Nitrogen-containing heterocyclic derivative as methionine adenylyltransferase 2A inhibitor

Abstract

The present invention relates to a compound, the compound is a compound represented by a formula (I), or an isomer, an isotope derivative, a polymorphic substance, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, and the definitions of A1, B1 and L are the same as the definitions in the specification. Also provided are pharmaceutical compositions and compounds of formula (I) for use in methods of treating related diseases by inhibition of MAT2A, including some cancers in which a gene encoding a methylthioadenosine phosphorylase (MTAP) is deleted and / or not fully functioning.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and relates to a nitrogen-containing heterocyclic derivative, a pharmaceutical composition containing the derivative, and its pharmaceutical uses, particularly its use in the preparation of antitumor drugs. Technical Background

[0002] Methionine adenosine transferase (MAT), also known as S-adenosylmethionine synthase, is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP, and is considered the rate-limiting enzyme in the methionine cycle. SAM is a major methyl donor for the synthesis of polyamines and glutathione in the methylation processes of nucleic acids, phospholipids, histones, biogenic amines, and proteins. Therefore, regulating SAM biosynthesis can affect cell growth, differentiation, and function. Studies have shown that tumor cell proliferation and metastasis are abnormally dependent on methionine, and inhibiting the methionine cycle can significantly inhibit stem cell proliferation and metastasis.

[0003] In mammalian tissues, the MAT gene primarily contains two distinct isoenzymes, encoded by MAT1 and MAT2. MAT1 is expressed only in the liver and is used to maintain the differentiation state of hepatocytes and bile duct epithelial cells. MAT2 is universally expressed in both normal and cancer cells. MAT2 comprises two subunits, MAT2A and MAT2B, serving as the catalytic and regulatory subunits, respectively. MAT2A is a key enzyme in the SAM synthesis pathway. Studies have shown that upregulation of MAT2A expression exists in various cancer cells, and knockout of the MAT2A gene leads to cancer cell death. Therefore, MAT2A is considered an important anti-tumor target.

[0004] Studies have shown that MAT2A is a synthetic lethal target in cancers deficient in methylthioadenosine phosphorylase (MTAP). MTAP is an enzyme widely expressed in normal tissues that degrades MTA, a byproduct of polyamine synthesis, into adenine and 5-methylthioadenosine-1-phosphate (MTR-1p). Marjon et al. (Cell Reports 15(3)(2016)574-587) reported that MTAP-deficient cancer cell lines are particularly sensitive to MAT2A inhibition. MTAP, located on chromosome 9p21, is similar to the tumor suppressor gene CDKN2A. Nearly 15% of human cancers exhibit MTAP gene deletion. MTAP deletion is not only present in tissue culture cells but also in primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, and mesothelioma. MTAP is a key enzyme in the methionine reuptake pathway and is currently the only known enzyme catalyzing the degradation of MTA. MTAP loss is thought to lead to MTA accumulation in cancer cells. Increased MTA activity inhibits protein arginine methyltransferase 5 (PRMT5), increasing PRMT5's sensitivity to further SAM deletion. Compared to cancer cells normally expressing MTAP, selective inhibition of MAT2A reduces the proliferative activity of MTAP-deficient cancer cells. These results suggest that MAT2A inhibitors may offer a novel treatment option for patients with tumors, including those lacking MTAP. Summary of the Invention

[0005] This invention provides a nitrogen-containing heterocyclic derivative and its pharmaceutically acceptable salts, which are inhibitors of methionine adenosine transferase 2A (MAT2A). Pharmaceutical compositions comprising such compounds and methods for treating diseases treatable by inhibiting MAT2A, such as cancer, including cancers characterized by reduced or inactive methionine adenosine phosphorylase (MTAP) activity, are also disclosed herein.

[0006] The present invention adopts the following technical solution:

[0007] A first aspect of the present invention provides a compound, said compound being a compound of formula (I), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof:

[0008]

[0009] Where A1 is selected from formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (VIII), and B1 is selected from formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (VII);

[0010]

[0011]

[0012] R1 is selected from -N(C) each time it appears. 1-6 alkyl)-, -C(R a (R) b )- and -C(R c (R) c )-;

[0013] R a and R b It forms a 3-5 membered cycloalkyl group with the attached C atom, wherein the 3-5 membered cycloalkyl group is optionally selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Substitution of alkylamino and cyano groups;

[0014] R2, R6, R9, R 12 R 15 and R 17 Each occurrence is independently selected from N and C(R). c );

[0015] R8, R 13 R 14 and R 16 Each occurrence is independently selected from -N(R) c )- and -C(R c (R) c )-;

[0016] R c Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Alkylamino and cyano groups;

[0017] R3 and R7 are each independently selected from halogens and C each time they appear. 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Alkylamino, cyano, 3-8 membered cycloalkyl, and 3-8 membered heterocycloalkyl;

[0018] R4 and R5 are each independently selected from H, halogen, and C each time they appear. 1-6 Alkyl, C1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Alkylamino and cyano groups, or R4 and R5, form 3-5 membered heterocyclic alkyl groups with the attached N atom;

[0019] n1 and n2 are each independently selected from 1, 2 and 3; preferably, n1 and n2 are each independently selected from 1 and 2;

[0020] L represents the chemical linking structure between A1 and B1, and its structure is -(B L ) q -;

[0021] B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, S(O), SO2, -NR L1 -、C(O),CR L1 =CR L2 C≡C, 3-10 cycloalkylene, 4-10 heterocyclic, 6-10 arylene, and 5-8 heterocyclic, wherein the 3-10 cycloalkylene, 4-10 heterocyclic, 6-10 arylene, and 5-8 heterocyclic are optionally surrounded by 1, 2, 3, 4, 5, or 6 Rs. L1 and / or R L2 Group substitution;

[0022] R L1 and R L2 Each time it appears, it is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Alkylamino, 3-5 membered cycloalkyl, 3-5 membered heterocyclic and cyano groups;

[0023] q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0024] When A1 is equation (II), B1 is equation (III), and R a and R b When R2 forms a 3-membered cycloalkyl group with the attached C atom, and R2 is N, L is not...

[0025] When A1 is equation (II), and R a and R b When it forms a 3-membered cycloalkyl group with the attached C atom, and R2 is N, L is At that time, B1 is not

[0026] When A1 is equation (Ⅲ) and B1 is equation (Ⅲ), L is

[0027]

[0028] R 10 and R 11 Each is independently selected from H, F, Cl, Br, I, amino, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and 3-5 membered cycloalkyl groups; and R 10 and R 11 Not both H; and when R 11 When it is CH3, R 10 Not H; or

[0029] When A1 is B1 is When L is or

[0030] When A1 is B1 is When L is

[0031] When A1 is L is At that time, B1 is

[0032] A1 and B1 are not simultaneously and

[0033] The compounds mentioned do not include any of the compounds disclosed in PCT / CN2024 / 080417.

[0034] In some implementation schemes,

[0035] When A1 is formula (II), B1 is formula (III) or formula (IV); or when A1 is formula (III), B1 is formula (II), formula (III), formula (IV), formula (V), formula (VI), or formula (VII); or when A1 is (IV), B1 is formula (II); or when A1 is formula (V), formula (VI), or formula (VIII), B1 is formula (III); preferably, A1 and B1 are selected from the following combinations: formula (II) and formula (III), formula (II) and formula (IV), formula (III) and formula (II), formula (III) and formula (III), formula (III) and formula (IV), formula (III) and formula (V), formula (III) and formula (VI), formula (III) and formula (VII), formula (IV) and formula (II), formula (V) and formula (III), or formula (VI) and formula (III); and / or

[0036] R a and R b It forms a 3-5 membered cycloalkyl group with the attached C atom, wherein the 3-5 membered cycloalkyl group is optionally selected from F, Cl, Br, I, C. 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups; preferably, R a and R b It forms a 3- or 4-membered cycloalkyl group with the attached C atom; and / or

[0037] R c Selected from H, F, Cl, Br, I, C 1-3 Alkyl and C 1-3 Halogenated alkyl; preferably, R c Selected from H, F, Cl, Br, methyl and ethyl; and / or

[0038] R3 and R7 are each independently selected from F, Cl, Br, I, and C each time they appear. 1-3 Alkyl, C 1-3 Halogenated alkyl groups and 3-5 membered cycloalkyl groups; more preferably, R3 and R7 are each independently selected from F, Cl, CF3 and CCl3 each time they appear; and / or

[0039] R4 and R5 are each independently selected from H, F, Cl, Br, I, and C each time they appear. 1-3 Alkyl and C 1-3 A haloalkyl group, or R4 and R5 forming a 3-5 membered heterocyclic alkyl group with the attached N atom; more preferably, R4 and R5 are each independently selected from H, methyl, and ethyl each time they appear, or R4 and R5 form a 3- or 4-membered heterocyclic alkyl group with the attached N atom; and / or

[0040] R L1 and R L2 Each time it appears, it is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, amino, hydroxyl, C 1-3 Alkylamino, 3-5 membered cycloalkyl, and cyano; preferably, R L1 and R L2 Each time it appears, it is independently selected from H, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, amino, hydroxyl, cyano, trifluoromethyl, trichloromethyl, 3-membered cycloalkyl, 4-membered cycloalkyl, and 5-membered cycloalkyl; and / or

[0041] q is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8.

[0042] In some implementation schemes,

[0043] The structure of formula (II) is selected from and / or

[0044] The structure of formula (III) is selected from and / or

[0045] The structure of formula (Ⅳ) is selected from and / or

[0046] The structure of formula (V) is selected from and / or

[0047] The structure of formula (VI) is selected from and / or

[0048] The structure of formula (Ⅶ) is selected from and / or

[0049] The structure of formula (VIII) is selected from

[0050] In some embodiments, the compound is a compound of formula (I-a), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof.

[0051]

[0052] Where A1 is selected from formula (II), formula (III) and formula (V), and B1 is selected from formula (III) and (IV);

[0053]

[0054] When A1 is equation (II), B1 is equation (III) or equation (IV); or when A1 is equation (III), B1 is equation (III) or equation (IV); or when A1 is equation (V), B1 is equation (III).

[0055] R1 and R8 are each independently selected from -N(C 1-6 alkyl)- and -C(R) a (R) b )-;

[0056] R a and R b It forms a 3-5 membered cycloalkyl group with the attached C atom, wherein the 3-5 membered cycloalkyl group may optionally be selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Substitution with alkylamino and cyano groups; preferably, R a and R bIt forms a 3-5 membered cycloalkyl group with the attached C atom, wherein the 3-5 membered cycloalkyl group may optionally be selected from F, Cl, Br, I, C. 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups;

[0057] R2 and R6 are each independently selected from N and C(R c );

[0058] R c Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Alkylamino and cyano groups; preferably, R c Selected from H, F, Cl, Br, I, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0059] R3 and R7 are each independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Alkylamino, cyano, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl; preferably, R3 and R7 are each independently selected from F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Halogenated alkyl groups and 3-5 membered cycloalkyl groups;

[0060] R4 and R5 are each independently selected from halogens and C each time they appear. 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Alkylamino, cyano; preferably, R4 and R5 are each independently selected from F, Cl, Br, I, C each time they appear. 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0061] n1 and n2 are each independently selected from 1, 2, and 3; preferably, n1 and n2 are each independently selected from 1 and 2;

[0062] L represents the chemical linking structure between A1 and B1, which is -(B L ) q -;

[0063] B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, SO, SO2, -NR L1 -、C(O),CR L1 =CR L2C≡C, 4-10 cycloalkylene, 4-10 heterocyclic, 6-10 aryl, and 5-8 heterocyclic, wherein the 4-10 cycloalkylene, 4-10 heterocyclic, 6-10 aryl, and 5-8 heterocyclic are optionally surrounded by 0, 1, 2, 3, 4, 5, or 6 Rs. L1 and / or R L2 Group substitution;

[0064] R L1 and R L2 Each time it appears, it is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Alkylamino and cyano; preferably, R L1 and R L2 Each time it appears, it is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Halogenated alkyl, amino, hydroxyl, C 1-3 Alkylamino and cyano groups;

[0065] q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0066] When A1 is equation (II), B1 is equation (III), and R a and R b When R2 forms a 3-membered cycloalkyl group with the attached C atom, and R2 is N, L is not...

[0067] Or, when A1 is equation (III) and B1 is equation (III) or equation (IV), L is...

[0068] R 10 and R 11 Each is independently selected from H, F, Cl, Br, I, amino, hydroxyl, cyano, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0069] Or when A1 is B1 is When L is Or when A1 is

[0070] B1 is When L is Or when A1 is B1 is When L is

[0071] In some embodiments, the compound is a compound of formula (I-b), or an isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof.

[0072]

[0073] Where A1 is selected from formula (II), formula (III), formula (IV) and formula (V), and B1 is selected from formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (VII);

[0074]

[0075] Preferably, when A1 is formula (II), B1 is formula (III) or formula (IV); or when A1 is formula (III), B1 is formula (II), formula (III), formula (V), formula (VI), or formula (VII); or when A1 is formula (VI), B1 is formula (II); or when A1 is formula (V), B1 is formula (III).

[0076] R 14 and R 13 Each occurrence is independently selected from -C(R) a (R) b )-、N(R c ) and -C(R c (R) c )-;

[0077] R1 and R8 are each independently selected from -N(C 1-6 alkyl)- and -C(R) a (R) b )-;

[0078] R2, R6, R9, R 15 and R 12 Each occurrence is independently selected from N and C(R). c );

[0079] R a and R b It forms a 3-5 membered cycloalkyl group with the attached C atom, wherein the 3-5 membered cycloalkyl group is optionally selected from deuterium, halogen, C. 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Substituents of alkylamino and cyano groups; preferably, R a and R b It forms a 3-5 membered cycloalkyl group with the attached C atom, wherein the 3-5 membered cycloalkyl group is optionally selected from F, Cl, Br, I, C. 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups;

[0080] R c Selected from H, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Alkylamino and cyano; preferably, R c Selected from H, F, Cl, Br, I, C 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0081] R3 and R7 are each independently selected from halogens and C each time they appear. 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Alkylamino, cyano, 3-8 membered cycloalkyl, and 3-8 membered heterocycloalkyl; preferably, R3 and R7 are each independently selected from F, Cl, Br, I, and C each time they appear. 1-3 Alkyl, C 1-3 Halogenated alkyl groups and 3-5 membered cycloalkyl groups;

[0082] R4 and R5 are each independently selected from halogens and C each time they appear. 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Alkylamino and cyano groups; preferably, R4 and R5 are each independently selected from F, Cl, Br, I, and C each time they appear. 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0083] n1 and n2 are each independently selected from 1, 2 and 3; preferably, n1 and n2 are each independently selected from 1 and 2;

[0084] L represents the chemical linking structure between A1 and B1, which is -(B L ) q -;

[0085] B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, SO, SO2, -NR L1 -、C(O),CR L1 =CR L2 C≡C, 4-10 cycloalkylene, 4-10 heterocyclic, 6-10 aryl, and 5-8 heterocyclic, wherein the 4-10 cycloalkylene, 4-10 heterocyclic, 6-10 aryl, and 5-8 heterocyclic are optionally surrounded by 0, 1, 2, 3, 4, 5, or 6 Rs. L1 and / or R L2 Group substitution;

[0086] R L1 and R L2 Each time it appears, it is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, amino, hydroxyl, C 1-6 Alkylamino, 3-5 membered cycloalkyl, 3-5 membered heterocyclic and cyano groups; preferably, R L1 and R L2 Each time it appears, it is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, C 1-3 Halogenated alkyl, amino, hydroxyl, C 1-3 Alkylamino, 3-5 membered cycloalkyl, and cyano groups;

[0087] q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

[0088] When A1 is equation (II), B1 is equation (III), and R a and R b When R2 forms a 3-membered cycloalkyl group with the attached C atom, and R2 is N, L is not...

[0089] When A1 is equation (Ⅲ) and B1 is equation (Ⅲ), L is

[0090] R 10 and R 11 Each is independently selected from H, F, Cl, Br, I, amino, hydroxyl, cyano, C 1-3 Alkyl and C 1-3 Halogenated alkyl; and R 10 and R 11 Not both H, and R 11 When it is CH3, R 10 Not H; or

[0091] When A1 is B1 is When L is or

[0092] When A1 is B1 is When L is

[0093] In some implementation schemes, B LEach occurrence is independently selected from: CH2, NH, C(O), CH=CH, 3-10 cycloalkylene, 4-10 heterocyclic, 6 aryl, and 5-6 heterocyclic, wherein the CH2, 3-10 cycloalkylene, 4-10 heterocyclic, 6 aryl, and 5-6 heterocyclic are optionally surrounded by 1, 2, or 3 F, Cl, Br, I, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Alkoxy, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl and C 1-3 Halogenated alkyl substitution; preferably, preferably, B L Each occurrence may be the same or different, and each is independently selected from: CH2, NH, C(O), CR L1 =CR L2 3-6-membered cycloalkylene, 4-6-membered monocyclic heterocyclicene, 7-10-membered spirocyclicene, 7-10-membered fused heterocyclicene, 6-membered arylene, and 5-6-membered heterocyclicene, wherein the 3-6-membered cycloalkylene, 4-6-membered monocyclic heterocyclicene, 7-10-membered spirocyclicene, 7-10-membered fused heterocyclicene, 6-8-membered arylene, and 5-6-membered heterocyclicene are optionally substituted with 1, 2, or 3 F, Cl, Br, hydroxyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trichloromethyl, and 3-membered cycloalkyl groups; preferably, B L Each occurrence is independently selected from: CH2, -C(C 1-3 Alkyl group (H)-, -C(OH)(H)-, -C(F)(H)-, -C(CF3)(H)-, NH, -C(O)-, CH=CH,

[0094] In some implementation schemes, B L Each occurrence is independently selected from: CH2, NH, CO, CH=CH, 4-10 cycloalkylene, 4-10 heterocyclic, 6 aryl, and 5-6 heterocyclic, wherein the CH2, 4-10 cycloalkylene, 4-10 heterocyclic, 6 aryl, and 5-6 heterocyclic are optionally surrounded by 0, 1, 2, or 3 F, Cl, Br, I, hydroxyl, C 1-3 Alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl and C 1-3 Halogenated alkyl substitution; preferably, B L Each occurrence is independently selected from: CH2, -C(C 1-3 Alkyl group (H)-, -C(OH)(H)-, -C(F)(H)-, -C(CF3)(H)-, NH, -C(O)-, CH=CH,

[0095]

[0096] In some implementation schemes, B L Each occurrence is independently selected from: CH2, NH, C(O), CH=CH, 4-10 cycloalkylene, 4-10 heterocyclic, 6 aryl, and 5-6 heterocyclic, wherein the CH2, 4-10 cycloalkylene, 4-10 heterocyclic, 6 aryl, and 5-6 heterocyclic are optionally surrounded by 0, 1, 2, or 3 F, Cl, Br, I, hydroxyl, C 1-3 Alkyl and C 1-3 Halogenated alkyl substitution; preferably, B L Each occurrence is independently selected from: CH2, -C(OH)(H)-, -C(F)(H)-, -C(CF3)(H)-, NH, -C(O)-, CH=CH,

[0097] In some implementations, L is selected from:

[0098]

[0099]

[0100] In some embodiments, the compound is selected from:

[0101]

[0102]

[0103]

[0104]

[0105]

[0106] A second aspect of the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises a therapeutically effective dose of the compound of the present invention and a pharmaceutically acceptable carrier or excipient.

[0107] A third aspect of the present invention provides the use of the compound described in the first aspect or the pharmaceutical composition of the second aspect of the present invention in the preparation of a medicament for treating MAT2A-related diseases; preferably, the MAT2A-related diseases are cancer or tumors. Detailed Implementation

[0108] The present invention will be further described below with reference to embodiments. These embodiments are merely illustrative and are in no way intended to limit the scope of the invention. Various modifications made by those skilled in the art based on the teachings of the present invention should be within the scope of protection claimed in the claims of this application.

[0109] Terms and Definitions

[0110] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings:

[0111] "alkyl" refers to a straight-chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc. Those skilled in the art will recognize that the term "alkyl" may include "alkylene" groups.

[0112] Unless otherwise stated, "alkylene" refers to a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group having 3 to 6 carbon atoms, such as methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, etc.

[0113] "Alkenyl" refers to a straight-chain monovalent hydrocarbon group containing 2 to 6 carbon atoms or a branched monovalent hydrocarbon group containing 3 to 6 carbon atoms, such as propenyl and butenyl.

[0114] "Alynyl" refers to a straight-chain monovalent hydrocarbon group with 2 to 6 carbon atoms or a branched monovalent hydrocarbon group with 3 to 6 carbon atoms that contains a triple bond, such as ethynyl, propynyl, butynyl, etc.

[0115] "Alkoxy" refers to the -OR group, where R is an alkyl group as defined above, such as methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, etc.

[0116] "Amino" refers to -NH2.

[0117] "alkylamino" refers to the -NHR group, where R is an alkyl group as defined above, such as methylamino, ethylamino, propylamino, or 2-propylamino.

[0118] "Aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group having 3 to 12 ring atoms, such as phenyl or naphthyl.

[0119] "Aryl group" refers to the -(alkylene)-R group, where R is an aryl group as defined above, such as benzyl, phenethyl, etc.

[0120] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0121] "Halogenated alkyl" refers to an alkyl group as defined above that is substituted with 1 to 5 halogen atoms, such as fluorine or chlorine atoms, including groups substituted with different halogens, such as -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When an alkyl group is substituted only with fluorine, it may be referred to as fluoroalkyl in this application.

[0122] "Hydroxyalkyl" refers to a straight-chain monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched monovalent hydrocarbon group having 3 to 6 carbon atoms, substituted with one or two hydroxyl groups, provided that if two hydroxyl groups are present, they are not simultaneously on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl.

[0123] As used alone or in combination in this invention, "oxygenation" means (=O).

[0124] As used herein, a "pharmaceutically acceptable salt" refers to a salt comprising an active compound prepared with a relatively non-toxic acid or base, depending on the specific substituents found on the compound described herein. When the compound disclosed herein contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base (pure or in a suitable inert solvent). Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid (pure or in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids, such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 1977, 66, pp. 1-19). Certain compounds of the present invention contain both basic and acidic functional groups, which allows the compound to be converted into either a basic addition salt or an acid addition salt.

[0125] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties (e.g., solubility in polar solvents), but for the purposes of this invention, these salts are equivalent to the parent form of the compound.

[0126] This invention also includes protected derivatives of the compounds disclosed herein. For example, when the compounds of this disclosure contain groups such as hydroxyl, carboxyl, thiol, or any group containing one or more nitrogen atoms, these groups may be protected by suitable protecting groups. A complete list of suitable protecting groups can be found in TW Greene, Protecting Groups in Organic Synthesis, 5th Edition, John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of the compounds of this disclosure may be prepared by methods well known in the art.

[0127] This invention also includes prodrugs of the said compounds, or pharmaceutically acceptable salts thereof. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of this invention. One example, without limitation, of a prodrug is a compound (“prodrug”) administered as an ester and then metabolized and hydrolyzed to a carboxylic acid, i.e., the active entity. Additionally, prodrugs can be converted into the compounds of this invention in an in vitro environment by chemical or biochemical methods. For example, when a prodrug is placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, it can be slowly converted into the compounds of this invention.

[0128] "Treatment" or "treatment" of a disease includes:

[0129] (1) Disease prevention, that is, preventing the development of clinical symptoms of disease in mammals that may be exposed to or susceptible to the disease but have not yet experienced or shown symptoms of the disease;

[0130] (2) Suppressing the disease, that is, preventing or alleviating the development of the disease or its clinical symptoms; or

[0131] (3) Relieve disease, that is, cause the disease or its clinical symptoms to subside.

[0132] The terms “inhibition,” “reduction,” or any variation thereof regarding MAT2A include any measurable reduction or complete inhibition to achieve the desired result. For example, a reduction in MAT2A activity compared to its normal activity may be a reduction of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range thereof.

[0133] Example

[0134] The following examples pertain to the intermediate compounds and final products identified in the specification and synthetic regimens. The preparation of the compounds of the present invention is described in detail using the following examples, but the described chemical reactions are disclosed in accordance with their general applicability to the preparation of the compounds of the present invention. Sometimes, the reactions may not be applicable to every compound as described in the present invention. Compounds in which this may occur are readily identifiable to those skilled in the art. In these cases, the reactions can be successfully carried out with conventional modifications known to those skilled in the art. In all preparation methods, all starting materials are known or can be readily prepared using known starting materials.

[0135] The starting materials, chemical reagents, and solvents used in this disclosure are all commercially available and were purchased from companies such as Anaiji Chemical, Shanghai Bide Pharmaceutical, Beijing Innocare, Jiangsu Aikon, Sinopharm Group, Beijing Bailingwei, and Yunnan Xinlanjing.

[0136] The structures of the compounds synthesized in this disclosure were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0137] Nuclear magnetic resonance (NMR) measurements were performed using a Bruke AVANCE-400 / 600 NMR spectrometer. The deuterated solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0138] Mass spectrometry (MS) measurements were performed using Waters Acquity Plus device implementation.

[0139] High-performance liquid chromatography (HPLC) preparation was carried out using a Waters 2489 system.

[0140] The medium-pressure rapid preparative chromatograph is a COMBIFLASH NEXTGEN 300+.

[0141] The thin-layer chromatography silica gel plates used are Silica gel 60 thin-layer chromatography silica gel plates (aluminum plates, containing fluorescence).

[0142] The silica gel (100-200 mesh, 200-300 mesh) used in silica gel thin-layer chromatography was purchased from Inokai.

[0143] The reaction process in the examples was detected using thin-layer chromatography (TLC). The systems used to monitor the developing solvent and the eluent used to purify the compounds by column chromatography included: petroleum ether / ethyl acetate system and dichloromethane / methanol system.

[0144] Table 1: Abbreviations and full names of substances used in this invention

[0145] abbreviation Full name DIEA N,N-Diisopropylethylamine DCE dichloroethane DMF dimethylformamide TBTU O-benzotriazole-N,N,N',N'-tetramethylureatetrafluoroboric acid THF Tetrahydrofuran NaHMDS Sodium bis(trimethylsilyl)amino

[0146] Example 1: Synthesis of Compound 1

[0147]

[0148] Synthetic route

[0149]

[0150] Synthesis method

[0151] The synthesis of compounds 1-4 is based on the synthesis of 337-4 in Example 337 of published patent application WO2024 / 183778. The synthesis of compounds 1-5 is based on the synthesis of 298-3 in Example 298 of published patent application WO2024 / 183778. The difference is that 6-bromo-3,3-dimethylindol-2-one in step one is replaced with 6'-bromospiro[cyclopropane-1,3'-indololin]-2'-one. The synthesis of compound 1 is based on the synthesis of 337 in Example 337 of published patent application WO2024 / 183778, except that 337-7 in that patent is replaced with compounds 1-5.

[0152] Compound 1: LC-MS (ESI) m / z: 566.2 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ10.45(s,1H),8.06(d,J=8.8Hz,1H),7.93(d,J=14.2Hz,1H),7.76(d ,J=8.2Hz,1H),7.73-7.71(m,1H),7.56(t,J=8.0Hz,1H),7.24-7.19(m,2H),7.06(d,J=14.2H z,1H),7.01(dd,J=7.9,3.0Hz,2H),6.90(d,J=7.7Hz,1H),6.46-6.41(m,1H),3.32(s,6H),1. 73-1.68(m,2H),1.68-1.63(m,2H),1.02-0.95(m,2H),0.87-0.83(m,1H),0.80-0.74(m,2H).

[0153] Example 2: Synthesis of Compound 2

[0154]

[0155] Synthetic route

[0156]

[0157] Synthesis method

[0158] The synthesis of compound 2-2 is based on the synthesis of 332-2 in Example 332 of published patent application WO2024 / 183778, and the synthesis of compound 2-5 is based on the synthesis of 298-3 in Example 298 of published patent application WO2024 / 183778. The synthesis of compound 2 is based on the synthesis of Example 306 of published patent application WO2024 / 183778.

[0159] Compound 2: LC-MS (ESI) m / z: 564.2 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.23(t,J=5.7Hz,1H),7.90(d,J=8.8Hz,1H),7.69(d,J=14.1Hz,1H),7.49(d,J=2.0Hz ,1H),7.31(d,J=8.0Hz,1H),7.21(dd,J=8.7,1.9Hz,1H),7.05(d,J=1.6Hz,1H),6.95(dd,J=8.0,1.6Hz,1H),6. 56(d,J=14.1Hz,1H),5.58(d,J=8.0Hz,2H),4.06(t,J=7.6Hz,2H),3.62(q,J=7.0Hz,2H),3.27(q,J=6.6Hz,2H) ,3.20(s,3H),1.76(d,J=7.4Hz,1H),1.62(s,6H),1.27(t,J=7.1Hz,3H),1.00-0.94(m,2H),0.76-0.70(m,2H).

[0160] Example 3: Synthesis of Compound 3

[0161]

[0162] Synthetic route

[0163]

[0164] Synthesis method

[0165] The synthesis method of compound 3 is described in Example 298 of the published patent application WO2024 / 183778.

[0166] Compound 3: LC-MS (ESI) m / z: 572.2 [M+H] + . 1HNMR(600MHz,DMSO-d6)δ8.33(t,J=5.8Hz,1H),7.85(d,J=8.8Hz,1H),7.79(d,J=14.3H z,1H),7.49(d,J=2.0Hz,1H),7.19-7.15(m,2H),7.00(d,J=7.7Hz,1H),6.91-6.85(m,2H ),4.28(s,2H),3.62(q,J=7.0Hz,2H),3.21(s,2H),3.20(s,3H),1.72-1.61(m,4H),1.26 (t,3H),1.02-0.96(m,2H),0.86(t,J=6.9Hz,1H),0.79-0.75(m,2H),0.49-0.40(m,4H).

[0167] Example 4: Synthesis of Compound 4

[0168]

[0169] Synthetic route

[0170]

[0171] Synthesis method

[0172] The synthesis method of compound 4 is based on Example 298 of the published patent application WO2024 / 183778.

[0173] Compound 4: LC-MS (ESI) m / z: 535.2 [M+H] + . 1 HNMR (600MHz, DMSO-d6) δ8.24(t,J=5.7Hz,1H),7.90(d,J=8.8Hz,1H),7.85(d,J=14.4Hz,1H),7.52(d,J=2.0Hz, 1H),7.23(d,J=1.6Hz,1H),7.20(dd,J=8.7,2.0Hz,1H),7.14(d,J=8.1Hz,1H),6.99(dd,J=8.1,1.5Hz,1H),6.72 (d,J=14.4Hz,1H),4.09(t,J=7.6Hz,2H),3.62(q,J=7.0Hz,2H),3.30(q,J=6.5Hz,3H),3.20(s,3H),1.79(p,J=7 .1Hz,2H),1.50-1.43(m,1H),1.26(t,J=7.2Hz,3H),0.99-0.94(m,2H),0.86(t,J=6.9Hz,2H),0.77-0.70(m,2H).

[0174] Example 5: Synthesis of Compound 5

[0175]

[0176] Synthetic route

[0177]

[0178] Synthesis method

[0179] The synthesis of compound 5 was performed according to Example 298 in the published patent application WO2024 / 183778.

[0180] Compound 5: LC-MS (ESI) m / z: 582.3 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.28(t,J=5.7Hz,1H),8.09(d,J=8.5Hz,1H),7.70(d,J=14.3Hz,1H),7.66(d,J=1.8Hz ,1H),7.46(dd,J=8.6,1.7Hz,1H),7.32(d,J=7.7Hz,1H),7.07(d,J=1.5Hz,1H),6.91(dd,J=7.8,1.4Hz,1H),6 .83(d,J=14.3Hz,1H),4.16(t,J=7.5Hz,2H),3.65(q,J=7.0Hz,2H),3.30(q,J=6.5Hz,2H),3.23(s,3H),2.00( m,5.2Hz,1H),1.79(p,J=7.0Hz,2H),1.32(s,6H),1.28(t,J=7.1Hz,3H),1.00-0.94(m,2H),0.79-0.73(m,2H).

[0181] Example 6: Synthesis of Compound 6

[0182]

[0183] Synthetic route

[0184]

[0185] Synthesis method

[0186] The synthesis of compound 6-3 is based on the synthesis of 298-3 in Example 298 of published patent application WO2024 / 183778. The difference is that 6-bromo-3,3-dimethylindol-2-one in step one is replaced with 6'-bromospiro[cyclopropane-1,3'-indololin]-2'-one. The synthesis of compound 6-4 is based on the synthesis of 176-2 in Example 176 of published patent application WO2024 / 183778, the difference being that 7-chloro-4-(dimethylamino)quinazoline-2(1H)-one in step one is replaced with 7-trifluoromethyl-4-(dimethylamino)quinazoline-2(1H)-one. The synthesis of compound 6 is based on Example 298 of published patent application WO2024 / 183778.

[0187] Compound 6: LC-MS (ESI) m / z: 566.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.27(t,J=5.7Hz,1H),8.17(d,J=8.5Hz,1H),7.77(d,J=14.3Hz,1H),7.67 (s,1H),7.45(dd,J=8.5,1.6Hz,1H),7.13(s,1H),6.99(d,J=7.7Hz,1H),6.88(dd,J=7.7,1.4Hz,1 H),6.81(d,J=14.3Hz,1H),4.16(t,J=7.5Hz,2H),3.33-3.27(m,2H),3.25(s,6H),2.04-1.97(m,1 H),1.85-1.73(m,2H),1.70-1.64(m,2H),1.64-1.58(m,2H),1.02-0.93(m,2H),0.81-0.70(m,2H).

[0188] Example 7 Synthesis of Compound 7

[0189]

[0190] Synthetic route

[0191]

[0192] Synthesis method

[0193] The method for synthesizing compound 7 is described in Example 298 of the published patent application WO2024 / 183778.

[0194] Compound 7: LC-MS (ESI) m / z: 569.2 [M+H] + . 1HNMR (600MHz, DMSO-d6) δ8.25(t,J=5.7Hz,1H),8.10(d,J=8.5Hz,1H),7.84(d,J=14.4Hz,1H),7.68(s,1H),7. 47(dd,J=8.6,1.7Hz,1H),7.21(d,J=1.6Hz,1H),7.14(d,J=8.1Hz,1H),6.99(dd,J=8.2,1.5Hz,1H),6.69(d,J =14.4Hz,1H),4.17(t,J=7.6Hz,2H),3.65(q,J=7.0Hz,2H),3.31(q,J=6.6Hz,3H),3.23(s,3H),2.04-1.97(m, 2H),1.80(p,J=7.1Hz,2H),1.28(t,J=7.0Hz,3H),1.00-0.92(m,2H),0.86(t,J=6.9Hz,1H),0.77-0.70(m,2H).

[0195] Example 8: Synthesis of Compound 8

[0196]

[0197] Synthetic route

[0198]

[0199] Synthesis method

[0200] The synthesis of compound 8-1 is based on the synthesis of 291-2 in Example 291 of published patent application WO2024 / 183778, except that 2,4,7-trichloroquinazoline in step one is replaced with 2,4-dichloro-7-methylquinazoline. The synthesis of compound 8-3 is based on the synthesis of 176-2 in Example 176 of published patent application WO2024 / 183778.

[0201] Step 4: Synthesis of Compound 8

[0202] Compound 8-4 (30 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (0.50 mL) at room temperature, and DIEA (28 mg, 0.22 mmol) was added dropwise. The mixture was stirred at room temperature for 20 minutes. HATU (50 mg, 0.13 mmol) and N,N-dimethylformamide solutions of compound 8-3 (30 mg, 0.11 mmol) were added dropwise sequentially to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate (5 mL × 3) and water (5 mL). The combined organic phases were washed once with saturated brine (5 mL), dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. The solvent was removed under reduced pressure, and the mixture was purified by silica gel chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain crude compound 8. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to give product 8, 15.98 mg, yield 27%.

[0203] Compound 8: LC-MS (ESI) m / z: 526.2 [M+H] + 263.6 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.28(t,J=5.7Hz,1H),7.86(dd,J=8.5,3.3Hz,1H),7.80(d,J=14.3Hz,1H),7.31(d,J=3.2Hz,1H),7. 15(d,J=1.4Hz,1H),7.07(dd,1H),7.00(d,J=7.8Hz,1H),6.89(dd,J=7.8,1.4Hz,1H),6.84(d,J=14.3Hz,1H),4.12(t,J=7.5H z,2H),3.71-3.68(m,2H),3.32(q,J=6.5Hz,2H),3.29-3.27(m,3H),2.44(s,3H),2.02(tt,J=8.4,5.1Hz,1H),1.83(p,J=7.2 Hz,2H),1.68(q,J=4.0,3.3Hz,2H),1.63(q,J=3.6Hz,2H),1.29(td,J=7.0,1.7Hz,3H),1.01-0.95(m,2H),0.79-0.73(m,2H).

[0204] Example 9: Synthesis of Compound 9

[0205]

[0206] Synthetic route

[0207]

[0208] Synthesis method

[0209] The synthesis of compound 9 was performed according to Example 298 of published patent application WO2024 / 183778. Compound 9-4 (30 mg, 0.11 mmol), compound 9-5 (35 mg, 0.11 mmol), and 4-dimethylaminopyridine (7.0 mg, 0.053 mmol) were dispersed in 1,2-dichloroethane (1.0 mL). N,N'-dicyclohexylcarbodiimide (33 mg, 0.17 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The solvent was removed from the reaction mixture under reduced pressure, and the residue was purified by preparative liquid chromatography. The preparative solution was freeze-dried to give product 9, 4.28 mg, in a yield of 6.8%.

[0210] Compound 9: LC-MS (ESI) m / z: 594.3 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.25(t,J=5.7Hz,1H),8.10(d,J=8.5Hz,1H),7.70–7.66(m,2H),7.59(d,J=7.7Hz,1H ),7.47(dd,J=8.5,1.6Hz,1H),7.02(d,J=1.4Hz,1H),6.96(dd,J=7.8,1.4Hz,1H),6.80(d,J=14.3Hz,1H),4.1 6(t,J=7.5Hz,2H),3.65(q,J=7.1Hz,4H),3.29(q,J=6.6Hz,2H),3.24(s,3H),2.37-2.31(m,2H),2.29-2.16( m,2H),2.04-1.97(m,1H),1.80(p,J=7.0Hz,2H),1.28(t,J=7.0Hz,3H),1.01-0.95(m,2H),0.80–0.74(m,2H).

[0211] Example 10: Synthesis of Compound 10

[0212]

[0213] Synthetic route

[0214]

[0215] Synthesis method

[0216] The synthesis of compound 10-1 is based on Example 291-2 of published patent application WO2024 / 183778, except that methyl ethylamine is replaced with methylamine hydrochloride freed from N,N-diisopropylethylamine. The synthesis of compound 10-3 is based on Example 176-2 of published patent application WO2024 / 183778.

[0217] Step 4: Synthesis of Compound 10

[0218] Compound 10⁻³ (33 mg, 0.11 mmol), compound 10⁻⁴ (30 mg, 0.11 mmol), and 4-dimethylaminopyridine (7.0 mg, 0.053 mmol) were dispersed in 1,2-dichloroethane (1.0 mL). N,N'-dicyclohexylcarbodiimide (34 mg, 0.17 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. The solvent was removed by vacuum distillation, and the residue was purified by preparative liquid chromatography. The preparative solution was freeze-dried to give product 10, 7.92 mg, with a yield of 13%.

[0219] Compound 10: LC-MS (ESI) m / z: 552.2 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ8.65(q,J=4.4Hz,1H),8.30-8.23(m,2H),7.78(d,J=14.4Hz,1H),7. 64(s,1H),7.55(d,J=8.4Hz,1H),7.14(s,1H),7.03-6.97(m,1H),6.88(d,J=7.8Hz,1H),6.81 (d,J=14.3Hz,1H),4.18(t,J=7.5Hz,2H),3.28(q,J=6.6Hz,2H),2.95(d,J=4.1Hz,3H),2.03- 2.00(m,1H),1.78(p,J=7.0Hz,2H),1.71-1.59(m,4H),1.00-0.95(m,2H),0.78-0.72(m,2H).

[0220] Example 11 Synthesis of Compound 11

[0221]

[0222] Synthetic route

[0223]

[0224] Synthesis method

[0225] The synthesis of compound 11-1 is based on 291-2 of embodiment 291 in published patent application WO2024 / 183778, except that the substrate 2,4,7-trichloroquinazoline is replaced with 2,4-dichloro-7-fluoroquinazoline. The synthesis of compound 11-3 is based on 176-2 of example 176 in published patent application WO2024 / 183778.

[0226] Step 4: Synthesis of Compound 11

[0227] At room temperature, compound 11-4 (30 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (0.50 mL), and DIEA (28 mg, 0.22 mmol) was added dropwise. The mixture was stirred at room temperature for 20 minutes. HATU (50 mg, 0.13 mmol) and N,N-dimethylformamide solutions of compound 11-3 (30 mg, 0.11 mmol) were added dropwise sequentially to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate (5 mL × 3) and water (5 mL). The combined organic phases were washed once with saturated brine (5 mL), dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The solvent was removed by vacuum distillation, and the mixture was purified by silica gel chromatography (eluent: dichloromethane / methanol = 10 / 1) to obtain crude compound 5. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to give product 11, 7.76 mg, with a yield of 13%.

[0228] Compound 11: LC-MS (ESI) m / z: 530.3 [M+H] + 265.6 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6)δ

[0229] 8.23(t,J=5.7Hz,1H),7.99(dd,J=9.1,6.2Hz,1H),7.78(d,J=14.3Hz,1H),7.34(dd,J=11.6,2.5Hz,1H),7. 15(d,J=1.4Hz,1H),7.04(td,J=8.6,2.4Hz,1H),6.99(d,J=7.8Hz,1H),6.88(dd,J=7.8,1.3Hz,1H),6.83(d ,J=14.3Hz,1H),4.07(t,J=7.6Hz,2H),3.64(q,J=7.0Hz,2H),3.31-3.28(m,2H),3.22(s,3H),2.03-2.00(m ,1H),1.79(p,J=7.2Hz,2H),1.72-1.60(m,4H),1.28(t,J=7.0Hz,3H),1.01-0.94(m,2H),0.79-0.69(m,2H).

[0230] Example 12 Synthesis of Compound 12

[0231]

[0232] Synthetic route

[0233]

[0234] Synthesis method

[0235] The synthesis of compounds 12-4 is based on the synthesis of 337-4 in Example 337 of published patent application WO2024 / 183778. The difference is that 2-fluoro-4-chlorobenzamide in step one is replaced with 2-trifluoromethyl-4-chlorobenzamide. The synthesis of compounds 12-5 is based on the synthesis of 298-3 in Example 298 of published patent application WO2024 / 183778. The difference is that 6-bromo-3,3-dimethylindol-2-one in step one is replaced with 6'-bromospiro[cyclopropane-1,3'-indololin]-2'-one. The synthesis of compound 12 is based on the synthesis of 337 in Example 337 of published patent application WO2024 / 183778.

[0236] Compound 12: LC-MS (ESI) m / z: 600.2 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ10.46(s,1H),8.27(d,J=8.5Hz,1H),7.93(d,J=14.2Hz,1H),7.78(dd,J=8.2 ,2.1Hz,1H),7.76-7.73(m,1H),7.57(t,J=8.0Hz,1H),7.49(dd,J=8.6,1.8Hz,1H),7.23-7.19(m,1H ),7.08-7.02(m,2H),7.01(d,J=7.8Hz,1H),6.90(dd,J=7.7,1.4Hz,1H),6.71-6.67(m,1H),3.32(s, 6H),2.03-2.00(m,1H),1.72-1.68(m,2H),1.68-1.64(m,2H),1.01-0.95(m,2H),0.80-0.75(m,2H).

[0237] Example 13 Synthesis of Compound 13

[0238]

[0239] Synthetic route

[0240]

[0241] Synthesis method

[0242] The synthesis of compound 13 was performed in accordance with the synthesis described in Example 54 of the published patent application WO2024 / 183778.

[0243] Compound 13: LC-MS (ESI) m / z: 343.1 [M / 2+H] + . 1H NMR (600MHz, DMSO-d6) δ8.23(t,J=5.7Hz,1H),7.90(d,J=8.8Hz,1H),7.69(d,J=14.1Hz,1H),7.49(d,J=2.0Hz ,1H),7.31(d,J=8.0Hz,1H),7.21(dd,J=8.7,1.9Hz,1H),7.05(d,J=1.6Hz,1H),6.95(dd,J=8.0,1.6Hz,1H),6. 56(d,J=14.1Hz,1H),5.58(d,J=8.0Hz,2H),4.06(t,J=7.6Hz,2H),3.62(q,J=7.0Hz,2H),3.27(q,J=6.6Hz,2H) ,3.20(s,3H),1.76(d,J=7.4Hz,1H),1.62(s,6H),1.27(t,J=7.1Hz,3H),1.00-0.94(m,2H),0.76-0.70(m,2H).

[0244] Example 14 Synthesis of Compound 14

[0245]

[0246] Synthetic route

[0247]

[0248] Synthesis method

[0249] The synthesis of compounds 14-4 is based on the synthesis of 293-3 in Example 293 of the published patent application WO2024 / 183778. The difference is that 6-bromo-3,3-dimethylindole-2-one in step one is replaced with 6'-bromospiro[cyclopropane-1,3'-dihydroindole]-2'-one, and the synthesis of compounds 14-5 in step four is based on compounds 123-7 of the published patent application WO2024 / 183778.

[0250] Compound 14: LC-MS (ESI) m / z: 582.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.03(d,J=8.8Hz,1H),7.72(t,1H),7.20(dd,J=8.8,2.1Hz,1H),6.90-6.84(m,2 H),6.72(dd,J=7.7,1.4Hz,1H),6.55(dd,J=7.8,4.6Hz,2H),6.45(d,J=2.2Hz,1H),3.91-3.75(m,2H),3 .56-3.45(m,2H),3.30(s,6H),3.21-3.11(m,1H),2.76(p,J=7.3Hz,1H),2.02(dt,J=12.3,6.0Hz,1H),1 .91(tt,J=8.4,5.1Hz,1H),1.83-1.71(m,1H),1.58-1.42(m,4H),0.95-0.83(m,2H),0.72-0.62(m,2H).

[0251] Example 15 Synthesis of Compound 1

[0252]

[0253] Synthetic route

[0254]

[0255] Synthesis method:

[0256] The synthesis method of compound 15 is based on Example 314 of the published patent application WO2024 / 183778, except that 7-bromo-2(1H)-quinoxalone in step one is replaced with 5-bromo-1-methylbenzimidazol-2(3H)-one, and 1-(6-bromopyridin-2-yl)-7-chloro-4-(ethyl(methyl)amino)quinoxalone-2(1H)-one in step four is replaced with 1-(6-bromopyridin-2-yl)-7-chloro-4-(dimethylamino)quinoxalone-2(1H)-one.

[0257] Compound 15: LC-MS (ESI) m / z: 570.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.03(d,J=8.8Hz,1H),7.72(dd,J=8.4,7.3Hz,1H),7.19(dd,J=8.8,2.1Hz,1H ),6.99(d,J=8.0Hz,1H),6.94(d,J=1.6Hz,1H),6.81(dd,J=8.0,1.6Hz,1H),6.54(dd,J=7.9,3.4Hz,2H ),6.44(d,J=2.1Hz,1H),3.90(d,J=7.3Hz,2H),3.55-3.45(m,2H),3.29(d,J=4.6Hz,12H),3.21-3.09( m,1H),2.86-2.71(m,1H),1.96-1.85(m,1H),1.82-1.72(m,1H),0.90-0.82(m,2H),0.68-0.58(m,2H).

[0258] Example 16 Synthesis of Compound 16

[0259]

[0260] Synthetic route

[0261]

[0262] Synthesis method

[0263] Step 1: Synthesis of Compound 16-1

[0264] At room temperature, 1 g (2.62 mmol) of 5-bromo-2-oxospiro[indole-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester was dissolved in 15 mL of dry DMF. The solution was cooled to 0 °C, and sodium hydride (160 mg, 4.00 mmol) was slowly added under a nitrogen atmosphere. After the addition was complete, the mixture was allowed to rise to room temperature for 2 hours. Then, iodomethane (450 mg, 3.17 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours after the addition was complete. The reaction was monitored by LC-MS to ensure completeness. The reaction was quenched by adding saturated ammonium chloride solution in an ice bath. The mixture was extracted with water and ethyl acetate, and the combined organic phases were concentrated. The final product was then separated by rapid column chromatography (PE:EA, 0-100%, 10 min) to give 1.01 g of the title compound as a white solid.

[0265] LC-MS (ESI) m / z: 395.1 [M+H] + Yield: 97%

[0266] Step 2: Synthesis of Compound 16-2

[0267] Compound 16-1 (1.01 g, 2.56 mmol) was dissolved in 12 mL of dioxane and 3 mL of water at room temperature. Pd(dppf)Cl2 (210 mg, 0.26 mmol), pinacol cyclopropylborate (1.1 g, 6.55 mmol), and potassium carbonate (1.1 g, 7.97 mmol) were added, and the mixture was heated to 100 °C and microwaved for 1 hour. The reaction was monitored by LC-MS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (PE:EA, 0-30%, 10 min) to give 920 mg of the yellow oily title compound.

[0268] LC-MS (ESI) m / z: 357.2 [M+H] + Yield: 100%

[0269] Step 3: Synthesis of Compound 16-3

[0270] Compound 16-2 was dissolved in 5 mL of dry dioxane at room temperature, and 5 mL of dioxane hydrochloride solution was added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by LC-MS until complete. The reaction solution was filtered and lyophilized to give 600 mg of the title compound as a yellow solid.

[0271] LC-MS (ESI) m / z: 257.2 [M+H] + Yield: 91%

[0272] Step 4: Synthesis of Compound 16

[0273] The synthesis of compound 16-4 is based on Example 101 in the published patent application WO2024 / 183778, except that methyl ethylamine in step one is replaced with dimethylamine.

[0274] At room temperature, compounds 16-3 (33 mg, 0.128 mmol) and 16-4 (50 mg, 0.125 mmol) were dissolved in 2 mL of dry DMF, and cesium carbonate (82 mg, 0.252 mmol) was added. The mixture was heated to 120 °C and stirred overnight. The reaction was monitored by LCMS until complete. The reaction solution was directly concentrated and separated by rapid column chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 20 mg of crude product, which was then separated by high performance liquid chromatography to obtain 8 mg of the title compound as a white solid.

[0275] Compound 16: LC-MS (ESI) m / z: 575.2 [M+H]+, yield: 11%. 1H NMR(400MHz,DMSO-d6)δ8.01(d,J=8.8Hz,1H),7.80(d,J=2.0Hz,1H),7.60(s,1H ),7.24(dd,J=8.8,1.9Hz,1H),7.16(d,J=1.7Hz,1H),7.00(dd,J=8.0,1.7Hz,1H ),6.89(d,J=8.0Hz,1H),5.29(s,2H),3.89-3.82(m,4H),3.26(s,6H),3.09(s,3 H),1.93-1.84(m,3H),1.81-1.73(m,2H),0.92-0.81(m,2H),0.65-0.56(m,2H).

[0276] Example 17 Synthesis of Compound 17

[0277]

[0278] Synthetic route

[0279]

[0280] Synthesis method

[0281] The synthesis of compound 17-1 is based on compound 123-7 in published patent application WO2024 / 183778. The synthesis of compound 17-3 is based on Example 14, except that in step one of MA-F-YP-046-1, tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate is replaced with 2-bromo-5-bromomethylthiazole.

[0282] Step 1: Synthesis of Compound 2

[0283] At room temperature, compound 1 (0.20 g, 0.53 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and Pd(dppf)Cl2 (60 mg, 0.053 mmol), pinacol cyclopropylborate (0.67 mg, 2.6 mmol), and potassium acetate (0.16 mg, 1.6 mmol) were added. The mixture was heated to 100 °C and stirred for two hours. The reaction was monitored by LC-MS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (MeCN:H2O, 40%) to obtain 0.2 g of crude compound 2, which could be used directly in the next step. LC-MS (ESI) m / z: 345 [M+H] + .

[0284] Step 2: Synthesis of Compound 17

[0285] At room temperature, compounds 17-2 (50 mg, 0.15 mmol) and 17-3 (50 mg, 0.15 mmol) were dissolved in 1 mL of N,N-dimethylformamide. An aqueous solution of potassium carbonate (60 mg, 0.44 mmol) (0.10 mL) and Pd(dppf)Cl2·DCM (11 mg, 0.015 mmol) were added. After complete purging with nitrogen, the mixture was heated to 100 °C and stirred overnight. The reaction was monitored by LC-MS to ensure complete reaction. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (MeOH:DCM, 5%) to obtain crude compound 4. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to give product 4, 3.84 mg, yield 4.5%.

[0286] Compound 17: LC-MS (ESI) m / z: 595.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.17(d,J=2.1Hz,1H),8.58(d,J=2.2Hz,1H),8.29(t,J=2.1Hz,1 H),8.11(s,1H),8.04(d,J=8.8Hz,1H),7.23(dd,J=8.8,2.1Hz,1H),6.98(d,J=1.5Hz,1H) ,6.87(d,J=7.7Hz,1H),6.73(dd,J=7.7,1.5Hz,1H),6.52(d,J=2.1Hz,1H),5.26(s,2H), 3.31(s,6H),1.99-1.87(m,1H),1.60-1.47(m,4H),0.97-0.88(m,2H),0.72-0.63(m,2H).

[0287] Example 18 Synthesis of Compound 18

[0288]

[0289] Synthetic route

[0290]

[0291] Synthesis method

[0292] The synthesis of compound 18-3 was performed according to the synthesis of 173-2 in Example 173 of the published patent application WO2024 / 183778, except that potassium carbonate was replaced with cesium carbonate in step one, and the solvent DMF was replaced with 1,4-dioxane. At room temperature, compound 18-3 (20 mg, 0.065 mmol) was dissolved in 0.5 mL of dry DMF, and DIEA (17 mg, 0.13 mmol) and HATU (29 mg, 0.077 mmol) were added. After stirring at room temperature for 20 minutes, compound 18-4 (20 mg, 0.077 mmol) was added, and the mixture was stirred at room temperature for another 30 minutes. The reaction was monitored by LC-MS to ensure complete reaction. After extraction with water and ethyl acetate, the organic phases were combined, washed twice with saturated brine, concentrated, and separated by rapid column chromatography (DCM: MeOH, 0-10%, 6%) to obtain 20 mg of crude product. Then, the crude product was purified by high performance liquid chromatography, and the prepared solution was freeze-dried to obtain 8.68 mg of compound 18, yield: 25%.

[0293] Compound 18: LC-MS (ESI) m / z: 548.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=8.8Hz,1H),7.87(d,J=2.0Hz,1H),7.25(d,J=1.8Hz,1 H),7.21(dd,J=8.7,2.0Hz,1H),7.02(dd,J=8.1,1.7Hz,1H),6.89(d,J=8.0Hz,1H),4.11 -4.00(m,3H),3.90-3.80(m,1H),3.79-3.61(m,2H),3.23(s,6H),3.11(s,3H),2.55(d,J =6.5Hz,2H),1.95-1.80(m,4H),1.77-1.57(m,3H),0.93-0.84(m,2H),0.70-0.60(m,2H).

[0294] Example 19 Synthesis of Compound 19

[0295]

[0296] Synthetic route

[0297]

[0298] Synthesis method:

[0299] Step 1: Synthesis of Compound 19-1

[0300] At room temperature, 5-bromo-1-methylbenzimidazol-2(3H)-one (500 mg, 2.20 mmol) was dissolved in 10 mL of dry DCM, and di-tert-butyl dicarbonate (960 mg, 4.4 mmol) and DMAP (645 mg, 5.28 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until complete. After extraction with water and ethyl acetate, the organic phases were combined and concentrated, followed by separation by rapid column chromatography (PE:EA, 0-100%, 10 min) to give 250 mg of the title compound as a white solid.

[0301] LC-MS (ESI) m / z: 327.2 [M+H] + Yield: 35%

[0302] Step 2: Synthesis of Compound 19-2

[0303] At room temperature, compound 19-1 (150 mg, 0.46 mmol) was dissolved in 3 mL of dioxane and 1 mL of water. Pd(dppf)Cl2 (37 mg, 0.0466 mmol), pinacol cyclopropylborate (193 mg, 1.15 mmol), and potassium carbonate (190 mg, 1.38 mmol) were added, and the mixture was heated to 100 °C and reacted for 1 hour. The reaction was monitored by LC-MS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (PE:EA, 0-30%, 10 min) to give 80 mg of the yellow oily title compound.

[0304] LC-MS (ESI) m / z: 389.2 [M+H] + Yield: 61%

[0305] Step 3: Synthesis of Compound 19-3

[0306] Compound 19-2 was dissolved in 2 mL of dry dioxane at room temperature, and 2 mL of dioxane hydrochloride solution was added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by LC-MS until complete. The reaction solution was filtered and lyophilized to give 50 mg of the title compound as a yellow solid.

[0307] LC-MS (ESI) m / z: 189.2 [M+H] + Yield: 96%

[0308] Step 4: Synthesis of Compound 19-4

[0309] Compound 19-3 (180 mg, 0.96 mmol) was dissolved in 5 mL of dry DMF, and 2-bromo-5-bromomethylthiazole (492 mg, 1.92 mmol) and cesium carbonate (935 mg, 2.88 mmol) were added. The mixture was stirred at 100 °C for 3 hours. The reaction was monitored by LCMS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (PE:EA, 0-30%, 10 min) to give 268 mg of the title compound as a yellow oil.

[0310] LC-MS (ESI) m / z: 364.2 [M+H] + Yield: 77%

[0311] Step 5: Synthesis of Compound 19

[0312] Compound 19-4 (40 mg, 0.11 mmol), (5-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)pyridin-3-yl)boronic acid (57 mg, 0.165 mmol), Pd(dppf)Cl2 (9 mg, 0.011 mmol), and potassium carbonate (46 mg, 0.33 mmol) were reacted at 100 °C for 1 hour. The reaction was monitored by LCMS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (DCM: MeOH, 0-10%, 10 min) to give 3.3 mg of the title compound as a white sample.

[0313] Compound 19: LC-MS (ESI) m / z: 584.2 [M+H] + Yield: 5%. 1 H NMR (400MHz, DMSO-d6) δ9.17(d,J=2.1Hz,1H),8.60(d,J=2.2Hz,1H),8.30(t,J=2.2Hz ,1H),8.12(s,1H),8.05(d,J=8.8Hz,1H),7.22(dd,J=8.8,2.1Hz,1H),7.09(d,J=1.6Hz ,1H),7.01(d,J=8.1Hz,1H),6.83(dd,J=8.1,1.6Hz,1H),6.53(d,J=2.0Hz,1H),5.35( s,2H),3.30(s,9H),1.93(td,J=8.3,4.1Hz,1H),0.96-0.89(m,2H),0.69-0.61(m,2H).

[0314] Example 20 Synthesis of Compound 20

[0315]

[0316] Synthetic route

[0317]

[0318] Synthesis method:

[0319] The synthesis method of compound 20 is the same as that in Example 314 of the published patent application WO2024 / 183778, except for step one.

[0320] Step 1: Synthesis of Compound 20-1

[0321] At room temperature, tert-butyl 5-bromo-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate (70 mg, 0.19 mmol) was dissolved in 3 mL of dry DMF. The solution was cooled to 0 °C, and sodium hydride (23 mg, 0.57 mmol) was slowly added under a nitrogen atmosphere. After the addition was complete, the mixture was allowed to rise to room temperature for 2 hours. Then, iodomethane (54 mg, 0.38 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours after the addition was complete. The reaction was monitored by LC-MS to ensure completeness. The reaction was quenched by adding saturated ammonium chloride solution in an ice bath. The mixture was extracted with water and ethyl acetate, and the combined organic phases were concentrated. The final product was then separated by rapid column chromatography (PE:EA, 0-100%, 10 min) to give 70 mg of the title compound as a white solid.

[0322] LC-MS (ESI) m / z: 381.2 [M+H] + Yield: 96%

[0323] Step 4: Synthesis of Compound 20

[0324] The synthesis method of compound 20 is based on Example 314 of the published patent application WO2024 / 183778, except that 1-(6-bromopyridin-2-yl)-7-chloro-4-(ethyl(methyl)amino)quinazoline-2(1H)-one in step four is replaced with 4-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)butyric acid.

[0325] Compound 20: LC-MS (ESI) m / z: 534.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.96 (dd, J=8.8, 3.2Hz, 1H), 7.81 (t, J=2.1Hz, 1H), 7.20 (dd, J=8.8, 1.9Hz, 1H), 7.11-6.98(m,2H),6.91(dd,J=8.3,4.5Hz,1H),4.03(dp,J=20.5,7.1Hz,2H),3.85(q,J=6.6Hz,1H),3.7 3(q,J=6.2Hz,1H),3.68(s,1H),3.63-3.51(m,1H),3.22(d,J=3.7Hz,6H),3.12(d,J=2.6Hz,3H),2.38(d ,J=3.1Hz,1H),2.30-2.02(m,2H),1.95-1.70(m,3H),1.23(s,1H),0.93-0.83(m,2H),0.69-0.50(m,2H).

[0326] Example 21 Synthesis of Compound 21

[0327]

[0328] Synthetic route

[0329]

[0330] Synthesis method

[0331] The synthesis method of compound 21 is based on Example 300 in the published patent application WO2024 / 183778, except that the raw materials in step one are replaced with 4-(dimethylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one and 4-(bromomethyl)piperidin-1-carboxylic acid tert-butyl ester, and 1-(6-bromopyridin-2-yl)-7-chloro-4-(ethyl(methyl)amino)quinazoline-2(1H)-one in step three are replaced with 21-3.

[0332] Compound 21: LC-MS (ESI) m / z: 653.2 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ8.16(d,J=8.4Hz,1H),8.03(d,J=8.8Hz,1H),7.80-7.69(m,2H),7.45(d d,J=8.6,1.7Hz,1H),7.20(dd,J=8.8,2.2Hz,1H),6.94(d,J=8.5Hz,1H),6.60(d,J=7.2Hz,1H), 6.46(d,J=2.1Hz,1H),4.21(d,J=3.5Hz,2H),4.11(d,J=7.3Hz,2H),3.28(d,J=24.9Hz,12H),2. 76(td,J=12.9,2.7Hz,2H),2.09-1.97(m,1H),1.71-1.55(m,2H),1.29(qd,J=12.2,4.1Hz,2H).

[0333] Example 22 Synthesis of Compound 22

[0334]

[0335] Synthetic route

[0336]

[0337] Synthesis method

[0338] The synthesis method of compound 22 is based on Example 314 of the published patent application WO2024 / 183778, except that the starting materials in step one are replaced with 5-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one and tert-butyl 4-(bromomethyl)piperidin-1-carboxylic acid. In step four, 1-(6-bromopyridin-2-yl)-7-chloro-4-(ethyl(methyl)amino)quinazolin-2(1H)-one is replaced with 22-4.

[0339] Compound 22: LC-MS (ESI) m / z: 584.2 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ8.03(d,J=8.8Hz,1H),7.74(t,J=7.9Hz,1H),7.20(dd,J=8.8,2.1Hz,1H),6.99(d,J= 8.0Hz,1H),6.96–6.93(m,2H),6.77(d,J=1.5Hz,1H),6.60(d,J=7.2Hz,1H),6.45(d,J=2.0Hz,1H),4.22(dt, J=13.4,3.5Hz,2H),3.71(d,J=7.3Hz,2H),3.34(t,2H),3.30(s,6H),3.28(s,3H),2.83-2.71(m,2H),2.13-2 .01(m,1H),1.98-1.89(m,1H),1.58(dd,J=13.4,3.5Hz,2H),0.96-0.87(m,2H),0.65(dt,J=6.4,3.2Hz,2H).

[0340] Example 23 Synthesis of Compound 23

[0341]

[0342] Synthetic route

[0343]

[0344] Synthesis method

[0345] The synthesis of compound 23-3 is based on the synthesis of 123-7 in Example 123 of published patent application WO2024 / 183778. The synthesis of compound 23-4 is based on the synthesis of 123-4 in Example 123 of published patent application WO2024 / 183778. The difference is that tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate in step three is replaced with tert-butyl 4-(bromomethyl)piperidine-1-carboxylate. The synthesis of compound 23 is based on the synthesis of 123 in Example 123 of published patent application WO2024 / 183778.

[0346] Compound 23: LC-MS (ESI) m / z: 310.1 [M / 2+H] + . 1H NMR (600MHz, DMSO-d6) δ8.07(dd,J=8.8,4.5Hz,2H),7.77(t,J=7.9Hz,1H),7.70(d,J=2.0H z,1H),7.29(dd,J=8.8,1.9Hz,1H),7.24(dd,J=8.8,2.1Hz,1H),6.98(d,J=8.6Hz,1H),6.63 (d,J=7.3Hz,1H),6.50(d,J=2.1Hz,1H),4.24(dt,J=13.4,3.6Hz,2H),4.06(d,J=7.4Hz,2H) ,3.34(s,12H),2.87-2.73(m,2H),2.12-2.00(m,1H),1.72-1.62(m,2H),1.33-1.25(m,2H).

[0347] Example 24 Synthesis of Compound 24

[0348]

[0349] Synthetic route

[0350]

[0351] Synthesis method

[0352] The synthesis method of compound 24 is based on Example 298 of the published patent application WO2024 / 183778, except that step one of the synthesis is performed.

[0353] Step 1: Synthesis of Compound 24-1

[0354] At room temperature, 300 mg (1.32 mmol) of 5-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one was dissolved in 5 mL of dry DMF, and ethyl 4-bromobutyrate (515 mg, 2.64 mmol) and cesium carbonate (1.29 g, 3.96 mmol) were added. The reaction was carried out overnight at 100 °C. The reaction was monitored by LC-MS until complete. After extraction with water and ethyl acetate, the organic phases were combined, washed twice with brine, concentrated, and then separated by rapid column chromatography (PE:EA, 0-100%, 10 min) to give 400 mg of the title compound as a white solid.

[0355] LC-MS (ESI) m / z: 341.2 [M+H] + Yield: 88.7%

[0356] Step 4: Synthesis of Compound 24

[0357] The synthesis method of compound 24 is based on Example 298 of the published patent application WO2024 / 183778, except that step 4, 293-3, is replaced with 1-(3-aminopropyl)-7-chloro-4-(ethyl(methyl)amino)quinazolin-2(1H)-one.

[0358] Compound 24: LC-MS (ESI) m / z: 551.3 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ7.93(t,J=5.6Hz,1H),7.88(d,J=8.8Hz,1H),7.45(d,J=2.0Hz,1H),7.18(dd,J=8 .8,1.9Hz,1H),6.98(d,J=8.0Hz,1H),6.88(d,J=1.6Hz,1H),6.78(dd,J=8.1,1.6Hz,1H),4.02(t,2H),3.8 1(t,J=6.9Hz,2H),3.61(q,J=7.0Hz,2H),3.28(s,3H),3.19(s,3H),3.12(q,J=6.5Hz,2H),2.12(t,J=7.5H z,2H),1.96-1.80(m,3H),1.73-1.60(m,2H),1.25(t,J=7.0Hz,3H),0.93-0.84(m,2H),0.69-0.55(m,2H).

[0359] Example 25 Synthesis of Compound 25

[0360]

[0361] Synthetic route

[0362]

[0363] Synthesis method:

[0364] The synthesis of compound 25 is based on Example 314 of the published patent application WO2024 / 183778, except that the starting materials in step one are replaced with 5-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one and tert-butyl 4-(bromomethyl)piperidin-1-carboxylate. Tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate is replaced with tert-butyl 3-(bromomethyl)azatidine-1-carboxylate. In step four, 1-(6-bromopyridin-2-yl)-7-chloro-4-(ethyl(methyl)amino)quinazolin-2(1H)-one is replaced with 25-4.

[0365] Compound 25: LC-MS (ESI) m / z: 556.2 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ8.03(d,J=8.8Hz,1H),7.74(dd,J=8.3,7.3Hz,1H),7.20(dd,J=8.8,2.1Hz, 1H),7.05–6.94(m,2H),6.81(dd,J=8.1,1.6Hz,1H),6.63(d,J=7.3Hz,1H),6.49(d,J=8.2Hz,1H),6 .41(d,J=2.1Hz,1H),4.13(d,J=7.4Hz,2H),3.96(t,J=8.1Hz,2H),3.78(dd,J=8.2,5.3Hz,2H),3.2 9(s,6H),3.28(s,3H),3.21-3.08(m,1H),1.96-1.88(m,1H),0.94-0.85(m,2H),0.73-0.58(m,2H).

[0366] Example 26 Synthesis of Compound 26

[0367]

[0368] Synthetic route

[0369]

[0370] Synthesis method

[0371] The synthesis of compound 26-3 is based on Example 293 of published patent application WO2024 / 183778. The difference is that 6-bromo-3,3-dimethylindol-2-one in step one is replaced with 6'-bromospiro[cyclopropane-1,3'-indololin]-2'-one, and tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate is replaced with tert-butyl 4-(bromomethyl)piperidine-1-carboxylate. The synthesis of compound 26-4 is based on the synthesis of 123-7 in Example 123 of published patent application WO2024 / 183778. The synthesis of compound 26 is based on the synthesis of 123 in Example 123 of published patent application WO2024 / 183778.

[0372] Compound 26: LC-MS (ESI) m / z: 595.3 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ8.03(d,J=8.8Hz,1H),7.75(dd,J=8.6,7.3Hz,1H),7.20(dd,J=8.8,2.1Hz,1H), 6.95(d,J=8.6Hz,1H),6.90–6.82(m,2H),6.68(dd,J=7.7,1.5Hz,1H),6.60(d,J=7.3Hz,1H),6.46(d,J=2 .1Hz,1H),4.23(d,J=13.1Hz,2H),3.64(d,J=7.3Hz,2H),3.30(s,6H),2.80(t,J=12.4Hz,2H),1.98-1.8 9(m,1H),1.67-1.58(m,2H),1.58-1.42(m,4H),1.30-1.19(m,4H),0.97-0.88(m,2H),0.72-0.65(m,2H).

[0373] Example 27 Synthesis of Compound 27

[0374]

[0375] Synthetic route

[0376]

[0377] Synthesis method

[0378] The synthesis of compound 27-3 is based on Example 293 of published patent application WO2024 / 183778. The difference is that 6-bromo-3,3-dimethylindol-2-one in step one is replaced with 6'-bromospiro[cyclopropane-1,3'-indololin]-2'-one, and tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate is replaced with tert-butyl 3-(bromomethyl)azacyclobutane-1-carboxylate. The synthesis of compound 27 is based on the synthesis in Example 123 of published patent application WO2024 / 183778.

[0379] Compound 27: LC-MS (ESI) m / z: 567.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.03(d,J=8.9Hz,1H),7.75(dd,J=8.3,7.4Hz,1H),7.21(dd,J=8.8,2.1Hz,1H),6. 92(d,J=1.5Hz,1H),6.86(d,J=7.7Hz,1H),6.72(dd,J=7.7,1.5Hz,1H),6.64(d,J=7.3Hz,1H),6.51(d,J=8 .1Hz,1H),6.41(d,J=2.1Hz,1H),4.11-3.94(m,4H),3.76(dd,J=8.2,5.2Hz,2H),3.30(s,6H),3.20-3.06( m,1H),1.98-1.88(m,1H),1.57-1.44(m,4H),1.18(t,J=7.1Hz,1H),0.96-0.89(m,2H),0.74-0.67(m,2H).

[0380] Example 28 Synthesis of Compound 28

[0381]

[0382] Synthetic route

[0383]

[0384] Synthesis method

[0385] Step 1: Synthesis of Compound 28-1

[0386] At room temperature, (5-aminopyridin-3-yl)methanol (500 mg, 4.03 mmol) was dissolved in 10 mL of dry DMF, and imidazole (550 mg, 8.09 mmol) was added. Then, TBS-Cl (700 mg, 4.64 mmol) was dissolved in DMF and added dropwise to the reaction system. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS until complete. After extraction with water and ethyl acetate, the combined organic phases were concentrated and then separated by rapid column chromatography (DCM:Me, 0-10%, 10 min) to obtain 910 mg of the yellow liquid title compound.

[0387] LC-MS (ESI) m / z: 239.2 [M+H] + Yield: 94%

[0388] Step 2: Synthesis of Compound 28-2

[0389] At room temperature, 2-fluoro-4-chlorobenzamide (700 mg, 4.02 mmol) was dissolved in 10 mL of DCE. The solution was cooled to 0 °C, and oxalyl chloride (780 mg, 6.05 mmol) was slowly added dropwise. The solution was then slowly heated to room temperature and then to 70 °C with stirring for 3 hours. Excess oxalyl chloride was then concentrated to remove excess oxalyl chloride, dissolved in 5 mL of DCE, and added dropwise to a 20 mL DCE solution of compound 1 (910 mg, 3.81 mmol). The reaction was maintained at room temperature for 20 minutes. A large amount of white solid precipitated. Filtration yielded 1.31 g of the title compound as a white solid.

[0390] LC-MS (ESI) m / z: 438.1 [M+H] + Yield: 78%

[0391] Step 3: Synthesis of Compound 28-3

[0392] Compound 28-2 (1.3 g, 2.97 mmol) was dissolved in 30 mL of DMF at room temperature. The solution was cooled to 0 °C, and sodium hydride (250 mg, 6.25 mmol) was added in portions. The mixture was stirred at room temperature for 10 minutes, then heated to 90 °C and stirred for 2 hours. The reaction was monitored by LC-MS until complete, and the reaction was quenched with water. The pH was then adjusted to approximately 6 with 1 M hydrochloric acid, resulting in the precipitation of a solid. The solid was filtered, and the filter cake was lyophilized to give 850 mg of the title compound as a white solid.

[0393] LC-MS (ESI) m / z: 418.1 [M+H] + Yield: 69%

[0394] Step 4: Synthesis of Compound 28-4

[0395] At room temperature, compound 28-3 (500 mg, 1.20 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and PyBOP (930 mg, 1.79 mmol) and a tetrahydrofuran solution of dimethylamine (2N, 1.5 mL) were added. After stirring at room temperature for 10 min, DBU (630 mg, 4.14 mmol) was slowly added dropwise. The mixture was then stirred at room temperature for 30 min, during which time the system changed from turbid to clear. The reaction was monitored by LCMS until complete, and the concentrate was separated by rapid column chromatography (DCM:Me, 0-10%, 10 min) to give 450 mg of the yellow oily title compound.

[0396] LC-MS (ESI) m / z: 445.2 [M+H] + Yield: 85%

[0397] Step 5: Synthesis of Compound 28-5

[0398] At room temperature, compound 28-4 (500 mg, 1.12 mmol) was dissolved in 10 mL of anhydrous THF, and 1.2 mL of TBAF (1 N) was added. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until complete, and the concentrate was separated by rapid column chromatography (H2O:MeCN, 0-100%, 20 min) to give 320 mg of the title compound as a white solid.

[0399] LC-MS (ESI) m / z: 331.1 [M+H] + Yield: 86%

[0400] Step Six: Synthesis of Compound 28-6

[0401] Compound 28-5 (320 mg, 0.97 mmol) was dissolved in 5 mL of anhydrous DCM at room temperature. After cooling to 0°C, boron tribromide (320 mg, 1.18 mmol) was slowly added dropwise. The mixture was then brought to room temperature and stirred for 1 hour. The reaction was monitored by LCMS until complete. The reaction was quenched with sodium bicarbonate solution, extracted with water and ethyl acetate, and the combined organic phases were concentrated. The mixture was then separated by rapid column chromatography (DCM:Me, 0-10%, 10 min) to give 200 mg of the title compound as a white solid.

[0402] LC-MS(ESI) m / z: 393 [M+H] + Yield: 53%

[0403] Step 7: Synthesis of Compound 28

[0404] The synthesis of compound 28-7 was performed in accordance with the synthesis of compound 16-3 in Example 16.

[0405] At room temperature, compounds 28-6 (50 mg, 0.17 mmol) and 28-7 (40 mg, 0.16 mmol) were dissolved in 2 mL of dry DMF, and cesium carbonate (120 mg, 0.37 mmol) was added. The mixture was heated to 80 °C and stirred overnight. The reaction was monitored by LCMS until complete. The reaction solution was directly concentrated and separated by rapid column chromatography (DCM: MeOH, 0-10%, 10 min) to obtain 20 mg of crude product, which was then separated by high performance liquid chromatography to obtain 11 mg of the title compound as a white solid.

[0406] Compound 28: LC-MS (ESI) m / z: 285.1 [M / 2+H] + Yield: 11%. 1H NMR (400MHz, DMSO-d6) δ8.84-8.66(m,1H),8.58-8.35(m,1H),8.07(d,J=8.8Hz,1H),7.96-7 .74(m,1H),7.24(dd,J=8.8,2.1Hz,1H),7.22-7.07(m,1H),7.00(d,J=8.1Hz,1H),6.89(d,J= 8.2Hz,1H),6.56-6.41(m,1H),4.00-3.64(m,2H),3.43-3.36(m,2H),3.32(s,6H),3.09(s,3 H),2.91(s,1H),2.78-2.62(m,1H),1.97-1.63(m,5H),0.95-0.86(m,2H),0.66-0.58(m,2H).

[0407] Example 29 Synthesis of Compound 29

[0408]

[0409] Synthetic route

[0410]

[0411] The synthesis of compound 29-3 is based on Example 123 of published patent application WO2024 / 183778, except that 2,4,7-trichloroquinazoline in step one is replaced with 2,4-dichloro-7-trifluoromethylquinazoline, and 1-Boc-3-bromomethylpyrrolidine in step three is replaced with (3R)-3-bromomethyl-1-pyrrolidinecarboxylate tert-butyl ester. The synthesis of compound 29-6 is based on Example 123 of published patent application WO2024 / 183778, except that 4-chloro-2-fluorobenzamide in step five is replaced with 2-chloro-6-trifluoromethylnicotinamide.

[0412] Compound 29: LC-MS (ESI) m / z: 688.3 [M+H] + 344.6 [M / 2+H] + . 1H NMR(600MHz,DMSO-d6)δ8.61(d,J=8.2Hz,1H),8.17(d,J=8.5Hz,1H),7.77(s,1H),7.66–7.59(m ,2H),7.46(d,J=8.6Hz,1H),6.46(dd,J=11.5,7.9Hz,2H),4.31(ddd,J=51.0,14.6,7.3Hz,2H),3 .76(q,J=7.0Hz,2H),3.56-3.47(m,2H),3.37(s,3H),3.28(s,1H),3.26(s,6H),3.19(dd,J=10. 6,7.4Hz,1H),2.69(p,J=7.3Hz,1H),2.05-2.01(m,1H),1.8-1.78(m,1H),1.32(t,J=7.0Hz,3H).

[0413] Example 30 Synthesis of Compound 30

[0414]

[0415] Synthetic route

[0416]

[0417] Synthesis method

[0418] Step 1: Synthesis of Compound 30-1

[0419] Under nitrogen protection, 2-fluoro-4-chlorobenzamide (0.46 g, 2.7 mmol) was dissolved in 1,2-dichloroethane (5.0 mL), cooled to 0 °C, and oxalyl chloride (0.50 g, 4.0 mmol) was slowly added dropwise. After the addition was complete, the mixture was heated to 55 °C and stirred for 1 hour, then heated to 80 °C and stirred for 2 hours. After the reaction solution cooled to room temperature, it was concentrated under reduced pressure to give a white solid. Under nitrogen protection, this solid was dissolved in 1,2-dichloroethane (2.0 mL), and the solution was slowly added dropwise at 0 °C to 1,2-dichloroethane (1.0 mL). After the addition was complete, the mixture was reacted at room temperature for 10 minutes until a large amount of white solid precipitated. The solid was filtered and dried to give compound 30-1, 0.96 g, with a yield of 97%. LC-MS (ESI) m / z: 406 [M+H] + .

[0420] Step 2: Synthesis of Compound 30-2

[0421] Compound 4 (0.96 g, 2.4 mol) was dissolved in N,N-dimethylformamide (20 mL). Under nitrogen protection, NaH (1.7 g, 60%, dispersed in paraffin) was added at 0 °C. After stirring for five minutes, the mixture was heated to 90 °C and reacted for two hours. After the reaction solution cooled to room temperature, excess water was added while stirring to quench the reaction. The pH was then adjusted to 6–7 with dilute hydrochloric acid solution, during which a large amount of white solid precipitated. The solid was filtered and dried to obtain 0.4 g of crude compound 30-2, which was used directly in the next step. LC-MS (ESI) m / z: 386 [M+H] + .

[0422] Step 3: Synthesis of Compound 30-3

[0423] Compound 30-2 (0.30 g, 0.78 mmol) was dissolved in 2.0 mL of anhydrous acetonitrile at room temperature. The solution was cooled to 0 °C, and DIEA (0.5 g, 3.9 mmol) and phosphorus oxychloride (0.3 g, 1.9 mmol) were added. The mixture was slowly heated to room temperature and then stirred at 80 °C for two hours. The reaction solution was concentrated to remove a large amount of phosphorus oxychloride, and then a tetrahydrofuran solution of dimethylamine (5.0 mL, 2 M in THF) was added. The mixture was stirred at room temperature for ten minutes. The reaction was monitored by LC-MS to ensure complete reaction. After concentration, the solution was purified by C-18 reversed-phase column chromatography (eluent: MeCN / H2O, 60%) to give 0.18 g of compound 30-3, in 56% yield. LC-MS (ESI) m / z: 413 [M+H] + .

[0424] Step 4: Synthesis of Compound 30-4

[0425] Compound 30-3 (0.15 g, 0.37 mmol) was dissolved in 2 mL of 1,4-dioxane at room temperature. (dppf)PdCl2·DCM (31 mg, 0.037 mmol), pinacol diboronate (0.14 g, 0.56 mmol), and potassium acetate (0.11 g, 1.1 mmol) were added. The mixture was heated to 120 °C and stirred for three hours. After the reaction was monitored by LC-MS to ensure completion, the reaction solution was filtered through diatomaceous earth. The filter cake was washed three times with methanol, and the filtrate was concentrated under reduced pressure. The residue was purified by C-18 reversed-phase column chromatography (MeCN: H2O, 40%) to give 0.55 g of compound 30-4 as a white solid, in 32% yield. LC-MS (ESI) m / z: 379 [M+H] + .

[0426] Step 5: Synthesis of Compound 30

[0427] At room temperature, compounds 30-4 (45 mg, 0.098 mmol) and 30-5 (78 mg, 0.20 mmol) were dissolved in 1 mL of a mixed solvent of 1,4-dioxane and 0.1 mL of N,N-dimethylformamide. An aqueous solution of potassium carbonate (40 mg, 0.029 mmol) (0.10 mL) and (dppf)PdCl2·DCM (40 mg, 0.049 mmol) were added. After complete purging with nitrogen, the mixture was heated to 120 °C and stirred for two hours. The reaction was monitored by LC-MS to ensure complete reaction. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (eluent: MeOH / DCM = 6%) to obtain 50 mg of crude compound 5. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain product 30, 24.01 mg, with a yield of 38%.

[0428] Compound 30: LC-MS (ESI) m / z: 653.1 [M+H] + 327.0 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.03(d,J=2.3Hz,1H),8.51(d,J=2.3Hz,1H),8.23(s,1H),8.09(d,J=8.8Hz,1H),7.98(d,J=8.8Hz,1 H),7.78(d,J=2.0Hz,1H),7.23(ddd,J=18.5,8.8,2.0Hz,2H),6.67(d,J=2.0Hz,1H),5.56(s,2H),3.34(s,6H),3.25(s,6H).

[0429] Example 31 Synthesis of Compound 31

[0430]

[0431] Synthetic route

[0432]

[0433] Synthesis method

[0434] Step 1: Synthesis of Compound 31-1

[0435] At room temperature, 4-bromobenzylamine (1 g, 5.38 mmol) was dissolved in 20 mL of dry DCM. Triethylamine (1.6 g, 15.8 mmol) was added, and the mixture was cooled to 0 °C. Methacryl chloride (670 mg, 6.44 mmol) was slowly added under a nitrogen atmosphere. After the addition was complete, the mixture was allowed to rise to room temperature for 1 hour. The reaction was monitored by LC-MS to ensure complete reaction. The reaction was quenched by dropwise addition of saturated sodium bicarbonate solution in an ice bath. After extraction with water and dichloromethane, the combined organic phases were concentrated and then separated by rapid column chromatography (PE:EA, 0-100%, 10 min) to give 1.48 g of the title compound as a white solid.

[0436] LC-MS (ESI) m / z: 254.0 [M+H] + Yield: 100%

[0437] Step 2: Synthesis of Compound 31-2

[0438] Compound 31-1 (1 g, 3.95 mmol) was dissolved in 12 mL of dioxane and 3 mL of water at room temperature. Pd(dppf)Cl2 (330 mg, 0.404 mmol), pinacol cyclopropylborate (2.6 g, 15.5 mmol), and potassium carbonate (1.6 g, 11.6 mmol) were added, and the mixture was heated to 100 °C and microwaved for 1 hour. The reaction was monitored by LC-MS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (PE:EA, 0-30%, 10 min) to give 490 mg of the yellow oily title compound.

[0439] LC-MS (ESI) m / z: 216.1 [M+H] + Yield: 58%

[0440] Step 3: Synthesis of compound 31-3

[0441] Compound 31-2 (410 mg, 1.91 mmol) and tert-butyl 3-bromopyrrolidine-1-carboxylate (950 mg, 3.8 mmol) were dissolved in 10 mL of toluene at room temperature. Pd(AcO)₂ (50 mg, 0.223 mmol), DPPF (210 mg, 0.379 mmol), and cesium carbonate (1.55 g, 4.75 mmol) were added, and the mixture was heated to 100 °C and reacted overnight in an oil bath. The reaction was monitored by LCMS until complete. The reaction solution was directly concentrated and separated by rapid column chromatography (PE:EA, 0-100%, 10 min) to obtain 300 mg of the yellow oily title compound.

[0442] LC-MS (ESI) m / z: 385.2 [M+H] + Yield: 65%

[0443] Step 5: Synthesis of Compound 31

[0444] The synthesis of compound 31 is based on the synthesis of 123 in Example 123 of the published patent application WO2024 / 183778. The difference is that compound 123-4 in WO2024 / 183778 is replaced with compound 31-4 in this example.

[0445] Compound 31: LC-MS (ESI) m / z: 583.3 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.03(d,J=8.8Hz,1H),7.68(t,J=7.8Hz,1H),7.21(dd,J=8.9,2.1Hz,1H),7.10(d,J=1.8 Hz,1H),6.99(dd,J=8.1,1.7Hz,1H),6.83(d,J=8.0Hz,1H),6.52(d,J=7.3Hz,1H),6.42-6.37(m,2H),3.31-3.26 (m,8H),3.24-3.16(m,1H),3.05-2.98(m,4H),2.73(t,J=9.8Hz,1H),2.09-2.02(m,1H),1.97-1.87(m,2H),1.74 -1.63(m,1H),1.60-1.50(m,1H),1.42-1.31(m,1H),1.25(s,3H),0.90(dd,J=8.5,2.5Hz,2H),0.68-0.58(m,2H).

[0446] Example 32 Synthesis of Compound 32

[0447]

[0448] Synthetic route

[0449]

[0450] Synthesis method

[0451] The synthesis method of compound 32 is the same as that in Example 30, except that 2-chloro-3-amino-5-bromopyridine in step one is replaced with 5-bromo-3-aminopyridine, and 4-chloro-2-fluorobenzamide is replaced with 2-chloro-6-trifluoromethylnicotinamide.

[0452] Compound 32: LC-MS (ESI) m / z: 654.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.08(d,J=2.1Hz,1H),8.73(d,J=8.2Hz,1H),8.57(d,J=2.2Hz,1H),8.27(t,J=2.1Hz,1H),8.18(s,1H),7.9 8(d,J=8.8Hz,1H),7.79(d,J=2.0Hz,1H),7.65(d,J=8.2Hz,1H),7.21(dd,J=8.8,1.9Hz,1H),5.55(s,2H),3.40(s,6H),3.25(s,6H).

[0453] Example 33 Synthesis of Compound 33

[0454]

[0455] Synthetic route

[0456]

[0457] The synthesis of compound 33-4 is based on the synthesis of 337-4 in Example 337 of the published patent application WO2024 / 183778, except that 2-fluoro-4-chlorobenzamide in step one is replaced with 2-fluoro-4-(trifluoromethyl)benzamide.

[0458] Step 1: Synthesis of Compound 33-1

[0459] 6'-Bromospiro[cyclopropane-1,3'-dihydroindole]-2'-one (0.30 g, 1.3 mmol), methyl 3-bromopropionate (0.32 g, 1.9 mmol), and cesium carbonate (1.2 g, 3.9 mmol) were dispersed in N,N-dimethylformamide (3.0 mL) solution and heated to 100 °C with stirring for three hours. After the reaction was complete as monitored by TLC, the reaction mixture was extracted with ethyl acetate (10 mL × 3) and water (10 mL), and the combined organic phases were washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the drying agent was filtered off, the solvent was removed by vacuum distillation, and the residue was purified by rapid column chromatography (eluent: ethyl acetate / petroleum ether = 8%) to give compound 33-1, 0.15 g. Yield: 36%. LC-MS (ESI) m / z: 324.0 [M+H] + .

[0460] Step 2: Synthesis of Compound 33-2

[0461] Compound 33-1 (0.15 g, 0.045 mmol) and pinacol cyclopropylborate (0.11 g, 0.068 mmol) were dissolved in 1,4-dioxane (2.0 mL) solution. A solution of potassium carbonate (0.19 g, 1.4 mmol) in water (0.3 mL) was added to the reaction mixture. The mixture was purged with nitrogen for three minutes, and then 1,1'-bis(diphenylphosphine)ferrocene[dichloride]palladium dichloromethane complex (0.037 g, 0.0045 mmol) was added. The mixture was heated to 100 °C and stirred overnight. After the reaction solution cooled to room temperature, it was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate and water, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. After the solvent was removed by vacuum evaporation, the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 10%) to give compound 33-2, 0.080 g, as a white oily substance, in 63% yield. LC-MS (ESI) m / z: 286.1 [M+H] + .

[0462] Step 3: Synthesis of compound 33-3

[0463] Compound 33-2 (80 mg, 0.028 mmol) was dispersed in methanol (2.0 mL) at room temperature. Lithium hydroxide monohydrate (24 mg, 0.056 mmol) was dissolved in water (0.30 mL) and added dropwise to the reaction mixture. The mixture was stirred overnight at room temperature. After vacuum distillation, a small amount of water was added to the residue, and 1N dilute hydrochloric acid was added dropwise to adjust the pH to 3–4. The mixture was stirred at room temperature for 10 minutes. Extraction was performed with ethyl acetate (5 mL × 6). The concentrated organic phases were combined to give compound 33-3, 50 mg, as a white solid, in 66% yield. LC-MS (ESI) m / z: 272.1 [M+H] + .

[0464] Step 4: Synthesis of Compound 33

[0465] At room temperature, compound 33-3 (25 mg, 0.072 mmol) was dissolved in N,N-dimethylformamide (0.50 mL), and a DMF solution of DIEA (19 mg, 0.014 mmol) and HATU (33 mg, 0.086 mmol) (0.3 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. A solution of compound 33-4 (20 mg, 0.072 mmol) in N,N-dimethylformamide (0.5 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for one hour. The reaction mixture was extracted with ethyl acetate and water. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography (eluent: dichloromethane / methanol = 12 / 1) to obtain 30 mg of crude compound 33. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain 33,22.01 mg of product, with a yield of 51%.

[0466] Compound 33: LC-MS (ESI) m / z: 602.2 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ10.25(s,1H),8.25(d,J=8.5Hz,1H),7.61(dd,J=8.3,2.1,1.1Hz,1H),7.59(t,J=2 .0Hz,1H),7.53(t,J=8.0Hz,1H),7.48(dd,J=8.6,1.8Hz,1H),7.01(ddd,J=7.7,2.1,1.0Hz,1H),6.87-6.82 (m,2H),6.70(dd,J=7.7,1.5Hz,1H),6.64(d,J=1.8Hz,1H),4.04(t,J=7.1Hz,2H),3.35(s,6H),2.69(t,J= 7.1Hz,2H),1.90-1.83(m,1H),1.54-1.50(m,2H),1.48-1.43(m,2H),0.88-0.81(m,2H),0.67-0.60(m,2H).

[0467] Example 34 Synthesis of Compound 34

[0468]

[0469] Synthetic route

[0470]

[0471] Synthesis method

[0472] Step 1: Synthesis of Compound 34-1

[0473] At room temperature, 5-bromo-1-methyl-2-indolone (1.05 g, 4.644 mmol) was dissolved in 10 mL of dioxane and 1 mL of water. Pd(dppf)Cl₂ (379 mg, 0.4644 mmol), pinacol cyclopropylborate (3.12 g, 18.576 mmol), and potassium carbonate (1.93 g, 13.932 mmol) were added, and the mixture was heated to 100 °C and reacted for 1 hour. The reaction was monitored by LC-MS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, concentrated, and then separated by rapid column chromatography (PE:EA, 0-30%, 10 min) to give 360 ​​mg of the yellow oily title compound.

[0474] LC-MS (ESI) m / z: 188.2 [M+H] + Yield: 41.1%

[0475] Step 2: Synthesis of Compound 34-2

[0476] Compound 34-1 (100 mg, 0.534 mmol) was dissolved in ethanol, and 1-tert-butoxycarbonylpiperidine-4-carboxaldehyde (228 mg, 1.068 mmol) and piperidine (182 mg, 2.136 mmol) were added. The mixture was heated to 80 °C and reacted for 1 hour. The reaction was monitored by LCMS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (PE:EA, 0-30%, 10 min) to give 190 mg of the yellow oily title compound.

[0477] LC-MS (ESI) m / z: 383.2 [M+H] + Yield: 93%

[0478] Step 3: Synthesis of Compound 34-3

[0479] Compound 34-2 (190 mg, 0.497 mmol) was dissolved in methanol, and palladium on carbon (11 mg, 0.1 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was filtered and concentrated to give 90 mg of the colorless oily title compound.

[0480] LC-MS (ESI) m / z: 385.2 [M+H] + Yield: 47.12%

[0481] Step 4: Synthesis of Compound 34-4

[0482] Compound 34-3 was dissolved in 2 mL of dry dioxane at room temperature, and 2 mL of dioxane hydrochloride solution was added dropwise. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS until complete. The reaction solution was filtered and lyophilized to give 40 mg of the title compound as a yellow solid.

[0483] LC-MS (ESI) m / z: 285.2 [M+H] + Yield: 60%

[0484] Step 5: Synthesis of Compound 34

[0485] Compound 34-4 (30 mg, 0.105 mmol) was dissolved in 2 mL of dry DMF, and 34-5 (40 mg, 0.105 mmol) and cesium carbonate (103 mg, 0.315 mmol) were added. The mixture was stirred at 100 °C for 3 hours. The reaction was monitored by LCMS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (PE:EA, 0-30%, 10 min) to give 2.3 mg of the title compound as a white solid.

[0486] Compound 34: LC-MS (ESI) m / z: 583.2 [M+H] + Yield: 3.74%. 1 H NMR (600MHz, DMSO-d6) δ8.04(d,J=8.8Hz,1H),7.75(dd,J=8.5,7.3Hz,1H),7.21(dd,J=8.8,2.1Hz,1H),7 .04-6.93(m,3H),6.86(d,J=8.0Hz,1H),6.61(d,J=7.3Hz,1H),6.46(d,J=2.1Hz,1H),4.19(d,J=13.1Hz, 2H),3.51(t,J=6.9Hz,1H),3.31(s,6H),3.09(s,3H),2.81(dt,J=23.2,12.6Hz,2H),1.95-1.87(m,2H),1 .75(dt,J=13.8,6.9Hz,1H),1.71-1.64(m,3H),1.20-1.06(m,2H),0.93-0.86(m,2H),0.67-0.54(m,2H).

[0487] Example 35 Synthesis of Compound 35

[0488]

[0489] Synthetic route

[0490]

[0491] Synthesis method

[0492] The synthesis method of compound 35 is the same as in Example 24, except that 5-bromo-1-methylbenzimidazole-2(3H)-one in step one is replaced with 6'-bromospiro[cyclopropane-1,3'-dihydroindole]-2'-one. In step four, 1-(3-aminopropyl)-7-chloro-4-(ethyl(methyl)amino)quinazoline-2(1H)-one is replaced with 1-(3-aminophenyl)-4-(dimethylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one.

[0493] Compound 35: LC-MS (ESI) m / z: 616.2 [M+H] + Yield: 10%. 1 H NMR (600MHz, DMSO-d6) δ10.17 (s, 1H), 8.25 (d, J = 8.5Hz, 1H), 7.66-7.59 (m, 2H), 7.55-7.42(m,2H),7.00(dd,J=7.8,1.7Hz,1H),6.85(d,J=7.2Hz,2H),6.74-6.62 (m,2H),3.78(t,J=7.0Hz,2H),3.34(s,6H),2.39(t,J=7.2Hz,2H),1.91(tt,J=8. 8,6.1Hz,3H),1.54-1.43(m,4H),0.90-0.83(m,2H),0.66(dd,J=5.0,1.9Hz,2H).

[0494] Example 36 Synthesis of Compound 36

[0495]

[0496] Synthetic route

[0497]

[0498] Synthesis method

[0499] Step 1: Synthesis of Compound 36-1

[0500] 4-Bromo-N-methylaniline (2.0 g, 11 mmol) was dissolved in dichloromethane (10 mL), and then triethylamine (2.2 g, 22 mmol) was added. After cooling to 0 °C, methacryloyl chloride (1.7 g, 16 mmol) was added dropwise to the reaction solution under a nitrogen atmosphere. After the addition was complete, the temperature was raised to room temperature and stirred for two hours. After the reaction was monitored by TLC until complete, the reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (20 mL × 3) and water (20 mL). The combined organic phases were washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, the drying agent was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by rapid column chromatography (eluent: ethyl acetate / petroleum ether = 6%) to give compound 36-1, 2.4 g. Yield: 86%. LC-MS (ESI) m / z: 254.0 [M+H] + .

[0501] Step 2: Synthesis of Compound 36-2

[0502] Compound 36-1 (2.0 g, 7.9 mmol) and pinacol cyclopropylborate (2.0 g, 12 mmol) were dissolved in 1,4-dioxane (20 mL) solution. A solution of potassium carbonate (3.3 g, 24 mmol) in water (4.0 mL) and a 1,1'-bis(diphenylphosphine)ferrocene[dichloride]palladium dichloromethane complex (0.64 g, 0.79 mmol) were added to the reaction mixture. After nitrogen purging, the mixture was heated to 100 °C and stirred for three hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, washed with ethyl acetate, concentrated under reduced pressure, and the residue was extracted with ethyl acetate and water. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 8%) to give compound 36-2, 1.2 g, as a white solid, in 70% yield. LC-MS (ESI) m / z: 216.1 [M+H] + .

[0503] Step 3: Synthesis of Compound 36-3

[0504] Compound 36-2 (0.5 g, 2.3 mmol), silver carbonate (1.3 g, 4.6 mmol), and methyl bromoacetate (1.1 g, 7.0 mmol) were dissolved in ethyl acetate (5.0 mL), heated to 110 °C, and stirred overnight. After cooling to room temperature, the reaction solution was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 19%) to give compound 36-3, 0.53 g, as a white oil, in 79% yield. LC-MS (ESI) m / z: 288.2 [M+H]+ .

[0505] Step 4: Synthesis of Compound 36-4

[0506] Compound 36-3 (0.47 g, 1.6 mmol) was dispersed in methanol (4.0 mL) at room temperature. Lithium hydroxide monohydrate (0.14 g, 3.2 mmol) was dissolved in water (1.0 mL) and added dropwise to the reaction mixture. The mixture was stirred at room temperature for one hour. After concentration under reduced pressure, a small amount of water was added to the residue, and 1 N dilute hydrochloric acid was added dropwise to adjust the pH to 3–4. The mixture was stirred at room temperature for 10 minutes. Extraction with ethyl acetate was performed, and the concentrated organic phases were combined to give compound 36-4, 0.4 g, as a white solid, in 89% yield. LC-MS (ESI) m / z: 274.1 [M+H] + .

[0507] Step 5: Synthesis of Compound 36

[0508] At room temperature, compound 36-4 (42 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (0.50 mL), and a DMF solution of DIEA (39 mg, 0.030 mmol) and HATU (69 mg, 0.18 mmol) in 0.3 mL was added dropwise, and the mixture was stirred at room temperature for 20 minutes. A solution of compound 36-5 (50 mg, 0.15 mmol) in N,N-dimethylformamide (0.5 mL) was added dropwise, and the mixture was stirred at room temperature for one hour. The reaction mixture was extracted with ethyl acetate and water. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography (eluent: dichloromethane / methanol = 12 / 1) to obtain crude compound 36, 40 mg. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain product 36, 16.12 mg, with a yield of 18%.

[0509] Compound 36: LC-MS (ESI) m / z: 584.3 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ8.09(d,J=8.5Hz,1H),7.78(t,J=5.6Hz,1H),7.57(s,1H),7.46(dd,J=8.5,1.6 Hz,1H),7.04(d,J=1.8Hz,1H),6.96(dd,J=8.0,1.8Hz,1H),6.87(d,J=8.0Hz,1H),4.04(t,J=7.6Hz,2H ),3.64(q,J=7.0Hz,2H),3.23(s,3H),3.11(s,3H),3.03(q,J=6.5Hz,2H),2.04-1.84(m,4H),1.75-1.6 7(m,1H),1.65-1.58(m,2H),1.28(t,J=7.0Hz,3H),1.24(s,3H),0.91-0.87(m,2H),0.67-0.59(m,2H).

[0510] Example 37 Synthesis of Compound 37

[0511]

[0512] Synthetic route

[0513]

[0514] Synthesis method

[0515] The synthesis of compound 37-1 is the same as that of compound 36-2 in Example 36.

[0516] Step 1: Synthesis of Compound 37-2

[0517] Compound 37-1 (0.17 g, 0.77 mmol), silver oxide (0.17 g, 0.73 mmol), and potassium trimethyl fluoroborate (0.15 g, 0.77 mmol) were dissolved in a mixed solution of toluene (2.0 mL) and water (0.1 mL) and stirred overnight at room temperature. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 23%) to give compound 2, 0.087 g, as a white oil, in 40% yield. LC-MS (ESI) m / z: 302.1 [M+H] + .

[0518] Step 2: Synthesis of Compound 37-3

[0519] Compound 37-2 (0.1 g, 0.33 mmol) was dispersed in methanol (1.0 mL) at room temperature. Lithium hydroxide monohydrate (0.028 g, 0.66 mmol) was dissolved in water (0.3 mL) and added dropwise to the reaction mixture. The mixture was stirred at room temperature for three hours. After concentration under reduced pressure, a small amount of water was added to the residue, and 1N dilute hydrochloric acid was added dropwise to adjust the pH to 3–4. The mixture was stirred at room temperature for 10 minutes. Extraction was performed with ethyl acetate, and the concentrated organic phases were combined to obtain crude compound 37-3, 0.10 g, as a white solid, which could be used directly in the next step. LC-MS (ESI) m / z: 288.2 [M+H] + .

[0520] Step 3: Synthesis of Compound 37

[0521] At room temperature, compound 37-3 (57 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (0.50 mL), and a DMF solution of DIEA (45 mg, 0.35 mmol) and HATU (79 mg, 0.21 mmol) in 0.3 mL was added dropwise, and the mixture was stirred at room temperature for 20 minutes. A solution of compound 37-4 (50 mg, 0.17 mmol) in N,N-dimethylformamide (0.5 mL) was added dropwise, and the mixture was stirred at room temperature for one hour. The reaction mixture was extracted with ethyl acetate and water. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography (eluent: dichloromethane / methanol = 12 / 1) to obtain crude compound 37, 40 mg. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain product 37, 18.92 mg, with a yield of 18%.

[0522] Compound 37: LC-MS (ESI) m / z: 598.3 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ8.10(d,J=8.5Hz,1H),7.82(t,J=5.7Hz,1H),7.60(s,1H),7.46(dd,J=8.6,1.6Hz,1 H),7.01(d,J=1.8Hz,1H),6.94(dd,J=8.0,1.8Hz,1H),6.85(d,J=8.0Hz,1H),4.07(dd,J=8.8,6.5Hz,2H),3. 65(q,J=7.0Hz,2H),3.24(s,3H),3.09(s,3H),3.08–3.05(m,2H),1.97-1.89(m,2H),1.90-1.84(m,1H),1.7 6-1.63(m,4H),1.28(t,J=7.0Hz,3H),1.21(s,3H),1.09-0.96(m,2H),0.89-0.85(m,2H),0.64-0.57(m,2H).

[0523] Example 38 Synthesis of Compound 38

[0524]

[0525] Synthetic route

[0526]

[0527] Synthesis method

[0528] The synthesis of compound 38-1 is the same as that of compound 36-2 in Example 36. The synthesis of compound 38-4 is described in Example 123-7 of the published patent application WO2024 / 183778.

[0529] Step 1: Synthesis of Compound 38-2

[0530] Compound 38-1 (0.18 g, 0.84 mmol), tert-butyl 4-bromopiperidin-1-carboxylate (0.44 g, 1.7 mmol), cesium carbonate (0.68 g, 2.1 mmol), 1,1'-bis(diphenylphosphine)ferrocene (0.046 g, 0.084 mmol), and palladium acetate (0.038 g, 0.17 mmol) were dissolved in toluene (1.0 mL). The mixture was heated to 90 °C and stirred overnight under a nitrogen atmosphere. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated brine, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 13%) to give compound 38-2, 0.22 g, as a white oil, in 65% yield. LC-MS (ESI) m / z: 399.3 [M+H]+ .

[0531] Step 2: Synthesis of Compound 38-3

[0532] Compound 38-2 (0.1 g, 0.24 mmol) was dispersed in 1,4-dioxane (2.0 mL) at room temperature. A solution of 1,4-dioxane in hydrochloric acid (2.0 mL, 4 M) was added dropwise to the reaction mixture. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to obtain crude compound 38-3, 0.24 g, as a white solid, which could be used directly in the next step. LC-MS (ESI) m / z: 299.2 [M+H] + .

[0533] Step 3: Synthesis of Compound 38

[0534] Compound 38-4 (0.12 g, 0.32 mmol), compound 38-3 (0.11 g, 0.38 mmol), and cesium carbonate (0.39 g, 0.95 mmol) were dissolved in N,N-dimethylformamide (2.0 mL) at room temperature. The mixture was heated to 120 °C and stirred for six hours under a nitrogen atmosphere. The reaction solution was extracted with ethyl acetate and water. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography (eluent: dichloromethane / methanol = 12 / 1) to obtain 55 mg of crude compound 38. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain 26.82 mg of product 38, with a yield of 14%.

[0535] Compound 38: LC-MS (ESI) m / z: 597.3 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ8.02(d,J=8.8Hz,1H),7.70(dd,J=8.6,7.3Hz,1H),7.20(dd,J=8.8,2.1Hz,1H),7.05(d,J=1.8Hz, 1H),6.98(dd,J=8.1,1.8Hz,1H),6.87(dd,J=14.8,8.3Hz,2H),6.56(d,J=7.3Hz,1H),6.39(d,J=2.1Hz,1H),3.97(dd,J=3 0.0,13.3Hz,2H),3.30(s,6H),3.11(s,3H),2.57(tt,J=13.0,3.2Hz,2H),1.92-1.87(m,1H),1.80(ddd,J=50.5,14.0,5.9 Hz,2H),1.28(d,J=13.3Hz,1H),1.20(s,3H),1.18-1.09(m,2H),1.03-0.95(m,1H),0.94-0.86(m,3H),0.68-0.55(m,2H).

[0536] Example 39 Synthesis of Compound 39

[0537]

[0538] Synthetic route

[0539]

[0540] Synthesis method:

[0541] The synthesis method of compound 39 is the same as that in Example 30, except that 4-chloro-2-fluorobenzamide in step one is replaced with 2-chloro-6-trifluoromethylnicotinamide.

[0542] Compound 39: LC-MS (ESI) m / z: 688.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.99(d,J=2.3Hz,1H),8.79(d,J=8.2Hz,1H),8.50(d,J=2.3Hz,1H),8.22(s,1H),7.98(d,J=8.8H z,1H),7.79(d,J=2.0Hz,1H),7.69(d,J=8.2Hz,1H),7.21(dd,J=8.8,1.9Hz,1H),5.55(s,2H),3.42(s,6H),3.24(s,6H).

[0543] Example 40 Synthesis of Compound 40

[0544]

[0545] Synthesis method

[0546] The synthesis method of compound 40 is the same as that in Example 30, except that in step five, (6-chloro-5-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)pyridin-3-yl)boronic acid is replaced with (5-(4-(dimethylamino)-2-oxo-7-(trifluoromethyl)pyridino[2,3-d]pyrimidin-1(2H)-yl)pyridin-3-yl)boronic acid, and 1-((2-bromothiazol-5-yl)methyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one is replaced with 1-((2-bromothiazol-5-yl)methyl)-4-(dimethylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one.

[0547] Compound 40: LC-MS (ESI) m / z: 688.2 [M+H] + Yield: 10%. 1 H NMR (400MHz, DMSO-d6) δ9.07(d,J=2.0Hz,1H),8.73(d,J=8.2Hz,1H),8.57(d,J=2.2Hz,1H),8.52(s,1H),8.27(t,J=2.1Hz,1H),8.16(s,1H),8.00 -7.94(m,1H),7.65(d,J=8.3Hz,1H),7.47(dd,J=8.6,1.6Hz,1H),5.65(s,2H),3.39(s,6H),3.28(s,6H).

[0548] Example 41 Synthesis of Compound 41

[0549]

[0550] Synthetic route

[0551]

[0552] Synthesis method

[0553] The synthesis method of compound 41 is as described in Example 30.

[0554] Compound 41: LC-MS (ESI) m / z: 688.1 [M+H] + 344.5 [M / 2+H] + . 1H NMR (400MHz, DMSO-d6) δ8.98(d,J=2.3Hz,1H),8.55(d,J=8.5Hz,1H),8.49(d,J=2.3Hz,1H),8.20(s,1H),8.18(d,J= 8.4Hz,1H),7.98(s,1H),7.47(dd,J=8.7,1.6Hz,1H),7.33(d,J=8.4Hz,1H),5.65(s,2H),3.38(s,6H),3.28(s,6H).

[0555] Example 42 Synthesis of Compound 42

[0556]

[0557] Synthesis method

[0558] The synthesis method of compound 42 is the same as that in Example 30, except that 2-fluoro-4-chlorobenzamide is replaced with 2,6-dichloronicotinamide in step one, the reaction temperature is room temperature in step two, and the reaction temperature is 80°C in steps four and five.

[0559] Compound 42: LC-MS (ESI) m / z: 654.0 [M+H] + 327.5 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.99(d,J=2.3Hz,1H),8.55(d,J=8.5Hz,1H),8.50(d,J=2.3Hz,1H),8.23(s,1H),7.98(dd,J=8 .8,2.9Hz,2H),7.79(d,J=2.0Hz,1H),7.33(d,J=8.5Hz,1H),7.22-7.20(m,1H),5.55(s,2H),3.39(s,6H),3.25(s,6H).

[0560] Example 43 Synthesis of Compound 43

[0561]

[0562] Synthesis method

[0563] The synthesis method of compound 43 is the same as that in Example 30, except that (6-chloro-5-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)pyridin-3-yl)boronic acid in step five is replaced with (6-chloro-5-(4-(dimethylamino)-2-oxo-7-(trifluoromethyl)pyridinyl[2,3-d]pyrimidin-1(2H)-yl)pyridin-3-yl)boronic acid, and 1-((2-bromothiazol-5-yl)methyl)-7-chloro-4-(dimethylamino)quinazoline-2(1H)-one is replaced with 1-((2-bromothiazol-5-yl)methyl)-4-(dimethylamino)-7-(trifluoromethyl)quinazoline-2(1H)-one.

[0564] Compound 43: LC-MS (ESI) m / z: 722.2 [M+H] + Yield: 10%. 1 H NMR (400MHz, DMSO-d6) δ8.98(d,J=2.3Hz,1H),8.78(d,J=8.2Hz,1H),8.50(d,J=2.3Hz,1H),8.18(d,J=10. 2Hz,2H),7.97(s,1H),7.69(d,J=8.2Hz,1H),7.46(d,J=8.5Hz,1H),5.65(s,2H),3.43(s,6H),3.28(s,6H).

[0565] Example 44 Synthesis of Compound 44

[0566]

[0567] Synthesis method

[0568] The synthesis method of compound 44 is the same as that in Example 30, except that in step five, (6-chloro-5-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)pyridin-3-yl)boronic acid is replaced with (6-chloro-5-(4-(dimethylamino)-2-oxo-7-(trifluoromethyl)pyridinyl[2,3-d]pyrimidin-1(2H)-yl)pyridin-3-yl)boronic acid, and 1-((2-bromothiazol-5-yl)methyl)-7-chloro-4-(dimethylamino)quinazoline-2(1H)-one is replaced with 1-((2-bromothiazol-5-yl)methyl)-4-(dimethylamino)-7-(trifluoromethyl)pyrimidin[2,3-d]pyrimidin-2(1H)-one.

[0569] Compound 44: LC-MS (ESI) m / z: 723.2 [M+H] + Yield: 8%. 1H NMR (400MHz, DMSO-d6) δ8.96(d,J=2.3Hz,1H),8.79(d,J=8.2Hz,1H),8.68(d,J=8.2Hz,1H),8 .47(s,1H),7.99(s,1H),7.68(dd,J=11.1,8.2Hz,2H),5.56(s,2H),3.43(s,8H),3.32(s,7H).

[0570] Example 45 Synthesis of Compound 45

[0571]

[0572] Synthesis method

[0573] The synthesis of compound 45 is described in Example 30.

[0574] Compound 45: LC-MS (ESI) m / z: 654.1 [M+H] + 327.5 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.03(d,J=2.3Hz,1H),8.49(d,J=2.3Hz,1H),8.45(d,J=8.5Hz,1H),8.10(d,J=8.9Hz,1H),8.02( s,1H),7.31(d,J=8.5Hz,1H),7.26(dd,J=8.8,2.1Hz,1H),6.68(d,J=2.1Hz,1H),5.52(s,2H),3.35(s,6H),3.28(s,6H).

[0575] Example 46 Synthesis of Compound 46

[0576]

[0577] Synthesis method

[0578] The synthesis method of compound 46 is the same as that in Example 30, except that (6-chloro-5-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)pyridin-3-yl)boronic acid in step five is replaced with (6-chloro-5-(4-(dimethylamino)-2-oxo-7-(trifluoromethyl)quinazoline-1(2H)-yl)pyridin-3-yl)boronic acid, and 1-((2-bromothiazol-5-yl)methyl)-7-chloro-4-(dimethylamino)quinazoline-2(1H)-one is replaced with 1-((2-bromothiazol-5-yl)methyl)-4-(dimethylamino)-7-(trifluoromethyl)pyrimidin[2,3-d]pyrimidin-2(1H)-one.

[0579] Compound 46: LC-MS (ESI) m / z: 722.2 [M+H] + Yield: 8%. 1 H NMR (400MHz, DMSO-d6) δ9.04(d,J=2.3Hz,1H),8.68(d,J=8.2Hz,1H),8.53(d,J=2.3Hz,1H),8.31(d,J=8.5Hz,1H),8.01( s,1H),7.66(d,J=8.2Hz,1H),7.53(dd,J=8.7,1.8Hz,1H),6.80(d,J=1.8Hz,1H),5.57(s,3H),3.38(s,6H),3.32(s,6H).

[0580] Example 47 Synthesis of Compound 47

[0581]

[0582] Synthesis method

[0583] The synthesis method of compound 47 is the same as that in Example 30, except that 1-((2-bromothiazol-5-yl)methyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one in step five is replaced with 1-((2-bromothiazol-5-yl)methyl)-4-(dimethylamino)-7-(trifluoromethyl)pyrimidin[2,3-d]pyrimidin-2(1H)-one.

[0584] Compound 47: LC-MS (ESI) m / z: 688.2 [M+H] + Yield: 9%. 1 H NMR (400MHz, DMSO-d6) δ9.01(d,J=2.3Hz,1H),8.68(d,J=8.2Hz,1H),8.48(d,J=2.3Hz,1H),8.10(d,J=8.8Hz,1H),8.00( s,1H),7.67(d,J=8.2Hz,1H),7.26(dd,J=8.8,2.1Hz,1H),6.67(d,J=2.0Hz,1H),5.57(s,2H),3.35(s,6H),3.32(s,6H).

[0585] Example 48 Synthesis of Compound 48

[0586]

[0587] Synthesis method

[0588] The synthesis method of compound 48 is as described in Example 30.

[0589] Compound 48: LC-MS (ESI) m / z: 688.1 [M+H] + 344.5 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6)δ

[0590] 9.06(d,J=2.3Hz,1H),8.54(d,J=2.3Hz,1H),8.45(d,J=8.4Hz,1H),8.31(d,J=8.5Hz,1H),8.03(s,1H),7.54 (dd,J=8.6,1.8Hz,1H),7.31(d,J=8.4Hz,1H),6.80(d,J=1.8Hz,1H),5.53(s,2H),3.39(s,6H),3.28(s,6H).

[0591] Example 49 Synthesis of Compound 49

[0592]

[0593] Synthesis method

[0594] The synthesis method of compound 49 is the same as that in Example 30.

[0595] Compound 49: LC-MS (ESI) m / z: 689.1 [M+H] + 345.0 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.99(d,J=2.4Hz,1H),8.79(d,J=8.2Hz,1H),8.49(d,J=2.3Hz,1H),8.45(d,J=8.4 Hz,1H),8.02(s,1H),7.70(d,J=8.2Hz,1H),7.31(d,J=8.4Hz,1H),5.52(s,2H),3.43(s,6H),3.28(s,6H).

[0596] Example 50 Synthesis of Compound 50

[0597]

[0598] Synthesis method

[0599] The synthesis method of compound 50 is as described in Example 30.

[0600] Compound 50: LC-MS (ESI) m / z: 687.1 [M+H] + 344.1 [M / 2+H]+ . 1 H NMR (400MHz, DMSO-d6) δ9.06(d,J=2.3Hz,1H),8.56(d,J=2.3Hz,1H),8.31(d,J=8.5Hz,1H),8.23(s,1H),7.98(d,J=8.8Hz,1H),7. 78(d,J=2.0Hz,1H),7.53(dd,J=8.8,1.8Hz,1H),7.21(dd,J=8.8,2.0Hz,1H),6.80(d,1H),5.56(s,2H),3.38(s,6H),3.24(s,6H).

[0601] Example 51 Synthesis of Compound 51

[0602]

[0603] Synthesis method

[0604] The synthesis method of compound 51 is as described in Example 30.

[0605] Compound 51: LC-MS (ESI) m / z: 687.1 [M+H] + 344.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.03(d,J=2.3Hz,1H),8.50(d,J=2.2Hz,1H),8.21(s,1H),8.17(d,J=8.5Hz,1H),8.09(d,J=8.8Hz,1H),7. 98(s,1H),7.46(dd,J=8.5,1.6Hz,1H),7.25(dd,J=8.8,2.1Hz,1H),6.67(d,J=2.1Hz,1H),5.65(s,2H),3.33(s,6H),3.28(s,6H).

[0606] Example 52 Synthesis of Compound 52

[0607]

[0608] Synthetic route

[0609]

[0610] Step 1: Synthesis of Compound 52-1

[0611] At room temperature, 2-bromo-5-methylthiazole (2 g, 11.2 mmol) was dissolved in 30 mL of dry THF. The solution was cooled to -78 °C, and 1.6 N n-butyllithium solution (10.5 mL, 16.8 mmol) was slowly added under a nitrogen atmosphere, with the temperature not exceeding -70 °C during the addition. After the addition was complete, the reaction was maintained at this low temperature for 1 hour. Then, tri-n-butyltin chloride (5.5 g, 17.0 mmol) was slowly added dropwise to the reaction system. After the addition was complete, the mixture was brought to room temperature and stirred overnight. The reaction was monitored by LC-MS to ensure completeness. The reaction was quenched by adding saturated sodium bicarbonate solution and potassium fluoride solution in an ice bath. After extraction with water and ethyl acetate, the combined organic phases were concentrated to give 4.3 g of the crude product, a yellow oily title compound. No Mass signal was observed; yield: 100%.

[0612] Step 2: Synthesis of Compound 52-2

[0613] At room temperature, 2-bromo-3-chloro-4-aminopyridine (2 g, 9.66 mmol) was dissolved in 30 mL of dry THF, and DMAP (1.76 g, 14.4 mmol) was added. Then, (Boc)₂O (8 g, 37.0 mmol) was added dropwise to the reaction system. After the addition was complete, the mixture was heated to 70 °C and stirred for 1 hour. The reaction was monitored by LCMS until complete. After cooling, the mixture was concentrated and directly separated by rapid column chromatography (PE:EA, 0-20%, 10 min) to obtain 2.7 g of the title compound as a white solid.

[0614] LC-MS(ESI) m / z: 407.0 [M+H] + Yield: 69%

[0615] Step 3: Synthesis of Compound 52-3

[0616] At room temperature, compound 52-2 (500 mg, 1.23 mmol) was dissolved in 10 mL of dry dioxane, and compound 52-1 (1 g) and tetraphenylphosphine palladium (142 mg, 0.123 mmol) were added. After purging with nitrogen, the mixture was microwaved at 150 °C for 20 min. The reaction was monitored by LCMS until complete. After cooling, the mixture was concentrated and directly separated by rapid column chromatography (PE:EA, 0-100%, 20 min) to obtain 230 mg of the yellow oily title compound.

[0617] LC-MS (ESI) m / z: 426.1 [M+H] + Yield: 44%

[0618] Step 4: Synthesis of Compound 52-4

[0619] At room temperature, compound 52-3 (100 mg, 0.235 mmol) was dissolved in 3 mL of dry carbon tetrachloride, and NBS (60 mg, 0.337 mmol) and AIBN (8 mg, 0.0488 mmol) were added. The mixture was heated to 90 °C and reacted for 1 hour. The reaction was difficult to detect with TLC, but LCMS showed that the reaction mainly consisted of products. After cooling, the sample was concentrated and directly separated by rapid column chromatography (PE:EA, 0-100%, 20 min) to obtain 90 mg of the yellow oily title compound.

[0620] LC-MS (ESI) m / z: 504.0 [M+H] + Yield: 76%

[0621] Step 5: Synthesis of Compound 52-5

[0622] Compound 52-4 (90 mg, 0.179 mmol) was dissolved in 2 mL of dry DMF at room temperature, and potassium phthalimide (33 mg, 0.178 mmol) was added. The reaction was allowed to proceed for 10 minutes at room temperature. The reaction was monitored by LCMS until complete. After extraction with water and ethyl acetate, the combined organic phases were concentrated and separated by rapid column chromatography (PE:EA, 0-100%, 20 min) to give 30 mg of the title compound as a yellow oil.

[0623] LC-MS (ESI) m / z: 571.1 [M+H] + Yield: 29%

[0624] Step Six: Synthesis of Compound 52-6

[0625] Compound 52-5 (180 mg, 0.315 mmol) was dissolved in 3 mL of dry dioxane at room temperature, and 3 mL of dioxane hydrochloride solution (4N) was added. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by LC-MS until complete. 110 mg of the title compound was obtained by direct filtration.

[0626] LC-MS (ESI) m / z: 371.0 [M+H] + Yield: 94%

[0627] Step 7: Synthesis of Compound 52-7

[0628] At room temperature, compound 52-6 (100 mg, 0.270 mmol) was dissolved in 5 mL of ethanol, and 0.5 mL of hydrazine hydrate was added. The mixture was heated to 80 °C and reacted for 1 hour. The reaction was monitored by LCMS until complete. After concentration, a suitable amount of dichloromethanol mixed solvent was added, and a white flocculent precipitate formed. The solid was filtered off, and the concentrated filtrate was precipitated again with a suitable amount of methanol and dichloromethanol. This process was repeated three times. The concentrated filtrate was then lyophilized to give 90 mg of the yellow solid title compound.

[0629] LC-MS (ESI) m / z: 241.0 [M+H] + Yield: 100%

[0630] Steps eight, nine, and ten:

[0631] The synthesis of compounds 52-8, 52-9, and 52 was performed in accordance with the synthesis of compound 50 in Example 50 of the published patent application WO2024 / 183778.

[0632] Compound 52: LC-MS (ESI) m / z: 327.0 [M / 2+H] + .

[0633] Preparation of formic acid system: 1 H NMR (400MHz, CD3OD) δ9.54(s,1H),8.57(s,1H),8.08(d,J=1.2Hz,2H),7.86(d,J=8.8Hz,1H),7.79(d,J=8.7Hz,1H) ,7.37(d,J=1.9Hz,1H),7.15(td,J=9.1,2.0Hz,2H),6.45(d,J=2.0Hz,1H),5.59(s,2H),3.47(s,6H),3.37(s,6H).

[0634] Preparation of trifluoroacetic acid system: 1 H NMR (400MHz, DMSO-d6) δ9.33(s,1H),8.69(s,1H),8.33(s,1H),8.11(d,J=8.9Hz,1H),8.00(d,J=8.8Hz,1H),7.84(d,J= 2.1Hz, 1H), 7.25 (ddd, J=16.6, 8.8, 2.0Hz, 2H), 6.71 (d, J=2.1Hz, 1H), 5.59 (d, J=1.8Hz, 2H), 3.36 (s, 6H), 3.26 (s, 6H).

[0635] Example 53 Synthesis of Compound 53

[0636]

[0637] Synthetic route

[0638]

[0639] Synthesis method

[0640] Step 1: Synthesis of Compound 53-1

[0641] At room temperature, 1.2 g (4.48 mmol) of 7-bromo-4-(dimethylamino)quinazolin-2(1H)-one was dissolved in 10 mL of dioxane and 2 mL of water. Pd(dppf)Cl2 (366 mg, 0.4486 mmol), pinacol cyclopropylborate (3.01 g, 17.92 mmol), and potassium carbonate (1.86 g, 13.44 mmol) were added, and the mixture was heated to 100 °C and reacted for 16 hours. The reaction was monitored by LC-MS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, concentrated, and then separated by rapid column chromatography (PE:EA, 0-30%, 10 min) to give 640 mg of the yellow oily title compound.

[0642] LC-MS (ESI) m / z: 230.2 [M+H] + Yield: 62.37%

[0643] Step 2: Synthesis of Compound 53-2

[0644] Compound 53-1 (640 mg, 2.786 mmol) was dissolved in 10 mL of dry DMF, and 2-bromo-5-bromomethylthiazole (1.43 g, 5.56 mmol) and cesium carbonate (1.16 g, 8.358 mmol) were added. The mixture was stirred at 100 °C for 3 hours. The reaction was monitored by LCMS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (PE:EA, 0-30%, 10 min) to give 230 mg of the title compound as a yellow oil.

[0645] LC-MS (ESI) m / z: 405.2 [M+H] + Yield: 20.33%

[0646] Step 3: Synthesis of Compound 53

[0647] Compound 53-2 (107 mg, 0.264 mmol), (6-chloro-5-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)pyridin-3-yl)boronic acid (50 mg, 0.132 mmol), Pd(dppf)Cl2 (11 mg, 0.0132 mmol), and potassium carbonate (55 mg, 0.0396 mmol) were reacted at 100 °C for 1 hour. The reaction was monitored by LCMS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (DCM: MeOH, 0-10%, 10 min) to give 10 mg of the white title compound.

[0648] Compound 53: LC-MS (ESI) m / z: 659.2 [M+H] +Yield: 11.5%. 1 H NMR(400MHz,DMSO-d6)δ9.03(d,J=2.3Hz,1H),8.50(d,J=2.3Hz,1H),8.23(s,1H),8.0 9(d,J=8.8Hz,1H),7.82(d,J=8.6Hz,1H),7.30(d,J=1.6Hz,1H),7.25(dd,J=8.8,2.1Hz ,1H),6.83(dd,J=8.6,1.5Hz,1H),6.67(d,J=2.0Hz,1H),5.56(s,2H),3.39(s,6H),3. 22(s,6H),2.07(tt,J=8.4,4.3Hz,1H),1.07(dd,J=8.2,2.4Hz,2H),0.86-0.81(m,3H).

[0649] Example 54 Synthesis of Compound 54

[0650]

[0651] Synthetic route

[0652]

[0653] Synthesis method

[0654] The synthesis method of compound 54 is as described in Example 30.

[0655] Compound 54: LC-MS (ESI) m / z: 344.6 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.17(d,J=2.0Hz,1H),8.71–8.64(m,2H),8.35(t,J=2.2Hz,1H),8.27(d,J=8.5Hz,1H),8.00(s ,1H),7.67(d,J=8.3Hz,1H),7.50(dd,J=8.6,1.8Hz,1H),6.71(d,J=1.8Hz,1H),5.56(s,2H),3.37(s,6H),3.32(s,6H).

[0656] Example 55 Synthesis of Compound 55

[0657]

[0658] Synthesis method

[0659] The synthesis method of compound 55 is as described in Example 30.

[0660] Compound 55: LC-MS (ESI) m / z: 327.6 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.19(d,J=2.0Hz,1H),8.65(d,J=2.3Hz,1H),8.46(d,J=8.5Hz,1H),8.36(t,J=2.2Hz,1H),8.27(d,J=8.5Hz ,1H),8.02(s,1H),7.50(dd,J=8.6,1.8Hz,1H),7.32(d,J=8.4Hz,1H),6.71(d,J=1.8Hz,1H),5.52(s,2H),3.36(s,6H),3.29(s,6H).

[0661] Example 56 Synthesis of Compound 56

[0662]

[0663] Synthesis method

[0664] The synthesis method of compound 56 is the same as that in Example 30, except that (6-chloro-5-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)pyridin-3-yl)boronic acid in step five is replaced with (5-(4-(dimethylamino)-2-oxo-7-(trifluoromethyl)pyridino[2,3-d]pyrimidin-1(2H)-yl)pyridin-3-yl)boronic acid, and 1-((2-bromothiazol-5-yl)methyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one is replaced with 1-((2-bromothiazol-5-yl)methyl)-4-(dimethylamino)-7-(trifluoromethyl)pyrimidin[2,3-d]pyrimidin-2(1H)-one.

[0665] Compound 56: LC-MS (ESI) m / z: 689.2 [M+H] + Yield: 10%. 1 H NMR(400MHz,DMSO-d6)δ9.06(d,J=2.1Hz,1H),8.71(dd,J=17.4,8.2Hz,2H),8.57(d,J=2.2Hz,1H) ,8.24(t,J=2.2Hz,1H),7.98(s,1H),7.66(t,J=8.0Hz,2H),5.56(s,2H),3.39(s,6H),3.32(s,6H).

[0666] Example 57 Synthesis of Compound 57

[0667]

[0668] Synthesis method

[0669] The synthesis method of compound 57 is as described in Example 30.

[0670] Compound 57: LC-MS (ESI) m / z: 660.1 [M+H] + 330.6 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.96(d,J=2.3Hz,1H),8.40(d,J=2.3Hz,1H),8.34(d,J=8.3Hz,1H),8.21(s,1H),7.98(d,J=8.8Hz,1H),7.80 (d,J=2.0Hz,1H),7.24-7.16(m,2H),5.55(s,2H),3.36(s,6H),3.25(s,6H),2.08-2.00(m,1H),0.90-0.76(m,2H),0.55-0.42(m,2H).

[0671] Example 58 Synthesis of Compound 58

[0672]

[0673] Synthesis method

[0674] The synthesis method of compound 58 is as described in Example 30.

[0675] Compound 58: LC-MS (ESI) m / z: 659.1 [M+H] + 330.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.04(d,J=2.3Hz,1H),8.48(d,J=2.3Hz,1H),8.23(s, 1H),7.96(dd,J=18.3,8.7Hz,2H),7.78(d,J=2.0Hz,1H),7.21(dd,J=8.8,2.0 Hz,1H),6.76(dd,J=8.6,1.7Hz,1H),6.32(d,J=1.7Hz,1H),5.56(s,2H),3.32 (s,6H),3.25(s,6H),1.94-1.85(m,1H),0.96-0.90(m,2H),0.71-0.61(m,2H).

[0676] Example 59 Synthesis of Compound 59

[0677]

[0678] Synthetic route

[0679]

[0680] Synthesis method

[0681] Step 1: Synthesis of Compound 59-1

[0682] 7-Chloro-4-(dimethylamino)quinazolin-2(1H)-one (200 mg, 0.86 mmol) was dissolved in 5 mL of dry DMF, and 4-bromo-2-(bromomethyl)thiazole (276 mg, 1.03 mmol) and cesium carbonate (874 mg, 2.58 mmol) were added. The mixture was stirred at 100 °C for 3 hours. The reaction was monitored by LCMS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (PE:EA, 0-30%, 10 min) to give 120 mg of the title compound as a yellow oil.

[0683] LC-MS (ESI) m / z: 399.2 [M+H] + Yield: 33.57%

[0684] Step 2: Synthesis of Compound 59

[0685] Compound 59-1 (106 mg, 0.265 mmol), (6-chloro-5-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)pyridin-3-yl)boronic acid (50 mg, 0.132 mmol), Pd(dppf)Cl2 (11 mg, 0.0132 mmol), and potassium carbonate (55 mg, 0.0396 mmol) were reacted at 100 °C for 1 hour. The reaction was monitored by LCMS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (DCM: MeOH, 0-10%, 10 min) to give 17 mg of the white title compound.

[0686] Compound 59: LC-MS (ESI) m / z: 653.2 [M+H] + Yield: 19.7%. 1H NMR (400MHz, DMSO-d6) δ9.13(d,J=2.3Hz,1H),8.51(d,J=2.3Hz,1H),8.34(s,1H),8.13(d,J=8.8Hz,1H),8.00(d,J=8.8Hz,1H),7.82(d ,J=2.0Hz,1H),7.29(dd,J=8.8,2.1Hz,1H),7.20(dd,J=8.8,2.0Hz,1H),6.69(d,J=2.0Hz,1H),5.62(s,2H),3.41(s,6H),3.27(s,6H).

[0687] Example 60: Synthesis of Compound 60

[0688]

[0689] Synthesis method

[0690] The synthesis method of compound 60 is the same as that in Example 59, except that the (6-chloro-5-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)pyridin-3-yl)boronic acid in step two is replaced with (6-chloro-5-(4-(dimethylamino)-2-oxo-7-(trifluoromethyl)pyridinyl[2,3-d]pyrimidin-1(2H)-yl)pyridin-3-yl)boronic acid.

[0691] Compound 60: LC-MS (ESI) m / z: 688.2 [M+H] + Yield: 10%. 1 H NMR (400MHz, DMSO-d6) δ9.07(d,J=2.3Hz,1H),8.81(d,J=8.2Hz,1H),8.48(d,J=2.2Hz,1H),8.31(s,1H),8.00(d,J=8.8H z,1H),7.77(d,J=2.0Hz,1H),7.72(d,J=8.3Hz,1H),7.20(dd,J=8.8,2.0Hz,1H),5.61(s,2H),3.44(s,6H),3.27(s,6H).

[0692] Example 61 Synthesis of Compound 61

[0693]

[0694] Synthesis method

[0695] The synthesis of compound 61 is based on Example 30, except that in step three, the tetrahydrofuran solution of dimethylamine is replaced with N-ethylmethylamine and diluted with tetrahydrofuran.

[0696] Compound 61: LC-MS (ESI) m / z: 667.1 [M+H] + 334.0 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.03(d,J=2.3Hz,1H),8.52(d,J=2.3Hz,1H),8.23(s,1H),8.00(dd,J=17.7,8.8Hz,2H),7.78(d,J=2.0Hz, 1H),7.23(ddd,J=21.1,8.8,2.0Hz,2H),6.67(d,J=2.1Hz,1H),5.56(s,2H),3.83-3.64(m,2H),3.24(s,6H),1.32(t,J=7.0Hz,3H).

[0697] Example 62 Synthesis of Compound 62

[0698]

[0699] Synthesis method

[0700] The synthesis method of compound 62 is as described in Example 30.

[0701] Compound 62: LC-MS (ESI) m / z: 665.1 [M+H] + 333.0 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.03(d,J=2.3Hz,1H),8.51(d,J=2.3Hz,1H),8.20(s,1H),8.09(d,J=8.9Hz,1H),7.77(dd,J=5.4,3.4Hz ,2H),7.23(ddd,J=17.7,8.8,2.0Hz,2H),6.67(d,J=2.0Hz,1H),5.56(s,2H),4.84-4.07(m,4H),3.32(s,6H),2.43-2.33(m,2H).

[0702] Example 63 Synthesis of Compound 63

[0703]

[0704] Synthesis method

[0705] The synthesis of compound 63 was performed according to Example 30, except that in step three, the tetrahydrofuran solution of dimethylamine was replaced with a tetrahydrofuran mixture of aziridine hydrochloride dissociated from N,N-diisopropylethylamine.

[0706] Compound 63: LC-MS (ESI) m / z: 665.1 [M+H] + 333.0 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.03(d,J=2.3Hz,1H),8.50(d,J=2.3Hz,1H),8.23(s,1H),7.98(d,J=8.8Hz,1H),7.86(d,J=8.8Hz,1H),7.78(d,J=2.0Hz, 1H),7.23(ddd,J=16.4,8.7,2.0Hz,2H),6.66(d,J=2.0Hz,1H),5.56(s,2 H),4.96-4.73(m,2H),4.40-4.14(m,2H),3.25(s,6H),2.47-2.40(m,2H).

[0707] Example 64 Synthesis of Compound 64

[0708]

[0709] Synthesis method

[0710] The synthesis method of compound 64 is as described in Example 30.

[0711] Compound 64: LC-MS (ESI) m / z: 667.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.03(d,J=2.3Hz,1H),8.51(d,J=2.3Hz,1H),8.23(s,1H),8.09(d,J=8.8Hz,1H),7.91(d,J=8.8Hz,1H),7.78(d,J=2.0Hz,1H), 7.25(dd,J=8.8,2.1Hz,1H),7.21(dd,J=8.8,1.9Hz,1H),6.67(d,J=2.1Hz, 1H),5.55(s,2H),3.65(q,J=7.0Hz,2H),3.23(s,3H),1.26(t,J=7.0Hz,3H).

[0712] Example 65 Synthesis of Compound 65

[0713]

[0714] Synthetic route

[0715]

[0716] Step 1: Synthesis of Compound 65-1

[0717] Methyl 5-bromo-1H-imidazolium-4-carboxylate (900 mg, 4.39 mmol) was dissolved in 15 mL of dry THF at room temperature. The solution was cooled to 0 °C, and sodium hydride (270 mg, 6.75 mmol) was slowly added under a nitrogen atmosphere. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 hour. Then, methyl iodoform (900 mg, 6.34 mmol) was slowly added dropwise to the reaction system. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS to ensure completeness. The reaction was quenched by adding saturated ammonium chloride solution dropwise under ice bath conditions. The organic phases were extracted with water and ethyl acetate, and the combined organic phases were concentrated. The residue was separated by rapid column chromatography (eluent: EA:PE = 30%) to give 850 mg of the title compound as a white solid.

[0718] LC-MS (ESI) m / z: 219.0 [M+H] + Yield: 88%.

[0719] Step 2: Synthesis of Compound 65-2

[0720] At room temperature, compound 65-1 (360 mg, 1.65 mmol) was dissolved in 4 mL of 1,4-dioxane and 1 mL of water. (dppf)PdCl2·DCM (135 mg, 0.165 mmol), 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline (500 mg, 1.97 mmol), and potassium phosphate (700 mg, 3.30 mmol) were added. The mixture was heated to 100 °C and stirred overnight. After the reaction was monitored by LC-MS until complete, the reaction solution was concentrated and separated by rapid column chromatography (eluent: EA:PE = 55%) to give 420 mg of the title compound as a purple solid.

[0721] LC-MS (ESI) m / z: 266.1 [M+H] + Yield: 96%.

[0722] Step 3: Synthesis of Compound 65-3

[0723] At room temperature, compound 65-2 (410 mg, 1.54 mmol) was dissolved in 5 mL of anhydrous ethanol, and p-toluenesulfonic acid (410 mg, 2.38 mmol) was added. The mixture was heated to 75 °C and stirred for 3 hours. After the reaction was monitored by LC-MS until complete, the reaction solution was concentrated and separated by rapid column chromatography (eluent: DCM:MeOH = 8%) to give 340 mg of the title compound as a powdery white solid.

[0724] LC-MS (ESI) m / z: 234.0 [M+H]+ Yield: 94%.

[0725] Step 4: Compound 65-4

[0726] The synthesis of compound 65-4 is based on the synthesis of 123-3 in Example 123 of the published patent application WO2024 / 183778.

[0727] Step 5: Synthesis of Compound 65

[0728] The synthesis of compound 65 is described in Example 30.

[0729] Compound 65: LC-MS (ESI) m / z: 663.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.02(d,J=2.3Hz,1H),8.54-8.47(m,2H),8.22(d,J=8.4Hz,2H),8.17(s,1H),8.08(d,J=8.8Hz,1H),8.01(d, J=2.0Hz,1H),7.42(dd,J=8.6,1.9Hz,1H),7.24(dd,J=8.8,2.1Hz,1H),6.66(d,J=2.0Hz,1H),5.91(s,2H),4.16(s,3H),3.33(s,6H).

[0730] Example 66 Synthesis of Compound 66

[0731]

[0732] Synthesis method

[0733] The synthesis of compound 66 is based on Example 30, except that in step three, the tetrahydrofuran solution of dimethylamine is replaced with a tetrahydrofuran mixture of methylamine hydrochloride dissociated from N,N-diisopropylethylamine.

[0734] Compound 66: LC-MS (ESI) m / z: 639.1 [M+H] + 320.0 [M / 2+H] + . 1H NMR(400MHz,DMSO-d6)δ9.03(d,J=2.3Hz,1H),8.82(q,J=5.6Hz,1H),8.52(d ,J=2.3Hz,1H),8.23(s,1H),8.15(dd,J=8.8,1.8Hz,1H),7.98(d,J=8.8Hz,1H ),7.78(d,J=2.0Hz,1H),7.33(dd,J=8.6,2.0Hz,1H),7.21(dd,J=8.8,1.9Hz ,1H),6.65(d,J=2.0Hz,1H),5.56(s,2H),3.24(s,6H),2.99(d,J=4.4Hz,3H).

[0735] Example 67 Synthesis of Compound 67

[0736]

[0737] Synthetic route

[0738]

[0739] Synthesis method

[0740] Step 1: Synthesis of Compound 67-1

[0741] Under nitrogen protection, 4-chloro-2-fluorobenzamide (1.8 g, 10.37 mmol) was dissolved in 1,2-dichloroethane (40 mL), cooled to 0 °C, and oxalyl chloride (1.97 g, 10.56 mmol) was slowly added dropwise. The mixture was heated to 70 °C and stirred for 2 hours. After the reaction solution cooled to room temperature, it was concentrated under reduced pressure. Under nitrogen protection, the solid was dissolved in 1,2-dichloroethane (10 mL), and this solution was slowly added dropwise to (2-bromothiazol-5-yl)methylamine (2 g, 10.37 mmol) in 1,2-dichloroethane (40 mL). The reaction was carried out at room temperature for 10 minutes until a large amount of white solid precipitated. The solid was filtered and dried to give compound 1, 1.94 g, with a yield of 47.65%. LC-MS (ESI) m / z: 392.2 [M+H] + .

[0742] Step 2: Synthesis of Compound 67-2

[0743] Compound 67-1 (1.94 g, 4.94 mol) was dissolved in N,N-dimethylformamide (60 mL). Under nitrogen protection, NaH (395 mg, 60%, dispersed in paraffin) was added at 0 °C. After stirring for five minutes, the mixture was heated to 90 °C and reacted for one hour. After the reaction solution cooled to room temperature, excess water was added while stirring to quench the reaction. The pH was then adjusted to 6–7 with dilute hydrochloric acid solution, during which a large amount of white solid precipitated. The solid was filtered and dried to obtain 1.3 g of crude compound 67-2, which was used directly in the next step. LC-MS (ESI) m / z: 372.2 [M+H] + .

[0744] Step 3: Synthesis of Compound 67-3

[0745] Compound 67-2 (300 mg, 0.805 mmol) was dissolved in 10 mL of anhydrous acetonitrile at room temperature. The solution was cooled to 0 °C, and DIEA (520 mg, 4.03 mmol) and phosphorus oxychloride (309 gm, 2.01 mmol) were added. The mixture was slowly heated to room temperature and then stirred at 80 °C for two hours. The reaction solution was concentrated to remove a large amount of phosphorus oxychloride. Then, a mixed solution of methylamine hydrochloride, DIEA, and THF was added, and the mixture was stirred at room temperature for ten minutes. The reaction was monitored by LC-MS to ensure complete reaction. After concentration, the solution was purified by C-18 reversed-phase column chromatography (eluent: MeCN / H2O, 60%) to give 230 mg of compound 3, with a yield of 74.07%. LC-MS (ESI) m / z: 385.2 [M+H] + .

[0746] Step 4: Synthesis of Compound 67

[0747] At room temperature, compound 67-3 (50 mg, 0.13 mmol) and (6-chloro-5-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)pyridin-3-yl)boronic acid (25 mg, 0.065 mmol) were dissolved in 1 mL of a mixed solvent of 1,4-dioxane and 0.1 mL of N,N-dimethylformamide. An aqueous solution of potassium carbonate (27 mg, 0.195 mmol) (0.10 mL) and (dppf)PdCl2·DCM (11 mg, 0.013 mmol) were added. After complete purging with nitrogen, the mixture was heated to 100 °C and stirred for two hours. The reaction was monitored by LC-MS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, concentrated, and then separated by rapid column chromatography (eluent: MeOH / DCM = 6%) to obtain 30 mg of crude compound 4. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain 10 mg of product 67, with a yield of 24%.

[0748] Compound 67: LC-MS (ESI) m / z: 639.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.03(d,J=2.3Hz,1H),8.58(q,J=4.4Hz,1H),8.51(d,J=2.3Hz,1H),8.21(s,1H),8.08(dd,J=12.4,8.8Hz,2H), 7.77(d,J=1.9Hz,1H),7.36(d,J=2.6Hz,2H),6.67(d,J=2.1Hz,1H),5.57(s,2H),3.59(s,3H),2.93(d,J=4.4Hz,3H),1.25-1.23(m,3H).

[0749] Example 68 Synthesis of Compound 68

[0750]

[0751] Synthetic route

[0752]

[0753] Step 1: Synthesis of Compound 68-2

[0754] At room temperature, compound 65-2 (50 mg, 0.188 mmol) was dissolved in 1 mL of toluene, and 5-bromo-2-chloro-3-iodopyridine (77 mg, 0.244 mmol), Pd2(dba)3 (18 mg, 0.0197 mmol), Xantphos (11 mg, 0.0190 mmol), and cesium carbonate (123 mg, 0.377 mmol) were added. The mixture was heated to 100 °C and stirred overnight. After the reaction was monitored by LC-MS until complete, the reaction solution was concentrated and separated by rapid column chromatography (eluent: DCM:MeOH = 7%) to give 71 mg of the title compound as a yellow solid.

[0755] LC-MS (ESI) m / z: 422.9 [M+H] + Yield: 89%.

[0756] Step 2: Synthesis of Compound 68-3

[0757] Compound 68-2 (70 mg, 0.165 mmol) was dissolved in 1.2 mL of 1,4-dioxane at room temperature. (dppf)PdCl2·DCM (14 mg, 0.0208 mmol), BPD (126 mg, 0.496 mmol), and potassium acetate (49 mg, 0.500 mmol) were added, and the mixture was heated to 100 °C and stirred for three hours. After the reaction was monitored by LC-MS to ensure completion, the reaction solution was purified by C-18 reversed-phase column chromatography (MeCN: H2O, 40%) to give 50 mg of the title compound as a yellow solid.

[0758] LC-MS (ESI) m / z: 389.0 [M+H] + Yield: 78%.

[0759] Step 3: Synthesis of Compound 68

[0760] The synthesis of compound 68 is described in Example 30.

[0761] Compound 68: LC-MS (ESI) m / z: 663.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.12(d,J=2.3Hz,1H),8.63(d,J=2.3Hz,1H),8.29(d,J=8.7Hz,1H),8.24(d,J=7.7Hz,2H),7.98(d,J=8.8Hz,1H),7. 79(d,J=2.0Hz,1H),7.44(dd,J=8.6,2.0Hz,1H),7.21(dd,J=8.7,2.0Hz,1H),6.81(d,J=2.0Hz,1H),5.56(s,2H),4.23(s,3H),3.24(s,6H).

[0762] Example 69: Synthesis of Compound 69

[0763]

[0764] Synthesis method

[0765] The synthesis of compound 69 is the same as in Example 30, except that in step three, the tetrahydrofuran solution of dimethylamine is replaced with a methanol solution of ammonia.

[0766] Compound 69: LC-MS (ESI) m / z: 625.0 [M+H] + 313.0 [M / 2+H] + . 1H NMR (400MHz, DMSO-d6) δ9.04(d,J=2.3Hz,1H),8.53(d,J=2.3Hz,1H),8.46(s,1H),8.34(s,1H),8.23(s,1H),8.19(d,J=8.7Hz,1H),7.98(d,J =8.8Hz,1H),7.78(d,J=2.0Hz,1H),7.33(dd,J=8.6,2.0Hz,1H),7.21(dd,J=8.8,2.0Hz,1H),6.67(d,J=2.0Hz,1H),5.56(s,2H),3.25(s,6H).

[0767] Example 70 Synthesis of Compound 70

[0768]

[0769] Synthetic route

[0770]

[0771] Synthesis method

[0772] Step 1: Synthesis of Compound 70-1

[0773] At room temperature, 2-bromo-5-methyl-1,3,4-thiadiazole (1 g, 5.59 mmol) was dissolved in 20 mL of dry carbon tetrachloride, and NBS (1.1 g, 6.18 mmol) and AIBN (100 mg, 0.610 mmol) were added. The mixture was heated to 80 °C and stirred overnight. The reaction was monitored by LC-MS until complete. The solvent was removed directly under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether) to give compound 70-1, 0.62 g. Yield: 43%. LC-MS (ESI) m / z: 258.9 [M+H] + .

[0774] Step 2: Synthesis of Compound 70-3

[0775] The synthesis of compound 70-3 is based on the synthesis of 101-3 in Example 101 of the published patent application WO2024 / 183778. The difference is that methyl ethylamine in step one of that patent is replaced with dimethylamine, and 2-bromo-5-bromomethylthiazole in step three is replaced with compound 70-1 in this patent.

[0776] Step 3: Synthesis of Compound 70

[0777] The synthesis of compound 70 is the same as that in Example 30, except that compound 30-5 is replaced with compound 70-3 in this route.

[0778] Compound 70: LC-MS (ESI) m / z: 328.6 [M / 2+H] + . 1 H NMR (600MHz, DMSO-d6) δ9.13(d,J=2.3Hz,1H),8.65(d,J=2.3Hz,1H),8.11(d,J=8.8Hz,1H),8.01(d,J=8.7Hz,1H),7. 73(d,J=2.0Hz,1H),7.26(ddd,J=12.9,8.7,2.0Hz,2H),6.73(d,J=2.0Hz,1H),5.76(s,2H),3.35(s,6H),3.28(s,6H).

[0779] Example 71 Synthesis of Compound 71

[0780]

[0781] Synthetic route

[0782]

[0783] Synthesis method

[0784] Step 1: Synthesis of Compound 71-1

[0785] At room temperature, 2,5-dibromo-3-nitropyridine (2 g, 7.12 mmol) was dissolved in 30 mL of ethanol and 8 mL of water, and reduced iron powder (2 g, 35.7 mmol) and ammonium chloride (2 g, 35.7 mmol) were added. The mixture was heated to 70 °C and stirred for 2 hours. The reaction was monitored by LC-MS until complete. The mixture was filtered through diatomaceous earth, the filter cake was washed twice with methanol, and the filtrate was concentrated and purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether) to give compound 71-1, 1.57 g. Yield: 88%. LC-MS (ESI) m / z: 250.9 [M+H] + .

[0786] Step 2: Synthesis of Compound 71-2

[0787] Compound 71-1 (1 g, 3.98 mmol) was dissolved in 12 mL of 1,4-dioxane and 3 mL of water at room temperature. Pd(dppf)Cl2·DCM (330 mg, 0.404 mmol), cyclopropyl borate (2 g, 11.9 mmol), and potassium carbonate (1.6 g, 11.6 mmol) were added, and the mixture was heated to 100 °C and stirred for 20 hours. After the reaction was monitored by LC-MS until complete, the reaction solution was concentrated and purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether) to give compound 71-2, 470 mg, in 55% yield. LC-MS (ESI) m / z: 213.0 [M+H] + .

[0788] Steps three, four, and five: Synthesis of compounds 71-3, 71-4, and 71-5

[0789] The synthesis of compounds 71-3, 71-4, and 71-5 is based on the synthesis of 123-7 in Example 123 of the published patent application WO2024 / 183778, except that the 2-bromo-6-aminopyridine in step five of that patent is replaced with compound 71-2 in this route.

[0790] Step Six: Synthesis of Compound 71-6

[0791] Compound 71-5 (65 mg, 0.154 mmol) was dissolved in 1 mL of dry dioxane at room temperature, and BPD (120 mg, 0.472 mmol), Pd(dppf)Cl2.DCM (13 mg, 0.0159 mmol), and potassium acetate (45 mg, 0.459 mmol) were added. After purging with nitrogen, the mixture was heated to 100 °C and reacted for 2 hours. The reaction was monitored by LC-MS until complete. After cooling, the mixture was concentrated and directly separated by rapid column chromatography (H2O:MeCN, 0-100%, 20 min) to give compound 71-6, 40 mg, in a yield of 69%. LC-MS (ESI) m / z: 385.1 [M+H] + .

[0792] Step 7: Synthesis of Compound 71

[0793] The synthesis of compound 71 is the same as that in Example 30, except that compound 30-4 is replaced with compound 71-6 in this route.

[0794] Compound 71: LC-MS (ESI) m / z: 330.1 [M / 2+H] + . 1H NMR (600MHz, DMSO-d6) δ9.02 (d, J=2.1Hz, 1H), 8.17-8.13 (m, 2H), 8.08 (d, J= 8.8Hz,1H),7.98(d,J=8.7Hz,1H),7.78(d,J=2.0Hz,1H),7.22(ddd,J=16.9,8 .8,2.0Hz,2H),6.43(d,J=2.1Hz,1H),5.53(s,2H),3.33(s,6H),3.24(s,6H) ,1.75-1.69(m,1H),1.12-1.06(m,1H),0.94-0.85(m,2H),0.83-0.76(m,1H).

[0795] Example 72 Synthesis of Compound 72

[0796]

[0797] Synthesis method

[0798] The synthesis method of compound 72 is as described in Example 30.

[0799] Compound 72: LC-MS (ESI) m / z: 625.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.04(d,J=2.3Hz,1H),8.51(d,J=2.3Hz,1H),8.21(s,2H),8.10(dd,J=8.8,4.4Hz,3H ),7.77(d,J=1.9Hz,1H),7.27(ddd,J=14.5,8.7,2.0Hz,2H),6.67(d,J=2.1Hz,1H),5.56(s,2H),3.32(s,6H).

[0800] Example 73 Synthesis of Compound 73

[0801]

[0802] Synthesis method

[0803] The synthesis method of compound 73 is as described in Example 30.

[0804] Compound 73: LC-MS (ESI) m / z: 625.2 [M+H] + . 1H NMR(400MHz, DMSO-d6)δ9.03(d,J=2.3Hz,1H),8.81(d,J=4.7Hz,1H),8.58(d, J=4.6Hz,1H),8.52(d,J=2.3Hz,1H),8.21(s,1H),8.15(d,J=8.6Hz,1H),8.06( d,J=8.7Hz,1H),7.77(d,J=2.0Hz,1H),7.31(ddd,J=15.3,8.6,1.9Hz,2H),6. 65(d,J=2.0Hz,1H),5.57(s,2H),2.99(d,J=4.5Hz,3H),2.92(d,J=4.5Hz,3H).

[0805] Example 74 Synthesis of Compound 74

[0806]

[0807] Synthetic route

[0808] Synthesis method:

[0809] Step 1: Synthesis of Compound 74-1

[0810] (2-bromothiazol-4-yl)methanol (1 g, 5.155 mmol) was dissolved in 20 mL of dichloromethane. Carbon tetrabromide (2.56 g, 7.733 mmol) was added at 0 °C, and the mixture was stirred for 10 min. Then, a mixture of triphenylphosphine (2.03 g, 7.733 mmol) and dichloromethane was added, and the mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS until complete. The mixture was extracted three times with water and DCM, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (PE:EA, 0-100%, 12 min) to give 900 mg of the title compound as a colorless oil.

[0811] LC-MS (ESI) m / z: 256.2 [M+H] + Yield: 67.97%

[0812] Step 2: Synthesis of Compound 74-2

[0813] 7-Chloro-4-(dimethylamino)quinazolin-2(1H)-one (300 mg, 1.34 mmol) was dissolved in 10 mL of dry DMF, and compound 1 (414 mg, 1.61 mmol) and cesium carbonate (1.31 g, 4.02 mmol) were added. The mixture was stirred at 100 °C for 3 hours. The reaction was monitored by LCMS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (DCM: MeOH, 0-10%, 12 min) to give 167 mg of the title compound as a yellow oil.

[0814] LC-MS (ESI) m / z: 399.2 [M+H] + Yield: 31.15%

[0815] Step 3: Synthesis of Compound 74-3

[0816] Compound 74-2 (148 mg, 0.37 mmol), (6-chloro-5-(7-chloro-4-(dimethylamino)-2-oxoquinazoline-1(2H)-yl)pyridin-3-yl)boronic acid (70 mg, 0.185 mmol), Pd(dppf)Cl2 (15 mg, 0.0185 mmol), and potassium carbonate (77 mg, 0.555 mmol) were reacted at 100 °C for 1 hour. The reaction was monitored by LCMS until complete. The mixture was extracted three times with water and EA, washed with saturated brine, and the combined organic phases were concentrated and separated by rapid column chromatography (DCM: MeOH, 0-10%, 10 min) to give 35 mg of the white title compound.

[0817] Compound 74: LC-MS (ESI) m / z: 653.2 [M+H] + Yield: 28.98%. 1 H NMR (600MHz, DMSO-d6) δ9.07(d,J=2.3Hz,1H),8.51(d,J=2.3Hz,1H),8.12(d,J=8.8Hz,1H),7.98(d,J=8.8Hz,1H),7.66(d,J=2.0Hz,1H),7.60 (d,J=1.0Hz,1H),7.28(dd,J=8.8,2.1Hz,1H),7.18(dd,J=8.8,2.0Hz,1H),6.77(d,J=2.1Hz,1H),5.50-5.41(m,2H),3.36(s,6H),3.26(s,6H).

[0818] Example 75 Synthesis of Compound 75

[0819]

[0820] Synthetic route

[0821]

[0822] Synthesis method

[0823] Step 1: Synthesis of Compound 75-2

[0824] The synthesis of compound 75-1 is the same as that of compound 75-2 in Example 71.

[0825] Compound 75-1 (200 mg, 0.939 mmol) was dissolved in 10 mL of acetonitrile at room temperature. P-Toluenesulfonic acid (530 mg, 2.79 mmol) was added, followed by the addition of potassium iodide (400 mg, 2.41 mmol) and sodium nitrite (130 mg, 1.88 mmol) dissolved in water. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS until complete. The reaction was quenched with sodium bicarbonate solution, and the mixture was extracted three times with water and ethyl acetate. The combined organic phases were concentrated and purified by silica gel chromatography (eluent: petroleum ether) to give compound 75-2, 130 mg. Yield: 43%. LC-MS (ESI) m / z: 323.9 [M+H] + .

[0826] Step 2: Synthesis of Compound 75-4

[0827] The synthesis of compound 75-3 was performed in accordance with the synthesis of compound 65-2 in Example 65.

[0828] Compound 75-3 (35 mg, 0.132 mmol) was dissolved in 1 mL of toluene at room temperature. Compound 2 (42 mg, 0.130 mmol), Pd2(dba)3 (12 mg, 0.0131 mmol), Xantphos (8 mg, 0.0138 mmol), and cesium carbonate (86 mg, 0.264 mmol) were added, and the mixture was heated to 100 °C and stirred overnight. After the reaction was monitored by LC-MS until complete, the reaction solution was concentrated and purified by silica gel chromatography (eluent: dichloromethane / methanol) to give compound 75-4, 60 mg, in 100% yield. LC-MS (ESI) m / z: 429.0 [M+H] + .

[0829] Step 3: Synthesis of Compound 75-5

[0830] Compound 75-4 (60 mg, 0.140 mmol) was dissolved in 1.5 mL of 1,4-dioxane at room temperature. Pd(dppf)Cl2·DCM (12 mg, 0.0146 mmol), BPD (107 mg, 0.421 mmol), and potassium acetate (42 mg, 0.429 mmol) were added, and the mixture was heated to 100 °C and stirred for three hours. After the reaction was monitored by LC-MS to ensure completion, the reaction solution was purified by C-18 reversed-phase column chromatography (MeCN: H2O, 40%) to give compound 75-5, 35 mg, in a yield of 63%. LC-MS (ESI) m / z: 395.1 [M+H]+.

[0831] Step 4: Synthesis of Compound 75

[0832] The synthesis of compound 75 is the same as that in Example 30, except that compound 75-4 is replaced with compound 75-5 in this route.

[0833] Compound 75: LC-MS (ESI) m / z: 335.2 [M / 2+H] + . 1 H NMR(400MHz,DMSO-d6)δ9.09(d,J=2.1Hz,1H),8.29(d,J=8.7Hz,1H),8.27-8.21(m,2H),8 .17(s,1H),7.97(d,J=8.7Hz,1H),7.78(d,J=2.0Hz,1H),7.42(dd,J=8.7,2.1Hz,1H),7.20 (dd,J=8.8,2.0Hz,1H),6.60(d,J=2.0Hz,1H),5.53(s,2H),4.23(s,3H),3.24(s,6H),1.55 -1.47(m,1H),1.13-1.03(m,1H),0.98-0.89(m,1H),0.89-0.78(m,1H),0.78-0.67(m,1H).

[0834] Example 76 Synthesis of Compound 76

[0835]

[0836] Synthetic route

[0837]

[0838] Synthesis method

[0839] The synthesis method of compound 76 is the same as that in Example 75, except that (2-bromothiazol-4-yl)methanol in step one is replaced with (5-bromothiazol-2-yl)methanol.

[0840] Compound 76: LC-MS (ESI) m / z: 653.2 [M+H] + Yield: 26%. 1 H NMR (400MHz, DMSO-d6) δ8.82(d,J=2.4Hz,1H),8.33(d,J=2.4Hz,1H),8.29(s,1H),8.10-8.06(m,1H),7.99(d,J=8 .8Hz,1H),7.57(d,J=2.0Hz,1H),7.29-7.21(m,2H),6.59(d,J=2.1Hz,1H),5.56(s,2H),3.32(s,6H),3.25(s,6H).

[0841] Example 77 Synthesis of Compound 77

[0842]

[0843] Synthetic route

[0844]

[0845] Synthesis method

[0846] Step 1: Synthesis of Compound 77-1

[0847] At room temperature, 2-methoxy-3-amino-5-bromopyridine (1 g, 4.93 mmol) was dissolved in 12 mL of dioxane, and BPD (3.8 g, 15.0 mmol), Pd(dppf)Cl2.DCM (400 mg, 0.490 mmol), and potassium acetate (1.44 g, 14.7 mmol) were added. After purging with nitrogen, the mixture was heated to 80 °C and reacted for 10 hours. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated and purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether) to give compound 77-1, 1.54 g, in 100% yield. LC-MS (ESI) m / z: 251.1 [M+H] + .

[0848] Step 2: Synthesis of Compound 77-2

[0849] Compound 77-1 (800 mg, 3.19 mmol) was dissolved in 10 mL of dioxane, 2 mL of water, and 1 mL of DMF at room temperature. Then, 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazolium-4-onitrile (500 mg, 1.66 mmol), Pd(dppf)Cl2.DCM (140 mg, 0.171 mmol), and potassium carbonate (690 mg, 5.00 mmol) were added. After purging with nitrogen, the mixture was heated to 100 °C and reacted for 3 hours. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated and purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether) to give compound 77-2, 750 mg, in 68% yield. LC-MS (ESI) m / z: 346.2 [M+H] + .

[0850] Steps three, four, five, and six: Synthesis of compounds 77-3, 77-4, 77-5, and 77

[0851] The synthesis of compounds 77-3, 77-4, 77-5, and 77 in steps three through six is ​​based on the synthesis in Example 55 of the published patent application WO2024 / 183778. The difference is that 55-4 in that patent is replaced with compound 77-2 in this route.

[0852] Compound 77: LC-MS (ESI) m / z: 316.6 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.86(d,J=2.3Hz,1H),8.21(d,J=2.3Hz,1H),8.09(d,J=8.8Hz,1H),7.98(d,J=8.8Hz,1H),7.71(s,1H),7.29(s, 1H),7.25(dd,J=8.8,2.1Hz,1H),7.20(dd,J=8.8,2.0Hz,1H),6.59(d,J=2.1Hz,1H),5.30(s,2H),3.87(s,3H),3.33(s,6H),3.25(s,6H).

[0853] Example 78 Synthesis of Compound 78

[0854]

[0855] Synthetic route

[0856]

[0857] Synthesis method

[0858] The synthesis of compound 78-4 is based on the synthesis of 337-4 in Example 337 of published patent application WO2024 / 183778, and the synthesis of compound 78-7 is based on the synthesis of 193-2 in Example 193 of published patent application WO2024 / 183778, except that ethyl 3-bromopropionate is replaced with methyl 3-bromopropionate in step five. The synthesis of compound 78 is based on Example 33.

[0859] Compound 78: LC-MS (ESI) m / z: 593.2 [M+H] + 297.1 [M / 2+H] + . 1 H NMR (400MHz, DMSO-d6)δ

[0860] 10.53(s,1H),8.75(d,J=2.3Hz,1H),8.23(d,J=2.2Hz,1H),8.07(d,J=8.9H z,1H),8.04(d,J=2.2Hz,1H),7.96(d,J=8.7Hz,1H),7.61(d,J=2.0Hz,1H), 7.24(dd,J=8.8,2.1Hz,1H),7.17(dd,J=8.7,1.9Hz,1H),6.43(d,J=2.1Hz, 1H), 4.32 (t, J = 7.2Hz, 2H), 3.32 (s, 6H), 3.22 (s, 6H), 2.73 (t, J = 7.2Hz, 2H).

[0861] Example 79: Synthesis of Compound 79

[0862]

[0863] Synthetic route

[0864]

[0865] Synthesis method

[0866] The synthesis of compound 79-6 is based on the synthesis of 123-2 in Example 123 of the published patent application WO2024 / 183778.

[0867] Step 1: Synthesis of Compound 79-1

[0868] A 20% aqueous solution of sodium hydroxide (20 mL) was added to a 50 mL flask, and benzyltriethylammonium bromide (0.15 g, 0.54 mmol) was added with stirring. 2-(4-(trifluoromethyl)pyridin-2-yl)acetonitrile (2.0 g, 10.7 mmol) and 1-Boc-3-(bromomethyl)pyrrolidine (3.4 g, 12.9 mmol) were added alternately in portions to the mixture. The reaction mixture was stirred overnight at room temperature. After no change was observed in the reaction mixture under TLC monitoring, the reaction mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the drying agent was filtered off, the solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography (eluent: ethyl acetate / petroleum ether = 0–20%) to give compound 79-1, 0.99 g. Yield: 25%. LC-MS (ESI) m / z: 314.2 [M+H] + .

[0869] Step 2: Synthesis of Compound 79-2

[0870] Compound 79-1 (0.99 g, 2.7 mmol) was dissolved in methanol (10 mL). A 20% aqueous solution of sodium hydroxide (0.20 mL), tetrabutylammonium bromide (9.0 mg, 0.027 mmol), and hydrogen peroxide (0.91 g, 8.0 mmol) were added sequentially to this solution, and the mixture was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: methanol / dichloromethane = 10%) to give compound 79-2, 157 mg, as a white oil, in 34% yield. LC-MS (ESI) m / z: 388.2 [M+H] + .

[0871] Step 3: Synthesis of Compound 79-3

[0872] At 0 °C, a 0.5 mL solution of compound 2 (0.20 g, 0.52 mmol) in ethanol was added dropwise to an ethanol solution of sodium ethoxide (20 wt%, 1.8 g, 5.2 mmol). After stirring at room temperature for half an hour, phosgene (119 mg, 1.0 mmol) was added dropwise to the reaction system. After the addition was complete, the temperature was raised to 70 °C and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: methanol / dichloromethane = 10%) to give compound 79-3, 0.14 g, as a yellow solid, in 65% yield. LC-MS (ESI) m / z: 430.1 [M+H] + .

[0873] Step 4: Synthesis of Compound 79-4

[0874] Compound 79-3 (0.16 g, 0.37 mmol) was dissolved in tetrahydrofuran (2.0 mL) at room temperature. Pyridine (59 mg, 0.75 mmol) and a tetrahydrofuran solution of dimethylamine (2 M, 34 mg, 0.75 mmol) were added sequentially. After cooling to 0 °C, elemental iodine (25 mg, 0.75 mmol) was added. The mixture was then heated to 50 °C and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: methanol / dichloromethane = 6%) to give compound 79-4, 0.14 g, as a yellow solid, in 85% yield. LC-MS (ESI) m / z: 441.2 [M+H] + .

[0875] Step 5: Synthesis of Compound 79-5

[0876] Compound 79-4 (0.14 g, 0.32 mmol) was dispersed in 1,4-dioxane (1.0 mL) at room temperature. A solution of 1,4-dioxane in hydrochloric acid (1.0 mL, 4 M) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for three hours. The reaction mixture was concentrated under reduced pressure to obtain crude compound 79-5. This solid was purified by silica gel chromatography (eluent: methanol / dichloromethane = 10%), yielding 65 mg of a yellow solid. LC-MS (ESI) m / z: 341.2 [M+H] + 171.2 [M / 2+H] + .

[0877] Step Six: Synthesis of Compound 79-7

[0878] Compound 6 (0.30 g, 1.3 mmol), tert-butyl 3-bromopropionate (0.56 g, 2.7 mmol), and cesium carbonate (1.3 g, 4.0 mmol) were dispersed in N,N-dimethylformamide (5.0 mL) solution and heated to 100 °C with stirring overnight. The reaction mixture was extracted with ethyl acetate (20 mL × 3) and water (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 10%–100%) to give compound 7, 0.13 g. Yield: 28%. LC-MS (ESI) m / z: 352.1 [M-56+H] + .

[0879] Step 7: Synthesis of Compound 79-8

[0880] Compound 79-7 (50 mg, 0.14 mmol) was dispersed in 1,4-dioxane (1.0 mL) at room temperature, and a 1,4-dioxane solution of hydrochloric acid (3.0 mL, 4 M) was added dropwise to the reaction mixture. The mixture was stirred overnight at room temperature. After concentration under reduced pressure, 45 mg of crude compound 79-8 was obtained as a white solid, which could be used directly in the next step. LC-MS (ESI) m / z: 296.1 [M+H] + .

[0881] Step 8: Synthesis of Compound 79

[0882] At room temperature, compound 79-8 (24 mg, 0.081 mmol) was dissolved in N,N-dimethylformamide (0.50 mL), and a DMF solution of DIEA (21 mg, 0.16 mmol) and HATU (37 mg, 0.097 mmol) (0.3 mL) was added dropwise. The mixture was stirred at room temperature for 20 minutes. Add dropwise 0.5 mL of N,N-dimethylformamide solution containing compound 78-5 (28 mg, 0.081 mmol) stirred with DIEA (21 mg, 0.16 mmol) to the reaction solution, and stir at room temperature for 20 minutes. Extract the reaction solution with ethyl acetate and water, combine the organic phases, wash once with saturated brine, dry to anhydrous sodium sulfate, filter to remove the drying agent, remove the solvent under reduced pressure, and purify the residue by silica gel chromatography (eluent: dichloromethane / methanol = 14 / 1) to obtain crude compound 79. The crude product is further purified by preparative liquid chromatography, and the preparative solution is freeze-dried to give product 79, 2.83 mg, yield 5.6%. LC-MS (ESI) m / z: 618.2 [M+H] + .

[0883] Example 80: Synthesis of Compound 80

[0884]

[0885] Synthetic route

[0886]

[0887] Synthesis method

[0888] The synthesis of compound 80-4 was performed according to Example 79, and the synthesis of compound 80-1 was performed according to the synthesis of 123-2 in Example 123 of the published patent application WO2024 / 183778.

[0889] Step 1: Synthesis of Compound 80-2

[0890] Compound 80-1 (1.0 g, 4.5 mmol), methyl 3-bromocyclobutanecarboxylate (1.7 g, 9.0 mmol), and cesium carbonate (4.4 g, 13 mmol) were dispersed in N,N-dimethylformamide (15 mL) solution and heated to 100 °C with stirring overnight. The reaction mixture was extracted with ethyl acetate (30 mL × 3) and water (30 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, the drying agent was filtered off, the solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 25%–100%) to give compound 80-2, 0.35 g, yield 23%. LC-MS (ESI) m / z: 336.1 [M+H] + .

[0891] Step 2: Synthesis of Compound 80-3

[0892] Compound 80-2 (0.34 g, 1.0 mmol) was dispersed in methanol (2.0 mL) at room temperature. Lithium hydroxide monohydrate (0.085 g, 2.0 mmol) was dissolved in water (0.5 mL) and added dropwise to the reaction mixture. The mixture was stirred at room temperature for three hours. After concentration under reduced pressure, a small amount of water was added to the residue, and 1N dilute hydrochloric acid was added dropwise to adjust the pH to 3–4. The mixture was stirred at room temperature for 10 minutes. Extraction with ethyl acetate was performed, and the concentrated organic phases were combined to obtain crude compound 80-3. This crude compound was purified by silica gel chromatography (eluent: methanol / dichloromethane = 10%) to give compound 80-3, 0.070 g, as a white solid, in 21% yield. LC-MS (ESI) m / z: 322.1 [M+H] + .

[0893] Step 3: Synthesis of Compound 80

[0894] At room temperature, compound 80-3 (44 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (0.50 mL), and a solution of DIEA (35 mg, 0.27 mmol) and HATU (62 mg, 0.16 mmol) in N,N-dimethylformamide (0.5 mL) was added dropwise, and the mixture was stirred at room temperature for 20 minutes. A solution of compound 80-4 (47 mg, 0.14 mmol) in N,N-dimethylformamide (0.5 mL) stirred with DIEA (35 mg, 0.27 mmol) was added dropwise, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was extracted with ethyl acetate and water. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was filtered off. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (eluent: dichloromethane / methanol = 16 / 1) to obtain crude compound 80. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to give 80 mg of the product, with a yield of 3.3%. LC-MS (ESI) m / z: 644.2 [M+H] + .

[0895] Example 81 Synthesis of Compound 81

[0896]

[0897] Synthetic route

[0898]

[0899] Synthesis method

[0900] The synthesis of compound 81-2 is based on the synthesis of 123-2 in Example 123 of the published patent application WO2024 / 183778.

[0901] Step 1: Synthesis of Compound 81-1

[0902] Disperse 0.20 g (0.99 mmol) of tert-butyl (3-(hydroxymethyl)cyclobutyl)carbamate in 2.0 mL of dichloromethane. After cooling to 0 °C, add carbon tetrabromide (0.49 g, 1.5 mmol) and triphenylphosphine (0.39 g, 1.5 mmol) sequentially. After addition, heat to room temperature and stir for two hours. Remove the solvent from the reaction mixture under reduced pressure. Purify the residue by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0%–30%) to obtain crude compound 81-1, which can be directly used in the next step, 0.20 g. Yield: 75%.

[0903] Step 2: Synthesis of Compound 81-3

[0904] Compound 81-2 (0.15 g, 0.67 mmol), compound 81-1 (0.20 g, 0.76 mmol), and cesium carbonate (0.66 g, 2.0 mmol) were dispersed in N,N-dimethylformamide (5.0 mL) solution and heated to 100 °C with stirring overnight. The reaction mixture was extracted with ethyl acetate (10 mL × 3) and water (150 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 31%–100%) to give compound 81-3, 46 mg. Yield: 17%. LC-MS (ESI) m / z: 407.2 [M+H] + .

[0905] Step 3: Synthesis of Compound 81-4

[0906] Compound 81-3 (46 mg, 0.11 mmol) was dispersed in 1,4-dioxane (0.50 mL) at room temperature. A solution of 1,4-dioxane in hydrochloric acid (1.0 mL, 4 M) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure to obtain 35 mg of crude compound 81-4 as a white solid, which could be used directly in the next step. LC-MS (ESI) m / z: 307.2 [M+H] + .

[0907] Step 4: Synthesis of Compound 81

[0908] At room temperature, compound 81-5 (20 mg, 0.062 mmol) was dissolved in N,N-dimethylformamide (0.50 mL), and a DMF solution of DIEA (16 mg, 0.12 mmol) and HATU (28 mg, 0.075 mmol) (0.5 mL) was added dropwise, and the mixture was stirred at room temperature for 20 minutes. A solution of compound 81-4 (20 mg, 0.062 mmol) in N,N-dimethylformamide (0.5 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was extracted with ethyl acetate and water. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography (eluent: dichloromethane / methanol = 9 / 1) to obtain crude compound 81. The crude compound was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to obtain compound 81, 5.31 mg. LC-MS (ESI) m / z: 610.2 [M+H] + .

[0909] Example 82 Synthesis of Compound 82

[0910]

[0911] Synthetic route

[0912]

[0913] Synthesis method

[0914] The synthesis method of compound 82 is the same as that in Example 81, except that in step one, tert-butyl (3-(hydroxymethyl)cyclobutyl)carbamate is replaced with 1-hydroxymethyl-1-(tert-butoxycarbonylaminomethyl)cyclopropane.

[0915] Compound 82: LC-MS (ESI) m / z: 610.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.05(t,J=5.7Hz,1H),7.95(d,J=8.8Hz,1H),7.91(d,J=8.6Hz,1H),7.42(d,J=2.0Hz,1H),7.25-7.17(m,3H),4.47 -4.38(m,2H),3.25(d,J=2.0Hz,12H),3.02(d,2H),2.90-2.76(m,3H),2.27-2.13(m,2H),2.00(q,J=6.9,6.3Hz,1H),0.38(d,J=7.1Hz,4H).

[0916] Example 83 Synthesis of Compound 83

[0917]

[0918] Synthesis method

[0919] The synthesis method of compound 83 is as described in Example 81. Compound 83: LC-MS (ESI) m / z: 644.2 [M+H] + .

[0920] Example 84 Synthesis of Compound 84

[0921]

[0922] Synthetic route

[0923] The synthesis method of compound 84 is as described in Example 81. Compound 84: LC-MS (ESI) m / z: 612.2 [M+H] + .

[0924] Example 85 Synthesis of Compound 85

[0925]

[0926] Synthetic route

[0927]

[0928] Synthesis method

[0929] The synthesis of compound 85-2 is based on the synthesis of 123-2 in Example 123 of the published patent application WO2024 / 183778.

[0930] Step 1: Synthesis of Compound 85-1

[0931] 0.90 g (6.24 mmol) of methyl 3-hydroxymethylcyclobutane carboxylate was dispersed in 5.0 mL of dichloromethane. After cooling to 0 °C, carbon tetrabromide (3.11 g, 9.36 mmol) and triphenylphosphine (2.46 g, 9.36 mmol) were added sequentially. After the addition was complete, the mixture was heated to room temperature and stirred for two hours. The solvent was removed from the reaction mixture under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0%–20%) to give crude compound 85-1, 1.30 g, which could be used directly in the next step. Yield: 100%.

[0932] Step 2: Synthesis of Compound 85-3

[0933] Compound 85-2 (0.50 g, 2.2 mmol), compound 85-1 (0.93 g, 4.5 mmol), and cesium carbonate (2.2 g, 6.7 mmol) were dispersed in a solution of N,N-dimethylformamide (10.0 mL), heated to 100 °C, and stirred overnight. The reaction mixture was extracted with ethyl acetate (100 mL × 3) and water (100 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, the drying agent was filtered off, the solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0%–100%) to give compound 85-3, 232 mg. Yield: 30%. LC-MS (ESI) m / z: 350 [M+H] + .

[0934] Step 3: Synthesis of Compound 85-4

[0935] Compound 85-3 (230 mg, 0.066 mmol) was dispersed in methanol (3.0 mL) at room temperature. An aqueous solution of lithium hydroxide monohydrate (55 mg, 1.3 mmol, 0.5 mL) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for three hours. The reaction solution was concentrated under reduced pressure, and water was added to the residue. 1N dilute hydrochloric acid was added dropwise while stirring to adjust the pH of the mixture to 5. The solution was then concentrated under reduced pressure and purified by rapid column chromatography (eluent: dichloromethane / methanol = 1:3 / 1) to give compound 85-4, 111 mg, as a pale yellow solid, in 50% yield. LC-MS (ESI) m / z: 336 [M+H] + .

[0936] Step 4: Synthesis of Compound 85-5

[0937] Compound 85-2 (0.30 g, 1.3 mmol), tert-butyl (3-bromocyclobutyl)carbamate (0.50 g, 2.0 mmol), and cesium carbonate (1.3 g, 4.0 mmol) were dispersed in N,N-dimethylformamide (5.0 mL) solution and heated to 100 °C with stirring overnight. The reaction mixture was extracted with ethyl acetate (50 mL × 3) and water (100 mL), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the solvent was removed by vacuum distillation, and the residue was purified by silica gel chromatography (eluent: ethyl acetate / petroleum ether = 24%–100%) to give compound 85-5, 14 mg. Yield: 3%. LC-MS (ESI) m / z: 393 [M+H] + .

[0938] Step 5: Synthesis of Compound 85-6

[0939] Compound 85-5 (7 mg, 0.018 mmol) was dispersed in 1,4-dioxane (0.30 mL) at room temperature. A solution of 1,4-dioxane in hydrochloric acid (1.0 mL, 4 M) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for three hours. After concentration under reduced pressure, crude compound 85-6, 4 mg, was obtained as a white solid and could be used directly in the next step. LC-MS (ESI) m / z: 293 [M+H] + .

[0940] Step Six: Synthesis of Compound 85

[0941] At room temperature, compound 85-4 (5 mg, 0.015 mmol) was dissolved in N,N-dimethylformamide (0.50 mL), and a DMF solution of DIEA (6 mg, 0.045 mmol) and HATU (7 mg, 0.018 mmol) in 0.5 mL was added dropwise, and the mixture was stirred at room temperature for 20 minutes. A solution of compound 85-6 (4 mg, 0.015 mmol) in N,N-dimethylformamide (0.5 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was extracted with ethyl acetate and water. The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The solvent was removed under reduced pressure, and the residue was purified by rapid column chromatography (eluent: dichloromethane / methanol = 13 / 1) to obtain crude compound 85. The crude product was further purified by preparative liquid chromatography, and the preparative solution was freeze-dried to give 1.23 mg of the product, with a yield of 13%. LC-MS (ESI) m / z: 610.2 [M+H] + .

[0942] Example 86 Synthesis of Compound 86

[0943]

[0944] Synthetic route

[0945]

[0946] Synthesis method

[0947] The procedure for compound 86-1 is as described in Example 85, and the synthesis of compound 86-2 is as described in Example 230 of the published patent application WO2024 / 183778.

[0948] Compound 86: LC-MS (ESI) m / z: 624.4 [M+H].

[0949] Example 87 Synthesis of Compound 87

[0950]

[0951] Synthetic route

[0952]

[0953] Synthesis method

[0954] The synthesis method of compound 87-4 is the same as that in Example 85, except that in step one, methyl 3-hydroxymethylcyclobutanecarboxylate is replaced with cis-3-hydroxymethylcyclobutanecarboxylate. The synthesis of compound 87-5 is the same as that in Example 176-2 of the published patent application WO2024 / 183778.

[0955] Compound 87: LC-MS (ESI) m / z: 598.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.99(dd,J=8.8,6.3Hz,2H),7.79(t,J=5.6Hz,1H),7.57(d ,J=2.0Hz,1H),7.48(d,J=2.0Hz,1H),7.22(ddd,J=8.9,7.1,1.9Hz,3H),4.12(d,J= 6.8Hz,2H),4.04(d,J=7.5Hz,2H),3.26(s,12H),3.15-3.07(m,2H),2.78(p,J=8.5H z,1H),2.58-2.53(m,1H),2.11-2.04(m,2H),1.99-1.96(m,2H),1.75-1.64(m,2H).

[0956] Example 88: Synthesis of Compound 88

[0957]

[0958] Synthetic route

[0959]

[0960] Synthesis method

[0961] The synthesis method of compound 88-4 is the same as that in Example 85, except that in step one, methyl 3-hydroxymethylcyclobutanecarboxylate is replaced with methyl trans-3-hydroxymethylcyclobutanecarboxylate. The synthesis of compound 88-5 is the same as that in Example 176-2 of the published patent application WO2024 / 183778.

[0962] Compound 88: LC-MS (ESI) m / z: 598.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.99(d,J=8.8Hz,2H),7.83(t,J=5.6Hz,1H),7.54(d,J =2.0Hz,1H),7.47(d,J=2.0Hz,1H),7.22(dt,J=8.8,2.3Hz,2H),4.25(d,J=7.7H z,2H),4.02(t,2H),3.25(d,J=4.7Hz,12H),3.15-3.09(m,2H),3.09-3.01(m,1 H),2.72-2.63(m,1H),2.18-2.10(m,2H),2.01-1.97(m,2H),1.72-1.64(m,2H).

[0963] Example 89: Synthesis of Compound 89

[0964]

[0965] Synthetic route

[0966]

[0967] Synthesis method

[0968] The synthesis of compound 89-5 is described in Example 79, except that in step one, 1-Boc-3-(bromomethyl)pyrrolidine is replaced with N-{[1-(bromomethyl)cyclopropyl]methyl} tert-butyl carbamate. The synthesis of compound 89 is described in Example 88.

[0969] Compound 89: LC-MS (ESI) m / z: 658.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.00 (dd, J=8.3, 5.2Hz, 2H), 7.86 (t, J=5.6Hz, 1H), 7.67 (s, 1H),7.55(d,J=2.0Hz,1H),7.23(dd,J=8.8,1.9Hz,1H),6.72(d,J=7.8Hz,1H),4.25( d,J=7.7Hz,2H),3.27(s,6H),3.13-3.03(m,1H),2.94(s,6H),2.93(s,2H),2.80(s, 2H),2.72-2.67(m,1H),2.17-2.07(m,2H),2.03-1.93(m,2H),0.31(d,J=5.3Hz,4H).

[0970] Example 90: Synthesis of Compound 90

[0971]

[0972] Synthetic route

[0973]

[0974] Synthesis method

[0975] The synthesis of compound 90-4 is performed in the same manner as 81.

[0976] Compound 90: LC-MS (ESI) m / z: 616.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.06(t,J=8.7,7.2Hz,1H),8.01-7.94(m,2H),7.60 -7.52(m,2H),7.24-7.19(m,2H),4.87-4.72(m,1H),4.43-4.37(m,1H),4.28 -4.22(m,2H),4.19-4.10(m,1H),3.44(dt,J=22.9,5.7Hz,2H),3.26(d,12H) ,3.15-3.05(m,1H),2.75-2.64(m,1H),2.14(m,2H),2.00(t,J=10.2Hz,2H).

[0977] Example 91 Synthesis of Compound 91

[0978]

[0979] Synthetic route

[0980]

[0981] Synthesis method

[0982] The synthesis of compound 91 is based on the synthesis of 193-2 in Example 193 of the published patent application WO2024 / 183778. The synthesis of compound 91-2 is based on 89.

[0983] Compound 91: LC-MS (ESI) m / z: 632.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.07–7.98(m,3H),7.72(s,1H),7.67(d,J=2.0Hz,1H),7.24(dd,J=8.8,2.0Hz,1H),6.75(dd,J=7.7,1.9Hz,1H),4.06 –3.98(m,2H),3.27(s,6H),2.98(d,J=5.5Hz,2H),2.96(s,6H),2.24(t,J=7.1Hz,2H),1.82–1.74(m,2H),1.24(d,J=3.5Hz,2H),0.35(s,4H).

[0984] Example 92 Synthesis of Compound 92

[0985]

[0986] Synthetic route

[0987]

[0988] Synthesis method

[0989] The synthesis of compound 92-1 was performed with reference to the synthesis of 193-2 in Example 193 of the published patent application WO2024 / 183778.

[0990] Compound 92: LC-MS (ESI) m / z: 590.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.27(t,J=5.8Hz,1H),8.01(dd,J=14.1,8.8Hz,2H),7.68(d,J=2.0 Hz,1H),7.62(t,J=1.6Hz,1H),7.24(ddd,J=9.1,7.7,1.9Hz,2H),4.84(dqd,J=48.3,5.6,2 .8Hz,1H),4.53-4.40(m,1H),4.27(ddd,J=32.5,15.4,2.7Hz,1H),4.03(dd,2H),3.49(dt, J=23.1,5.5Hz,2H),3.29(s,6H),3.27(s,6H),2.29(t,J=7.1Hz,2H),1.81(p,J=7.2Hz,2H).

[0991] Example 93 Synthesis of Compound 93

[0992]

[0993] Synthetic route

[0994]

[0995] Synthesis method

[0996] The synthesis of compound 93-1 is based on the synthesis of 123-2 in Example 123 of the published patent application WO2024 / 183778. The synthesis of compound 93-3 is based on Example 81.

[0997] Compound 93: LC-MS (ESI) m / z: 638.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ8.01(dd,J=8.8,2.4Hz,2H),7.60(dd,J=19.1,2.1Hz,2H),7.24(dt,J=8 .8,1.6Hz,2H),4.31(d,J=13.0Hz,1H),4.12(d,J=6.8Hz,2H),4.06-3.94(m,2H),3.66(d,J=13.4 Hz,1H),3.28(s,6H),3.28(s,6H),3.14-3.02(m,1H),2.89-2.76(m,1H),2.59-2.53(m,1H),2.4 7-2.41(m,1H),2.18-2.05(m,2H),2.03-1.91(m,3H),1.58(d,J=12.8Hz,2H),1.18-1.03(m,2H).

[0998] Experimental Example 1: Test of MAT2A inhibitory activity of the compound of the present invention

[0999] Table 2: Reagents and Consumables

[1000]

[1001]

[1002] Detection methods

[1003] MAT2A protein 225 nM (2.5x), L-methionine 500 μM (5x), and ATP 500 μM (5x) were prepared separately using Assay buffer (50 mM Tris, pH 7.5 + 50 mM KCl + 10 mM MgCl2 + 0.01% Brij-35 + 1 mM DTT + 0.1% BGG). L-methionine and ATP were mixed 1:1 and set aside.

[1004] Compound configuration:

[1005] In Plate 1 of a 96-well plate, 1 μL of 10 mM compound stock solution was added to 24 μL of DMSO and placed in the first well of the 96-well plate. The solution was then diluted 4-fold to 8 concentration points (8 μL of the previous concentration sample + 24 μL of DMSO in sequence) and mixed well.

[1006] In the 96-well plate 2, add 78 μL of Assay buffer to each well, and add 2 μL of each concentration from plate 1 to the corresponding well in plate 2, and mix well.

[1007] Take a 384-well plate, add 2 μL of Cpd and 4 μL of MAT2A to each well, centrifuge at 1000 rpm for 1 min, and incubate at 25°C with shaking for 30 min;

[1008] Add 4 μL of L-methionine and ATP to each well, centrifuge at 1000 rpm for 1 min, and incubate at 25°C with shaking for 70 min.

[1009] Add 2 μL of Phosphoworks Colorimetric Phosphate Assay Kit to the corresponding well, centrifuge at 1000 rpm for 1 min, and incubate at 25 °C with shaking for 20 min;

[1010] AG-270 and AGI-24512 were used as positive control compounds, and absorbance values ​​were read at a wavelength of 620 nm using an ELISA reader.

[1011] The inhibition rate of each compound at each concentration point was calculated using the following formula, and the IC50 was obtained by curve fitting using Graphpad Prism 8.0 software. 50 value.

[1012]

[1013] The experimental results are shown in Table 3:

[1014] Table 3: IC50 values ​​of the MAT2A inhibitory activity of the compounds of this invention 50 value

[1015]

[1016]

[1017] The results show that the compounds of the present invention have a strong inhibitory effect on MAT2A, and most of the compounds of the present invention have better enzymatic activity than the positive control compounds AG-270 and AGI-24512. They can be used as therapeutic drugs for MAT2A-related diseases, including some cancers in which the gene encoding methionine phosphorylase (MTAP) is deleted and / or not fully functional.

[1018] The present invention has been described through the above embodiments. However, it should be understood that the above embodiments are for illustrative purposes only and are not intended to limit the invention to the scope of the described embodiments. Furthermore, those skilled in the art will understand that the present invention is not limited to the above embodiments, and many more variations and modifications can be made based on the teachings of the present invention, all of which fall within the scope of protection claimed by the present invention. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound, said compound being a compound of formula (I), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof: Where A1 is selected from formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (VIII), and B1 is selected from formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (VII); R1is, at each occurrence, selected from the group consisting of -N(C 1-6 alkyl)-, -C(R a )(R b )- and -C(R c )(R c )-; R a and R b form a 3-5 membered cycloalkyl with the attached C atom, which is optionally substituted with a substituent selected from the group consisting of a deuterium atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, an amino group, a hydroxyl group, a C 1-6 alkylamino group, and a cyano group; R2, R6, R9, R 12 , R 15 and R 17 are each independently at each occurrence selected from N and C(R c ); R8, R 13 , R 14 , and R 16 are each independently selected for each occurrence from -N(R c )- and -C(R c )(R c )-; R c selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, hydroxy, C 1-6 alkylamino and cyano; R3and R7are each independently at each occurrence selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, hydroxy, C 1-6 alkylamino, cyano, 3-8 membered cycloalkyl, and 3-8 membered heterocycloalkyl; R4and R5are each independently for each occurrence selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, hydroxy, C 1-6 alkylamino, and cyano, or R4and R5, together with the attached N atom, form a 3-5 membered heterocycloalkyl group; n1 and n2 are each independently selected from 1, 2 and 3; preferably, n1 and n2 are each independently selected from 1 and 2; L is a chemical linking structure connecting A1and B1, which structure is -(B L ) q -; B L at each occurrence, is the same or different, and each is independently selected from: CR L1 R L2 , O, S, S(O), SO2, -NR L1 -, C(O), CR L1 =CR L2 , C≡C, 3-10 membered cycloalkylene, 4-10 membered heterocyclylene, 6-10 membered arlyene, and 5-8 membered heteroarylene, wherein the 3-10 membered cycloalkylene, 4-10 membered heterocyclylene, 6-10 membered arlyene, and 5-8 membered heteroarylene are optionally substituted with 1, 2, 3, 4, 5, or 6 R L1 and / or R L2 groups; R L1 and R L2 each occurrence is independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, amino, hydroxy, C 1-6 alkylamino, 3-5 membered cycloalkyl, 3-5 membered heterocyclyl, and cyano; q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; when A1is of formula (II), B1is of formula (III), and R a and R b with the attached C atom forms a 3-membered cycloalkyl group, L is not when A1 is of formula (II), and R a and R b L is when B1 is not When A1is of formula (III) and B1is of formula (III), L is R 10 and R 11 are each independently selected from the group consisting of H, F, Cl, Br, I, amino, hydroxyl, cyano, C 1-3 alkyl, C 1-3 haloalkyl, and 3- to 5-membered cycloalkyl; and R 10 and R 11 are not simultaneously H; and when R 11 is CH3, R 10 is not H; or When A1 is B1 is L is or When A1 is B1 is L is or When A1 is L is B1 is or A1and B1are not simultaneously and The compounds mentioned do not include any of the compounds disclosed in PCT / CN2024 / 080417.

2. The compound of claim 1, wherein, When A1 is formula (II), B1 is formula (III) or formula (IV); or when A1 is formula (III), B1 is formula (II), formula (III), formula (IV), formula (V), formula (VI), or formula (VII); or when A1 is (IV), B1 is formula (II); or when A1 is formula (V), formula (VI), or formula (VIII), B1 is formula (III); preferably, A1 and B1 are selected from the following combinations: formula (II) and formula (III), formula (II) and formula (IV), formula (III) and formula (II), formula (III) and formula (III), formula (III) and formula (IV), formula (III) and formula (V), formula (III) and formula (VI), formula (III) and formula (VII), formula (IV) and formula (II), formula (V) and formula (III), or formula (VI) and formula (III); and / or R a and R b form a 3- to 5-membered cycloalkyl with the attached C atom, which is optionally substituted with substituents selected from the group consisting of F, Cl, Br, I, C 1-3 alkyl and C 1-3 haloalkyl; preferably, R a and R b form a 3- or 4-membered cycloalkyl with the attached C atom; and / or R c selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 haloalkyl; preferably, R c selected from H, F, Cl, Br, methyl and ethyl; and / or R3and R7are each independently at each occurrence selected from the group consisting of F, Cl, Br, I, C 1-3 alkyl, C 1-3 haloalkyl, and 3- to 5-membered cycloalkyl; more preferably, R3and R7are each independently at each occurrence selected from the group consisting of F, Cl, CF3, and CCl3; and / or R4and R5are each independently for each occurrence selected from the group consisting of H, F, CI, Br, I, C 1-3 alkyl and C 1-3 haloalkyl, or R4and R5, together with the attached N atom, form a 3-5 membered heterocycloalkyl; more preferably, R4and R5are each independently for each occurrence selected from the group consisting of H, methyl and ethyl, or R4and R5, together with the attached N atom, form a 3 or 4 membered heterocycloalkyl; and / or R L1 and R L2 each independently at each occurrence is selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, amino, hydroxyl, C 1-3 alkylamino, 3-5 membered cycloalkyl, and cyano; preferably, R L1 and R L2 each independently at each occurrence is selected from the group consisting of H, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, amino, hydroxyl, cyano, trifluoromethyl, trichloromethyl, 3 membered cycloalkyl, 4 membered cycloalkyl, and 5 membered cycloalkyl; and / or q is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8.

3. The compound according to claim 1 or 2, wherein, The structure of formula (II) is selected from and / or The structure of formula (III) is selected from and / or said formula (IV) structure is selected from and / or The structure of formula (V) is selected from and / or said structure of formula (VI) is selected from and / or said formula (VII) structure is selected from and / or said structure of formula (VIII) is selected from 4. A compound, said compound being a compound of formula (I-a), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof: Where A1 is selected from formula (II), formula (III) and formula (V), and B1 is selected from formula (III) and (IV); When A1 is equation (II), B1 is equation (III) or equation (IV); or when A1 is equation (III), B1 is equation (III) or equation (IV); or when A1 is equation (V), B1 is equation (III). R1and R8are each independently selected from the group consisting of -N(C 1-6 alkyl)- and -C(R a )(R b )-; R a and R b form a 3-5 membered cycloalkyl with the attached C atom, which 3-5 membered cycloalkyl can optionally be substituted with a substituent selected from the group consisting of a deuterium atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, an amino group, a hydroxyl group, a C 1-6 alkylamino group, and a cyano group; preferably, R a and R b form a 3-5 membered cycloalkyl with the attached C atom, which 3-5 membered cycloalkyl can optionally be substituted with a substituent selected from the group consisting of F, Cl, Br, I, a C 1-3 alkyl group, and a C 1-3 haloalkyl group; R2and R6are each independently selected from N and C(R c ); R c selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, hydroxy, C 1-6 alkylamino, and cyano; preferably, R c selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 haloalkyl; R3and R7are each independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, hydroxyl, C 1-6 alkylamino, cyano, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, ; preferably, R3and R7are each independently selected from the group consisting of F, Cl, Br, I, C 1-3 alkyl, C 1-3 haloalkyl and 3-5 membered cycloalkyl; R4and R5are each independently at each occurrence selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, hydroxyl, C 1-6 alkylamino, cyano; preferably, R4and R5are each independently at each occurrence selected from the group consisting of F, Cl, Br, I, C 1-3 alkyl and C 1-3 haloalkyl; n1 and n2 are each independently selected from 1, 2, and 3; preferably, n1 and n2 are each independently selected from 1 and 2; L is a chemical linking structure connecting A1and B1, which is -(B L ) q -; B L each occurrence is the same or different, and each is independently selected from: CR L1 R L2 , O, S, SO, SO2, -NR L1 -, C(O), CR L1 =CR L2 , C≡C, 4-10 membered cycloalkylene, 4-10 membered heterocyclylene, 6-10 membered arlyene, and 5-8 membered heteroarylene, wherein said 4-10 membered cycloalkylene, 4-10 membered heterocyclylene, 6-10 membered arlyene, and 5-8 membered heteroarylene is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R L1 and / or R L2 groups; R L1 and R L2 each occurrence is independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, hydroxyl, C 1-6 alkylamino, and cyano; preferably, R L1 and R L2 each occurrence is independently selected from the group consisting of H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 haloalkyl, amino, hydroxyl, C 1-3 alkylamino, and cyano; q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; when A1is of formula (II), B1is of formula (III), and R a and R b with the attached C atom forms a 3-membered cycloalkyl group, L is not or when A1is of formula (III), B1is of formula (III) or formula (IV), L is R 10 and R 11 each independently is selected from the group consisting of H, F, Cl, Br, I, amino, hydroxyl, cyano, C 1-3 alkyl and C 1-3 haloalkyl; or when A1is B1is L is or when A1is B1is L is or when A1is B1is L is 5. A compound, said compound being a compound of formula (I-b), or an isomer, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt, or solvate thereof: Where A1 is selected from formula (II), formula (III), formula (IV) and formula (V), and B1 is selected from formula (II), formula (III), formula (IV), formula (V), formula (VI) and formula (VII); Preferably, when A1 is of formula (II), B1 is of formula (III) or formula (IV); or when A1 is of formula (III), B1 is of formula (II), formula (III), formula (V), formula (VI) or formula (VII); or when A1 is of formula (VI), B1 is of formula (II); or when A1 is of formula (V), B1 is of formula (III); R 14 and R 13 each independently for each occurrence is selected from -C(R a )(R b )-, N(R c ), and -C(R c )(R c )-; R1and R8are each independently selected from the group consisting of -N(C 1-6 alkyl)- and -C(R a )(R b )-; R2, R6, R9, R 15 and R 12 each occurrence is independently selected from N and C(R c ); R a and R b form a 3-5 membered cycloalkyl with the attached C atom, which is optionally substituted with a substituent selected from the group consisting of a deuterium atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, hydroxyl, C 1-6 alkylamino, and cyano; preferably, R a and R b form a 3-5 membered cycloalkyl with the attached C atom, which is optionally substituted with a substituent selected from the group consisting of F, Cl, Br, I, C 1-3 alkyl, and C 1-3 haloalkyl; R c selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, hydroxy, C 1-6 alkylamino and cyano; preferably, R c selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 haloalkyl; R3and R7are each independently for each occurrence selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, hydroxyl, C 1-6 alkylamino, cyano, 3-8 membered cycloalkyl, and 3-8 membered heterocycloalkyl; preferably, R3and R7are each independently for each occurrence selected from the group consisting of F, Cl, Br, I, C 1-3 alkyl, C 1-3 haloalkyl, and 3-5 membered cycloalkyl; R4and R5are each independently at each occurrence selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, hydroxyl, C 1-6 alkylamino, and cyano; preferably, R4and R5are each independently at each occurrence selected from the group consisting of F, Cl, Br, I, C 1-3 alkyl, and C 1-3 haloalkyl; n1 and n2 are each independently selected from 1, 2 and 3; preferably, n1 and n2 are each independently selected from 1 and 2; L is a chemical linking structure connecting A1and B1, which is -(B L ) q -; B L each occurrence is the same or different, and each is independently selected from: CR L1 R L2 , O, S, SO, SO2, -NR L1 -, C(O), CR L1 =CR L2 , C≡C, 4-10 membered cycloalkylene, 4-10 membered heterocyclylene, 6-10 membered arlyene, and 5-8 membered heteroarylene, wherein said 4-10 membered cycloalkylene, 4-10 membered heterocyclylene, 6-10 membered arlyene, and 5-8 membered heteroarylene is optionally substituted with 0, 1, 2, 3, 4, 5, or 6 R L1 and / or R L2 groups; R L1 and R L2 each occurrence is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, amino, hydroxyl, C 1-6 alkylamino, 3-5 membered cycloalkyl, 3-5 membered heterocyclyl, and cyano; preferably, R L1 and R L2 each occurrence is independently selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 haloalkyl, amino, hydroxyl, C 1-3 alkylamino, 3-5 membered cycloalkyl, and cyano; q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; when A1is of formula (II), B1is of formula (III), and R a and R b with the attached C atom forms a 3-membered cycloalkyl group, L is not When A1is of formula (III) and B1is of formula (III), L is R 10 and R 11 are each independently selected from the group consisting of H, F, Cl, Br, I, amino, hydroxyl, cyano, C 1-3 alkyl and C 1-3 haloalkyl; and R 10 and R 11 are not simultaneously H, and R 11 is CH3, R 10 is not H; or When A1 is B1 is L is or When A1 is B1 is L is 6. The compound of any one of claims 1-5, wherein, B L each occurrence is selected independently from CH2, NH, C(O), CH=CH, 3-10 membered cycloalkylene, 4-10 membered heterocyclyl ene, 6 membered arylene, and 5-6 membered heteroarylene, wherein said CH2, 3-10 membered cycloalkylene, 4-10 membered heterocyclyl ene, 6 membered arylene, and 5-6 membered heteroarylene are optionally substituted with 1, 2, or 3 F, Cl, Br, I, hydroxyl, cyano, amino, C 1-3 alkyl, C 1-3 alkoxy, 3 membered cycloalkyl, 4 membered cycloalkyl, 5 membered cycloalkyl, and C 1-3 haloalkyl; preferably, preferably, B L each occurrence is the same or different, and is independently selected from CH2, NH, C(O), CR L1 =CR L2 , 3-6 membered cycloalkylene, 4-6 membered monocyclic heterocyclyl ene, 7-10 membered spiroheterocyclyl ene, 7-10 membered fused heterocyclyl ene, 6 membered arylene, and 5-6 membered heteroarylene, wherein said 3-6 membered cycloalkylene, 4-6 membered monocyclic heterocyclyl ene, 7-10 membered spiroheterocyclyl ene, 7-10 membered fused heterocyclyl ene, 6-8 membered arylene, and 5-6 membered heteroarylene are optionally substituted with 1, 2, or 3 F, Cl, Br, hydroxyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trichloromethyl, and 3 membered cycloalkyl; preferably, B L each occurrence is independently selected from CH2, -C(C 1-3 alkyl)(H)-, -C(OH)(H)-, -C(F)(H)-, -C(CF3)(H)-, NH, -C(O)-, CH=CH, or B L Each occurrence is independently selected from: CH2, NH, CO, CH=CH, 4-10 cycloalkylene, 4-10 heterocyclic, 6 aryl, and 5-6 heterocyclic, wherein the CH2, 4-10 cycloalkylene, 4-10 heterocyclic, 6 aryl, and 5-6 heterocyclic are optionally surrounded by 0, 1, 2, or 3 F, Cl, Br, I, hydroxyl, C 1-3 Alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl and C 1-3 Halogenated alkyl substitution; preferably, B L Each occurrence is independently selected from: CH2, -C(C 1-3 Alkyl group (H)-, -C(OH)(H)-, -C(F)(H)-, -C(CF3)(H)-, NH, -C(O)-, CH=CH, or B L each occurrence is independently selected from the group consisting of CH2, NH, C(O), CH=CH, 4-10 membered cycloalkylene, 4-10 membered heterocyclylene, 6 membered arylene, and 5-6 membered heteroarylene, wherein said CH2, 4-10 membered cycloalkylene, 4-10 membered heterocyclylene, 6 membered arylene, and 5-6 membered heteroarylene is optionally substituted with 0, 1, 2, or 3 F, Cl, Br, I, hydroxyl, C 1-3 alkyl, and C 1-3 haloalkyl; preferably, B L each occurrence is independently selected from the group consisting of CH2, -C(OH)(H)-, -C(F)(H)-, -C(CF3)(H)-, NH, -C(O)-, CH=CH, 7. The compound of any one of claims 1-6, wherein L is selected from:

8. The compound of any one of claims 1-7, wherein the compound is selected from:

9. A pharmaceutical composition, characterized by the pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-8 and a pharmaceutically acceptable carrier or excipient.

10. Use of the compound of any one of claims 1-8 or the pharmaceutical composition of claim 9 for the manufacture of a medicament for treating a MAT2A-associated disease; preferably, the MAT2A-associated disease is a cancer or a tumor.

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