mL) was added to quench the reaction mixture, followed by the addition of saturated saline (100 mL). The mixture was extracted twice with EA (150 mL * 2), the organic phases were combined, concentrated, and the crude product was purified by column chromatography to obtain compound IntB1-7 (10.1 g, Y: 55.9%).

[0228] LC-MS: m / z = 781 [M+1] + .

[0229] Synthesize IntB1-8:

[0230] IntB1-7 (7.82 g, 10 mmol), THF (40 mL), and TBAF (1 M, 40 mL) were added to a 250 mL single-necked flask, and the mixture was reacted overnight at 50 °C. After the reaction was confirmed to be complete by LC-MS, water was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined, washed with water and saturated sodium chloride, concentrated, and purified by column chromatography to obtain compound IntB1-8 (4.45 g, Y: 82.0%).

[0231] LC-MS: m / z = 543 [M+1] + .

[0232] Synthesize IntB1:

[0233] IntB1-8 (1 g, 1.84 mmol) and dipicolinate (701 mg, 2.76 mmol) were added to a 250 mL single-necked flask and dissolved in Tol (10 mL). Then, potassium acetate (361 mg, 3.68 mmol) and Pd(dppf)Cl2 (135 mg, 0.184 mmol) were added. After three purgings with argon gas, the mixture was heated to 90 °C and reacted for 5 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography to obtain compound IntB1 (710 mg, Y: 65.3%).

[0234] LC-MS: m / z = 591 [M+1] + .

[0235] Preparation Example 4: Synthesis of IntB2:

[0236] Synthesize IntB2-1:

[0237] 5-Fluoro-3-bromo-2-cyanopyridine (25 g, 124.38 mmol), THF (275 mL), TEA (12.59 g, 124.38 mmol), and 1-Boc-piperazine (34.7 g, 186.57 mmol) were added to a 500 mL single-necked flask, and the mixture was heated to 60 °C and stirred for 20 h. After the reaction was confirmed to be complete by LC-MS, the mixture was concentrated and extracted three times with water (150 mL), saturated sodium bicarbonate solution (50 mL), and EA (100 mL * 3). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was then slurried with PE (100 mL) and filtered to obtain a solid compound IntB2-1 (45.2 g, Y: 99%).

[0238] LC-MS: m / z = 367 [M+1] + .

[0239] Synthesize IntB2-2:

[0240] IntB2-1 (36.6 g, 99.69 mmol) and anhydrous THF (350 mL) were added to a 1 L three-necked flask. After argon protection, the mixture was cooled to -5 to 0 °C, and methyl magnesium bromide (3 M, 100 mL) was added dropwise. After the addition was complete, the mixture was reacted at 0 °C for 0.5 h, and then moved to room temperature for 2 h. After the reaction was confirmed to be complete by LC-MS, saturated ammonium chloride (200 mL) was added to quench the reaction, followed by the addition of saturated sodium chloride (100 mL). The mixture was extracted three times with EA (200 mL * 3), the organic phases were combined, washed with saturated sodium chloride, concentrated, and purified by column chromatography to obtain the pale yellow compound IntB2-2 (22.2 g, Y: 58%).

[0241] LC-MS: m / z = 384 [M+1] + .

[0242] Synthesize IntB2-3:

[0243] Formic acid (15.19 g, 329.91 mmol) was added to a 500 mL three-necked flask. After argon protection, the mixture was cooled to 0 °C, and TEA (171.6 g, 1.696 mol) was added dropwise. Then, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (630 mg, 0.99 mmol) was added, and the mixture was heated to 40 °C and stirred for 15 minutes. The mixture was then cooled to room temperature, and IntB2-2 (25.34 g, 65.98 mmol) was added in portions. The mixture was then heated to 50 °C and reacted overnight. After the reaction was confirmed to be complete by LC-MS, the reaction solution was directly concentrated, and the crude product was purified by column chromatography to obtain compound IntB2-3 (22.4 g, Y: 88%, ee%: 95.6%).

[0244] LC-MS: m / z = 386 [M+1] + .

[0245] Synthesis of IntB2-4:

[0246] IntB2-3 (1.994 g, 4.744 mmol) and DMF (20 mL) were added to a 100 mL three-necked flask. After argon protection, the mixture was cooled to 0 °C, and NaH (228 mg, 5.693 mmol, 60%) was added in portions. The reaction was carried out at 0 °C for 1 h. Then, iodomethane (808 mg, 5.693 mmol) was added dropwise, and the reaction was continued at 0 °C for 2 h. After the reaction was confirmed to be complete by LC-MS, saturated ammonium chloride (100 mL) was added dropwise to quench the reaction mixture, followed by the addition of saturated sodium chloride (200 mL). The mixture was extracted four times with EA (300 mL * 4), the organic phases were combined, concentrated, and the crude product was purified by rapid column chromatography to obtain compound IntB2-4 (1.71 g, Y: 90%).

[0247] LC-MS: m / z = 400[M+1] + .

[0248] Synthesize IntB2-5:

[0249] IntB2-1 (1.71 g, 4.275 mmol) and neopentyl diboronate (2.41 g, 10.69 mmol) were added to a 100 mL single-necked flask and dissolved in Dioxane (30 mL). Then, potassium acetate (1.05 g, 10.69 mmol) and Pd(dppf)Cl2 (313 mg, 0.428 mmol) were added. After three purgings with argon gas, the mixture was heated to 90 °C and reacted overnight. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered, and the filtrate was directly concentrated to obtain the crude compound IntB2-5 (4.32 g).

[0250] LC-MS: m / z = 434[M+1] + .

[0251] Synthesize IntB2-6:

[0252] IntB2-5 (crude product 4.32 g, 4.275 mmol) and IntC2 (3.04 g, 4.703 mmol) were added to a 100 mL single-necked flask and dissolved in Dioxane (40 mL) / H2O (8 mL). Then, potassium carbonate (1.77 g, 12.83 mmol) and Pd(dppf)Cl2 (588 mg, 0.428 mmol) were added. After three purgings with argon gas, the mixture was heated to 70 °C and reacted overnight. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by column chromatography to obtain compound IntB2-6 (2.42 g, Y: 67.4%).

[0253] LC-MS: m / z = 839.4 [M+1] + .

[0254] Synthesize IntB2-7:

[0255] IntB2-6 (2.42 g, 2.883 mmol) and THF (400 mL) were added to a 1 L single-necked flask. After argon protection, the mixture was cooled to 0 °C, and NaH (577 mg, 14.41 mmol) was added in portions. The mixture was stirred at 0 °C for 0.5 h, and then iodoethane (900 mg, 5.766 mmol) was added dropwise. The reaction was continued at 0 °C for 1 h, and then iodoethane (675 mg, 4.325 mmol) was added. The mixture was allowed to react naturally overnight in an ice bath. After the reaction was confirmed to be complete by LC-MS, ice water (50 mL) was added to quench the reaction mixture, followed by the addition of saturated saline (100 mL). The mixture was extracted twice with EA (150 mL * 2), the organic phases were combined, concentrated, and the crude product was purified by column chromatography to obtain compound IntB2-7 (2.07 g, Y: 82.8%).

[0256] LC-MS: m / z = 867.4 [M+1] + .

[0257] Synthesizing IntB2-8:

[0258] IntB2-7 (2.07 g, 2.39 mmol), THF (40 mL), and TBAF (1 M, 10 mL) were added to a 250 mL single-necked flask, and the mixture was reacted overnight at 50 °C. After the reaction was confirmed to be complete by LC-MS, water was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined, washed with water and saturated sodium chloride, concentrated, and purified by column chromatography to obtain compound IntB2-8 (1.31 g, Y: 87.1%).

[0259] LC-MS: m / z = 629.3 [M+1]+ .

[0260] Synthesize IntB2-9:

[0261] IntB2-8 (1.31 g, 2.08 mmol), DCM (20 mL), and TFA (2 mL) were added to a 100 mL single-necked flask and stirred at room temperature for 5 h. After the reaction was confirmed to be complete by LC-MS, saturated sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was separated. The aqueous phase was extracted three times with DCM, the organic phases were combined, washed with saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated to obtain compound IntB2-9 (1.12 g, Y: 100%).

[0262] LC-MS: m / z = 529.2 [M+1] + .

[0263] Synthesize IntB2-10:

[0264] IntB2-9 (242 mg, 0.457 mmol), MeOH (10 mL), 1-ethoxy-1-trimethoxycyclopropane (478 mg, 2.742 mmol), and glacial acetic acid (274 mg, 4.57 mmol) were added to a 100 mL single-necked flask. The mixture was stirred at room temperature for 30 min, and then sodium cyanoborohydride (86 mg, 1.371 mmol) was added. The mixture was then heated to reflux for 20 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, and the residue was flash purified to obtain a foamy solid product, IntB2-10 (161 mg, Y: 61.9%).

[0265] LC-MS: m / z = 569.2 [M+1] + .

[0266] Synthesizing IntB2:

[0267] IntB2-10 (161 mg, 0.283 mmol) and dibenzoyl borate (108 mg, 0.424 mmol) were added to a 50 mL single-necked flask and dissolved in Tol (10 mL). Then, potassium acetate (56 mg, 0.567 mmol) and Pd(dppf)Cl2 (23 mg, 0.03 mmol) were added. After three purgings with argon gas, the mixture was heated to 90 °C and reacted for 5 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography to obtain compound IntB2 (150 mg, Y: 86%).

[0268] LC-MS: m / z = 617.4 [M+1] + .

[0269] Preparation Example 5: Synthesis of IntB3:

[0270] Synthesis of IntB3-2:

[0271] IntB3-1 (10 g, 47.15 mmol) and DMF (330 mL) were added to a 1 L three-necked flask. The mixture was cooled to 0–5 °C in an ice bath under argon protection. Then, NIS (12.73 g, 56.58 mmol, added in 5 portions, 10 min apart) was added in batches. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 4 h. After the reaction was completed by LC-MS, the mixture was slowly poured into ice water (700 mL), extracted twice with EA (300 mL * 2), and the combined organic phases were washed with saturated sodium chloride solution (500 mL * 2), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to obtain the product (9.465 g, yield: 59%).

[0272] LC-MS: m / z = 338[M+1] + .

[0273] Synthesis of IntB3-3:

[0274] In a 100 mL single-necked flask, IntB3-2 (6.386 g, 18.89 mmol), (S)-1-(5-ethynyl-6-(1-methoxyethyl)pyridin-3-yl)-4-methylpiperazine (4.9 g, 18.89 mmol), DMF (50 mL), TEA (13.1 mL, 94.42 mmol), CuI (360 mg, 1.89 mmol), and Pd(PPh3)2Cl2 (1.326 g, 1.89 mmol) were added. The mixture was reacted overnight at 100 °C under argon protection, and the reaction was detected by LC / MS. After cooling to room temperature, water (150 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL x 3). The organic phase was evaporated to dryness and purified by column chromatography to give a yellow bubbly solid (4.92 g, yield: 55%).

[0275] LC-MS: m / z = 469.1 [M+1] + .

[0276] Synthesis of IntB3-4:

[0277] In a 50 mL single-necked flask, IntB3-3 (4.92 g, 10.48 mmol), DMF (10 mL), and PdCl2 (372 mg, 2.10 mmol) were added. The mixture was heated to 100 °C overnight under argon protection. The reaction was confirmed by LC-MS. After cooling to room temperature, the mixture was directly purified by flash chromatography followed by column chromatography to obtain a yellow bubbly solid (3.112 g, yield: 64%).

[0278] LC-MS: m / z = 469 [M+1] + .

[0279] Synthesis of IntB3-5:

[0280] 10 mL of DMF was added to a 50 mL three-necked flask. POCl3 (4.2 mL, 16.57 mmol) was slowly added dropwise under ice bath conditions, followed by stirring for 1 hour. A 10 mL solution of IntB3-4 (778 mg, 1.66 mmol) in DMF was then added dropwise. After the addition was complete, the mixture was heated to 45 °C and stirred for 2 hours. LC-MS analysis showed no remaining starting material. The reaction mixture was carefully poured into a 200 mL saturated NaHCO3 solution under ice bath conditions. The pH was adjusted to 7–8, and the mixture was extracted with EA (50 mL x 3). The combined organic phases were washed once with a saturated sodium chloride solution (100 mL), concentrated, and then slurried with acetonitrile (10 mL). The mixture was then filtered to obtain a light brown solid (520 mg, yield: 63%).

[0281] LC-MS: m / z = 497.1 [M+1] + .

[0282] Synthesis of IntB3-6:

[0283] THF (400 mL) and methyl isobutyrate (30 g, 294 mmol) were added to a 1 L three-necked flask. The mixture was cooled to -78 °C under argon protection, and then LDA (147 mL, 2 M in THF, 294 mmol) was added dropwise while maintaining the temperature below -70 °C. After the addition was complete, the mixture was kept at this temperature and stirred for 1 h. Then, a THF (100 mL) solution of the above compound IntB3-5 (23 g, 46.3 mmol) was added dropwise below -70 °C. After the addition was complete, the mixture was slowly raised to room temperature and stirred for 2 h. After the reaction was complete as detected by LC-MS, the mixture was carefully poured into a saturated ammonium chloride solution (1 L), extracted with EA (500 mL * 2), and the combined organic phases were washed with saturated sodium chloride solution (500 mL * 2). The mixture was concentrated, and the residue was purified by column chromatography to give a light brown foamy solid product (21.2 g, yield: 76.4%).

[0284] LC-MS: m / z = 599.2 [M+1] + .

[0285] Synthesis of IntB3-7:

[0286] IntB3-6 (21.2 g, 35.4 mmol), DCM (420 mL), and Et3SiH (32.8 g, 283.2 mmol) were added to a 1 L single-necked flask. The mixture was cooled to 0–5 °C in an ice bath under argon protection, and then TFA (40.3 g, 354 mmol) was added. The mixture was stirred at room temperature for 20 h. After the reaction was completed as detected by LC-MS, the mixture was concentrated, and the residue was added to EA (300 mL) / saturated sodium bicarbonate solution (300 mL, pH adjusted to 7–8). The mixture was stirred and separated. The aqueous phase was extracted again with EA (200 mL * 2), and the combined organic phases were washed with saturated sodium chloride solution (200 mL * 2), concentrated, and the residue was purified by column chromatography to give a light brown foamy solid product (15.3 g, yield: 74.1%).

[0287] LC-MS: m / z = 583.2 [M+1] + .

[0288] Synthesis of IntB3-8:

[0289] IntB3-7 (15.3 g, 26.2 mmol) and THF (310 mL) were added to a 1 L three-necked flask. The mixture was cooled to 0–5 °C in an ice bath under argon protection, followed by the dropwise addition of LiBH4 (40 mL, 2 M in THF, 80 mmol). After the addition was complete, the mixture was brought to room temperature and stirred for 20 h. After the reaction was completed by LC-MS, the mixture was quenched by the dropwise addition of saturated ammonium chloride solution (300 mL) at 0–5 °C, extracted with EA (200 mL * 2), and the combined organic phases were washed with saturated sodium chloride solution (200 mL * 2). The mixture was concentrated, and the residue was purified by column chromatography to give a light brown solid product (9.3 g, yield: 63.9%).

[0290] LC-MS: m / z = 555.2 [M+1] + .

[0291] Synthesis of IntB3:

[0292] In a 1L single-necked flask, the above-mentioned compound IntB3-8 (9.3 g, 16.75 mmol), bis-pinacol boryl ester (4.1 g, 25.2 mmol), toluene (200 mL), and anhydrous potassium acetate (4.92 g, 50.25 mmol) were added. After purging with argon, Pd(dppf)Cl2 (1.23 g, 1.675 mmol) was added. The mixture was heated to 80 °C and stirred for 20 h under argon protection. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, the filter cake was washed with toluene, the filtrate was concentrated, and the residue was purified by column chromatography to give a brown foamy solid product (6.2 g, yield: 61.4%).

[0293] LC-MS: m / z = 603.4 [M+1] + .

[0294] Using different raw materials and referring to similar synthetic methods for IntB1, IntB2, and IntB3, the target compounds IntB4-IntB35 in Table 1 were obtained.

[0295] Table 1

[0296] Preparation Example 4: Synthesis of IntB36:

[0297] Synthesize IntB36-1:

[0298] 5-Fluoro-3-bromo-2-cyanopyridine (50 g, 248.8 mmol), THF (500 mL), TEA (25.1 g, 248.8 mmol), and 1-Cbz-piperazine (60.3 g, 273.6 mmol) were added to a 1 L single-necked flask, and the mixture was heated to 60 °C and stirred for 5 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated to approximately 200 mL, and then water (500 mL) was added. Sodium bicarbonate (25 g) was slowly added while stirring at room temperature. After the addition was complete, the mixture was stirred at room temperature for 1 h, filtered, and the filter cake was washed three times with water, dried under vacuum, and then dried to obtain a white solid product (94 g, yield: 94%).

[0299] LC-MS: m / z = 401.1 [M+1] + .

[0300] Synthesize IntB36-2:

[0301] Add IntB36-1 (72.4 g, 180.5 mmol) and anhydrous THF (1 L) to a 2 L three-necked flask. After argon protection, cool the flask to -5 to 0 °C in an ice-salt bath. Add methyl magnesium bromide (3 M, 150.5 mL, 451.4 mmol) dropwise while maintaining the temperature below 5 °C. After the addition is complete, maintain the mixture at -5 to 5 °C with stirring for 1 h, then allow it to rise naturally to room temperature and continue stirring for 20 h. After LC-MS detection shows the starting material has disappeared, quench the mixture with water (500 mL), add NaOH (10 g), and then add Cb2Cl (21.5 g). Continue stirring the mixture at room temperature for 3 h. After the reaction was detected by LC-MS to be complete, saturated ammonium chloride (500 mL) was added to quench the reaction, and then EA (300 mL * 3) was added to extract three times. The organic phases were combined, washed with saturated sodium chloride, concentrated, and the residue was purified by column chromatography (EA:PE = 4:0 to 4:1 to 2:1 to 1:1) to give the pale yellow compound IntB36-2 (51.4 g, Y: 68%).

[0302] LC-MS: m / z = 418.1 [M+1] + .

[0303] Synthesize IntB36-3:

[0304] Formic acid (28.3 g, 615.0 mmol) was added to a 1 L single-necked flask. After argon protection, the mixture was cooled to 0 °C, and TEA (310.6 g, 3.075 mol) was added dropwise. Then (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (1.174 g, 1.845 mmol) was added, and the mixture was heated to 40 °C and stirred for 15 minutes. The mixture was then cooled to room temperature, and IntB36-2 (51.4 g, 123.0 mmol) was added in portions. The mixture was then heated to 50 °C and reacted overnight. After the reaction was confirmed to be complete by LC-MS, the reaction solution was directly concentrated, and the crude product was purified by column chromatography to obtain compound IntB36-3 (49 g, Y: 94.8%, ee%: 95.0%).

[0305] LC-MS: m / z = 420.1 [M+1] + .

[0306] Synthesizing IntB36-4:

[0307] IntB36-3 (24.6 g, 58.53 mmol) and DMF (250 mL) were added to a 500 mL single-necked flask. After argon protection, the mixture was cooled to 0 °C. NaH (2.81 g, 70.23 mmol, 60%) was then added in portions, and the mixture was stirred at 0 °C for 1 h. Then, a DMF (5 mL) solution of iodomethane (9.97 g, 70.23 mmol) was added dropwise. After the addition was complete, the mixture was kept at 0 °C for another 1 h, then allowed to rise naturally to room temperature and stirred for 5 h. After the reaction was confirmed to be complete by LC-MS, saturated ammonium chloride (200 mL) was added dropwise to quench the reaction mixture. Water (300 mL) was then added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered, the filter cake was washed three times with water, and dried under vacuum to obtain a light brown solid product (24 g, Y: 94%).

[0308] LC-MS: m / z = 434.1 [M+1] + .

[0309] Synthesize IntB36-5:

[0310] IntB36-4 (9 g, 20.72 mmol), neopentyl glycol diboronate (7.02 g, 31.08 mmol), Xphos (198 mg, 0.41 mmol), potassium tert-pentoxide (6.1 g, 43.52 mmol), 2-methyltetrahydrofuran (135 mL), and MeOH (45 mL) were added to a 500 mL single-necked flask. After purging the mixture with argon, Xphos-Pd-G3 (175 mg, 0.21 mmol) was added. The mixture was then heated to 70 °C and stirred for 2 h under argon purging protection. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with Diox. The filtrate was concentrated to dryness, and the crude product was used directly in the next step.

[0311] Synthesize IntB36-6:

[0312] Add the above-mentioned IntB36-5 (crude product, 20.72 mmol), IntC2 (16.1 g, 24.86 mmol), and Dioxane (150 mL) / H2O (30 mL) to a 500 mL single-necked flask, then add potassium carbonate (8.59 g, 62.25 mmol) and Pd(dppf)Cl2 (758 mg, 1.036 mmol). After three argon purging protection cycles, the mixture was heated to 70 °C and reacted overnight. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by column chromatography (EA:PE = 3:0 to 3:1 to 2:1 to 1:1) to obtain impurities (12.9 g, Y: 71.3%).

[0313] LC-MS: m / z = 873.3 [M+1] + .

[0314] Synthesizing IntB36-7:

[0315] Add IntB36-6 (6.2 g, 7.105 mmol) and DMF (120 mL) to a 250 mL single-necked flask. After argon protection, cool to 0 °C, then add cesium carbonate (6.95 g, 21.315 mmol). Stir the mixture in an ice bath for 0.5 h. Then add iodoethane (2.217 g, 14.21 mmol), and allow the mixture to rise naturally to room temperature while stirring for 20 h. After the reaction is complete as detected by LC-MS, quench the mixture with ice water (200 mL), then add saturated saline (200 mL), and extract twice with EA (150 mL * 2). Combine the organic phases, concentrate, and use the crude product directly for the next step.

[0316] Synthesis of IntB36-8-P1:

[0317] Add the above-mentioned crude IntB36-7 (7.105 mmol), THF (80 mL), and TBAF (1 M, 35 mL) to a 250 mL single-necked flask, and react overnight at 50 °C. After the reaction was confirmed to be complete by LC-MS, water was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined, washed with water and saturated sodium chloride, concentrated, and the residue was purified by column chromatography (EA:PE = 3:0 to 3:1 to 2:1 to 1:1 to 1:3) to obtain the target axially chiral compound IntB36-8-P1 (2.0 g, Y: 42.5%, the least polar spot) and its isomer IntB36-8-P2 (1.67 g, Y: 35.5%).

[0318] LC-MS: m / z = 663.3 [M+1] + .

[0319] Synthesize IntB36:

[0320] Add IntB36-8-P1 (2.0 g, 3.018 mmol), boric acid (407 mg, 4.53 mmol), Xphos (30 mg, 0.06 mmol), potassium tert-pentanoxide (889 mg, 6.34 mmol), 2-methyltetrahydrofuran (60 mL), and MeOH (20 mL) to a 50 mL single-necked flask. Then add Xphos-Pd-G3 (25 mg, 0.03 mmol) under argon purging protection. Stir the mixture at 30 °C for 6 h under argon purging protection. After the reaction is complete as determined by LC-MS, filter the reaction mixture, concentrate the filtrate, and use the crude product directly in the next step.

[0321] LC-MS: m / z = 629.3 [M+1] + .

[0322] Preparation Example 5: Synthesis of IntB37:

[0323] Synthesize IntB37-1:

[0324] Add (S)-3-bromo-2-(1-methoxyethyl)pyridine (90 g, 417 mmol) and THF (900 mL) to a 2 L three-necked flask. Under argon purging protection, lower the temperature to -30 to -20 °C. Then, control the temperature below -15 °C and add dropwise isopropyl magnesium chloride and lithium chloride solution (385 mL, 1.3 M in THF, 0.5 mol). After the addition is complete, maintain the temperature and stir the mixture for 2 h. Then, control the temperature below -15 °C and add dropwise 3,3-dimethyldihydro-2H-pyran-2,6(3H)-dione (56.4 g, 0.397 mol). After the addition is complete, maintain the temperature and stir the mixture for 20 h. After the LC-MS analysis showed that the reaction was basically complete, the mixture was quenched by adding water (250 mL), followed by adding glacial acetic acid (50 mL). The mixture was concentrated to approximately one-third of its original volume. Then, EA (500 mL) and water (250 mL) were added to the residue, and the mixture was stirred and separated. The aqueous phase was extracted twice more with EA (250 mL x 2). The combined organic phases were washed twice with saturated sodium chloride and concentrated to dryness. The crude product was used for the next step.

[0325] LC-MS: m / z = 280.1 [M+1] + .

[0326] Synthesize IntB37-2:

[0327] Add the above-mentioned IntB37-1 (crude product, 397 mmol), 4-bromophenylhydrazine hydrochloride (65.2 g, 292 mmol), and water (395 mL) to a 2 L single-necked flask. Add concentrated H2SO4 (116.8 g, 1.168 mol) dropwise to the mixture under ice bath. After the addition is complete, heat the mixture to 100 °C under argon protection and stir for 48 h. After the reaction is complete as detected by LC-MS, cool the mixture and then add 20% NaOH solution dropwise under ice bath to adjust the pH to 5–6. A viscous solid precipitates from the system. Continue to add EA (250 mL) / PE (250 mL), stir and slurry at room temperature for 1 h, filter, and then slurry the filter cake again with EA (100 mL) / PE (250 mL) / water (200 mL) for 0.5 h. Filter, rinse the filter cake with water, dry under vacuum, and obtain an off-white solid (56 g, Y: 44.5%).

[0328] LC-MS: m / z = 431.1 [M+1] + .

[0329] Synthesize IntB37-3:

[0330] IntB37-2 (56 g, 129.9 mmol), EtOH (560 mL), and DMF (1 mL) were added to a 2 L single-necked flask, followed by the dropwise addition of SOCl2 (23.2 g, 194.9 mmol) under ice bath conditions. After the addition was complete, the mixture was heated to 60 °C and stirred for 20 h. After the reaction was complete as detected by LC-MS, the mixture was cooled, and saturated sodium bicarbonate solution was added dropwise under ice bath conditions to adjust the pH to 7–8. A large amount of solid precipitated from the system. After stirring at room temperature for 1 h, the mixture was filtered, the filter cake was washed three times with water, dried under vacuum, and then dried to obtain a white solid (52 g, Y: 87.2%).

[0331] LC-MS: m / z = 459.1 [M+1] + .

[0332] Synthesizing IntB37-4:

[0333] IntB37-3 (25.5 g, 55.56 mmol), NMP (250 mL), and cesium carbonate (88.7 g, 272.1 mmol) were added to a 500 mL single-necked flask, followed by the dropwise addition of 2,2,2-trifluoroethyltrifluoromethanesulfonate (89.4 g, 385.2 mmol) under ice bath conditions. After the addition was complete, the mixture was heated to 50 °C under argon protection and stirred for 40 h. After the reaction was basically completed as detected by LC-MS, the mixture was quenched with water (500 mL), and then extracted twice with EA (250 mL * 2). The combined organic phases were washed with saturated sodium chloride solution, concentrated, and the residue was purified by column chromatography to obtain a yellow foamy solid product (32.5 g, Y: >100%).

[0334] LC-MS: m / z = 541.1 [M+1] + .

[0335] Synthesis of IntB37-5-P1:

[0336] To a 500 mL single-necked flask, add the above-mentioned compound IntB37-4 (32.5 g, overweight, 55.56 mmol) and EtOH (150 mL), followed by anhydrous calcium chloride (6.17 g, 55.56 mmol). After the mixture is stirred until dissolved at room temperature, add NaBH4 (5.25 g, 138.9 mmol) in portions and stir overnight at room temperature. LC-MS analysis showed that the reaction was incomplete, so anhydrous calcium chloride (6.17 g, 55.56 mmol) was added, followed by NaBH4 (2.63 g, 68.7 mmol) in portions, and the reaction was continued at room temperature with stirring for 20 h. After the LC-MS detection was completed, the mixture was quenched with 100 mL of ice water. After concentration to remove most of the EtOH, the residue was added to EA (500 mL), stirred at room temperature for 1 h, and then filtered through diatomaceous earth. The filter cake was washed twice with EA (100 mL). The filtrate was added to water (300 mL), stirred, separated, and the organic phase was washed with saturated sodium chloride solution, concentrated, and purified by column chromatography (EA:PE = 3:0 to 3:1 to 2:1 to 1:1 to 1:3 to DCM:MeOH = 25:1). The elution was first separated into the target configuration compound IntB37-5-P1 (11.9 g, Y: 42.9%) and the isomer IntB37-5-P2 (8.3 g, Y: 29.9%, eluted in DCM:MeOH system).

[0337] The above isomer IntB37-5-P2 (8.3 g, 16.63 mmol) was added to diphenyl ether (83 mL), and the mixture was stirred at 150 °C for 2 h under argon protection. The mixture was then purified by column chromatography to obtain the target configuration compound IntB37-5-P1 (4.2 g, Y: 50.6%).

[0338] LC-MS: m / z = 499.1 [M+1] + .

[0339] Synthesizing IntB37-6:

[0340] IntB37-5-P1 (17 g, 34.05 mmol) and THF (170 mL) were added to a 500 mL single-necked flask and stirred to dissolve. Then, HBPin (6.54 g, 51.07 mmol), B2Pin2 (17.3 g, 68.1 mmol), Me4Phen (643 mg, 2.72 mmol), and [Ir(OMe)(COD)]2 (452 ​​mg, 0.68 mmol) were added. After purging with argon, the reaction was carried out overnight at 50 °C. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated and flash purified to obtain the target compound (15.2 g, Y: 82.3%).

[0341] LC-MS: m / z = 543.1 [M+1]+ .

[0342] Synthesizing IntB37-7:

[0343] N-Cbz piperazine (40.62 g, 184.64 mmol), trimethyl phosphate (9.55 g, 68.2 mmol), and DCM (200 mL) were added to a 500 mL three-necked flask. Copper acetate (16.7 g, 91.96 mmol) was then added under ice bath conditions, followed by stirring with dry air at room temperature for 1 h. IntB37-6 (10.0 g, 18.44 mmol) was then added, and the reaction was stirred with dry air at room temperature for 48 h. After the reaction was basically complete as detected by LC-MS, the system was quenched with water (200 mL), followed by stirring with ammonia (10 mL) for 15 min, and then separated. The aqueous phase was extracted again with DCM (100 mL * 2), and the combined organic phases were washed twice with saturated sodium chloride solution. The pH was adjusted to 4–5 with water (100 mL) and saturated citric acid solution, and the mixture was stirred vigorously at room temperature for 15 min, followed by separation. The organic phase was washed once more with saturated sodium chloride solution and concentrated. The residue was purified by column chromatography (EA:PE = 2:0 to 2:1 to DCM:MeOH = 20:1) to give a white, foamy solid product (10.3 g, Y: 78%).

[0344] LC-MS: m / z = 717.2 [M+1] + .

[0345] Synthesizing IntB37:

[0346] Add IntB37-7 (10 g, 13.96 mmol), boric acid (1.88 g, 20.94 mmol), Xphos (140 mg, 0.28 mmol), potassium tert-pentanoxide (4.15 g, 29.6 mmol), 2-methyltetrahydrofuran (180 mL), and MeOH (60 mL) to a 50 mL single-necked flask. Then add Xphos-Pd-G3 (117 mg, 0.14 mmol) under argon purging protection. The mixture is stirred at 30 °C for 6 h under argon purging protection. After the reaction is complete as determined by LC-MS, the reaction solution is filtered, the filtrate is concentrated, and the crude product is used directly in the next step.

[0347] LC-MS: m / z = 683.3 [M+1] + .

[0348] Using different raw materials and referring to similar synthetic methods in IntB36 and IntB37, the target compounds IntB38-IntB68 in Table 2 were obtained.

[0349] Table 2

[0350] Preparation Example 6: Synthesis of IntC1:

[0351] Synthesis of IntC1-2:

[0352] IntCl-1 (56.4 g, 200 mmol) and DCM (500 mL) were added to a 1 L single-necked flask and stirred until dissolved. Then, 4-dimethylaminopyridine (1.22 g, 10 mmol) and triethylamine (60.7 g, 600 mmol) were added sequentially. Under argon protection, the mixture was cooled to 0 °C, and acetic anhydride (20.4 g, 200 mmol) was added dropwise. After the addition was complete, the mixture was allowed to rise naturally to room temperature and reacted overnight. After LC-MS analysis to confirm the completeness of the reaction, the reaction solution was washed with water and saturated sodium chloride. The organic phase was concentrated and purified by column chromatography to obtain a pale yellow oily compound, IntCl-2.

[0353] LC-MS: m / z = 324[M+1] + .

[0354] Synthesis of IntC1-3:

[0355] IntCl-2 (50 g, 154.2 mmol) and Dioxane (500 mL) were added to a 1 L single-necked flask and stirred until dissolved. Then, bis(dppf)Cl2 (97.9 g, 385.5 mmol), potassium acetate (37.8 g, 385.5 mmol), and Pd(dppf)Cl2 (11.3 g, 15.42 mmol) were added. After three purgings with argon gas, the mixture was heated to 90 °C and reacted for 3 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, diluted with EA, washed with water and saturated sodium chloride, concentrated the organic phase, and purified by column chromatography to obtain a white solid compound, IntCl-3.

[0356] LC-MS: m / z = 372[M+1] + .

[0357] Synthesis of IntC1-4:

[0358] IntCl-3 (40 g, 107.7 mmol), methyl (S)-2-(BOC-amino)-3-(4-bromo-2-thiazolyl)propionate (43.3 g, 118.5 mmol), and Dioxane (400 mL) / H2O (80 mL) were added to a 1 L single-necked flask. After stirring and dissolving, potassium phosphate (57.1 g, 269.3 mmol) and Pd(dppf)Cl2 (7.88 g, 10.77 mmol) were added. After three purgings with argon gas, the mixture was heated to 90 °C and reacted for 16 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, diluted with EA, washed with water and saturated sodium chloride, concentrated the organic phase, and purified by column chromatography to obtain a yellow oily compound, IntCl-4.

[0359] LC-MS: m / z = 530 [M+1] + .

[0360] Synthesis of IntC1-5:

[0361] Add IntC1-4 (30 g, 56.6 mmol) and DMF (300 mL) to a 500 mL single-necked flask, stir to dissolve, then add NIS (12.73 g, 56.6 mmol), and react at 50 °C for 1–2 h. After the reaction is complete as detected by LC-MS, pour the reaction solution into ice water, extract twice with EA, combine the organic phases, wash with water and saturated sodium chloride respectively, concentrate the organic phase, and purify by column chromatography to obtain the yellow solid compound IntC1-5.

[0362] LC-MS: m / z = 656 [M+1] + .

[0363] Synthesizing IntC1:

[0364] IntC1-5 (15 g, 22.88 mmol), potassium acetate (6.73 g, 68.64 mmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (1.88 g, 4.58 mmol), tris(dibenzylacetone)dipalladium (2.1 g, 2.29 mmol), and Tol (500 mL) were added to a 500 mL single-necked flask. Then, pinacol borane (14.6 g, 114.4 mmol) was added. After three purgings with argon gas, the mixture was heated to 50 °C and reacted for 5 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered, concentrated, and purified by column chromatography to obtain a yellow oily compound, IntC1.

[0365] LC-MS: m / z = 656 [M+1] + .

[0366] Preparation Example 7: Synthesis of IntC2:

[0367] Synthesis of IntC2-1:

[0368] 40 g of methyl 4-hydroxy-3,3-dimethylbutyrate (302.66 mmol), 26.8 g of imidazole (393.46 mmol), and 400 mL of DCM were added to a 2 L single-necked flask. A solution of 150 mL of DCM containing 87.35 g of TBDPSCl (317.79 mmol) was added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 3 h. After the reaction was complete, the mixture was filtered by TLC / LC-MS. The filtrate was concentrated, and the residue was purified by column chromatography to obtain a colorless oily product (108 g, Y: 96%).

[0369] Synthesis of IntC2-2:

[0370] The above-mentioned compound IntC2-1 (108 g, 291.45 mmol), EtOH / H2O (400 mL / 400 mL), and KOH (32.7 g, 583 mmol) were added to a 1 L single-necked flask. The mixture was stirred at room temperature for 30 min, then refluxed for 2 h. After the reaction was completed as detected by LC-MS, the mixture was concentrated to about half its original volume, and then EA (500 mL) was added. The pH was adjusted to 3–4 with 2N HCl, stirred, and separated. The aqueous phase was extracted again with EA (500 mL). The combined organic phases were washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a white solid product (101.3 g, Y: 97%).

[0371] Synthesis of IntC2-3:

[0372] The above-mentioned compound IntC2-2 (49 g, 137.53 mmol), DMF (1.06 mL, 13.75 mmol), and DCM (500 mL) were added to a 2 L single-necked flask. The mixture was kept under argon protection and cooled to -10 to -5 °C in an ice-salt bath. Then, a solution of oxalyl chloride (117 mL, 233.64 mmol) in DCM (100 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 h. After the reaction was confirmed to be complete by LC-MS, the mixture was concentrated to dryness to obtain a colorless oily crude product (52.7 g, Y: >100%).

[0373] Synthesis of IntC2-4:

[0374] Add the above compound IntC2-3 (52.7 g, crude product, 137.53 mmol) and DCM (200 mL) to a 1 L three-necked flask, and protect the mixture with argon gas. Cool to -15 to -10 °C in an ice-salt bath, then slowly add SnCl4 (140.5 mL of 1 M in DCM, 140.5 mmol). After the addition is complete, maintain the reaction temperature for 0.5 h. Then, slowly add a DCM (200 mL) solution of 5-bromo-1H-indole (27.55 g, 140.54 mmol) at -15 to -5 °C. After the addition is complete, continue to maintain the reaction temperature for 2 h. After the reaction was detected by LC-MS, the mixture was quenched by adding H2O (500 mL), stirred at room temperature for 30 min, filtered through diatomaceous earth, the filter cake was washed with DCM, the filtrate was separated, the aqueous phase was extracted with DCM again, the combined organic phases were washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was purified by column chromatography to obtain a yellow solid product (52 g, Y: 69%).

[0375] LC-MS: m / z = 534.1 [M+1] + .

[0376] Synthesizing IntC2-5:

[0377] The above-mentioned compound IntC2-4 (52 g, 97.27 mmol) and THF (520 mL) were added to a 1 L three-necked flask under argon protection. The mixture was cooled to -10 to 0 °C in an ice-salt bath, and then LiBH4 (146 mL 2 M in THF, 292 mmol) was slowly added dropwise. After the addition was complete, the mixture was kept at this temperature for 0.5 h. The temperature was then raised to 60 °C and the mixture was stirred for 40 h. After the reaction was basically completed by LC-MS, the mixture was quenched by slowly adding saturated ammonium chloride solution (100 mL) at room temperature. After stirring at room temperature for 1 h, saturated sodium chloride solution (250 mL) was added, and the mixture was stirred. The aqueous phase was separated and extracted with EA (250 mL). The organic phases were combined and concentrated, and the residue was purified by column chromatography to give a white solid product (40.1 g, Y: 74%).

[0378] LC-MS: m / z = 520.1 [M+1] + .

[0379] Synthesizing IntC2:

[0380] The above-mentioned compound IntC2-5 (25.1 g, 48.21 mmol), silver trifluoromethanesulfonate (13.627 g, 53.03 mmol), and THF (250 mL) were added to a 1 L single-necked flask, followed by the addition of elemental iodine (12.237 g, 48.21 mmol) in THF (50 mL). The mixture was stirred at room temperature for 3 h. After the reaction was confirmed to be complete by LC-MS, saturated sodium thiosulfate solution (100 mL) and water (100 mL) were added to the mixture, and the mixture was stirred at room temperature for 1 h. The mixture was then filtered through diatomaceous earth, the filter cake was washed with EA, the filtrate was separated, the aqueous phase was extracted again with EA (100 mL), the combined organic phases were washed with saturated sodium chloride solution, concentrated to dryness, and the residue was purified by column chromatography to give a light brown oily product (31.2 g, Y: 100%).

[0381] LC-MS: m / z = 646.1 [M+1] + .

[0382] Using different raw materials and referring to similar synthesis methods in IntC1 and IntC2, the target compounds IntC3-IntC5 in Table 3 were obtained.

[0383] Table 3

[0384] Preparation Example 8: Synthesis of IntD1:

[0385] IntD1-1 (50 g, 146.2 mmol) and THF (500 mL) were added to a 1 L single-necked flask and stirred until dissolved. Then, cuprous iodide (2.78 g, 14.62 mmol), bis(triphenylphosphine)palladium dichloride (10.26 g, 14.62 mmol), triethylamine (29.6 g, 292.4 mmol), and IntD1-2 (22 g, 175.44 mmol) were added sequentially. After three purgings with argon gas, the reaction was carried out at room temperature for 3–5 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography to obtain a pale yellow oily compound, IntD1. LC-MS: m / z = 339 [M+1] + .

[0386] Using different raw materials and referring to similar synthetic methods in IntD1, the target compounds IntD2-IntD15 in Table 4 were obtained.

[0387] Table 4

[0388] Preparation Example 9: Synthesis of IntE1:

[0389] IntD1-1 (7 g, 20.47 mmol), K2CO3 (29.6 g, 292.4 mmol), Xantphos (1.18 g, 2.04 mmol), phosphorus dimethyl oxide (2.4 g, 30.77 mmol), and Diox (200 mL) were added to a 1 L single-necked flask. After purging with argon, Pd(OAc)2 (462 mg, 2.04 mmol) was added. The mixture was heated to 100 °C under argon protection and reacted for 20 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography to obtain a brown oily compound, IntE1. LC-MS: m / z = 292.0 [M+1] + .

[0390] Using different raw materials and referring to similar synthetic methods in IntE1, the target compounds IntE2-IntE14 in Table 5 were obtained.

[0391] Table 5

[0392] Preparation Example 10: Synthesis of IntF1:

[0393] Synthesis of IntF1-1:

[0394] In a 250 mL single-necked flask, the following compounds were added: IntE1 (2.91 g, 10.0 mmol), trimethylsilylacetylene (4.9 g, 50.0 mmol), DMF (50 mL), TEA (5.05 g, 50.0 mmol), CuI (1.9 g, 10.0 mmol), and Pd(PPh3)2Cl2 (702 mg, 1.0 mmol). The mixture was reacted overnight at 100 °C under argon protection, and the reaction was monitored by LC / MS until completion. The mixture was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with EA. The filtrate was then mixed with water (150 mL) and ethyl acetate (50 mL), separated, and the aqueous phase was extracted again with EA. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was used directly in the next step.

[0395] LC-MS: m / z = 310.1 [M+1] + .

[0396] Synthesis of IntF1-2:

[0397] In a 250 mL single-necked flask, the above-mentioned compound IntF1-1 (crude product, 10.0 mmol), THF (50 mL), and TBAF (15 mL, 1 M in THF, 15.0 mmol) were added. The mixture was stirred at room temperature for 4 h, and the reaction was detected by LC / MS. Water (100 mL) and ethyl acetate (50 mL) were added to the mixture, and the mixture was separated. The aqueous phase was extracted again with EA, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was purified by column chromatography to give a yellow bubbly solid (1.1 g, yield: 46.4%).

[0398] LC-MS: m / z = 238.0 [M+1] + .

[0399] Synthesis of IntF1-3:

[0400] In a 100 mL single-necked flask, IntB3-2 (1.56 g, 4.64 mmol), IntF1-2 (1.1 g, 4.64 mmol), DMF (50 mL), TEA (2.34 g, 23.2 mmol), CuI (445 mg, 2.32 mmol), and Pd(PPh3)2Cl2 (326 mg, 0.464 mmol) were added. The mixture was reacted at 100 °C for 20 h under argon protection, and the reaction was detected by LC / MS. The mixture was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with EA. The filtrate was added with water (100 mL) and ethyl acetate (50 mL), separated, and the aqueous phase was extracted again with EA. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was purified by column chromatography to give a yellow bubbly solid (890 mg, yield: 42.9%).

[0401] LC-MS: m / z = 447.1 [M+1] + .

[0402] Synthesis of IntF1-4:

[0403] In a 50 mL single-necked flask, IntF1-3 (890 mg, 1.99 mmol), DMF (10 mL), and PdCl2 (71 mg, 0.4 mmol) were added. The mixture was heated to 100 °C overnight under argon protection. The reaction was confirmed by LC-MS. After cooling to room temperature, the mixture was directly flash-purified to give a yellow bubbly solid (650 mg, yield: 73%).

[0404] LC-MS: m / z = 447.1 [M+1] + .

[0405] Synthesis of IntF1-5:

[0406] 10 mL of DMF was added to a 50 mL three-necked flask. POCl3 (3.7 mL, 14.54 mmol) was slowly added dropwise under ice bath conditions, followed by stirring for 1 hour. Then, a 5 mL solution of IntF1-4 (650 mg, 1.454 mmol) in DMF was added dropwise. After the addition was complete, the mixture was heated to 45 °C and stirred for 2 hours. LC-MS analysis showed no remaining starting material. The reaction mixture was carefully poured into a saturated NaHCO3 solution (200 mL) under ice bath conditions. The pH was adjusted to 7–8, and the mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (100 mL), concentrated, and the residue was purified by column chromatography to obtain a light brown solid (568 mg, yield: 82%).

[0407] LC-MS: m / z = 476.1 [M+1] + .

[0408] Synthesis of IntF1-6:

[0409] THF (10 mL) and methyl isobutyrate (608 mg, 5.96 mmol) were added to a 100 mL three-necked flask. The mixture was cooled to -78 °C under argon protection, and then LDA (3 mL, 2 M in THF, 6.0 mmol) was added dropwise while maintaining the temperature below -70 °C. After the addition was complete, the mixture was kept at this temperature and stirred for 1 h. Then, a THF (10 mL) solution of the above compound IntF1-5 (568 mg, 1.193 mmol) was added dropwise below -70 °C. After the addition was complete, the mixture was slowly raised to room temperature and stirred for 2 h. After the reaction was complete as detected by LC-MS, the mixture was carefully poured into a saturated ammonium chloride solution (50 mL), extracted with EA (30 mL * 2), and the combined organic phases were washed with saturated sodium chloride solution (50 mL * 2). The mixture was concentrated, and the residue was purified by column chromatography to obtain a light brown foamy solid product (427 mg, yield: 62%).

[0410] LC-MS: m / z = 577.2 [M+1] + .

[0411] Synthesis of IntF1-7:

[0412] IntF1-6 (427 mg, 0.74 mmol), DCM (20 mL), and Et3SiH (860 mg, 7.41 mmol) were added to a 100 mL single-necked flask. The mixture was cooled to 0–5 °C in an ice bath under argon protection, followed by the addition of TFA (42 mg, 0.37 mmol). The mixture was stirred at room temperature for 20 h. After the reaction was complete as detected by LC-MS, the mixture was concentrated. The residue was added to 30 mL of saturated sodium bicarbonate solution to adjust the pH to 7–8, stirred, and separated. The aqueous phase was extracted again with DCM (20 mL * 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL * 2), concentrated, and the residue was purified by column chromatography to give a light brown foamy solid product (302 mg, yield: 72.7%).

[0413] LC-MS: m / z = 561.1 [M+1] + .

[0414] Synthesis of IntF1-8:

[0415] IntF1-7 (302 mg, 0.538 mmol) and THF (10 mL) were added to a 50 mL single-necked flask. The mixture was cooled to 0–5 °C in an ice bath under argon protection, followed by the addition of LiBH4 (1 mL, 2 M in THF, 2.0 mmol). The mixture was then stirred at room temperature for 20 h. After the reaction was completed by LC-MS, the mixture was quenched by adding 20 mL of saturated ammonium chloride solution dropwise at 0–5 °C. The mixture was extracted with EA (20 mL * 2), and the combined organic phases were washed with 20 mL of saturated sodium chloride solution. The mixture was concentrated, and the residue was purified by column chromatography to give a light brown solid product (145 mg, yield: 50.5%).

[0416] LC-MS: m / z = 533.1 [M+1] + .

[0417] Synthesis of IntF1:

[0418] In a 50 mL single-necked flask, the above-mentioned compound IntF1-8 (145 mg, 0.272 mmol), bis-pinacol boryl ester (89 mg, 0.544 mmol), toluene (10 mL), and anhydrous potassium acetate (80 mg, 0.816 mmol) were added. After purging with argon, Pd(dppf)2Cl2 (41 mg, 0.05 mmol) was added. The mixture was heated to 80 °C and stirred for 20 h under argon protection. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, the filter cake was washed with toluene, the filtrate was concentrated, and the residue was purified by column chromatography to give a brown foamy solid product (87 mg, yield: 55.1%).

[0419] LC-MS: m / z = 581.3 [M+1] + .

[0420] Using different raw materials and referring to similar synthesis methods in IntF1, the target compounds IntF2-IntF4 in Table 6 were obtained.

[0421] Table 6

[0422] Example 1 (1S,2S)-N-((6) 4 S,4S,Z)-1 2 -(5-(4-Cyclopropylpiperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptacycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (compound 1) and isomers 1A, 1B, 1C, and 1D

[0423] Synthesis 1-1:

[0424] IntB2 (522 mg, 0.847 mmol), (S)-3-(4-bromothiazol-2-yl)-2-((tert-butyloxycarbonyl)amino)propionate (371 mg, 1.016 mmol), toluene (6 mL), dioxane (2 mL), and H2O (2 mL) were added to a 100 mL single-necked flask. Then, K3PO4 (539 mg, 2.541 mmol) and Pd(dppf)Cl2 (62 mg, 0.085 mmol) were added. After three purgings with argon gas, the mixture was heated to 70 °C and reacted for 12 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was directly concentrated and purified by column chromatography to obtain compound 1-1.

[0425] LC-MS: m / z = 775.4 [M+1] + .

[0426] Synthesis 1-2:

[0427] Add compound 1-1 (304 mg, 0.4 mmol) to a 50 mL single-necked flask, dissolve it in THF (3 mL), MeOH (1 mL), and H₂O (3 mL), then add lithium hydroxide monohydrate (50 mg, 1.2 mmol), and stir the mixture at room temperature for 0.5–1 h. After the reaction is complete as determined by LC-MS, adjust the pH of the reaction solution to 7 with 1 M hydrochloric acid, add a small amount of saturated saline solution, extract three times with EA, combine the organic phases, dry to anhydrous sodium sulfate, filter, and concentrate to obtain compound 1-2.

[0428] LC-MS: m / z = 761.4 [M+1] + .

[0429] Synthesis 1-3:

[0430] Compounds 1-2 (152 mg, 0.204 mmol), IntA1 hydrochloride (39 mg, 0.204 mmol), and DMF (2 mL) were added to a 25 mL single-necked flask. Then, DIPEA (53 mg, 0.408 mmol) and HATU (93 mg, 0.245 mmol) were added, and the mixture was stirred at room temperature for 1 h. After the reaction was confirmed to be complete by LC-MS, saturated brine was added, and the mixture was extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compounds 1-3.

[0431] LC-MS: m / z = 899.5 [M+1] + .

[0432] Synthesis 1-4:

[0433] Add compound 1-3 (101 mg, 0.114 mmol) to a 50 mL single-necked flask, dissolve in THF (3 mL), MeOH (1 mL), and H₂O (3 mL), then add lithium hydroxide monohydrate (15 mg, 0.342 mmol), and stir at room temperature for 0.5–1 h. After the reaction is complete as determined by LC-MS, adjust the pH of the reaction solution to 5–6 with 1 M hydrochloric acid, add a small amount of saturated saline, extract three times with EA, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain compounds 1-4.

[0434] LC-MS: m / z = 885.4 [M+1] + .

[0435] Synthesis 1-5:

[0436] Compounds 1-4 (81 mg, 0.093 mmol) and ACN (5 mL) were added to a 50 mL single-necked flask, followed by N,N,N',N'-tetramethylchloromethamine hexafluorophosphate (783 mg, 2.79 mmol) and N-methylimidazole (229 mg, 2.79 mmol). The mixture was stirred at room temperature for 1 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was directly concentrated and purified by Flash to obtain compounds 1-5.

[0437] LC-MS: m / z = 867.4 [M+1] + .

[0438] Synthesis 1-6:

[0439] Compounds 1-5 (60 mg, 0.071 mmol) and DCM (2 mL) were added to a 25 mL single-necked flask, followed by TFA (162 mg, 1.42 mmol). The mixture was stirred at room temperature for 2-3 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was directly concentrated to obtain compounds 1-6.

[0440] LC-MS: m / z = 767.4 [M+1] + .

[0441] Synthesized compound 1:

[0442] Add 1-6 (50 mg, 0.067 mmol), (1S,2S)-2-methylcyclopropyl-1-carboxylic acid (13 mg, 0.134 mmol), and DMF (2 mL) to a 25 mL single-necked flask, then add DIPEA (17 mg, 0.134 mmol) and HATU (31 mg, 0.08 mmol), and stir at room temperature for 1-2 h. After the reaction is complete as detected by LC-MS, add saturated brine to the reaction solution, extract three times with EA, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate to obtain crude product, and purify by Pre-TLC to obtain compound 1. This compound is then resolved by SFC to obtain compounds 1A, 1B, 1C, and 1D, respectively.

[0443] LC-MS: m / z = 849.4 [M+1] + .

[0444] Using different raw materials and following a similar synthesis method as in Example 1, target compounds 2-32 were obtained as shown in Table 7.

[0445] Table 7

[0446] Example 2 (1S,2S)-N-((4S,Z)-12 -(5-(dimethylphosphoryl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-11-ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of -diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptacycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (compound 69)

[0447] Synthesis 69-1:

[0448] IntCl (2.0 g, 3.05 mmol), IntE1 (890 mg, 3.05 mmol), and Dioxane (200 mL) / H2O (20 mL) were added to a 500 mL single-necked flask. Then, potassium phosphate (1.62 g, 7.64 mmol) and Pd(dppf)Cl2 (224 mg, 0.305 mmol) were added. After three purgings with argon gas, the mixture was heated to 80 °C and reacted for 16 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered through diatomaceous earth, concentrated, and purified by column chromatography to obtain compound 69-1 (1.62 g, yield: 71.7%).

[0449] LC-MS: m / z = 741.3 [M+1] + .

[0450] Synthesis 69-2:

[0451] Add 69-1 (1.2 g, 1.62 mmol) and DMF (40 mL) to a 250 mL single-necked flask, stir to dissolve, then add cesium carbonate (1.06 g, 3.24 mmol) and iodoethane (379 mg, 2.43 mmol) sequentially, and stir the reaction overnight at room temperature. After the reaction was confirmed to be complete by LC-MS, add ice water to the reaction solution, extract twice with EA, combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, and concentrate to obtain crude compound 69-2.

[0452] LC-MS: m / z = 769.3 [M+1] + .

[0453] Synthesis 69-3:

[0454] Compound 69-2 (crude product, 1.62 mmol) and THF (10 mL) / MeOH (10 mL) / H2O (2 mL) were added to a 100 mL single-necked flask, followed by the addition of lithium hydroxide monohydrate (340 mg, 8.1 mmol). The mixture was stirred at room temperature for 2–3 h. After the reaction was confirmed to be complete by LC-MS, the pH of the reaction solution was adjusted to 5–6 with 2 M hydrochloric acid, concentrated, and the residue was flash purified to obtain compound 69-3 (595 mg, yield: 51.6%).

[0455] LC-MS: m / z = 713.3 [M+1] + .

[0456] Synthesis 69-4:

[0457] Add 69-3 (200 mg, 0.28 mmol), IntA1 (48 mg, 0.31 mmol), and DCM (10 mL) to a 50 mL single-necked flask. After stirring to dissolve, add HOBt (57 mg, 0.42 mmol), EDCI (80 mg, 0.42 mmol), and DIPEA (108 mg, 0.84 mmol) sequentially. Stir the mixture overnight at room temperature. After the reaction is complete as determined by LC-MS, add water to the system, extract twice with DCM, combine the organic phases, wash with saturated brine, concentrate the organic phase, and purify by column chromatography to obtain compound 69-4 (134 mg, yield: 56.3%).

[0458] LC-MS: m / z = 851.4 [M+1] + .

[0459] Synthesis 69-5:

[0460] Add 69-4 (134 mg, 0.158 mmol) and THF (5 mL) / MeOH (5 mL) / H2O (5 mL) to a 50 mL single-necked flask, then add lithium hydroxide monohydrate (66 mg, 1.58 mmol), and stir at room temperature for 3-5 h. After the reaction is complete as determined by LC-MS, adjust the pH of the reaction solution to 5-6 with 2 M hydrochloric acid, extract twice with EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain crude compound 69-5.

[0461] LC-MS: m / z = 837.4 [M+1] + .

[0462] Synthesis 69-6:

[0463] Add the above-mentioned 69-5 (crude product, 0.158 mmol) and DCM (10 mL) to a 50 mL single-necked flask, stir to dissolve, then add HOBt (135 mg, 1.0 mmol), EDCI (192 mg, 1.0 mmol), DMAP (122 mg, 1.0 mmol), and DIPEA (387 mg, 3.0 mmol) sequentially, and stir the reaction overnight at room temperature. After the reaction was confirmed to be complete by LC-MS, water was added to the system, and the mixture was extracted twice with DCM. The organic phases were combined, washed with saturated brine, concentrated, and the residue was flash purified to give compound 69-6 (76 mg, yield: 58.8%).

[0464] LC-MS: m / z = 819.3 [M+1] + .

[0465] Synthesize 69-7:

[0466] Add 69-6 (76 mg, 0.093 mmol) and DCM (5 mL) to a 25 mL single-necked flask, stir to dissolve, then add TFA (527 mg, 4.62 mmol), and stir at room temperature for 3 h. After the reaction is complete as determined by LC-MS, concentrate the reaction solution, adjust the pH to 8-9 with saturated sodium bicarbonate solution under ice bath conditions, extract three times with DCM, combine the organic phases, wash with saturated brine, dry to anhydrous sodium sulfate, filter, and concentrate to obtain compound 69-7.

[0467] LC-MS: m / z = 719.3 [M+1] + .

[0468] Synthesis 69:

[0469] Add 69-7 (30 mg, 0.042 mmol), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (5 mg, 0.05 mmol), and DMF (2 mL) to a 10 mL single-necked flask. After argon protection, cool to 0 °C, then add DIPEA (26 mg, 0.2 mmol) and (2-oxime-cyanoethyl acetate)-N,N-dimethylmorpholinourea hexafluorophosphonate (56 mg, 0.13 mmol). React at 0 °C for 1–2 h. After the reaction is complete as determined by LC-MS, add saturated brine to the reaction mixture, extract three times with EA, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate to obtain the crude product, and Flash purification to obtain compound 69 (9 mg, yield: 26.8%).

[0470] LC-MS: m / z = 801.3 [M+1] + .

[0471] Using different raw materials and similar synthesis methods as in Example 1 or Example 2, target compounds 70-92 and 372-381 in Table 8 were obtained.

[0472] Table 8

[0473] Example 3 (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-(oxecyclobutan-3-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide or (1r,2R,3S)-N-((6 4 R,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-(oxecyclobutan-3-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of 168A or 168B of 2-diaza-2(4,2)-thiazo-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (compound 168A or compound 168B)

[0474] Synthesis of 168-1:

[0475] Add (S)-3-bromo-2-(1-methoxyethyl)pyridine (25 g, 115.7 mmol), 4A molecular sieve (25 g), and Diox (600 mL) to a 1 L single-necked flask, and stir until the starting materials are dissolved. Then add neopentyl glycol diboronate (65.3 g, 289.2 mmol), potassium acetate (28.4 g, 289.2 mmol), and Pd(dppf)Cl2 (8.5 g, 11.57 mmol). After purging with argon three times, react at 90 °C overnight. After the reaction is confirmed to be complete by LC-MS, cool to room temperature, filter the reaction solution through diatomaceous earth, wash the filter cake with DCM, and concentrate the filtrate to obtain crude compound 168-1 (94 g), which can be used directly in the next step.

[0476] LC-MS: m / z = 182.2 [M-68+1] + .

[0477] Synthesis of 168-2:

[0478] Add 168-1 (crude product 94g, 115.7mmol) and IntC2 (83.2g, 128.7mmol) to a 2L single-necked flask, dissolve in Dioxane (1L) / H2O (200mL), then add potassium carbonate (48g, 347.1mmol) and Pd(dppf)Cl2 (8.5g, 11.57mmol), purge three times with argon gas, and react at 85℃ for 48h. After the reaction is complete as detected by LC-MS, filter the reaction solution through diatomaceous earth, wash the filter cake with EA, and concentrate the filtrate; add water (500mL) to the crude product, extract with EA (500mL*2), combine the organic phases, wash with saturated sodium chloride, concentrate the organic phase, and purify by column chromatography to obtain compound 168-2 (49.5g, Y: 65%).

[0479] LC-MS: m / z = 655.3 [M+1] + .

[0480] Synthesis of 168-3:

[0481] Add 168-2 (40 g, 61 mmol) and DMF (600 mL) to a 1 L single-necked flask. After argon protection, cool to 0 °C, add Cs₂CO₃ (59.6 g, 183 mmol), stir at 0 °C for 0.5 h, then add iodoethane (28.5 g, 183 mmol) dropwise. Allow the mixture to warm naturally overnight in an ice bath. After the reaction is complete as determined by LC-MS, add ice water (1 L) to the reaction mixture, extract with EA (500 mL * 2), combine the organic phases, wash with saturated sodium chloride, concentrate the organic phase, and purify by column chromatography to obtain compound 168-3 (36.2 g, Y: 87%).

[0482] LC-MS: m / z = 683.3 [M+1] + .

[0483] Synthesis of 168-4-P1:

[0484] Add 168-3 (36.2 g, 52.94 mmol), THF (250 mL), and TBAF (1 M in THF, 265 mL) to a 1 L single-necked flask, and react overnight at 50 °C. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, and the residue was added to water (300 mL), extracted with EA (300 mL * 2), the organic phases were combined, washed twice with water and then with saturated sodium chloride, concentrated, and purified by column chromatography to obtain compound 168-4 (22.9 g, the product is a pair of isomers, which can be separated by TLC).

[0485] Further column chromatography purification of the above 168-4 (EA:PE = 4:0 to 4:1 to 3:1 to 2:1 to DCM:MeOH = 20:1) can separate the target axial chiral compound 168-4-P1 (13.5 g) and the isomer 168-4-P2 (9.1 g).

[0486] Isomer P2 (9.1 g) was added to diphenyl ether (91 mL), and the mixture was stirred at 150 °C for 2 h under argon protection. The mixture was then purified by column chromatography to obtain the target axially chiral compound 168-4-P1 (5.2 g).

[0487] LC-MS: m / z = 445.4 [M+1] + .

[0488] Synthesis of 168-5:

[0489] 168-4-P1 (19.9 g, 44.68 mmol) and n-heptane / THF (180 mL / 90 mL) were added to a 500 mL single-necked flask and stirred to dissolve. Then, HBPin (11.4 g, 89.36 mmol), B2Pin2 (34 g, 134.04 mmol), Me4Phen (2.1 g, 8.94 mmol), and [Ir(OMe)(COD)]2 (1.19 g, 1.79 mmol) were added. After purging with argon, the reaction was carried out overnight at 50 °C. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated and flash purified to obtain compound 168-5 (19 g, Y: 61%).

[0490] LC-MS: m / z = 489.2 [M+1] + .

[0491] Synthesis of 168-6:

[0492] 1-(3-oxacyclobutyl)piperazine (2.04 g, 14.3 mmol), 4A molecular sieve (2 g), Py (566 mg, 7.15 mmol), TEA (724 mg, 7.15 mmol), and ultradry DCM (50 mL) were added to a 100 mL three-necked flask. The mixture was stirred at room temperature with air purging, and then 168-5 (1 g, 1.43 mmol) was added. The mixture was allowed to react overnight at room temperature with the flask open. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated and purified by column chromatography to obtain compound 168-6 (590 mg, Y: 70%).

[0493] LC-MS: m / z = 585.4 [M+1] + .

[0494] Synthesis of 168-7:

[0495] Add 168-6 (590 mg, 1 mmol), B2(OH)4 (135 mg, 1.5 mmol), KOPiv (294 mg, 2.1 mmol), Xphos (10 mg, 0.02 mmol), Xphos-Pd-G3 (8.5 mg, 0.01 mmol), and 2-MeTHF / MeOH (9 mL / 3 mL) to a 50 mL single-necked flask. After purging with argon, react at 30 °C. After the reaction is confirmed to be complete by LC-MS, filter and concentrate the reaction solution to obtain crude product 168-7, which can be used directly in the next step.

[0496] LC-MS: m / z = 551.5 [M+1] + .

[0497] Synthesis of 168-8:

[0498] Crude product 168-7 (1 mmol), methyl (S)-2-(Boc-amino)-3-(4-bromo-2-thiazolyl)propionate (384 mg, 1.05 mmol), K₂CO₃ (276 mg, 2 mmol), Pd(dtbpf)Cl₂ (33 mg, 0.05 mmol), and Diox / H₂O (10 mL / 3 mL) were added to a 50 mL single-necked flask. After purging with argon, the reaction was carried out at 75 °C. After the reaction was confirmed to be complete by LC-MS, the reaction solution 168-8 was used directly for the next step.

[0499] LC-MS: m / z = 791.4 [M+1] + .

[0500] Synthesis of 168-9:

[0501] LiOH·H2O (210 mg, 5 mmol) was added to reaction solution 168-8, and the reaction was carried out at room temperature. After the reaction was confirmed to be complete by LC-MS, compound 168-9 (736 mg, Y: 94%) was obtained by flash purification.

[0502] LC-MS: m / z = 777.4 [M+1] + .

[0503] Synthesis of 168-10:

[0504] 168-9 (443 mg, 0.57 mmol), IntA2 (217 mg, 0.627 mmol), and ACN / DCM (10 mL / 2 mL) were added to a 50 mL single-necked flask. After argon protection, the mixture was cooled to 0-5 °C, and NMI (234 mg, 2.85 mmol) and TCFH (240 mg, 0.855 mmol) were added sequentially. The mixture was reacted in an ice bath for 1 h. After the reaction was confirmed to be complete by LC-MS, water was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated, and flash purified to obtain compound 168-10 (454 mg, Y: 80%).

[0505] LC-MS: m / z = 991.5 [M+1] + .

[0506] Synthesis of 168-11:

[0507] 168-10 (454 mg, 0.458 mmol) and MeOH (20 mL) were added to a 100 mL single-necked flask, followed by the addition of 20% Pd(OH)2 / C (400 mg). After purging with hydrogen, the mixture was reacted at room temperature for 3 h. After the reaction was confirmed to be complete by LC-MS, the mixture was filtered and concentrated to obtain compound 168-11 (394 mg, Y: 95%).

[0508] LC-MS: m / z = 901.5 [M+1] + .

[0509] Synthesis of 168-12:

[0510] Add DIPEA (170 mg, 1.312 mmol), DMAP (27 mg, 0.219 mmol), HOBt (118 mg, 0.874 mmol), EDCI (252 mg, 1.312 mmol), and DCM (16 mL) to a 100 mL single-necked flask. Stir at room temperature, then add dropwise a 4 mL solution of DCM containing 168-11 (394 mg, 0.437 mmol). Let the mixture react overnight at room temperature. After the reaction was confirmed to be complete by LC-MS, concentrate the reaction solution and flash LC-MS to obtain compound 168-12 (181 mg, Y: 46%).

[0511] LC-MS: m / z = 883.5 [M+1] + .

[0512] Synthesis of 168-13:

[0513] Add 168-12 (181 mg, 0.205 mmol) and DCM (2 mL) to a 50 mL single-necked flask, stir at room temperature, then add TFA (2.5 mL) and react at room temperature for 1 h. After the reaction is complete as determined by LC-MS, concentrate the reaction solution, add DCM, adjust the pH to 7-8 with saturated sodium bicarbonate solution, extract three times with DCM, combine the organic phases, dry to anhydrous sodium sulfate, filter, and concentrate to obtain compound 168-13 (159 mg, Y: 98%).

[0514] LC-MS: m / z = 783.4 [M+1] + .

[0515] Synthesis of 168A and 168B:

[0516] Add 168-13 (159 mg, 0.203 mmol) and DCM (5 mL) to a 50 mL single-necked flask. After argon protection, cool to 0-5 °C, then add NMM (41 mg, 0.406 mmol), (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (28 mg, 0.244 mmol), HOBt (6 mg, 0.041 mmol), and EDCI (70 mg, 0.365 mmol) sequentially. Allow the mixture to react overnight in an ice bath. After the reaction was confirmed to be complete by LC-MS, concentrate the reaction solution, first Flash purify, then Pre-TLC (DCM:MeOH = 20:1 development) to obtain compounds 168A (100 mg, Y: 57%) and 168B (9 mg).

[0517] LC-MS: m / z = 865.4 [M+1] + .

[0518] Example 4 (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(5-(4-(L-prolyl)piperazin-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of 169-diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (compound 169)

[0519] Synthesis of 169-1:

[0520] Benzyl-1-piperazine carbonate (29.86 g, 135.55 mmol), 4A molecular sieve (50 g), Py (5.36 g, 67.78 mmol), TEA (6.85 g, 67.78 mmol), and ultra-dry DCM (300 mL) were added to a 500 mL three-necked flask. The mixture was stirred at room temperature with aeration, and then 168-5 (9.45 g, 13.55 mmol) was added. The mixture was allowed to react overnight at room temperature with aeration. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated and purified by column chromatography to obtain compound 169-1 (5.8 g, Y: 64%).

[0521] LC-MS: m / z = 663.3 [M+1] + .

[0522] Synthesis of 169-2:

[0523] Add 169-1 (5.8 g, 8.74 mmol), B2(OH)4 (1.18 g, 13.11 mmol), KOPiv (2.57 g, 18.35 mmol), Xphos (83 mg, 0.175 mmol), Xphos-Pd-G3 (74 mg, 0.087 mmol), and 2-MeTHF / MeOH (90 mL / 30 mL) to a 250 mL single-necked flask. After purging with argon, the reaction mixture was reacted at 30 °C. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered and concentrated to obtain crude product 169-2 (8.6 g), which was used directly in the next step.

[0524] LC-MS: m / z = 629.4 [M+1] + .

[0525] Synthesis of 169-3:

[0526] Crude product 169-2 (8.74 mmol), methyl (S)-2-(Boc-amino)-3-(4-bromo-2-thiazolyl)propionate (3.35 g, 9.18 mmol), K₂CO₃ (2.42 g, 17.48 mmol), Pd(dtbpf)Cl₂ (285 mg, 0.437 mmol), and Diox / H₂O (100 mL / 30 mL) were added to a 250 mL single-necked flask. After purging with argon, the reaction was carried out at 75 °C. After the reaction was confirmed to be complete by LC-MS, the reaction solution 169-3 was used directly for the next step.

[0527] LC-MS: m / z = 869.4 [M+1] + .

[0528] Synthesis of 169-4:

[0529] LiOH·H2O (1.84 g, 43.7 mmol) was added to reaction solution 169-3 and the reaction was carried out at room temperature. After the reaction was confirmed to be complete by LC-MS, the pH was adjusted to 6-7 with saturated citric acid solution, and then concentrated to half of the solvent. After flash purification and lyophilization, compound 169-4 (6.28 g, Y: 84%) was obtained.

[0530] LC-MS: m / z = 855.4 [M+1] + .

[0531] Synthesis of 169-5:

[0532] 169-4 (9.02 g, 10.55 mmol), IntA2 (4.02 g, 11.60 mmol), and ACN / DCM (250 mL / 50 mL) were added to a 500 mL single-necked flask. After argon protection, the mixture was cooled to 0–5 °C, and NMI (4.33 g, 52.75 mmol) and TCFH (4.44 g, 15.83 mmol) were added sequentially. The mixture was reacted in an ice bath for 1 h. After the reaction was confirmed to be complete by LC-MS, water was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated, and purified by column chromatography to obtain compound 169-5 (10.15 g, Y: 90%).

[0533] LC-MS: m / z = 1069.5 [M+1] + .

[0534] Synthesis of 169-6:

[0535] 169-5 (10.15 g, 9.49 mmol) and THF / H2O (100 mL / 20 mL) were added to a 250 mL single-necked flask and cooled to 0-5 °C. Then, LiOH·H2O (599 mg, 14.24 mmol) was added, and the mixture was reacted at room temperature for 1 h. After the reaction was confirmed to be complete by LC-MS, the pH was adjusted to 6-7 with saturated citric acid solution, THF was removed by concentration, and the mixture was flash purified to obtain compound 169-6 (8.86 g, Y: 95%).

[0536] LC-MS: m / z = 979.4 [M+1] + .

[0537] Synthesis of 169-7:

[0538] DIPEA (2.24 g, 17.36 mmol), DMAP (530 mg, 4.34 mmol), HOBt (2.35 g, 17.36 mmol), EDCI (5 g, 26.04 mmol), and DCM (350 mL) were added to a 500 mL single-necked flask and stirred at room temperature. Then, 100 mL of DCM solution (8.5 g, 8.68 mmol) of 169-6 was slowly added dropwise to the system. After the addition was complete, the reaction was allowed to proceed overnight at room temperature. After the reaction was confirmed to be complete by LC-MS, water (200 mL) was added to the reaction solution, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated, and purified by column chromatography to obtain the compound (7.21 g, containing isomers, which were resolved to give 4.21 g).

[0539] Isomers were separated by prep-HPLC. The method and results are as follows:

[0540] Instrument: Agilent, Prep-LC: 1290InfinityII;

[0541] Column: Welch Xtimate C18:30*150mm,5um

[0542] Wave length: 254nm / 214nm

[0543] phase A: H2O (0.1% FA); phase B: ACN

[0544] Gradient:

[0545] Table 9

[0546] RT: 169-7 (target product): 12.6 min, 169-7 iso: 11.7 min (mixture of isomers)

[0547] LC-MS: m / z = 961.5 [M+1] + .

[0548] Synthesis of 169-8:

[0549] 169-7 (4.21 g, 4.37 mmol) and DCM (53 mL) were added to a 250 mL single-necked flask and stirred at room temperature. Then, TFA (53 mL) was added to the system and the reaction was allowed to proceed at room temperature for 1 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, DCM was added, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted four times with DCM, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 169-8 (3.79 g, Y: 100%).

[0550] LC-MS: m / z = 861.4 [M+1] + .

[0551] Synthesis of 169-9:

[0552] 169-8 (2.79 g, 3.24 mmol) and DCM (50 mL) were added to a 100 mL single-necked flask. After argon protection, the mixture was cooled to 0-5 °C, and then NMM (983 mg, 9.72 mmol), (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (444 mg, 3.89 mmol), HOBt (88 mg, 0.648 mmol), and EDCI (1.12 g, 5.83 mmol) were added sequentially. The mixture was allowed to react overnight in an ice bath. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated and flash purified to obtain compound 169-9 (2.8 g, Y: 90%).

[0553] LC-MS: m / z = 957.5 [M+1] + .

[0554] Synthesis of 169-10:

[0555] 169-9 (2.8 g, 2.925 mmol) and MeOH (150 mL) were added to a 250 mL single-necked flask, followed by the addition of 20% Pd(OH)2 / C (2.8 g). After hydrogen purging, the reaction was allowed to proceed at room temperature for 3 h. After LC-MS analysis to confirm the completeness of the reaction, the reaction solution was filtered to obtain compound 169-10 (2.4 g, Y: 100%).

[0556] LC-MS: m / z = 823.4 [M+1] + .

[0557] Synthesis of 169-11:

[0558] 169-10 (50 mg, 0.061 mmol) and DCM (2 mL) were added to a 25 mL single-necked flask. After argon protection, NMM (19 mg, 0.183 mmol), Boc-L-proline (16 mg, 0.073 mmol), HOBt (2 mg, 0.012 mmol), and EDCI (21 mg, 0.11 mmol) were added sequentially, and the reaction was carried out at room temperature. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, purified first by Flash, and then purified by Pre-TLC to obtain compound 169-11 (35 mg, Y: 56%).

[0559] LC-MS: m / z = 1020.5 [M+1] + .

[0560] Synthesis of 169:

[0561] Add 169-11 (32 mg, 0.031 mmol) and DCM (2 mL) to a 25 mL single-necked flask, stir at room temperature, then add TFA (1 mL) to the system and react at room temperature for 1-2 h. After the reaction is complete as detected by LC-MS, concentrate the reaction solution, add ACN, adjust the pH to alkaline with TEA, concentrate, and then lyophilize by flash to obtain a white solid compound 169- (25 mg, Y: 86%).

[0562] LC-MS: m / z = 920.5 [M+1].

[0563] Example 5 N-((6) 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-(oxecyclobutan-3-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of 184-diaza-2(4,2)-thiazo-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-1-carboxamide (compound 184)

[0564] Synthesis of 184:

[0565] 168-13 (20 mg, 0.025 mmol) and DCM (2 mL) were added to a 25 mL single-necked flask. After argon protection, the mixture was cooled to 0-5 °C, and NMM (8 mg, 0.076 mmol), bicyclo[2.2.1]heptane-1-carboxylic acid (4 mg, 0.031 mmol), HOBt (0.7 mg, 0.005 mmol), and EDCI (9 mg, 0.045 mmol) were added sequentially. The mixture was allowed to react overnight in an ice bath. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, purified by Flash chromatography, and then purified by Pre-TLC (DCM:MeOH = 20:1 development). The solution was then lyophilized to obtain compound 184 (18 mg, Y: 82%).

[0566] LC-MS: m / z = 905.4 [M+1] + .

[0567] Example 6 N-((6) 4 S,4S,Z)-11-ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-(oxecyclobutan-3-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of 190-diaza-2(4,2)-thiazo-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-4-yl)bicyclo[4.1.0]heptane-7-carboxamide (compound 190)

[0568] Synthesis of 190-1:

[0569] 169-8 (379 mg, 0.44 mmol) and DCM (10 mL) were added to a 100 mL single-necked flask. After argon protection, the mixture was cooled to 0-5 °C, and NMM (134 mg, 1.32 mmol), bicyclo[4.1.0]heptane-7-carboxylic acid (74 mg, 0.528 mmol), HOBt (12 mg, 0.088 mmol), and EDCI (152 mg, 0.792 mmol) were added sequentially. The mixture was allowed to react overnight under ice bath conditions. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, and the residue was flash purified to give compound 190-1 (411 mg, Y: 95%).

[0570] LC-MS: m / z = 983.5 [M+1] + .

[0571] Synthesis of 190-2:

[0572] 190-1 (411 mg, 0.418 mmol) and MeOH (20 mL) were added to a 50 mL single-necked flask, followed by the addition of 20% Pd(OH)2 / C (400 mg). After purging with hydrogen, the mixture was reacted at room temperature for 3 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated to dryness to obtain a grayish-white solid compound 190-2 (360 mg, Y: 100%).

[0573] LC-MS: m / z = 849.4 [M+1] + .

[0574] Synthesis of 190:

[0575] Add 190-2 (32 mg, 0.038 mmol), oxadiazon (13.6 mg, 0.188 mmol), MeOH (3 mL), and AcOH (20 mg) to a 25 mL single-necked flask. Stir the mixture at room temperature for 1 h, then add NaBH3CN (7 mg, 0.113 mmol). Stir the mixture at room temperature for 48 h. After the reaction is complete as determined by LC-MS, concentrate the mixture, purify the residue using Flash chromatography, and lyophilize to obtain a white solid product (18 mg, Y: 52.7%).

[0576] LC-MS: m / z = 905.5 [M+1].

[0577] Example 7 N-((4S,Z)-11-ethyl-1 2 -(2-((S)-1-(methoxy-d3)ethyl)-5-(4-(oxecyclobutan-3-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of 2-diaza-2(4,2)-thiazo-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-4-yl)cycloheptaneformamide (compound 231)

[0578] Synthesis of 231-1:

[0579] Add IntB38 (5.75 g, 5.76 mmol), methyl (S)-2-(Boc-amino)-3-(4-bromo-2-thiazolyl)propionate (2.21 g, 6.048 mmol), K2CO3 (1.59 g, 11.52 mmol), Pd(dtbpf)Cl2 (188 mg, 0.288 mmol), and Diox / H2O (60 mL / 20 mL) to a 50 mL single-necked flask. After purging with argon gas, the mixture was heated to 75 °C and reacted for 20 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was used directly for the next step.

[0580] LC-MS: m / z = 872.4 [M+1] + .

[0581] Synthesis of 231-2:

[0582] LiOH·H2O (1.21 g, 28.8 mmol) was added to the above reaction solution 232-1, and the mixture was stirred at room temperature for 2 h. After the reaction was confirmed to be complete by LC-MS, the pH of the mixture was adjusted to 6-7 with citric acid solution, and then concentrated to a small amount. The residue was flash purified and lyophilized to obtain a yellow solid product (4.39 g, Y: 88%).

[0583] LC-MS: m / z = 858.4 [M+1] + .

[0584] Synthesis of 231-3:

[0585] Add 231-2 (4.39 g, 5.116 mmol), IntA2 (1.949 g, 5.628 mmol), and ACN / DCM (75 mL / 15 mL) to a 500 mL single-necked flask. After argon protection, cool to 0-5 °C, then add NMI (2.1 g, 25.58 mmol) and TCFH (2.15 g, 7.674 mmol) sequentially. React in an ice bath for 1 h. After the reaction is confirmed to be complete by LC-MS, add water to the reaction solution, extract three times with DCM, combine the organic phases, concentrate, and obtain a crude yellow-brown compound (4.45 g, Y: 81%). This crude product is used directly in the next step.

[0586] LC-MS: m / z = 1072.5 [M+1] + .

[0587] Synthesis of 231-4:

[0588] Compound 231-3 (4.45 g, 4.15 mmol), LiOH·H2O (349 mg, 8.3 mmol), THF (75 mL), and water (15 mL) were added to a 250 mL single-necked flask and reacted at room temperature for 1 h. After the reaction was confirmed to be complete by LC-MS, the pH was adjusted to 6–7 with citric acid solution, and then the THF was removed by concentration. The residue was purified by flash filtration and lyophilized to obtain the compound (3.975 g, Y: 97%).

[0589] LC-MS: m / z = 982.5 [M+1] + .

[0590] Synthesis of 231-5:

[0591] DIPEA (1.05 g, 8.09 mmol), DMAP (247 mg, 2.02 mmol), HOBt (1.09 g, 8.09 mmol), EDCI (2.33 g, 12.14 mmol), and DCM (160 mL) were added to a 500 mL single-necked flask. The mixture was stirred for 10 min under argon protection, followed by slow dropwise addition of 40 mL of DCM solution (3.975 g, 4.05 mmol) of 231-4. After the addition was complete, the mixture was stirred at room temperature for 20 h. After the reaction was complete as detected by LC-MS, the mixture was concentrated, and the residue was Flash purified. The target fraction was adjusted to alkali with saturated sodium bicarbonate, extracted with EA, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the target product (2.65 g, Y: 67.8%, HPLC showed ~20% isomers).

[0592] LC-MS: m / z = 964.5 [M+1] + .

[0593] Synthesis of 231-6:

[0594] Add 231-5 (1.53 g, 1.587 mmol) and MeOH (50 mL) to a 100 mL single-necked flask, then add 20% Pd(OH)2 / C (1.53 g). After purging with hydrogen, react at room temperature for 3 h. After the reaction is complete as detected by LC-MS, filter, concentrate the filtrate, pass the residue through a flash filter, adjust the target fraction with sodium bicarbonate aqueous solution, extract with DCM, dry the organic phase, concentrate to dryness, and give an off-white solid product (1.225 g, Y: 93%).

[0595] LC-MS: m / z = 830.4 [M+1] + .

[0596] Synthesis of 231-7:

[0597] Add 231-6 (500 mg, 0.602 mmol), oxetanone (217 mg, 3.012 mmol), MeOH (10 mL), and AcOH (30 mg) to a 100 mL single-necked flask. Stir the mixture at room temperature for 1 h, then add NaBH3CN (114 mg, 1.806 mmol). Stir the mixture at room temperature for 20 h. After the reaction is complete as detected by LC-MS, concentrate the mixture, purify the residue using Flash chromatography, and lyophilize to obtain a white solid product (490 mg, Y: 92%).

[0598] LC-MS: m / z = 886.5 [M+1] + .

[0599] Synthesis of 231-8:

[0600] Add 231-7 (490 mg, 0.553 mmol) and DCM (7 mL) to a 100 mL single-necked flask, stir at room temperature, then add TFA (6.7 mL) and react at room temperature for 1 h. After the reaction is complete as determined by LC-MS, concentrate the reaction solution, add DCM, adjust the pH to 7-8 with saturated sodium bicarbonate solution, extract three times with DCM, combine the organic phases, dry to anhydrous sodium sulfate, filter, and concentrate to obtain the compound (454 mg, Y: 104%).

[0601] LC-MS: m / z = 786.4 [M+1] + .

[0602] Synthesis of 231:

[0603] Add 231-8 (20 mg, 0.025 mmol) and DCM (2 mL) to a 50 mL single-necked flask. After argon protection, cool to 0-5 °C, then add NMM (8 mg, 0.075 mmol), cycloheptane-1-carboxylic acid (4.3 mg, 0.031 mmol), HOBt (1 mg, 0.005 mmol), and EDCI (9 mg, 0.045 mmol) sequentially. Allow the mixture to react overnight in an ice bath. After the reaction was confirmed to be complete by LC-MS, concentrate the reaction solution, purify it using Flash, and freeze-dry to obtain compound 231 (20 mg, Y: 88%).

[0604] LC-MS: m / z = 910.5 [M+1] + .

[0605] Example 8 N-((4S,Z)-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-11 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-4-yl)cycloheptane-4-en-1-carboxamide (compound 233) and N-((6 4 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-1 1 H-8-Oza-6 2 6 3 Synthesis of -diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-4-yl)cycloheptane-4-en-1-carboxamide (compound 365)

[0606] Synthesis of 233-1:

[0607] IntB37 (22.5 g, crude product, 22.33 mmol), (S)-2-(Boc-amino)-3-(4-bromo-2-thiazolyl)propionate (8.563 g, 23.45 mmol), K2CO3 (6.172 g, 44.66 mmol), Pd(dtbpf)Cl2 (728 mg, 1.11 mmol), and Diox / H2O (330 mL / 100 mL) were added to a 1 L single-necked flask. After purging with argon, the mixture was heated to 75 °C and reacted for 20 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was used directly for the next step.

[0608] LC-MS: m / z = 923.4 [M+1] + .

[0609] Synthesis of 233-2:

[0610] LiOH·H₂O (4.69 g, 111.67 mmol) was added to the above reaction solution 233-1, and the mixture was stirred at room temperature for 2 h. LC-MS analysis showed that the reaction was incomplete, so LiOH·H₂O (4.69 g, 111.67 mmol) was added again, and the reaction was stirred for another 4 h. After the reaction was complete as determined by LC-MS analysis, the pH of the mixture was adjusted to 6–7 with citric acid solution, then concentrated to a small amount. The residue was flash purified, lyophilized, and a brown solid product (17.6 g, Y: 83%) was obtained.

[0611] LC-MS: m / z = 909.4 [M+1] + .

[0612] Synthesis of 233-3:

[0613] Add 233-2 (12.8 g, 14.08 mmol), IntA2 (5.36 g, 15.49 mmol), and ACN / DCM (300 mL / 60 mL) to a 500 mL single-necked flask. After argon protection, cool to 0-5 °C, then add NMI (6.935 g, 84.48 mmol) and TCFH (5.926 g, 21.12 mmol) sequentially. React in an ice bath for 1 h. After the reaction is confirmed to be complete by LC-MS, add water to the reaction solution, extract three times with DCM, combine the organic phases, concentrate, and obtain a crude yellow-brown compound (17.2 g, Y: 85%). This crude product is used directly in the next step.

[0614] LC-MS: m / z = 1123.5 [M+1] + .

[0615] Synthesis of 233-4:

[0616] Compound 233-3 (17.2 g, 16.43 mmol), LiOH·H2O (1.035 g, 24.64 mmol), THF (150 mL), and water (30 mL) were added to a 500 mL single-necked flask and reacted at room temperature for 2 h. After the reaction was confirmed to be complete by LC-MS, the pH was adjusted to 6–7 with citric acid solution, and then the THF was removed by concentration. The residue was purified by flash filtration and lyophilized to obtain the compound (16.8 g, Y: 99%).

[0617] LC-MS: m / z = 1033.4 [M+1] + .

[0618] Synthesis of 233-5:

[0619] DIPEA (5.917 g, 45.78 mmol), DMAP (932 mg, 7.63 mmol), HOBt (4.124 g, 30.52 mmol), EDCI (8.776 g, 45.78 mmol), and DCM (600 mL) were added to a 1 L single-necked flask. The mixture was stirred for 10 min under argon protection, followed by slow dropwise addition of 150 mL of DCM solution (15.767 g, 15.266 mmol). After the addition was complete, the mixture was stirred at room temperature for 20 h. After the reaction was complete as detected by LC-MS, the mixture was concentrated, and the residue was Flash purified. The target fraction was adjusted to alkali with saturated sodium bicarbonate, extracted with EA, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the target product (8.2 g, Y: 50%, HPLC showed ~20% isomers).

[0620] LC-MS: m / z = 1015.4 [M+1] + .

[0621] Synthesis of 233-6:

[0622] Add 1.02 g (1.0 mmol) of 233-5 and 30 mL of MeOH to a 100 mL single-necked flask, then add 1 g of 20% Pd(OH)2 / C. After purging with hydrogen, react at room temperature for 3 h. After the reaction is complete as detected by LC-MS, filter, concentrate the filtrate, pass the residue through a flash filter, adjust the target fraction with sodium bicarbonate aqueous solution, extract with DCM, dry the organic phase, concentrate to dryness, and give an off-white solid product (870 mg, Y: 99%).

[0623] LC-MS: m / z = 881.4 [M+1] + .

[0624] Synthesis of 233-7:

[0625] Add 233-6 (100 mg, 0.114 mmol), paraformaldehyde (17 mg, 0.57 mmol), MeOH (3 mL), and AcOH (20 mg) to a 100 mL single-necked flask. Stir the mixture at room temperature for 1 h, then add NaBH3CN (21 mg, 0.342 mmol). Stir the mixture at room temperature for 20 h. After the reaction is complete as detected by LC-MS, concentrate the mixture, purify the residue using Flash chromatography, and lyophilize to obtain a white solid product (75 mg, Y: 73.5%).

[0626] LC-MS: m / z = 895.5 [M+1] + .

[0627] Synthesis of 233-8:

[0628] Add 233-7 (75 mg, 0.083 mmol) and DCM (5 mL) to a 100 mL single-necked flask, stir at room temperature, then add TFA (3 mL) to the system and react at room temperature for 1 h. After the reaction is complete as detected by LC-MS, concentrate the reaction solution, add DCM, adjust the pH to 7-8 with saturated sodium bicarbonate solution, extract three times with DCM, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to obtain the compound (70 mg, Y: 106%).

[0629] LC-MS: m / z = 795.4 [M+1] + .

[0630] Synthesis of 233:

[0631] Add 233-8 (20 mg, 0.025 mmol) and DCM (2 mL) to a 50 mL single-necked flask. After argon protection, cool to 0-5 °C, then add NMM (8 mg, 0.075 mmol), cycloheptane-1-carboxylic acid (4.3 mg, 0.031 mmol), HOBt (1 mg, 0.005 mmol), and EDCI (9 mg, 0.045 mmol) sequentially. Allow the mixture to react overnight in an ice bath. After the reaction was confirmed to be complete by LC-MS, concentrate the reaction solution, purify it using Flash, and freeze-dry to obtain compound 233 (16 mg, Y: 70%, HPLC showed ~20% isomers).

[0632] LC-MS: m / z = 917.4 [M+1] + .

[0633] Synthesis of 365:

[0634] The above compound 233 (10 mg) was prepared by prep-TLC (development system DCM:MeOH = 15:1), separated, extracted, and lyophilized to obtain the target compound (6.3 mg).

[0635] LC-MS: m / z = 917.4 [M+1] + .

[0636] Example 9 N-((4S,Z)-12-(2-((S)-1-methoxyethyl)-5-(4-(oxecyclobutane-3-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-1 1 H-8-Oza-6 2 6 3-diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-4-yl)cycloheptane-4-en-1-carboxamide (compound 235) and N-((6 4 S,4S,Z)-12-(2-((S)-1-methoxyethyl)-5-(4-(oxecyclobutane-3-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-1 1 H-8-Oza-6 2 6 3 Synthesis of -diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-4-yl)cycloheptane-4-en-1-carboxamide (compound 367)

[0637] Synthesis of 235-1:

[0638] Add 233-6 (88 mg, 0.10 mmol), oxetanone (36 mg, 0.50 mmol), MeOH (3 mL), and AcOH (20 mg) to a 100 mL single-necked flask. Stir the mixture at room temperature for 1 h, then add NaBH3CN (19 mg, 0.30 mmol). Stir the mixture at room temperature for 20 h. After the reaction is complete as detected by LC-MS, concentrate the mixture, purify the residue using Flash chromatography, and lyophilize to obtain a white solid product (47 mg, Y: 49.6%).

[0639] LC-MS: m / z = 937.4 [M+1] + .

[0640] Synthesis of 235-2:

[0641] Add 235-1 (47 mg, 0.05 mmol) and DCM (5 mL) to a 100 mL single-necked flask, stir at room temperature, then add TFA (1 mL) to the system and react at room temperature for 1 h. After the reaction is complete as detected by LC-MS, concentrate the reaction solution, add DCM, adjust the pH to 7-8 with saturated sodium bicarbonate solution, extract three times with DCM, combine the organic phases, dry to anhydrous sodium sulfate, filter, and concentrate to obtain the compound (46 mg, Y: 110%).

[0642] LC-MS: m / z = 837.4 [M+1] + .

[0643] Synthesis of 235:

[0644] Add 235-2 (46 mg, 0.05 mmol) and DCM (2 mL) to a 50 mL single-necked flask. After argon protection, cool to 0-5 °C, then add NMM (16 mg, 0.15 mmol), cyclohepta-4-en-1-carboxylic acid (7.5 mg, 0.053 mmol), HOBt (1.5 mg, 0.01 mmol), and EDCI (17 mg, 0.09 mmol). Allow the mixture to react overnight in an ice bath. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, purified by flash filtration, and lyophilized to obtain compound 235 (29 mg, Y: 60%, HPLC showed ~20% isomers).

[0645] LC-MS: m / z = 959.4 [M+1] + .

[0646] Synthesis of 367:

[0647] The above compound 235 (20 mg) was separated by prep-TLC (development system DCM:MeOH = 15:1), extracted, and lyophilized to obtain the target compound (12 mg, HPLC: 97.39%).

[0648] LC-MS: m / z = 959.4 [M+1] + .

[0649] Example 10 N-((6) 4 S,4S,Z)-12-(2-((S)-1-methoxyethyl)-5-(4-((S)-oxetane-2-carbonyl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-1 1 H-8-Oza-6 2 6 3 Synthesis of 2-diaza-2(4,2)-thiazo-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-4-yl)bicyclo[4.1.0]heptane-7-carboxamide (compound 256)

[0650] Synthesis of 256-1:

[0651] Add 233-5 (4.1 g, 4.04 mmol, prepared according to method 169-7, isomers removed) and DCM (41 mL) to a 250 mL single-necked flask, stir at room temperature, then add TFA (40 mL) dropwise to the system, and react at room temperature for 1 h. After the reaction is complete as detected by LC-MS, concentrate the reaction solution, add DCM to the residue, adjust the pH to 7-8 with saturated sodium bicarbonate solution, extract three times with DCM, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to obtain the compound (3.52 g, Y: 95.2%).

[0652] LC-MS: m / z = 915.4 [M+1] + .

[0653] Synthesis of 256-2:

[0654] Add 256-1 (1.3 g, 1.42 mmol) and DCM (30 mL) to a 100 mL single-necked flask. After argon protection, cool to 0-5 °C, then add NMM (430 mg, 4.26 mmol), bicyclo[4.1.0]heptane-7-carboxylic acid (199 mg, 1.42 mmol), HOBt (38 mg, 0.28 mmol), and EDCI (491 mg, 2.56 mmol) sequentially. Allow the mixture to react overnight in an ice bath. After the reaction was confirmed to be complete by LC-MS, concentrate the reaction solution, flash-purify the residue, and lyophilize to obtain a light brown solid product (1.36 g, Y: 92.4%).

[0655] LC-MS: m / z = 1037.5 [M+1] + .

[0656] Synthesis of 256-3:

[0657] 256-2 (1.36 g, 1.31 mmol) and MeOH (40 mL) were added to a 100 mL single-necked flask, followed by the addition of 20% Pd(OH)2 / C (1.31 g). After hydrogen purging, the reaction was allowed to proceed at room temperature for 3 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was filtered, the filter cake was washed with MeOH, and the filtrate was concentrated to dryness to obtain a grayish-white solid compound 256-3 (1.12 g, Y: 94.6%).

[0658] LC-MS: m / z = 903.4 [M+1] + .

[0659] Synthesis of 256:

[0660] Add 256-3 (40 mg, 0.0443 mmol) and DCM (3 mL) to a 10 mL single-necked flask. After argon protection, cool to 0-5 °C, then add NMM (13 mg, 0.1329 mmol), (S)-oxetane-2-carboxylic acid (5.4 mg, 0.0532 mmol), HOBt (1 mg, 0.009 mmol), and EDCI (15 mg, 0.0797 mmol) sequentially. Allow the mixture to react overnight in an ice bath. After the reaction is complete as determined by LC-MS, concentrate the reaction solution, prepare the residue by prep-HPLC, and lyophilize to obtain a light brown solid product (26 mg, Y: 59.5%).

[0661] LC-MS: m / z = 987.4 [M+1] + .

[0662] The prep-HPLC preparation method is as follows:

[0663] Sample name: WJ-256-Method

[0664] Instrument: Agilent 1290infinity II

[0665] Column: Xtimate C18 30*150mm,5um

[0666] Wave length: 214nm / 254nm

[0667] Phase A: H2O (0.1% FA)

[0668] phase B: ACN

[0669] Gradient:

[0670] Table 10

[0671] Example 11 N-((6) 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4-(oxecyclobutan-3-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of 2-diaza-2(4,2)-thiazo-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-4-yl)cycloheptane-4-en-1-carboxamide (compound 292)

[0672] Synthesis of 292:

[0673] Add 168-13 (40 mg, 0.051 mmol) and DCM (3 mL) to a 10 mL single-necked flask. After argon protection, cool to 0-5 °C, then add NMM (13 mg, 0.1329 mmol), cyclohepta-4-ene-1-carboxylic acid (7.5 mg, 0.0536 mmol), HOBt (1 mg, 0.009 mmol), and EDCI (15 mg, 0.0797 mmol) sequentially. Incubate overnight in an ice bath. After the reaction is complete as determined by LC-MS, concentrate the reaction solution, purify the residue by prep-TLC, and lyophilize to obtain a light brown solid product (18 mg, Y: 39%).

[0674] LC-MS: m / z = 905.5 [M+1] + .

[0675] Example 12 tert-butyl 4-(5-((6) 4 S,4S,Z)-4-(cycloheptane-4-en-1-carbamate)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-1 2 Synthesis of 394 (S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid ester (compound 394)

[0676] Synthesis of 394-1:

[0677] Add 233-5 (4.467 g, 4.4 mmol, prepared and separated according to method 169-7, isomers removed) and DCM (45 mL) to a 250 mL single-necked flask, stir at room temperature, then add TFA (20 mL) to the system, and react at room temperature for 1 h. After the reaction is complete as detected by LC-MS, concentrate the reaction solution, add DCM to the residue, adjust the pH to 7-8 with saturated sodium bicarbonate solution, extract the aqueous phase three times with DCM, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate to obtain the compound (4.144 g, Y: 103%).

[0678] LC-MS: m / z = 915.4 [M+1] + .

[0679] Synthesis of 394-2:

[0680] Add the above-mentioned 394-1 (4.144 g, 4.4 mmol), TEA (890 mg, 8.8 mmol), and DCM (80 mL) to a 250 mL single-necked flask. Cool to 0-5 °C in an ice bath under argon protection, then add FmocCl (1.71 g, 6.6 mmol) dropwise. After the addition is complete, raise the mixture to room temperature and stir for 2 h. After the reaction is complete as detected by LC-MS, concentrate the mixture, and purify the residue by Flash (0.1% TFA:ACN = 50%:50% (100 mL) to ACN = 50% to 95% (500 mL) to ACN = 95% (500 mL, product output)). Concentrate the target fraction under reduced pressure to about 1 / 5 of the volume, then add DCM (100 mL) and saturated sodium bicarbonate solution (10 mL), extract, separate, and extract the aqueous phase twice more with DCM. Combine the organic phases, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate to dryness, and give an off-white solid product (4.64 g, Y: 92%).

[0681] LC-MS: m / z = 1137.4 [M+1] + .

[0682] Synthesis of 394-3:

[0683] Add 394-2 (4.64 g, 4.08 mmol), Boc2O (2.23 g, 10.2 mmol), and MeOH (130 mL) / THF (20 mL) to a 250 mL single-necked flask, then add 20% Pd(OH)2 / C (4 g). After purging with hydrogen, react at room temperature for 1 h. After the reaction is complete as detected by LC-MS, filter, concentrate the filtrate, and purify the residue by column chromatography (PE:EA = 1:0 to 2:1 to DCM:MeOH = 50:1 to 25:1) to obtain a white solid product (4.348 g, Y: 96%).

[0684] LC-MS: m / z = 1103.5 [M+1] + .

[0685] Synthesis of 394-4:

[0686] Add 394-3 (4.348 g, 3.941 mmol), diethylamine (13.5 mL), and ACN (25 mL) to a 100 mL single-necked flask. Stir the mixture at room temperature for 30 min. After the reaction was completed, the mixture was purified by Flash (0.1% TFA:ACN = 20%:20% (100 mL) to ACN = 20% to 70% (500 mL, product output) to ACN = 95% (200 mL)). Adjust the pH to 7-8 with saturated sodium bicarbonate solution to the target fraction, then extract with DCM (100 mL * 3). Combine the organic phases, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, and concentrate to dryness to give a white solid product (3.086 g, Y: 88%).

[0687] LC-MS: m / z = 881.4 [M+1] + .

[0688] Synthesis of 394:

[0689] 394-4 (1.5 g, 1.703 mmol) and DCM (40 mL) were added to a 100 mL single-necked flask. Under argon protection, NMM (517 mg, 5.109 mmol), cycloheptane-1-carboxylic acid (286 mg, 2.043 mmol), HOBt (46 mg, 0.341 mmol), and EDCI (588 mg, 3.065 mmol) were added sequentially, and the mixture was reacted overnight at room temperature. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, purified by flash filtration, and lyophilized to obtain compound 394 (1.6 g, Y: 94%).

[0690] LC-MS: m / z = 1003.5 [M+1] + .

[0691] Example 13 Trifluoroethyl 4-(5-((6) 4 S,4S,Z)-4-(cycloheptane-4-en-1-carbamate)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-1 2 Synthesis of 398 (S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid ester (compound 398)

[0692] Synthesis of 316:

[0693] 394 (1.6 g, 1.595 mmol) and DCM (20 mL) were added to a 100 mL single-necked flask and stirred at room temperature. Then, TFA (4.2 mL) was added to the system and the reaction was allowed to proceed at room temperature for 1 h. After the reaction was confirmed to be complete by LC-MS, the reaction solution was concentrated, and the residue was added to DCM. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The aqueous phase was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the compound (1.49 g, Y: 103%).

[0694] LC-MS: m / z = 903.4 [M+1] + .

[0695] Synthesis of 398:

[0696] Trifluoroethanol (500 mg, 5.0 mmol), THF (10 mL), and TEA (1.01 g, 10.0 mmol) were added to a 100 mL single-necked flask. The mixture was cooled to 0–5 °C in an ice bath under argon protection, and then a solution of 4-nitrophenyl chloroformate (1.1 g, 5.5 mmol) in THF (10 mL) was added dropwise. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 3 h. After the reaction was completed by TLC, the mixture was concentrated, and the residue was purified by column chromatography (PE:EA = 20:0 to 20:1), yielding 491 mg of impurity.

[0697] In a separate 25 ml single-necked flask, add the above impurity (10 mg), 398-1 (30 mg), ACN (3 ml), and DIPEA (13 mg). Stir the mixture at room temperature for 1 h. After the reaction is complete as detected by LC-MS, concentrate the mixture, flash-purify the residue, and lyophilize to obtain a white solid product (33 mg).

[0698] LC-MS: m / z = 1029.4 [M+1] + .

[0699] Using different raw materials and referring to similar synthesis methods in Examples 3-13, the corresponding target compounds in Table 11 were obtained.

[0700] Table 11

[0701] The NMR data for some of the compounds in this patent are listed in Table 12 below:

[0702] Table 12

[0703] Biological Example 1: Detection of pERK and ERK protein levels in AsPC-1 cells using compounds - ELISA

[0704] AsPC-1 cells were seeded at 1000 cells per well in a 96-well plate. After one day of growth, the test compound (5 nM) was added. After 3 hours of compound treatment, the cells were fixed and the pERK level in the cells was measured using In-Cell Western blotting. The results were compared with the DMSO group, and the percentage of pERK activity inhibited by the compound was calculated.

[0705] Table 13. Inhibitory activity of the compounds of the present invention against intracellular pERK levels in AsPC-1 cells.

[0706] + indicates an inhibition rate of 50% or less.

[0707] ++ indicates an inhibition rate of 50% to 90%.

[0708] +++ indicates an inhibition rate greater than 90%.

[0709] Example 2: Detection of pERK and ERK protein levels in H1975 cells using compounds - In-Cell Western blotting

[0710] H1975 cells were seeded in 96-well plates. After one day of growth, serially diluted test compounds (maximum concentration: 50 nM) were added. After 3 hours of treatment, the cells were fixed, and the pERK level in the lysate was measured using In-Cell Western blotting. The results were compared with the DMSO group, and the percentage of pERK activity inhibited by the compound and the IC50 were calculated. 50 .

[0711] Biological Example 3: Antiproliferative activity of the compound against AsPC-1 / Capan-1 / H358 cells, etc.

[0712] AsPC-1 / Capan-1 / H358 cells were seeded in 384-well plates. After one day of growth, serially diluted compounds (maximum 100 nM, 5-fold dilution, for a total of five doses) were added. Five days after adding the compounds, Cell Titer Glow (Promega, G9681) was added to evaluate cell growth, and IC50 was calculated. 50 The values ​​are shown in Tables 14 and 16 below.

[0713] Table 14. Antiproliferative activity of the compounds of the present invention against AsPC-1 / Capan-1 cells

[0714] + indicates the compound's IC. 50 Greater than 50 nM; ++ indicates the compound's IC50 value. 50 The range is 5 to 50 nM; +++ indicates the IC50 of the compound. 50 Less than 5 nM; ND indicates not tested; the control compound is RMC6236, synthesized with reference to compound A122 in patent WO2022060836 (page 70, Table 1a); the control compound 2 is compound 6A in patent WO2024 / 067857 (page 79).

[0715] Biological Example 4: Antiproliferative Activity of Compounds on Miapaca2 / H1975 Cells

[0716] Miapaca2 / H1975 cells were seeded in ultra-low adsorption 96-well plates (corning, 7007). After one day of growth, serially diluted compounds (maximum 50 nM, 5-fold dilution, for a total of five doses) were added. Five days after adding the compounds, Cell Titer Glow (Promega, G9681) was added to evaluate cell growth, and IC50 was calculated. 50 The values ​​are shown in Tables 15 and 16 below.

[0717] Table 15. Antiproliferative activity of the compounds of the present invention against Miapaca2 cells

[0718] Table 16. Antiproliferative activity of the compounds of the present invention against H358 / H1975 cells

[0719] + indicates the compound's IC. 50 Greater than 50 nM; ++ indicates the compound's IC50 value is greater than 50 nM. 50The range is 5 to 50 nM; +++ indicates the IC50 of the compound. 50 Less than 5 nM; ND indicates not tested; control compound is RMC6236; control compound 2 is compound 6A in patent WO2024 / 067857 (page 79).

[0720] Biological Example 5: Pharmacokinetic Evaluation in Mice

[0721] The compound was administered via intravenous injection and oral gavage. The intravenous dose was 2 mg / kg, and the oral dose was 10 mg / kg. Fifteen female ICR mice were used in each group. Three non-contiguous time points were collected from each mouse, with three mice at each time point. Sampling time points were before administration, and 5 min, 15 min, 30 min, 1 h, 3 h, 5 h, 8 h, 12 h, and 24 h after administration. Approximately 80 μL of blood was collected from the orbital sinus at each time point after administration. All whole blood samples were collected in tubes containing EDTA K2, centrifuged at 4 °C (1500 rpm) for 10 min, and the plasma was separated and stored at -80 °C for analysis. The concentration of the compound in plasma was determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS), and the corresponding pharmacokinetic parameters were calculated based on the plasma concentration-time curve.

[0722] Table 17. In vivo pharmacokinetic evaluation results of the compounds

[0723] Note: *The control compound is RMC6236. # This indicates that the oral dose of this compound is 5 mg / kg.

[0724] Biological Example 6: Pharmacokinetic Evaluation in Rats

[0725] The compound was administered via intravenous injection and oral gavage. The intravenous dose was 1 mg / kg, and the oral dose was 5 mg / kg. Three male SD rats were used in each group. Blood samples were collected from the jugular vein at 5 min, 15 min, 30 min, 1 h, 3 h, 5 h, 8 h, 12 h, and 24 h after administration. All whole blood samples were collected in tubes containing EDTA K2, centrifuged at 4 °C (1500 rpm) for 10 min, and the plasma was separated and stored at -80 °C for analysis. The concentration of the compound in the plasma was determined by liquid chromatography-tandem mass spectrometry, and the corresponding pharmacokinetic parameters were determined based on the plasma concentration-time curve.

[0726] Table 18 shows the pharmacokinetic evaluation results of the compounds in rats.

[0727] *The control compound was RMC6236, and the PO group dose was 10 mg / kg.

[0728] Biological Example 7: Evaluation of Antitumor Activity in Mice

[0729] Miapaca2 / Capan-1 / AsPC-1 tumor cells were routinely cultured in 1640 medium containing 10% fetal bovine serum at 37°C in a 5% CO2 incubator. After passage, cells were collected when the desired cell count was reached. 1×10⁶ cells were then cultured. 7 One MiaPACA-2 / Capan-1 / AsPC-1 cell was injected into the left side of each nude mouse, and the tumor was allowed to grow to 150 mm. 3 Afterwards, the animals were randomly divided into groups to begin drug administration. Tumor volume and mouse weight were measured every Tuesday and Thursday. Nude mice were sacrificed on day 21 of drug administration, tumors were collected and weighed, and tumor inhibition capacity and weight changes were calculated.

[0730] Table 19 In vivo efficacy experiments of AsPC

[0731] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of general formula (2) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates: In general formula (2): Ring D is (C5-C14) heterocyclic alkyl, (C6-C14) aryl, or (5-14) heteroaryl; X1 and X2 are each independently N or CR d ; X3 is CR 10 or NR 10 X4 is either C or N, and X3 and X4 are not both N at the same time; Indicates a single or double bond, and when X3 or X4 is N, the bond connected to it is... Represented as a single bond; R 7 For -OR a -NR a R b (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace; R 8 Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, or -OR. a -NR a R b -C(O)R a -CO2R a -S(O) p R a -S(O) p NR a R b -CONR a R b -C(=NR) a )-NR b R c -NR a COR b -NR a CONR b R c -NR a CO2R b -NR a S(O) p NR b R c -NR a S(O) p R b (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace; R 9 -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a -NR a R b -C(O)R a -CO2R a -S(O) p R a -S(O) p NR a R b -CONR a R b -C(=NR) a )-NR b R c -NR a COR b -NR a CONR b R c -NR a CO2R b -NR a S(O) p NR b R c -NR a S(O) p R b (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace; R 10 The radical is -H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently optionally surrounded by 1, 2, 3, or 4 R radicals. d replace; R 11 -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a -NR a R b -C(O)R a -CO2R a -S(O) p R a -S(O) p NR a R b -CONR a R b -C(=NR) a )-NR b R c -NR a COR b -NR a CONR b R c -NR a CO2R b -NR a S(O) p NR b R c -NR a S(O) p R b (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace; R a R b and R c Each of the following is independently H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C 1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3 or 4 Rs. e replace; Or R a and R b R b and R c Or R a and R c Together with one or more atoms to which they are attached, they form (3-12-membered) heterocyclic alkyl groups, wherein the (3-12-membered) heterocyclic alkyl groups may optionally be composed of 1, 2, 3 or 4 R atoms. e replace; R d Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, or -OR. e (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C1-C8)alkylene-(C3-C14)alkylene-(C2-C8)alkylene-(C2-C8)heteroaryl, 8) Alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3 or 4 Rs. e replace; Or when 2 R d When attached to the same atom, an oxo group can be formed or a (C3-C8) cycloalkyl or (3-8) heterocycloalkyl group can be formed with the attached atom. The (C3-C8) cycloalkyl or (3-8) heterocycloalkyl group can each be independently and optionally bound by 1, 2, 3, or 4 R groups. e replace; R e Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, or -OR. f -NR f R g -C(O)R f -CO2R f -S(O) p R f -S(O) p NR f R g -CONR f R g -C(=NR) f )-NR f R h -NR f COR g -NR f CONR g R h -NR f CO2R g -NR f S(O) p NR g R h -NR f S(O) p R g (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl; R f R g and R h Each can be independently H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl; n and p are integers of 0, 1, 2, 3, and 4, respectively.

2. The compound of claim 1 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (2), R 7 It is (C3-C6) cycloalkyl, preferably cyclopropyl, wherein the cyclopropyl group is substituted with 1, 2, 3, or 4 H, D, methyl, halomethyl, or deutermethyl groups; R 7 More preferably 3. The compound as described in claim 1 or 2, or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, wherein in the general formula (2), X1 and X2 are each independently N or CR. d R d X1 is -H, -D, or halogen; X1 is preferably CH, CF, or N, and X2 is preferably CH.

4. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 1-3, wherein the structural unit in the general formula (2) is... for Preferred 5. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 1-4, wherein in the general formula (2), R 9 -H, -D, halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl; R 9 Preferably, it is -H, -D, halogen, methyl, or -CF3.

6. The compound of any one of claims 1-5, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein in the general formula (2), R 10 for 7. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 1-6, wherein in the general formula (2), R 8 -H, -D, halogen, hydroxyl, amino, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl; R 8 Preferably, it is -H, -D, halogen, methyl, hydroxyl, or amino.

8. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 1-7, wherein in the general formula (2), ring D is The asterisk (*) indicates that it is connected to an aromatic ring.

9. The compound of any one of claims 1-8, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound has one of the following structures:

10. A compound of general formula (3) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates: In general formula (3): Ring E is Where * indicates that it is connected to the carbon atom of the ester group; Ring F is (C6-C14)aryl or (5-14)heteroaryl; Ring G is (C5-C14) heterocyclic alkyl, (C6-C14) aryl, or (5-14) heteroaryl; X1 and X2 are each independently N or CR d ; X3 is CR 3 or NR 3 X4 is either C or N, and X3 and X4 are not both N at the same time; Indicates a single or double bond, and when X3 or X4 is N, the bond connected to it is... Represented as a single bond; R 12 For -OR a -NR a R b (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace; R 3 The radical is -H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently optionally surrounded by 1, 2, 3, or 4 R radicals. d replace; R 13 -H, -D, halogen, hydroxyl, amino, cyano, nitro, -OR a -NR a R b -C(O)R a -CO2R a -S(O) p R a -S(O) p NR a R b -CONR a R b -C(=NR) a )-NR b R c -NR a COR b -NR a CONR b R c -NR a CO2R b -NR a S(O) p NR b R c -NR a S(O) p R b -POR a R b -PSR a R b -N(=S(O)R a R b ), -BR a R b -(C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently optionally surrounded by 1, 2, 3, or 4 Rs. d replace; Or R 13 and R 3 The atoms to which it is attached constitute a 6-10 membered heterocyclic alkyl group, each of which may be independently and optionally bound by 1, 2, 3 or 4 R atoms. d replace; R 15 Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, carbonyl, or -OR. a -NR a R b -C(O)R a -CO2R a -S(O) p R a -S(O) p NR a R b -CONR a R b -C(=NR) a )-NR b R c -NR a COR b -NR a CONR b R c -NR a CO2R b -NR a S(O) p NR b R c -NR a S(O) p R b (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace; R 16 Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, or -OR. a -NR a R b -C(O)R a -CO2R a -S(O) p R a -S(O) p NR a R b -CONR a R b -C(=NR) a )-NR b R c -NR a COR b -NR a CONR b R c -NR a CO2R b -NR a S(O) p NR b R c -NR a S(O) p R b -POR a R b -PSR a R b -N(=S(O)R a R b ), -BR a R b (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl, wherein the (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, or (5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3, or 4 R's. d replace; R 14 Each is an independent structural unit Where Y1 is S or O, and Y2 is O or NR. c ; R a R b and R c Each of the following is independently H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C 1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3 or 4 Rs. e replace; Or R a and R b R b and R c Or R a and R c Together with one or more atoms to which they are attached, they form (3-12-membered) heterocyclic alkyl groups, wherein the (3-12-membered) heterocyclic alkyl groups may optionally be composed of 1, 2, 3 or 4 R atoms. e replace; R d Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, or -OR. e (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C1-C8)alkylene-(C3-C14)alkylene-(C2-C8)alkylene-(C2-C8)heteroaryl, 8) Alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3 or 4 Rs. e replace; Or when 2 R d When attached to the same atom, an oxo group can be formed or a (C3-C8) cycloalkyl or (3-8) heterocycloalkyl group can be formed with the attached atom. The (C3-C8) cycloalkyl or (3-8) heterocycloalkyl group can each be independently and optionally bound by 1, 2, 3, or 4 R groups. e replace; R e Each can be independently represented as -H, -D, halogen, hydroxyl, amino, cyano, nitro, or -OR. f -NR f R g -C(O)R f -CO2R f -S(O) p R f -S(O) p NR f R g -CONR f R g -C(=NR) f )-NR f R h -NR f COR g -NR f CONR g R h -NR f CO2R g -NR f S(O) p NR g R h -NR f S(O) p R g (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl; R f R g and R h Each can be independently H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl; n and p are integers of 0, 1, 2, and 3 respectively.

11. The compound of claim 10 or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (3), R 12 It is (C3-C6) cycloalkyl, preferably cyclopropyl, wherein the cyclopropyl group is substituted with 1, 2, 3, or 4 H, D, methyl, halomethyl, or deutermethyl groups; R 12 More preferably 12. The compound of claim 10 or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (3), X1 and X2 are each independently N or CR. d R d X1 is -H, -D, or halogen; X1 is preferably CH, CF, or N, and X2 is preferably CH.

13. The compound of claim 12 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (3), the structural unit for Preferred 14. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 10-13, wherein in the general formula (3), ring G is a benzene ring or a 6-membered heteroaromatic ring; ring G is preferably a benzene ring or a pyridine ring.

15. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 10-14, wherein in the general formula (3), R 15 Each of the following groups is independently -H, -D, halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C5)cycloalkyl, (3-5-membered)heterocyclic alkyl, (C6-C10)aryl, or (5-10-membered)heteroaryl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C5)cycloalkyl, (3-5-membered)heterocyclic alkyl, (C6-C10)aryl, or (5-10-membered)heteroaryl groups may be independently and optionally surrounded by 1, 2, 3, or 4 R groups. d Replace; R 15 Preferably, it is -H, -D, halogen, or (C1-C3) alkyl.

16. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 10-15, wherein the structural unit in the general formula (3) is... for The asterisk (*) indicates that the carbon atom is attached to the ester group.

17. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 10-16, wherein in the general formula (3), R 13 -H, -D, halogen, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl; R 13 Preferably, it is -H, -D, halogen, methyl, or -CF3.

18. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 10-17, wherein in the general formula (3), R 3 for 19. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 10-18, wherein in the general formula (3), R 13 and R 3 The atoms to which it is attached constitute a 6-10 membered heterocyclic alkyl group, each of which may be independently and optionally bound by 1, 2, 3 or 4 R atoms. d replace.

20. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 10-19, wherein in the general formula (3), R 16 -H, -D, halogen, hydroxyl, amino, (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl; R 16 Preferably, it is -H, -D, halogen, methyl, hydroxyl, or amino.

21. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 10-20, wherein in the general formula (3), ring F is The asterisk (*) indicates that it is connected to an aromatic ring.

22. The compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as described in any one of claims 10-21, wherein in the general formula (3), R 14 Each is an independent structural unit Where Y1 is S or O, and Y2 is O or NR. c ;R a R b and R c Each of the following is independently H, (C1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocycloalkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocycloalkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl, wherein (C 1-C8)alkyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C14)cycloalkyl, (3-14-membered)heterocyclic alkyl, (C6-C14)aryl, (5-14-membered)heteroaryl, -(C1-C8)alkylene-(C3-C14)cycloalkyl, -(C1-C8)alkylene-(3-14-membered)heterocyclic alkyl, -(C1-C8)alkylene-(C6-C14)aryl, -(C1-C8)alkylene-(5-14-membered)heteroaryl can each be independently and optionally surrounded by 1, 2, 3 or 4 Rs. e Replace; or R a and R b R b and R c Or R a and R c Together with one or more atoms to which they are attached, they form (3-12-membered) heterocyclic alkyl groups, wherein the (3-12-membered) heterocyclic alkyl groups may optionally be composed of 1, 2, 3 or 4 R atoms. e Replace; R 14 Preferred R 14 More preferably 23. The compound of any one of claims 10-22, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the compound has one of the following structures:

24. A pharmaceutical composition, characterized in that, It contains pharmaceutically acceptable excipients or carriers, and the compound or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as any one of claims 1-23 as active ingredients.

25. Use of a compound as described in any one of claims 1-23, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as described in claim 24, in the preparation of a medicament for treating, modulating and / or preventing diseases associated with RAS inhibitors.

26. The use as claimed in claim 25, wherein the disease is cancer, the cancer is a hematologic malignancy and a solid tumor, preferably breast cancer, colon cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, hematologic malignancy, lymphoma, prostate cancer, liver cancer, cervical cancer, neuroblastoma, melanoma or intracranial tumor.

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