Heterocyclic compound, preparation method therefor, and use thereof

Abstract

The present invention relates to the field of medicines, and in particular to a heterocyclic compound, a preparation method therefor, and a use thereof. The heterocyclic compound is specifically as shown in formula (I), and the definition of each group in the formula is detailed in the description. The present invention further relates to a pharmaceutical composition containing the compound, and a use thereof in the preparation of a drug for preventing and / or treating PI3K-related diseases or disorders.

Description

Heterocyclic compounds, their preparation methods and uses

[0001] This application claims priority to Chinese patent application 2024118495816, filed on December 13, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure pertains to the pharmaceutical field, specifically relating to a pyrimidinethiophene compound and its preparation and uses. Background Technology

[0003] Phosphatidylinositol 3-kinase (PI3K) is a key regulatory kinase in the PI3K / AKT / mTOR signaling pathway, participating in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. PI3K signaling is one of the common aberrant activation pathways in cancer and is considered closely related to a range of human cancers. Based on the different structures of the four subunits of the catalytic subunit p110, PI3K has four isoforms: α, β, γ, and δ. The α-type is expressed in various tissues and organs, such as breast cancer, colorectal cancer, and head and neck cancer. The PIK3CA gene, encoding the p110α subunit, is the most commonly mutated gene. Alpelisib, approved in 2019 in combination with fulvestrant for HR+ / Her2- advanced metastatic breast cancer with PI3Kα mutations, was the first approved selective PI3Kα inhibitor; however, it also has some significant adverse reactions, such as hyperglycemia. Therefore, there is an urgent clinical need for a variety of drugs that can effectively inhibit PI3K, providing patients with more treatment options. Summary of the Invention

[0004] The purpose of this disclosure is to provide a class of novel heterocyclic compounds that can serve as PI3K inhibitors. The compounds disclosed herein possess advantages such as high activity and low toxicity, and are expected to exhibit favorable physicochemical properties and pharmaceutical characteristics.

[0005] One aspect of this disclosure provides a compound of formula (I), or a stable deuterated derivative thereof, stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug:

[0006] In the formula,

[0007] X1 is O, N, NH, CH or S;

[0008] X2 is either N or CH;

[0009] X3 is either N or C;

[0010] X4 can be O, N, NH, CH or S;

[0011] X5 is either N or CH;

[0012] X6 is either N or C;

[0013] Furthermore, X2, X3, and X5 are not all N at the same time;

[0014] This indicates that the connection between any two adjacent atoms within a ring can be a single bond or a double bond;

[0015] L1 is selected from the following group:

[0016] L2 is -(CR) 2 R 3 ) 1-4 -、-(CR 2 R 3 ) 1-4 -NR 4 -、-C 6-10 Aryl-NR 4 -、-(CR 2 R 3 ) 1-4 -C 6-10 Aryl-NR 4 -;

[0017] R 2 R 3 R 4 Each is defined independently as follows:

[0018] R 2 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl;

[0019] R 3 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl;

[0020] R 4 C is hydrogen or substituted or unsubstituted. 1-6 alkyl;

[0021] or

[0022] R 2 and R 3 They connect to form -(CH2)n-; n is 2, 3, 4 or 5;

[0023] R 4 C is hydrogen or substituted or unsubstituted. 1-6 Alkyl; or,

[0024] R 2C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl;

[0025] R 3 and R 4 They connect to form -(CH2)n-; n is 2, 3, 4 or 5;

[0026] R 1 For substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl or substituted or unsubstituted C 2-6 alkynyl group;

[0027] R 5 Selected from the following group:

[0028] In each of the above groups, the substitution refers to each group being independently replaced by 1, 2, 3, 4, 5, or 6 groups selected from group S1; the groups in group S1 are each independently selected from the following group: -SF5, deuterium, oxo (=O), thio (=S), =CR e R f =NR e Halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-20 Cycloalkyl, 3 to 20-membered heterocyclic groups, C 6-14 Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -OC 3-20 Cycloalkyl, -O-3 to 20-membered heterocyclic groups, -OC 6-14 Aryl, -O-5 or 6-membered monocyclic heteroaryl, -O-8 to 10-membered bicyclic heteroaryl, -C≡CC 3-20 Cycloalkyl, -C≡C-3 to 20-membered heterocyclic groups, -C≡CC 6-14 Aryl, -C≡C-5 or 6-membered monocyclic heteroaryl, -C≡C-8 to 10-membered bicyclic heteroaryl, -C≡CC 1-4 Alkyl-C 3-20 cycloalkyl, -C≡CC 1-4 Alkyl-3 to 20-membered heterocyclic groups, -C≡CC 1-4 Alkyl-C 6-14 Aryl, -C≡CC 1-4 Alkyl-5 or 6-membered monocyclic heteroaryl, -C≡CC 1-4 Alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C1-6 Alkyl, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-C 3-20 cycloalkyl, -C 1-4 Alkyl-OC 3-20 cycloalkyl, -C 1-4 Alkyl-3 to 20-membered heterocyclic groups, -C 1-4 Alkyl-O-3 to 20-membered heterocyclic groups, -C 1-4 Alkyl-C 6-14 Aryl, -C 1-4 Alkyl-OC 6-14 Aryl, -C 1-4 Alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkyl-O-8 to 10-membered bicyclic heteroaryl, -OC 1- 4-alkyl-hydroxyl, -OC 1-4 Alkyl-cyano, -OC 1-4 Alkyl-C 1-6 Alkyl, -OC 1-4 Alkyl-C 1-6 Alkoxy, -OC 1-4 Alkyl-C 3-20 cycloalkyl, -OC 1-4 Alkyl-OC 3-20 cycloalkyl, -OC 1-4 Alkyl-3 to 20-membered heterocyclic groups, -OC 1-4 Alkyl-O-3 to 20-membered heterocyclic groups, -OC 1-4 Alkyl-C 6-14 Aryl, -OC 1-4 Alkyl-OC 6-14 Aryl, -OC 1-4 Alkyl-5 or 6-membered monocyclic heteroaryl, -OC 1-4 Alkyl-O-5 or 6-membered monocyclic heteroaryl, -OC 1-4 Alkyl-8 to 10-membered bicyclic heteroaryl, -OC 1-4 Alkyl-O-8 to 10-membered bicyclic heteroaryl, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-20 Cycloalkyl, -S(=O)2-3 to 20-membered heterocyclic groups, -C(=O)OC 1-6 Alkyl group, -C(=O)OC 3-20 Cycloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-20Cycloalkyl, -C(=O)-C 6-14 Aryl, -NR a1 R b1 -C(=O)-NR a1 R b1 -C(=O)-NR d1 -C 1-4 Alkyl-R c1 -OR c1 -C 1-4 Alkyl-S(=O)2-C 1-6 Alkyl, -C 1-4 Alkyl-S(=O)2-C 3-20 cycloalkyl, -C 1-4 Alkyl-S(=O)2-3 to 20-membered heterocyclic groups, -C 1-4 Alkyl-C(=O)OC 1-6 Alkyl, -C 1-4 Alkyl-C(=O)OC 3-20 cycloalkyl, -C 1-4 Alkyl-C(=O)-C 1-6 Alkyl, -C 1-4 Alkyl-C(=O)-C 3-20 cycloalkyl, -C 1-4 Alkyl-C(=O)-C 6-14 Aryl, -C(=O)-5 or 6-membered monocyclic heteroaryl, -C(=O)-8 to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 Alkyl-C 3-20 Cycloalkyl, -C(=O)-C 1-6 Alkyl-3 to 20-membered heterocyclic groups, -C(=O)-C 1-6 Alkyl-C 6-14 Aryl, -C(=O)-C 1-6 Alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 Alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkyl-NR a1 R b1 -C 1-4 Alkyl-C(=O)-NR a1 R b1 -C≡CC(=O)-NR a1 R b1 -C≡CC 1-4 Alkyl-C(=O)-NR a1 R b1 -C 1-4 Alkyl-OR c1 -C 1-4 Alkyl-P(=O)-(C 1-6Alkyl)2、-P(=O)-(C 1-6 Alkyl)2, -C 1-4 Alkyl-NR d1 -C(=O)-R c1 -C 1-4 Alkyl-NR d1 -C(=O)-NR a1 R b1 -C 1-4 Alkyl-NR d1 -S(=O)2-R c1 -C 1-4 Alkyl-S(=O)2-NR a1 R b1 -C 1-4 Alkyl-NR d1 -S(=O)2-NR a1 R b1 -NR d1 -C(=O)-R c1 -NR d1 -C(=O)-C 1-4 Alkyl-R c1 -NR d1 -C(=O)-NR a1 R b1 -NR d1 -S(=O)2-R c1 -S(=O)2-NR a1 R b1 -NR d1 -S(=O)2-NR a1 R b1 and -P(=O)-(C 1-6 Alkyl)2; wherein, the C 1-6 Alkyl, the C 1-6 Alkoxy, the C 2-6 alkenyl, the C 2-6 Each alkynyl group is independently and optionally replaced by one, two, or three groups selected from halogens, deuterium, cyano, or hydroxyl groups; the C 3-20 cycloalkyl groups, the 3- to 20-membered heterocyclic groups, the C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each optionally substituted by 1, 2, 3, or 4 groups selected from group S2.

[0029] In the above groups, each R a1 R b1 Each independently represents H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6Alkyl, deuterated C 1-6 Alkyl, Halogenated C 2-6 alkenyl, deuterated C 2-6 alkenyl, halogenated C 2-6 alkynyl, halogenated C 2-6 alkynyl group, -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-deuterated C 1-6 Alkyl, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C 1-4 Alkyl-deuterated C 1-6 Alkoxy, C 3-6 cycloalkyl, -C 1-4 Alkyl-C 3-6 cycloalkyl, -C 1-4 Alkyl-OC 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C 1-4 Alkyl-3 to 6-membered heterocyclic groups, -C 1- 4-alkyl-O-3 to 6-membered heterocyclic groups, phenyl, -C 1-4 Alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-5 or 6-membered monocyclic heteroaryl, 8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkyl-8 to 10-membered bicyclic heteroaryl, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-6 Cycloalkyl, -S(=O)2-3 to 6-membered heterocyclic groups, -C 1-4 Alkyl-S(=O)2-C 1-6 Alkyl, -C 1-4 Alkyl-S(=O)2-C 3-6 cycloalkyl, -C 1-4 Alkyl-S(=O)2-3 to 6-membered heterocyclic groups, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 Cycloalkyl or -C(=O)-3 to 6-membered heterocyclic groups; wherein, the C 3-6 The cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by one or two groups selected from the group consisting of: halogen, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, deuterated C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-4 Alkyl-P(=O)-(C 1-6 alkyl)2 and -P(=O)-(C 1-6 Alkyl)2; or

[0030] Each R a1 and R b1 Together with the nitrogen atoms attached to them, they form 3 to 20-membered heterocyclic groups; wherein each of the 3 to 20-membered heterocyclic groups is independently and optionally substituted by one or two groups selected from the group consisting of: halogen, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1- 6-alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-4 Alkyl-P(=O)-(C 1-6 alkyl)2 and -P(=O)-(C 1-6 Alkyl)2;

[0031] In the above groups, each R d1 Each independently represents H and C. 1-6 Alkyl or deuterated C 1-6 alkyl;

[0032] In the above groups, each R c1 Each independently represents H and C. 1-6 Alkyl, -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-NR a1 R b1 Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-deuterated C 1-6 Alkyl, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C1-4 Alkyl-deuterated C 1-6 Alkoxy, C 3-6 cycloalkyl, -C 1-4 Alkyl-C 3-6 cycloalkyl, -C 1-4 Alkyl-OC 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C 1-4 Alkyl-3 to 6-membered heterocyclic groups, -C 1-4 Alkyl-O-3 to 6-membered heterocyclic groups, phenyl, -C 1-4 Alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-5 or 6-membered monocyclic heteroaryl, 8 to 10-membered bicyclic heteroaryl, or -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl groups; the C 3-6 The cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by one or two groups selected from the group consisting of: halogen, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-4 Alkyl-P(=O)-(C 1-6 alkyl)2 or -P(=O)-(C 1-6 Alkyl)2;

[0033] Among the above groups, each group of S2 is independently selected from the following group: deuterium, oxo (=O), thio (=S), =CR e R f =NR e Halogen, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-(C=O)-NHC 1-6 Alkyl, -(C=O)-N(C 1-6 Alkyl)2, -C 1-4 Alkyl-P(=O)-(C1-6 Alkyl)2、-P(=O)-(C 1-6 Alkyl)2、-(C=O)C 1-6 Alkyl groups and -SF5;

[0034] Of the above groups, the -C 1-4 Alkyl group - is unsubstituted; or -C 1-4 The 1, 2, 3, or 4 hydrogen atoms on the alkyl group are each independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -CH2-hydroxy, -CH2-cyano, phenyl, C 3-6 Substituted with cycloalkyl groups; or C 1-4 Two hydrogen atoms on the same carbon atom of an alkyl group are simultaneously converted to -(CH2). j - Substitution further forms a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; or C 1-4 Two hydrogen atoms on the same carbon atom of an alkyl group are simultaneously converted to CR. e R f replace;

[0035] Of the above groups, R e Each is independently H, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0036] Of the above groups, R f Each is independently H, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl;

[0037] In each of the above-mentioned groups, one or more (e.g., 1, 2, 3, or 4) ring atoms of the 3- to 6-membered heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 3- to 20-membered heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, or 4) ring atoms of the 5- or 6-membered monocyclic heteroaryl group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; and one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 8- to 10-membered bicyclic heteroaryl group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus.

[0038] When the ring atom is a sulfur atom, the sulfur atom is optionally replaced by one or two atoms selected from oxo and =NR. e Group substitution; R e Definitions are the same as before;

[0039] When the ring atom is a phosphorus atom, the phosphorus atom is optionally surrounded by one or two atoms selected from oxo and =NR. e Group substitution; R e The definition is the same as before.

[0040] In one embodiment, among the above-mentioned groups, each R a1 R b1 Each independently represents H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-deuterated C 1-6 Alkyl, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C 1-4 Alkyl-deuterated C 1-6 Alkoxy, C 3-6 cycloalkyl, -C 1-4 Alkyl-C 3-6 cycloalkyl, -C 1-4 Alkyl-OC 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C 1-4 Alkyl-3 to 6-membered heterocyclic groups, -C 1-4 Alkyl-O-3 to 6-membered heterocyclic groups, phenyl, -C 1-4 Alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-5 or 6-membered monocyclic heteroaryl, 8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkyl-8 to 10-membered bicyclic heteroaryl, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-6 Cycloalkyl, -S(=O)2-3 to 6-membered heterocyclic groups, -C 1-4 Alkyl-S(=O)2-C 1-6 Alkyl, -C 1-4 Alkyl-S(=O)2-C 3-6 cycloalkyl, -C 1-4 Alkyl-S(=O)2-3 to 6-membered heterocyclic groups, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 Cycloalkyl or -C(=O)-3 to 6-membered heterocyclic groups; wherein, the C 3-6The cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by one or two groups selected from the group consisting of: halogen, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-4 Alkyl-P(=O)-(C 1-6 alkyl)2 and -P(=O)-(C 1-6 Alkyl)2.

[0041] In one implementation, X1 is CH or S.

[0042] In one implementation, X2 is N or CH.

[0043] In one implementation, X3 is N or C.

[0044] In one implementation, X4 is N or CH.

[0045] In one implementation, X5 is N or CH.

[0046] In one embodiment, the compound represented by formula (I) is as shown in formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX):

[0047] In the formula, L1, L2, R 1 R 5 The definition is the same as above.

[0048] In one embodiment, the compound represented by formula (I) is as shown in formula (IIA):

[0049] In the formula, L1 and R 1 R 2 R 3 R 4 R 5 The definition is the same as above.

[0050] In one embodiment, the compound represented by formula (I) is as shown in formula (IIB):

[0051] In the formula, R 1R 2 R 3 R 4 The definition is the same as above.

[0052] In one embodiment, the compound represented by formula (I) is as shown in formula (IIC):

[0053] In the formula, R 2 R 3 R 4 Same definition as above;

[0054] R 8 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl;

[0055] R 6 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl;

[0056] R 7 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl.

[0057] In one embodiment, the compound represented by formula (I) is as shown in formula (IID):

[0058] In the formula, R 2 R 3 R 4 Same definition as above;

[0059] R 9 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl.

[0060] In one embodiment, the compound represented by formula (I) is as shown in formula (IIIA):

[0061] In the formula, L1 and R 1 R 2 R 3 R 4 R 5 The definition is the same as above.

[0062] In one embodiment, the compound represented by formula (I) is as shown in formula (IIIB):

[0063] In the formula, R 1 R 2 R 3 R 4 The definition is the same as above.

[0064] In one embodiment, the compound represented by formula (I) is as shown in formula (IIIC):

[0065] In the formula, R 2 R 3 R 4 Same definition as above;

[0066] R 8 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl;

[0067] R 6 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl;

[0068] R 7 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl.

[0069] In one embodiment, the compound represented by formula (I) is as shown in formula (IIID):

[0070] In the formula, R 2 R 3 R 4 Same definition as above;

[0071] R 9 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl.

[0072] In one embodiment, the compound represented by formula (I) is as shown in formula (IVA):

[0073] In the formula, L1 and R 1 R 2 R 3 R 4 R 5 The definition is the same as above.

[0074] In one embodiment, the compound represented by formula (I) is as shown in formula (IIB):

[0075] In the formula, R 1 R 2 R 3 R 4 The definition is the same as above.

[0076] In one embodiment, the compound represented by formula (I) is as shown in formula (IVC):

[0077] In the formula, R2 R 3 R 4 Same definition as above;

[0078] R 8 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl;

[0079] R 6 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl;

[0080] R 7 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl.

[0081] In one embodiment, the compound represented by formula (I) is as shown in formula (IVD):

[0082] In the formula, R 2 R 3 R 4 Same definition as above;

[0083] R 9 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl.

[0084] In one embodiment, the compound represented by formula (I) is as shown in formula (VA):

[0085] In the formula, L1 and R 1 R 2 R 3 R 4 R 5 The definition is the same as above.

[0086] In one embodiment, the compound represented by formula (I) is as shown in formula (VB):

[0087] In the formula, R 1 R 2 R 3 R 4 The definition is the same as above.

[0088] In one embodiment, the compound represented by formula (I) is as shown in formula (VC):

[0089] In the formula, R 2 R 3 R 4 Same definition as above;

[0090] R 8C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl;

[0091] R 6 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl;

[0092] R 7 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl.

[0093] In one embodiment, the compound represented by formula (I) is as shown in formula (VD):

[0094] In the formula, R 2 R 3 R 4 Same definition as above;

[0095] R 9 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl.

[0096] In one embodiment, the compound represented by formula (I) is as shown in formula (VIA):

[0097] In the formula, L1 and R 1 R 2 R 3 R 4 R 5 The definition is the same as above.

[0098] In one embodiment, the compound represented by formula (I) is as shown in formula (VIB):

[0099] In the formula, R 1 R 2 R 3 R 4 The definition is the same as above.

[0100] In one embodiment, the compound represented by formula (I) is as shown in formula (VIC):

[0101] In the formula, R 2 R 3 R 4 Same definition as above;

[0102] R 8 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl;

[0103] R 6 C is hydrogen, halogen, or substituted or unsubstituted.1-6 alkyl;

[0104] R 7 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl.

[0105] In one embodiment, the compound represented by formula (I) is as shown in formula (VID):

[0106] In the formula, R 2 R 3 R 4 Same definition as above;

[0107] R 9 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl.

[0108] In one implementation scheme, L2 is

[0109] In one implementation scheme, L2 is

[0110] In one implementation scheme, L2 is

[0111] In one implementation scheme, L2 is

[0112] In one implementation scheme, R 1 For tert-butyl, vinyl,

[0113] In one embodiment, the compound is selected from the group consisting of:

[0114] Another aspect of this disclosure provides a pharmaceutical composition comprising the aforementioned compound, or a stable deuterated derivative, stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable carrier.

[0115] This disclosure also provides the aforementioned compound as a medicament.

[0116] As used herein, the term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or subject. Representative carriers include water, oils, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals.

[0117] In embodiments of the present invention, the pharmaceutical composition may be administered in any of the following ways: orally, by spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, or extra-intestinal administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion, or via an external implantation device. Oral, intraperitoneal, or intravenous administration is preferred. Aqueous suspension formulations typically involve mixing the active ingredient with suitable emulsifiers and suspending agents. If desired, sweeteners, flavorings, or colorings may be added to the above oral formulations. When used topically, particularly for treating affected areas or organs easily accessible by topical application, such as the eyes, skin, or lower gastrointestinal neurological disorders, the compounds of the present invention can be formulated into different topical formulations depending on the affected area or organ. For topical ocular application, the compounds of the present invention can be formulated as a micronized suspension or solution using an isotonic sterile saline solution of a specific pH, with or without preservatives such as benzyl alcohol chloride. For ophthalmic use, the compounds can also be formulated into ointment forms such as petrolatum. When applied topically to the skin, the compounds of the present invention can be formulated into suitable ointment, lotion, or cream formulations, wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used in ointment formulations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsified wax, and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water. The compounds of the present invention can also be administered in sterile injectable formulations, including sterile injectable water or oil suspensions or sterile injectable solutions. Carriers and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils, such as monoglycerides or diglycerides, can also be used as solvents or suspension media.

[0118] This disclosure also provides the use of the aforementioned compound, or a stable deuterated derivative thereof, stereoisomer, pharmaceutically acceptable salt, solvate or prodrug, or the aforementioned pharmaceutical composition, in the preparation of a medicament for the prevention and / or treatment of a disease or condition; said disease or condition being a PI3K-related disease or condition.

[0119] Another aspect of this disclosure provides a method for preventing and / or treating PI3K-related diseases or conditions, the method comprising the steps of: administering to a subject in need a therapeutically effective amount of the aforementioned compound of this disclosure, or a stable deuterated derivative, stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof; or administering to a subject in need a therapeutically effective amount of the aforementioned pharmaceutical composition.

[0120] This disclosure also provides, in another aspect, the aforementioned compound, or a stable deuterated derivative, stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug, or pharmaceutical composition as described above, for the prevention and / or treatment of diseases or conditions that are PI3K-related diseases or conditions.

[0121] This disclosure also provides the use of the aforementioned compound, or a stable deuterated derivative, stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug, or the aforementioned pharmaceutical composition, in a medicament for the prevention and / or treatment of a disease or condition; said disease or condition being a PI3K-related disease or condition.

[0122] In one embodiment, the PI3K-related diseases or conditions include solid tumors or hematologic malignancies. Solid tumors include, but are not limited to, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal adenoma, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular carcinoma, adrenal cancer, gastric cancer, glioma, glioblastoma, neuroblastoma, endometrial cancer, melanoma, kidney cancer, renal cell carcinoma, renal pelvis cancer, bladder cancer, uterine cancer, cervical cancer, vaginal cancer, ovarian cancer, esophageal cancer, brain cancer, oral cancer, pharyngeal cancer, laryngeal cancer, small bowel cancer, head and neck squamous cell carcinoma, head and neck tumors, villous colonic adenoma, and sarcoma. The hematologic malignancies mentioned include, but are not limited to, leukemias such as lymphocytic leukemia (e.g., chronic lymphocytic leukemia, acute lymphoblastic leukemia); myeloid leukemias such as acute myeloid leukemia, chronic myeloid leukemia; lymphomas (e.g., B-cell lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, diffuse large B-cell lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma); and myelomas (e.g., multiple myeloma, myelofibrosis). The PI3K-related diseases or conditions also include Alzheimer's disease, aging, diabetes, cardiovascular disease, CNS-related diseases, immune diseases, allergies, Parkinson's disease, asthma, rheumatoid arthritis, and chronic obstructive pulmonary disease.

[0123] In one implementation, the PI3K-related diseases or conditions include cancer, Alzheimer's disease, aging, diabetes, cardiovascular disease, CNS-related diseases, immune diseases, allergies, Parkinson's disease, asthma, rheumatoid arthritis, and chronic obstructive pulmonary disease.

[0124] In one embodiment, the cancer is selected from: lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, thyroid cancer, adrenal cancer, gastric cancer, glioma, glioblastoma, neuroblastoma, endometrial cancer, melanoma, intrahepatic bile duct cancer, hepatocellular carcinoma, bladder cancer, endometrial cancer, cervical cancer, vaginal cancer, ovarian cancer, esophageal cancer, brain cancer, oral cancer, pharyngeal cancer, laryngeal cancer, small intestinal cancer, renal cell carcinoma, renal pelvis cancer, head and neck squamous cell carcinoma, villous colonic adenoma, sarcoma, leukemia, lymphoma, and myeloma.

[0125] In one embodiment, the use or method further includes administering additional anticancer therapy. In some embodiments, the additional anticancer therapy is a HER2 inhibitor, EGFR inhibitor, RAS inhibitor, SHP2 inhibitor, SOS1 inhibitor, RAF inhibitor, MEK inhibitor, ERK inhibitor, PTEN inhibitor, AKT inhibitor, mTORC1 inhibitor, BRAF inhibitor, PD-L1 inhibitor, PD-1 inhibitor, CDK4 / 6 inhibitor, or a combination thereof.

[0126] Another aspect of this disclosure provides a method for treating cancer in a subject with this need, the method comprising:

[0127] (a) Determining that the cancer is associated with PI3K; and

[0128] (b) administering to the subject a therapeutically effective amount of the aforementioned compound of this disclosure, or a stable deuterated derivative, stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof; or administering to the subject a therapeutically effective amount of the aforementioned pharmaceutical composition of this disclosure.

[0129] In one embodiment, the administration is carried out via routes such as parenteral, intraperitoneal, intradermal, intracardiac, intravenous, intracranial, intraspinal, intracavitary, intraluminal, intrasynovial, intrathecal, intrathecal, intramuscular, intravitreal, intravenous, intra-arterial, oral, buccal, sublingual, transdermal, local, tracheal, rectal, subcutaneous, or local administration.

[0130] Another aspect of this disclosure provides a method for inhibiting PI3K in cells, the method comprising the steps of: contacting the cells with the aforementioned compound of this disclosure, or a stable deuterated derivative, stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug; or contacting the cells with the aforementioned pharmaceutical composition of this disclosure. The cells may be in vivo or in vitro.

[0131] This disclosure also provides the use of the aforementioned compound, or a stable deuterated derivative thereof, stereoisomer, pharmaceutically acceptable salt, solvate or prodrug, or pharmaceutical composition as described above, in the preparation of PI3K inhibitors.

[0132] The compounds represented by formula (I) of this invention can be prepared using synthetic methods known in the art or in combination with methods known in the art. The solvents, temperatures, and other reaction conditions given in this invention are exemplary and can be varied according to methods well known in the art. The compounds of the examples described in this invention can be synthesized according to the methods described in the examples, depending on their specific structures, using appropriate starting materials, or can be synthesized using methods similar to those described in the examples. The starting materials used to synthesize the compounds of the examples of this invention can be prepared by known synthetic methods or similar methods described in the literature, or obtained from commercial sources. The compounds of the examples can be further resolved, as needed, by methods well known in the art, such as crystallization, chromatography, etc., to obtain their stereoisomers or tautomers, the resolution conditions of which are readily obtained by those skilled in the art through conventional means or limited experimentation.

[0133] As further explanation, the compound of formula (IIB) of the present invention can be synthesized by the following method, wherein the solvent, temperature and other reaction conditions in each step can be the same or similar to those described in the examples below, or reaction conditions known in the art can be used.

[0134] Among them, R 1 R 2 R 3 R 4 The definition is the same as above.

[0135] Referring to the above synthetic route, by... Replace with Compounds of formula (IIIB), (IVB), (VB), and (VIB) can be prepared by combining them with known synthetic methods.

[0136] Definitions and Terms

[0137] As used in this text, the term "subject" refers to an animal, specifically a mammal. Humans are preferred.

[0138] As used herein, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. In embodiments of the invention, when treating a patient according to the invention, the amount of a given drug depends on many factors, such as the specific dosing regimen, the type and severity of the disease or condition, and the unique characteristics of the patient or host requiring treatment (e.g., weight). However, depending on the specific surrounding circumstances, including, for example, the specific drug used, the route of administration, the condition being treated, and the patient or host being treated, the dosage can be conventionally determined by methods known in the art. Typically, for adult treatment, the dosage is typically in the range of 0.02-5000 mg / day, for example, about 1-1500 mg / day. This required dosage can conveniently be expressed as a single dose, or concurrent (or over a short period of time) or fractions at appropriate intervals, such as two, three, four, or more doses per day. Those skilled in the art will understand that although the above dosage ranges are given, the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.

[0139] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the pharmacological activity of the parent compound. Such salts include: salts formed by addition to an inorganic acid or an organic acid, such as nitric acid, phosphoric acid, carbonic acid, etc.; organic acids such as propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, gluconic acid, stearic acid, mucoacinic acid, etc.; or salts formed when an acidic proton present on the parent compound is replaced by a metal ion, such as an alkali metal ion or an alkaline earth metal ion; or coordination compounds formed with an organic base, such as ethanolamine, etc. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing an acid radical or a base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in their free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. In addition to the salt form, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. Furthermore, the prodrugs can be converted into the compounds of the present invention in the in vivo environment via chemical or biochemical methods.

[0140] As used herein, the term "solvent" refers to a substance formed by combining a compound of the present invention with a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include acetic acid, etc. Solvents include stoichiometric solvates and non-stoichiometric solvates. Some compounds of the present invention may exist in either a solvated or non-solventized form. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of the present invention.

[0141] As used in this text, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers primarily include cis-trans isomers and optical isomers. The compounds of this invention can exist in stereoisomer form and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, tautomers, enantiomers, diastereomers, and trans-blocked isomers. The compounds of this invention can also exist in any combination or mixture of the aforementioned stereoisomers, such as meso compounds, racemic compounds, and equal mixtures of trans-blocked isomers. Examples include a single enantiomer, a single diastereomer or a mixture of more than one, or a single trans-blocked isomer or a mixture thereof. When the compounds of this invention contain an olefinic double bond, unless otherwise specified, they include cis and trans isomers, and any combination thereof. The trans-blocked isomers of this invention are stereoisomers with axial or planar chirality resulting from restricted intramolecular rotation. Furthermore, stereoisomers with excellent activity are preferred as pharmaceuticals. The compounds of the present invention have optical isomers derived from asymmetric carbon, etc., and if necessary, a single isomer can be obtained by separation by methods known in the art, such as crystallization or chiral chromatography.

[0142] As used in this article, the term =CR e R f Substitution refers to the process by which an atom of the molecule binds to a carbon atom via a double bond. e R f The carbon atoms (C) in the middle are bonded together. That is, the atoms of this molecule are bonded together. Replaced. As used herein, the term = NR e Substitution refers to the process by which an atom of the molecule bonds with an NR atom through a double bond. e The nitrogen atom (N) is bonded together. That is, the atoms of this molecule are bonded together. The atoms of the molecule are replaced. As used herein, oxoation refers to the bonding of an atom of the molecule to an oxygen atom (O) via a double bond. That is, the atoms of the molecule are replaced. The thiolation refers to the substitution of atoms in the molecule with sulfur atoms (S) via double bonds. That is, the atoms in the molecule are replaced. The group that is replaced. As used herein, when an alkyl group or similar group is located in the middle of a structural formula, that group is a subunit. For example, an alkyl group can be an alkylene group or similar.

[0143] As used herein, the term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. The term C 1-6 Alkyl groups refer to straight-chain or branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. More preferably, C14 is used. 1-4 Alkyl group. More preferably C10. 1-3 Alkyl groups. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and their various branched isomers. The alkyl groups described in this invention can be substituted or unsubstituted; when substituted, the substituents are preferably one or more substituent groups described in this application.

[0144] As used herein, the term "alkoxy" refers to a group having an -O-alkyl structure, wherein the definition of alkyl is as described above. The term "C" 1-6 "Alkoxy group" refers to an alkoxy group having 1 to 6 carbon atoms. Preferably, it is C64-66. 1-4 Alkyl group. More preferably, C10. 1-3 Alkoxy groups. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, and n-pentoxy. The alkoxy group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more substituent groups described in this application.

[0145] As used herein, the term "alkenyl" refers to an alkyl group as defined above that has one or more carbon-carbon double bonds at any point in the chain, and the term "C" refers to an alkyl group having one or more carbon-carbon double bonds at any point in the chain. 2-6 "Alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon double bonds. Preferably, it is C64-C ... 2-4 Alkenyl (i.e., alkenyl groups having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds). Specific examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, pentenyl, hexenyl, butadienyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more substituent groups described in this application.

[0146] As used herein, the term "alkynyl" refers to an alkyl group as defined above that has one or more carbon-carbon triple bonds at any point in the chain, and the term "C" refers to an alkyl group. 2-6"Alkyne group" refers to an alkyne group having 2 to 6 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon triple bond. Preferably, it is C64-C ... 2-4 The alkynyl group (i.e., an alkynyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds). Specific examples include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more substituent groups described in this application.

[0147] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0148] As used in this article, the term "halogenated" refers to fluorinated, chlorinated, brominated, or iodinated products.

[0149] As used herein, the term "halogenated alkyl" refers to an alkyl group in which one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are replaced by halogen atoms, wherein the definition of alkyl is as described above. The term "halogenated C" 1-6 "Alkyl" refers to a haloalkyl group having 1 to 6 carbon atoms. Haloalkyl groups are preferred. 1-4 Alkyl group. More preferably, halogenated C. 1- 3. Alkyl groups. Specific examples include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, and trifluoroethyl. The haloalkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more substituent groups described in this application.

[0150] As used in this article, the term "deuteration" refers to the replacement of one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms in a group with deuterium atoms.

[0151] As used herein, the terms "cycloalkyl" and "cycloalkyl ring" are used interchangeably to refer to a cyclic hydrocarbon group that is saturated or partially unsaturated, either monocyclic or polycyclic. The cyclic carbon atom of the cycloalkyl group may optionally be substituted with one or more (e.g., 1, 2, 3, 4, 5, etc.) oxo groups to form a cyclic ketone structure. The term "C..." 3-20 "Cycloalkyl" refers to a cycloalkyl group having 3 to 20 ring carbon atoms. It can include monocyclic cycloalkyl, spirocyclic cycloalkyl, fused cycloalkyl, and bridged cycloalkyl. Preferably, it has 3 carbon atoms. 3-12 cycloalkyl (e.g., C10) 3-6 cycloalkyl, etc.), C 5-20 Spirocycloalkyl, C 5-20 Polycyclic alkyl, C 5-20 Bridged cycloalkyl groups, etc.

[0152] As used in this article, the term "C" 3-6"Cycloalkyl" refers to a cycloalkyl group having 3 to 6 ring carbon atoms. It can be monocyclic (specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl); or bicyclic (specific examples include, but are not limited to, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, and cyclopropyl-cyclopentyl).

[0153] As used herein, the terms "spirocycloalkyl" and "spirocycloalkyl ring" refer to saturated or partially unsaturated polycyclic hydrocarbon groups formed by two or more monocyclic rings sharing a single carbon atom (called a spiro atom). Based on the number of shared spiro atoms between rings, they can be classified as monospirocycloalkyl, bispirocycloalkyl, and polyspirocycloalkyl. The terms "5 to 20-membered spirocycloalkyl" or "C..." 5-20 "Spirocycloalkyl" refers to a spirocycloalkyl group having 5 to 20 ring carbon atoms. Preferably, it has 6 to 14 members (i.e., C1 to C2). 6- 14 Spirocycloalkyl. More preferably, it is a 6- to 14-membered monospirocycloalkyl. More preferably, it is a 7- to 11-membered (i.e., C14) cycloalkyl group. 7-11 Spirocycloalkyl. More preferably, it is a 7- to 11-membered monospirocycloalkyl. More preferably, it is a 7-, 8-, 9-, 10-, or 11-membered monospirocycloalkyl. Specific examples of spirocycloalkyl include, but are not limited to: These spirocycloalkyl groups can be attached to the rest of the molecule via any one of the ring atoms.

[0154] As used herein, the terms "fused cycloalkyl" and "fused cycloalkyl ring" refer to a saturated or partially unsaturated polycyclic hydrocarbon group formed by two or more monocyclic rings sharing an adjacent pair of carbon atoms. Depending on the number of rings formed, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl. The terms "5- to 20-membered fused cycloalkyl" or "C" are also used. 5-20 "Fused cyclic alkyl" refers to a fused cyclic alkyl group having 5 to 20 ring carbon atoms. Preferably, it is a 6- to 14-membered (i.e., C14- to C24-membered) cyclic alkyl group. 6-14 Fused cycloalkyl group. More preferably, it is a 6- to 14-membered difused cycloalkyl group. More preferably, it is a 7- to 10-membered (i.e., C14) cycloalkyl group. 7-10 Fused cycloalkyl group. More preferably, it is a 7- to 10-membered difused cycloalkyl group. More preferably, it is an 8-, 9-, or 10-membered difused cycloalkyl group. Specific examples of fused cycloalkyl groups include, but are not limited to: These fused alkyl groups can be connected to the rest of the molecule via any one of the ring atoms.

[0155] As used herein, the terms "bridged cycloalkyl" and "bridged cycloalkyl ring" refer to saturated or partially unsaturated polycyclic hydrocarbon groups formed by two or more monocyclic rings sharing two non-directly connected carbon atoms. Based on the number of rings formed, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl. The terms "5- to 20-membered bridged cycloalkyl" and "C" are also used. 5-20 "Bridged cycloalkyl" refers to a bridged cycloalkyl group having 5 to 20 ring carbon atoms. Preferably, it is a 6- to 14-membered (i.e., C14- to C24-membered) cycloalkyl group. 6-14Bridged cycloalkyl group. More preferably 7 to 10 quinary (i.e., C10-10 quinary) 7-10 Bridged cycloalkyl groups. Specific examples of bridged cycloalkyl groups include, but are not limited to: These bridged cycloalkyl groups can be connected to the rest of the molecule through any one of the ring atoms.

[0156] The aforementioned cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the substituent groups described in this application.

[0157] As used herein, the terms “heterocyclic group” and “heterocyclic ring” are used interchangeably to refer to a cyclic hydrocarbon group consisting of a saturated or partially unsaturated monocyclic or polycyclic ring, wherein one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur, excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. When the ring atom is a nitrogen atom, it may be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or another substituent as defined herein) and / or the nitrogen atom may form a quaternary ammonium salt. When the heteroatom is a sulfur atom, the sulfur atom may be optionally oxidized (e.g., S (=O)). m 'm' is an integer from 0 to 2. When the heteroatom is a phosphorus atom, the phosphorus atom can be optionally oxidized (e.g., P (=O)). m "m" is an integer (0, 1, or 2). Examples include monocyclic heterocyclic groups, spirocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups. The ring carbon atoms of the heterocyclic group may optionally be substituted by one or more (e.g., 1, 2, 3, 4, or 5) oxo groups to form cyclic ketones, cyclic lactones, or cyclic lactam structures. The term "3 to 20-membered heterocyclic group" refers to a heterocyclic group having 3 to 20 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, 5, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. The 3 to 20-membered heterocyclic groups are preferably 3 to 10-membered heterocyclic groups, 5 to 20-membered spirocyclic groups, 5 to 20-membered fused heterocyclic groups, 5 to 20-membered bridged heterocyclic groups, etc.

[0158] The term "3- to 10-membered heterocyclic group" refers to a cyclic hydrocarbon group having 3 to 10 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5) ring atoms are saturated or partially unsaturated heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. The term "3- to 6-membered heterocyclic group" refers to a cyclic hydrocarbon group having 3 to 6 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5) ring atoms are saturated or partially unsaturated heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. The heterocyclic group can be monocyclic (specific examples include those described in the definition of 3- to 8-membered heterocyclic groups) or bicyclic (specific examples include, but are not limited to, cyclopropylcyclotetrahydropyrrole rings, cyclopropylcyclotetrahydrofuran rings, etc.).

[0159] As used herein, the term "3- to 8-membered heterocyclic group" refers to a cyclic hydrocarbon group having 3 to 8 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5, etc.) ring atoms are saturated or partially unsaturated heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. Preferably, it is a 3- to 6-membered heterocyclic group having 3 to 6 ring atoms, wherein one or more (e.g., 1 or 2, etc.) ring atoms are heteroatoms. More preferably, it is a 4- to 6-membered heterocyclic group having 4 to 6 ring atoms, wherein one or more (e.g., 1 or 2, etc.) ring atoms are heteroatoms. Even more preferably, it is a 5- or 6-membered heterocyclic group having 5 or 6 ring atoms, wherein one or more (e.g., 1 or 2, etc.) ring atoms are heteroatoms.Specific examples of monocyclic heterocyclic groups include, but are not limited to, aziridine, ethylene oxide, aziridine, aziridine-2-one, oxazolidinyl, oxazolidinyl-2-one ... Morpholin-3-one 1,1-dioxide, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazacyclobutadiene, 1,2-dihydrooxocyclobutadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazine, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidine-2(1H)-one, 1,4-dioxane-2-one, 5,6-dihydro-2H-pyran-2-one, 5,6-Dihydropyrimidin-4(3H)-one, 3,4-Dihydropyridin-2(1H)-one, 5,6-Dihydropyridin-2(1H)-one, 5,6-Dihydropyrimidin-4(1H)-one, pyrimidin-4(3H)-one, pyrimidin-4(1H)-one, 4,5-Dihydro-1H-imidazolium, 2,3-Dihydro-1H-imidazolium, 2,3-Dihydrooxazole, 1,3-Dioxacyclopentene, 2,3-Dihydrothiophene, 2,5-Dihydrothiophene, 3,4-Dihydro-2H-1,4-oxazine, 3,4-Dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-Tetrahydropyrazine, 1,3-Dihydro-2H-pyrrole-2- Ketones, 1,5-dihydro-2H-pyrrole-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxacyclopenten-2-one, oxazol-2(3H)-one, 1,3-dihydro-2H-imidazol-2-one, furan-2,5-dione, 3,6-dihydropyridin-2(1H)-one, pyridin-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, 1,2,3,4-tetrahydropyrimidine, etc.

[0160] The two ring atoms attached to the monocyclic heterocyclic group ring, including CC and NC, can optionally be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups as defined in this invention to form fused polycyclic rings. Preferably, the two ring atoms attached to the monocyclic heterocyclic group forming the fused ring are CC.

[0161] As used herein, the terms "spiroheterocyclic group" and "spiroheterocyclic ring" refer to polycyclic heterocyclic groups formed by two or more saturated or partially unsaturated monocyclic rings sharing a single carbon atom (called a spiro atom), wherein one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Each monocyclic ring may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Based on the number of shared spiro atoms between rings, they can be classified as monospirocyclic, dispirocyclic, or polyspirocyclic groups. The term "5 to 20-membered spiroheterocyclic group" refers to a spiroheterocyclic group having 5 to 20 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, 5, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. Preferably, the 6- to 14-membered spiroheterocyclic group has 6 to 14 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5) of the ring atoms are heteroatoms. More preferably, the 7- to 11-membered spiroheterocyclic group has 7 to 11 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5) of the ring atoms are heteroatoms. Most preferably, 7-, 8-, and 10-membered monospiroheterocyclic groups are spiroheterocyclic groups. Specific examples of spiroheterocyclic groups include, but are not limited to:

[0162] These spirocyclic groups can be connected to the rest of the molecule by any suitable ring atom.

[0163] As used herein, the terms "fused heterocyclic group" and "fused heterocyclic ring" refer to a polycyclic heterocyclic group formed by two or more saturated or partially unsaturated monocyclic rings sharing a pair of adjacent ring atoms, wherein one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Each monocyclic ring may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The shared pair of adjacent ring atoms can be C-C or NC. Based on the number of constituent rings, fused heterocyclic groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic. The term "5- to 20-membered fused heterocyclic group" refers to a fused heterocyclic group having 5 to 20 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, 5, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. Preferably, it is a 6- to 14-membered fused heterocyclic group having 6 to 14 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5) ring atoms are heteroatoms. More preferably, it is a 6- to 10-membered fused heterocyclic group having 6 to 10 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5) ring atoms are heteroatoms. Even more preferably, it is an 8- to 10-membered fused heterocyclic group having 8 to 10 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5) ring atoms are heteroatoms. Most preferably, it is an 8-, 9-, or 10-membered bicyclic fused heterocyclic group. Specific examples of fused heterocyclic groups include, but are not limited to:

[0164] These fused heterocyclic groups can be connected to the rest of the molecule by any suitable ring atom.

[0165] As used herein, the terms "bridged heterocyclic group" and "bridged heterocyclic ring" refer to a polycyclic heterocyclic group formed by two or more saturated or partially unsaturated monocyclic rings sharing two non-directly connected ring atoms, wherein one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Depending on the number of rings formed, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged alkyl groups. The term "5 to 20-membered bridged heterocyclic group" refers to a bridged heterocyclic group having 5 to 20 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, 5, etc.) ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. Each monocyclic ring may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Preferred are 6 to 14-membered bridged heterocyclic groups. More preferably are 7 to 10-membered bridged heterocyclic groups. Specific examples of bridged heterocyclic groups include, but are not limited to:

[0166] These bridging heterocyclic groups can be connected to the rest of the molecule via any suitable ring atom.

[0167] In this invention, various heterocyclic groups can be optionally substituted. When substituted, the substituents are preferably one or more substituent groups described in this application.

[0168] As used herein, the terms "aryl," "aryl ring," and "aromatic ring" are used interchangeably to refer to an all-carbon monocyclic, all-carbon non-fused polycyclic (rings connected by covalent bonds, not fused), or all-carbon fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group, wherein at least one ring in the group is aromatic, i.e., has a conjugated π-electron system. The term "C" is used in conjunction with the preceding text. 6-14 "Aryl" refers to an aryl group having 6 to 14 ring atoms. Preferably, it is C14. 6-10 Aryl group. The C 6-14 Aryl groups include monocyclic aryl groups, non-fused polycyclic aryl groups, and aromatic fused polycyclic groups, among which examples of monocyclic aryl groups include phenyl groups, and examples of non-fused polycyclic aryl groups include biphenyl groups.

[0169] In this invention, when C 6-14 When the aryl group is an aromatic fused polycyclic ring, the aromatic fused polycyclic ring can be a polycyclic group formed by the fusion of a monoaryl ring with one or more monoaryl rings, and non-limiting examples include naphthyl, anthracene, etc.

[0170] In some embodiments of the present invention, when C 6-14 When the aryl group is an aromatic fused polycyclic ring, the aromatic fused polycyclic ring can also be a polycyclic group formed by the fusion of a monoaryl ring (such as phenyl) with one or more non-aromatic rings, wherein the ring connected to the parent structure is an aromatic ring or a non-aromatic ring. The non-aromatic ring includes, but is not limited to, 3- to 6-membered monocyclic heterocyclic rings (preferably 5- or 6-membered monocyclic heterocyclic rings, wherein the ring carbon atom of the monocyclic heterocyclic ring can be replaced by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), and 3- to 6-membered monocyclic cycloalkyl rings (preferably 5- or 6-membered monocyclic cycloalkyl rings, wherein the ring carbon atom of the monocyclic cycloalkyl ring can be replaced by 1 or 2 oxo groups to form a cyclic ketone structure). The above-mentioned polycyclic group fused with a monoaryl ring and one or more non-aromatic rings can be connected to other groups or the parent structure through a nitrogen atom or a carbon atom, wherein the ring connected to the parent structure is a monoaryl ring or a non-aromatic ring.

[0171] In this invention, various aryl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more substituent groups described in this application.

[0172] As used herein, the terms “heteroaryl,” “heteroaryl ring,” and “heteroaryl ring” are used interchangeably to refer to a monocyclic or fused polycyclic (i.e., sharing adjacent ring atom pairs, which may be CC or NC) group in which the ring atom is substituted by at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, etc.) heteroatom independently selected from phosphorus, nitrogen, oxygen, or sulfur. The heteroaryl group has 6, 10, or 14 shared π electrons, and at least one ring in the group is aromatic. When the ring atom is a nitrogen atom, it may be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or another substituent as defined herein) and / or the nitrogen atom may form a quaternary ammonium salt. When the heteroatom is a sulfur atom, the sulfur atom may be optionally oxidized (e.g., S (=O)). m 'm' is an integer from 0 to 2. When the heteroatom is a phosphorus atom, the phosphorus atom can be optionally oxidized (e.g., P (=O)). m "m" is an integer 0, 1, or 2. The term "5 to 14-membered heteroaryl" refers to a heteroaryl having 5 to 14 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5) of the ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. Preferably, it is a 5 to 10-membered heteroaryl having 5 to 10 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5) of the ring atoms are heteroatoms. The 5 to 14-membered heteroaryl can be a monocyclic heteroaryl, a fused bicyclic heteroaryl, a fused tricyclic heteroaryl, etc.

[0173] As used herein, the term "5- or 6-membered monocyclic heteroaryl" refers to a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5) of the ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. Specific examples of monocyclic heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazolium, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.

[0174] As used herein, the term "8- to 10-membered bicyclic heteroaryl" refers to a fused bicyclic heteroaryl having 8 to 10 ring atoms, wherein one or more (e.g., 1, 2, 3, 4, or 5) of the ring atoms are heteroatoms selected from phosphorus, nitrogen, oxygen, or sulfur. The fused bicyclic heteroaryl can be a bicyclic group (preferably a 9- or 10-membered bicyclic heteroaryl ring) formed by fusion of a monoaryl ring (such as phenyl) and a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring), or a bicyclic group formed by fusion of a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and another monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring).

[0175] Any two ring atoms attached to the aforementioned monocyclic heteroaryl ring, including CC, NC, and NN, can be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups, such as monocyclic cycloalkyl rings, monocyclic heterocyclic rings, monoaryl rings, and 5- or 6-membered monocyclic heteroaryl rings, as defined in this invention, to form fused polycyclic rings. The two ring atoms attached to the monocyclic heteroaryl ring forming the fused ring with other rings are preferably CC, and non-limitingly include the following forms:

[0176] The above groups are passed through The marked ring atoms are connected to other parts of the molecule.

[0177] Non-limiting examples of 8- to 10-membered bicyclic heteroaryl groups include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazol, benzo[d]isothiazol, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazol, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cyclophosphine, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthoidine, 1,7-naphthoidine, 1,6-naphthoidine, 1,5-naphthoidine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, etc.

[0178] Specific examples of bicyclic heteroaryl groups include, but are not limited to: These groups can be attached to the rest of the molecule via any suitable ring atom. The ring attached to the parent structure can be a monocyclic heteroaryl ring or a benzene ring.

[0179] In some embodiments of the present invention, the fused bicyclic heteroaryl or fused tricyclic heteroaryl can be a polycyclic group formed by fusion of a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) with one or more non-aromatic rings, wherein the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring. The non-aromatic ring includes, but is not limited to, 3- to 6-membered monocyclic heterocyclic rings (preferably 5- or 6-membered monocyclic heterocyclic rings, wherein the ring carbon atom of the monocyclic heterocyclic ring can be replaced by 1 to 2 oxo groups to form a cyclic lactam or cyclic lactone structure), 3- to 6-membered monocyclic cycloalkyl rings (preferably 5- or 6-membered monocyclic cycloalkyl rings, wherein the ring carbon atom of the monocyclic cycloalkyl ring can be replaced by 1 or 2 oxo groups to form a cyclic ketone structure), etc. The polycyclic group formed by fusion of the above-mentioned monocyclic heteroaryl ring with one or more non-aromatic rings can be connected to other groups or the parent structure through a nitrogen atom or a carbon atom, wherein the ring connected to the parent structure is a monocyclic heteroaryl ring or a non-aromatic ring.

[0180] The various heteroaryl groups of the present invention can be substituted or unsubstituted. When substituted, the substituents are preferably one or more substituent groups described in this application.

[0181] As used in this article, the term "hydroxyl group" refers to -OH.

[0182] As used in this article, the term "cyano" refers to -CN.

[0183] As used in this article, the term "nitro" refers to -NO2.

[0184] As used in this article, the term "benzyl" refers to -CH2-benzene.

[0185] As used in this article, the term "oxo" refers to =O.

[0186] As used in this article, the term "carboxyl group" refers to -C(=O)OH.

[0187] The aforementioned alkyl, heteroalkyl, alkoxy, alkynyl, alkenyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups described in this application.

[0188] As used herein, the term "substitution" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are replaced. The terms "optional substitution" or "optionally substituted" mean that substitution is optional, and unless otherwise specified, the type and number of substituents can be arbitrary on a chemically feasible basis.

[0189] Indicates the location of chemical bond connections.

[0190] This indicates the presence or absence of double bonds between any two adjacent atoms within the ring, implying that it includes various cases such as saturated ring systems, unsaturated non-aromatic ring systems with double bonds, and aromatic ring systems.

[0191] In this disclosure, the term is used. and The absolute configuration representing the center of a solid. Unless otherwise specified. Including potential uses Both scenarios are possible, provided the structure allows it.

[0192] When the ring appears Furthermore, if the connection location is uncertain, it indicates that the connection site is located at... Any atom on the monocyclic ring, as long as its valence allows.

[0193] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0194] In any embodiment, any or all hydrogen atoms present in the compound, or hydrogen atoms in a specific group or portion of the compound, may be replaced by deuterium or tritium. One to a maximum number of hydrogen atoms present in the compound may be replaced by deuterium. One to a maximum number of hydrogen atoms present in any group of the general formula compound or a specific compound may be replaced by deuterium. For example, when a group is described as ethyl, the ethyl group may be C2H5 or a C2H5 in which x (1 to 5) hydrogen atoms are replaced by deuterium, such as C2D. x H 5-x When a group is described as a deuterated ethyl group, the deuterated ethyl group can be a C2H5 with x (1 to 5) hydrogen atoms replaced by deuterium, such as C2D. x H 5-x The stable deuterated derivatives of the present invention are preferably stable deuterated isotope derivatives obtained by replacing any deuterated hydrogen atom in each formula with 1 to a maximum number (e.g., 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, etc.) of deuterium atoms.

[0195] Unless otherwise specified, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 32 P, 33 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. Isotope-labeled compounds (e.g., labeled with...) 3 H and 14 Compounds of C can be used in the determination of the tissue distribution of compounds or substrates. Tritium (i.e.,3 H) and carbon-14 (i.e., ... 14 C) Isotopes are available because they are easy to prepare and detect. Alternatively, heavier isotopes, such as deuterium (i.e.,...), can be used. 2 H) substitution can provide certain therapeutic benefits due to enhanced metabolic stability (e.g., increased half-life in vivo or reduced dose requirement). In some embodiments, one or more hydrogen atoms are... 2 H or 3 H substitution, or one or more carbon atoms being... 13 C or 14 Carbon-enriched carbon substitution. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared by following a procedure similar to that disclosed for the compounds of the invention described herein, by replacing unlabeled reagents with isotopically labeled reagents.

[0196] As used herein, the term "cancer" refers to malignant tumors originating from various tissues or organs such as epithelial tissue, hematopoietic system, lymphatic system, and mesenchymal tissue, including but not limited to primary tumors, secondary tumors (metastatic tumors), precancerous lesions, and recurrent or refractory tumors with malignant proliferation, invasiveness, and metastasis. The term "tumor" encompasses the aforementioned cancer-related malignant tumors, as well as benign or borderline tumors related to the occurrence and development of cancer. The core characteristics of malignant tumors are uncontrolled abnormal cell proliferation, invasion of surrounding tissues, and distant metastasis, which can lead to tissue damage, functional impairment, and harm to life and health. Detailed Implementation

[0197] The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0198] The present invention will be described in detail below through embodiments, but this does not imply any adverse limitations on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0199] The structure of the compound was determined by methods such as nuclear magnetic resonance (NMR) and mass spectrometry (MS).

[0200] NMR measurements were performed using a Bruker Avance NEO 400 or Bruker Avance NEO 500 NMR spectrometer. Chemical shifts (δ) were expressed in parts per million (ppm). The solvents used for measurement were as shown in the examples, with tetramethylsilane (TMS) as the internal standard.

[0201] MS measurements were performed using an Agilent 1100 liquid chromatograph.

[0202] High performance liquid chromatography (HPLC) analysis was performed using a Waters 2695 HPLC system.

[0203] Thin-layer chromatography (TLC) uses either Qingdao GF254 or Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used in TLC have a diameter of 0.15mm-0.2mm. The diameter of the silica gel plates used for TLC separation and purification is 0.4mm-0.5mm.

[0204] Column chromatography typically uses the ISCO CombiFlash NextGen 300 column chromatography system with Agela Flash Column Silica-Cs series silica columns.

[0205] Preparation Example 1: Synthesis of Intermediate 1

[0206] Step 1: Morpholine (30 mL) was added to a methanol (500 mL) solution of 30 g (0.147 mol) of 2,4-dichlorothiophene[2,3-d]pyrimidine. The reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with ethyl acetate (1000 mL) and water (300 mL). The organic matter was washed with brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give a white solid compound 1-a (20 g, yield: 54%).

[0207] Step 2: To a solution of compound 1-a (20 g, 0.078 mol) in tetrahydrofuran (200 mL), add n-butyllithium (5.9 g, 0.093 mol) and DMF (9 mL). Stir the reaction mixture at -78 °C for 3 hours. After completion, dilute the reaction mixture with ethyl acetate (1000 mL) and water (300 mL). Wash the organic matter with brine (20 mL), dry with Na₂SO₄, and concentrate. Purify the residue by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 1-b (15 g, yield: 68%) as a white solid.

[0208] Step 3: To a solution of compound 1-b (15 g, 53 mmol) in 1,2-dichloroethane (100 mL), add piperazine-1-carboxylic acid tert-butyl ester (13.8 g, 74 mmol) and NaBH(OAc)3 (13.5 g, 64 mmol). Stir at room temperature for 16 hours. Dilute the reaction mixture with dichloromethane (500 mL) and water (500 mL). Wash the organic matter with brine (200 mL), dry with Na2SO4, and concentrate. Purify the residue by column chromatography (petroleum ether:ethyl acetate = 1:1) to give a white solid compound 1-c (5 g, yield: 21%). LCMS (ESI): [M+H] + =454.2,RT=1.70min. 1 H NMR(500MHz,MeOD-d4)δ7.42(s,1H),3.99–3.90(m,4H),3.87–3.75(m,6H),3.44(s,4H),2.53–2.35(m,4H),1.45(s,9H).

[0209] Step 4: Dimethyl dicarbonate (33.5 g, 0.25 mol) and t-BuOK (42 g, 0.375 mol) were added to a solution of 5-bromo-4-(trifluoromethyl)pyridine-2-amine (30 g, 0.125 mol) in tetrahydrofuran (500 mL). The reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with ethyl acetate (1000 mL) and water (300 mL). The organic matter was washed with brine (200 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give compound 1-d (26.8 g, yield: 71.9%) as a white solid.

[0210] Step 5: Under a nitrogen atmosphere, n-BuLi (46 mL, 117 mmol) was added dropwise to a tetrahydrofuran (10 mL) solution of compound 1-d (26.8 g, 89.9 mmol). The mixture was stirred at -78 °C for 0.5 hours. Then, triisopropyl borate (20.3 g, 107.8 mmol) was added dropwise. The resulting mixture was stirred overnight at -78 °C under nitrogen atmosphere. The mixture was cooled to 0 °C and diluted with ethyl acetate (500 mL) and water (500 mL). The organic matter was washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give a grayish-white solid compound 1-e (10.5 g, yield: 44.2%). LCMS (ESI): [M+H] + =632.4,RT=1.48min. 1 H NMR (400MHz, DMSO-d6) δ10.72–10.58(m,1H),8.48(d,J=14.1Hz,3H),8.20–8.01(m,1H),3.69(d,J=11.5Hz,3H).

[0211] Step 6: Compound 1-c (46 mg, 0.1 mmol, CAS: 955978-97-9), compound 1-e (38 mg, 0.14 mmol), tetra(triphenylphosphine)palladium (51 mg, 0.044 mmol), and potassium carbonate (46 mg, 0.33 mmol) were placed in a reaction tube, and toluene / ethanol / water (50 μL / 20 μL / 10 μL) was added. The tube was then sealed and reacted at 100 °C for 12 h. After the reaction was completed, the mixture was evaporated to dryness and purified by silica gel column chromatography (dichloromethane / ethanol = 50:1) to obtain compound 1-f (53 mg), a yellow solid. 1 HNMR(600MHz, CDCl3)δ8.85(s,1H),8.42(s,1H),7.17(s,1H),3.92-3.95(m,4H),3.85 -3.93(m,7H),3.78(3,2H),3.46(t,J=8.0Hz,4H),2.49(t,J=8.0Hz,4H),1.46(s,9H).

[0212] Step 7: Dissolve compound 1-f (50 mg, 0.078 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (0.5 mL) with stirring, react for 2 hours, dilute with dichloromethane (50 mL), wash with saturated sodium bicarbonate and saturated brine, dry the organic phase with anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain compound intermediate 1 (40 mg), a gray solid, which was used directly in the next step of the reaction without purification.

[0213] Preparation Example 2: Synthesis of Intermediate 2

[0214] Step 1: Intermediate 1 (135 mg, 0.25 mmol), HOBt (7 mg, 0.05 mmol), and N-Boc glycine (71 mg, 0.25 mmol) were placed in a single-necked flask. After purging with argon three times, a dichloromethane dispersion (15 mL) was added. The reaction system was cooled completely at 0 °C. NMM (76 mg, 0.75 mmol) and EDC (52 mg, 0.275 mmol) were added to the reaction system, and the reaction was allowed to return to room temperature. After 3 h, the reaction was monitored by TLC. Once the reactants were completely consumed, the mixture was purified by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 1:30) to obtain a white solid compound 2-a (110 mg, yield: 64%).

[0215] Step 2: Dissolve compound 2-a (100 mg) in dichloromethane (10 mL), cool at 0 °C, add trifluoroacetic acid (4 mL), and allow to return to room temperature for approximately 10 min. TLC (dichloromethane / methanol = 10:1) monitoring showed complete consumption of the starting material (Rf = 0.8). The reaction system was concentrated to obtain intermediate compound 2, which was directly used in the next reaction step.

[0216] Preparation Example 3: Synthesis of Intermediate 3

[0217] Step 1: Morpholine (30 mL) was added to a methanol (500 mL) solution of 3,5-dibromopyrazin-2-amine (30 g, 0.119 mol). The reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with ethyl acetate (1000 mL) and water (300 mL). The organic matter was washed with brine (20 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give a white solid compound 3-a (25 g, yield: 80%).

[0218] Step 2: Ethyl 3-bromo-2-oxopropionate (11 mL) was added to a DME (500 mL) solution of compound 3-a (25 g, 0.096 mol). The reaction mixture was stirred at 100 °C for 2 hours. After completion, the reaction mixture was diluted with ethyl acetate (1000 mL) and water (300 mL). The organic matter was washed with brine (20 mL), dried over Na₂SO₄, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give compound 3-b (20 g, yield: 58%) as a white solid.

[0219] Step 3: Under a nitrogen atmosphere, at -78°C, add DIBAL-H (38 mL, 117 mmol) dropwise to a solution of compound 3-b (20 g, 56 mmol) in dichloromethane (100 mL). Stir at -78°C for 0.5 hours. Dilute the reaction mixture with ethyl acetate (500 mL) and water (500 mL). Wash the organic matter with brine (20 mL), dry with Na₂SO₄, and concentrate. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give a white solid compound 3-c (10 g, yield: 57%).

[0220] Step 4: To a solution of compound 3-c (10 g, 32 mmol) in 1,2-dichloroethane (100 mL), piperazine-1-carboxylic acid tert-butyl ester (13.8 g, 74 mmol) and Na(OAc)3BH (13.5 g, 64 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reactants were diluted with dichloromethane (500 mL) and water (500 mL). The organic matter was washed with brine (200 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to give intermediate 3 (5 g, yield: 32%) as a white solid. LCMS (ESI): [M+H] + =481.2,RT=1.75min. 1 H NMR (400MHz, CD3OD) δ7.91(s,1H),7.69(s,1H),4.31–4.20(m,4H),3.85–3.77(m,4H),3.70(s,2H),3.44(s,4H),2.57–2.46(m,4H),1.44(s,9H).

[0221] Example 1: Synthesis of compound Z1

[0222] Step 1: Intermediate 1 (37 mg, 68 μmol), HOBt (2.1 mg, 14 μmol), and compound 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid (14.1 mg, 68 μmol) were added to a round-bottom flask. Dichloromethane (3 mL, with methanol added as a solubilizer if necessary) was added to dissolve the compounds. The reaction system was cooled completely at 0 °C. NMM (20.2 mg, 0.2 mmol) and EDC (14.1 μL, 80 μmol) were added to the reaction system, and the reaction was allowed to return to room temperature. After 1 hour, the reaction was monitored by TLC. Once the reactants were consumed, the mixture was purified by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 50:1) to obtain a white solid compound 1-1 (32 mg, yield: 65%). 1HNMR(600MHz, CDCl3)δ8.84(s,1H),8.41(s,1H),8.11(s,1H),7.16(s,1H),3.94-3.93(m,3H ),3.86-3.83(m,6H),3.77(s,2H),2.52-2.53(m,4H),1.61(s,6H),1.42(s,9H),1.25(s,4H).

[0223] Step 2: Dissolve compound 1-1 (32 mg, 44 μmol) in 3 mL of dichloromethane, add 0.3 mL of trifluoroacetic acid at 0 °C, and stir at room temperature for 1 hour until the starting material is completely consumed. Concentrate the reaction system to obtain crude compound 1-2, which is used directly in the next reaction without purification.

[0224] Step 3: Dissolve crude compounds 1-2 in dichloromethane (3 mL), add triethylamine (50 μL, 0.35 mmol) and acryloyl chloride (15 μL, 0.18 mmol) at 0 °C, and stir at room temperature for 2 hours until the reactants are completely consumed. Quench the reaction system with saturated sodium bicarbonate aqueous solution, separate the layers, extract the aqueous phase five times with dichloromethane, combine all organic phases, dry with Na2SO4, concentrate the organic phase, and purify by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 30:1) to obtain compound (5-(6-((4-(1-acrylamidocyclopropane-1-carbonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z1, 5 mg, 2-step yield: 17%). 1 H NMR (600MHz, CDCl3) δ8.7(s,1H),8.35(s,1H),7.14(s,1H),6.20(d,J=18.0Hz,1H),6.00-6.05(m,1 H),5.59(d,J=12.0Hz,1H),5.25(s,1H),3.71-3.89(m,15H),2.96-3.00(m,6H),2.47(s,4H).ESI-MS m / z[M+H] + =675.3223.

[0225] Example 2: Synthesis of compound Z2

[0226] Step 1: Intermediate 1 (33 mg, 68 μmol), HOBt (2.1 mg, 14 μmol), and compound 2-((tert-Butoxycarbonyl)amino)-2-methylpropionic acid (14.1 mg, 68 μmol) were added to a round-bottom flask, followed by 2 mL of dichloromethane. The compounds were dissolved. The reaction system was cooled completely at 0 °C. NMM (20.2 mg, 0.2 mmol) and EDC (14.1 μL, 80 μmol) were added to the reaction system, and the mixture was allowed to return to room temperature. After 1 hour, the reaction was monitored by TLC. Once the reactants were consumed, the mixture was purified by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 20:1) to obtain a white solid compound 2-1 (20 mg, yield: 45%). 1 H NMR (400MHz, CDCl3) δ8.87(s,1H),8.79(s,1H),8.43(s,1H),7.16(s,1H),3.96-3.83(m,12H),3 .83(d,J=4.2Hz,4H),2.61(s,1H),2.53(s,1H),2.51(m,4H),1.49(d,J=6.7Hz,6H),1.43(s,9H).

[0227] Step 2: Dissolve compound 2-1 (32 mg, 44 μmol) in dichloromethane (3 mL), add trifluoroacetic acid (0.3 mL) at 0 °C, and stir at room temperature for 1 hour until the starting material is completely consumed. Concentrate the reaction system to obtain crude compound 2-2, which is directly used in the next reaction without purification.

[0228] Step 3: Dissolve the crude compound 2-2 in dichloromethane (2 mL), and add triethylamine (50 μL, 0.35 mmol) and acryloyl chloride (15 μL, 0.18 mmol) at 0 °C. Stir at room temperature for 3 hours until the reactants are completely consumed. Quench the reaction mixture with saturated sodium bicarbonate solution, separate the phases, extract the aqueous phase five times with dichloromethane, combine all organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 20:1) to obtain compound (5-(6-((4-(2-acrylamido-2-methylpropionyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z2, 3 mg, 2-step yield: 15%). 1H NMR (600MHz, CDCl3) δ8.81(s,1H),8.41(s,1H),7.89(s,1H),7.17(s,1H),6.90(s,1H),6.26(d,J=16.9Hz,1H),6.10(dd,J=16.9,10.2Hz,1 H),5.63(d,J=10.3Hz,1H),3.93(t,J=4.7Hz,4H),3.87-3.81(m,8H),3.78(s,3H),3.71(d,J=12.9Hz,2H),2.54(s,4H),1.69(s,6H).ESI-MS m / z[M+H] + =677.651.

[0229] Example 3: Synthesis of compound Z3

[0230] Step 1: Intermediate 1 (36 mg, 67 μmol), HOBt (2 mg), and (tert-butoxycarbonyl)-L-alanine (12.8 mg, 67 μmol) were placed in a single-necked flask. After purging with argon three times, dichloromethane (3 mL) was added to disperse the mixture. The reaction system was cooled to 0 °C, and NMM (20 mg) and EDC (14 mg) were added. The mixture was then allowed to return to room temperature. After 3 hours, the reaction was monitored by TLC. Once the reactants were consumed, the mixture was purified by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 30:1) to obtain a white solid compound 3-1 (31 mg, yield: 66%). 1 H NMR (600MHz, CDCl3) δ8.89(d,J=2.5Hz,1H),8.44(s,1H),7.17(s,1H),5.58(d,J=10.2Hz,1H),4.61(d,J=28.1Hz,1H),3.93(d,J=9.4 Hz,4H),3.87-3.81(m,8H),3.78(s,2H),3.59-3.56(m,3H),3.50(d,J=14.2Hz,1H),2.57(s,4H),1.42(s,9H),1.29(d,J=6.8Hz,3H).

[0231] Step 2: Dissolve compound 3-1 (30 mg, 0.04 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (0.3 mL) at 0 °C, and stir at room temperature until the reactants are completely consumed. Concentrate the reaction system to obtain crude compound 3-2, which is used directly in the next reaction without purification.

[0232] Step 3: Dissolve crude compound 3-2 in dichloromethane (2 mL), add triethylamine (0.3 mL) and acryloyl chloride (30 μL) at 0 °C, and stir at room temperature until the reactants are completely consumed. Quench the reaction system with saturated sodium bicarbonate aqueous solution, separate the liquid and extract the aqueous phase five times with dichloromethane, combine all organic phases, dry with anhydrous sodium sulfate, filter and concentrate, and purify by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 20:1) to obtain compound (5-(6-((4-(acryloyl-L-alanyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z3, 16 mg, yield: 58%), white solid. 1 H NMR (600MHz, CDCl3) δ8.93-8.87(m,1H),8.44(s,1H),7.17(s,1H),6.82(t,J=6.2Hz,1H),6.28(dd, J=17.0,1.5Hz,1H),6.13(dd,J=17.0,10.3Hz,1H),5.65(dt,J=10.3,1.9Hz,1H),4.97(p,J=6.9Hz,1 H),3.93(t,J=4.7Hz,4H),3.87-3.81(m,7H),3.79(s,2H),3.63(ddd,J=13.4,6.4,3.2Hz,1H),3.59- 3.49(m,2H),2.62-2.58(m,2H),2.56-2.46(m,2H),1.85-1.70(m,2H),1.35(d,J=6.8Hz,3H).ESI-MS m / z[M+H] + =663.620.

[0233] Example 4: Synthesis of compound Z4

[0234] Step 1: Intermediate 1 (40 mg, 74 μmol), HOBt (2.1 mg, 15 μmol), and N-(tert-butoxycarbonyl)-N-methylglycine (14.1 mg, 74 μmol) were added to a round-bottom flask. After purging with argon three times, dichloromethane (3 mL) was added to dissolve the compound. The reaction system was cooled completely at 0 °C. NMM (22.6 mg, 22 μmol) and EDC (13.2 μL, 74 μmol) were added to the reaction system, and the reaction was allowed to return to room temperature. After 1 hour, the reaction was monitored by TLC. When the reactants were completely consumed, the mixture was purified by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 10:1) to give a white solid compound 4-1 (25 mg, yield: 48%). 1H NMR (600MHz, CDCl3) δ8.88(d,J=2.5Hz,1H),8.73(d,J=44.2Hz,1H),8.43(s,1H),7.17(s,1H),5.29(s,1H),4.05(s,2H),4.01 -3.91(m,6H),3.90-3.74(m,12H),3.70-3.57(m,3H),3.47(d,J=8.3Hz,4H),2.92(d,J=5.4Hz,4H),2.54(s,6H),1.46(s,9H).

[0235] Step 2: Dissolve compound 4-1 (25 mg, 35 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (0.3 mL) at 0 °C, and stir at room temperature for 1 hour until the starting material is completely consumed. Concentrate the reaction system to obtain crude compound 4-2, which is used directly in the next reaction without purification.

[0236] Step 3: Dissolve the crude compound 4-2 in dichloromethane (3 mL), add triethylamine (50 μL, 0.3528 mmol) and acryloyl chloride (15 μL, 18 μmol) at 0 °C, and stir at room temperature for 2 hours until the reactants are completely consumed. Quench the reaction system with saturated sodium bicarbonate aqueous solution, separate the layers, extract the aqueous phase five times with dichloromethane, combine all organic phases, dry with anhydrous sodium sulfate, filter and concentrate, and purify by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 30:1) to obtain compound (5-(6-((4-(N-acryloyl-N-methylglyceryl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z4, 16.9 mg, 2-step yield: 73%). 1 H NMR (400MHz, CDCl3) δ8.82(s,1H),8.41(s,1H),8.09(d,J=7.1Hz,1H),7.83(s,1H),7.17(s,1H),6.64(dd,J=16.7,10.5Hz,1H),6.35(dd,J=16.8,2. 1Hz,1H),5.74(d,J=10.4Hz,1H),4.34-4.22(m,2H),3.94(s,4H),3.85(d, J=4.9Hz,8H),3.67(s,2H),3.52(s,2H),3.18(s,3H),2.56(s,4H).ESI-MS m / z[M+H] + =663.57.

[0237] Example 5: Synthesis of compound Z5

[0238] Step 1: Intermediate 1 (36 mg, 0.06 mmol), HOBt (2 mg, 0.012 mmol), and (tert-butyloxycarbonyl)-L-proline (14 mg, 0.06 mmol) were placed in a single-necked flask. After purging with argon three times, dichloromethane (3 mL) was added to disperse the mixture. The reaction system was cooled completely at 0 °C. NMM (20 mg, 0.2 mmol) and EDC (13 mg, 0.066 mmol) were added to the reaction system, and the mixture was allowed to return to room temperature. After 3 hours, the reaction was monitored by TLC. Once the reactants were consumed, the mixture was purified by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 30:1) to obtain a white solid compound 5-1 (35 mg, yield: 70%). 1 HNMR(600MHz, CDCl3) δ8.90(d,J=4.0Hz,1H),8.44(s,1H),7.17(d,J=3.4Hz,1H),3. 95-3.91(m,4H),3.88-3.81(m,7H),3.78(d,J=8.8Hz,2H),3.68-3.62(m,1H),3.61- 3.53(m,2H),3.48(ddt,J=17.2,10.4,2.8Hz,2H),2.67-2.45(m,4H),2.23-2.06(m, 1H), 2.03 (s, 2H), 1.90-1.78 (m, 2H), 1.42 (d, J = 31.0Hz, 10H), 1.24 (t, J = 7.1Hz, 1H).

[0239] Step 2: Dissolve compound 5-1 (32 mg, 0.043 mmol) in CH2Cl2 (2 mL), add trifluoroacetic acid (0.3 mL) at 0 °C, and stir at room temperature until the reactants are completely consumed. Concentrate the reaction system to obtain crude compound 5-2, which is used directly in the next step of the reaction without purification.

[0240] Step 3: Dissolve crude compound 5-2 in CH2Cl2 (2 mL), add triethylamine (77 μL) and acryloyl chloride (23 μL) at 0 °C, and stir at room temperature until the reactants are completely consumed. Quench the reaction mixture with water, separate the liquid and aqueous phases, extract the aqueous phase five times with dichloromethane, combine all organic phases, dry with anhydrous sodium sulfate, filter and concentrate, and purify by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 20:1) to obtain methyl (5-(6-((4-(acryloyl-L-prolyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z5, 24 mg, yield: 80%). 1H NMR (400MHz, CDCl3) δ9.08(s,1H),8.89(s,1H),8.44(s,1H),7.17(s,1H),6.48(dd,J=16.8,10.1Hz,1H),6.36(dd,J=16. 9,2.2Hz,1H),5.68(dd,J=10.1,2.2Hz,1H),4.94(dd,J=8.3,3.8Hz,1H),3.93(t,J=4.6Hz,5H),3.86-3.77(m,8H),3.64( dt,J=9.6,7.1Hz,1H),3.48(ddd,J=35.1,12.6,7.4Hz,2H),2.61(dt,J=15.1,4.4Hz,3H),2.50(ddd,J=11.4,8.3,3.2Hz, 1H),2.27-2.15(m,1H),2.15-2.05(m,1H),1.98(dt,J=10.6,6.4Hz,1H),1.94-1.86(m,1H),1.24(t,J=7.1Hz,3H).ESI-MS m / z[M+H] + =689.24.

[0241] Example 6: Synthesis of compound Z6

[0242] Step 1: In a round-bottom flask, argon gas was purged three times with compound (E)-4-bromobut-2-enoic acid (100 mg, 0.61 mmol), followed by the addition of dichloromethane (5 mL) and a catalytic amount of DMF (5 mg, 0.068 mmol). Oxaloyl chloride (155 mg, 1.22 mmol) was slowly added dropwise to the above system in an ice bath with stirring. The reaction was carried out at 0 °C for 1-2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a yellow oily liquid compound 6-1 (110 mg).

[0243] Step 2: Dissolve compound 2-a (100 mg) in dichloromethane (10 mL), cool at 0 °C, add trifluoroacetic acid (4 mL), and allow to return to room temperature for approximately 10 min. Monitor by thin-layer chromatography (dichloromethane:methanol = 10:1). The starting material (Rf = 0.8) was completely consumed. Concentrate the reaction system to obtain crude compound intermediate 2, which was directly used in the next reaction step.

[0244] Step 3: Dissolve intermediate 2 (85 mg, 0.143 mmol) in dichloromethane (10 mL), add triethylamine (290 mg), cool the reaction system at 0 °C, add compound 6-1 (144 mg, 1.43 mmol), and allow to return to room temperature for approximately 30 min. TLC (dichloromethane:methanol = 10:1) monitoring showed complete consumption of the starting material (Rf = 0.2). Concentrate the reaction system to obtain crude compound 6-3, which was directly used in the next step of the reaction.

[0245] Step 4: Dissolve compound 6-3 (15 mg, 0.02 mmol) in tetrahydrofuran (4 mL), add potassium carbonate (28 mg, 0.2 mmol) and Et2NH (73 mg, 1 mmol), seal the reaction system and react at 75 °C. Monitor by TLC (dichloromethane:methanol = 10:1). After the raw materials are completely consumed, concentrate the reaction system and obtain a brownish-yellow solid (E)-(5-(6-((4-(4-(diethylamino)but-2-enoyl)glycero)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z6, 8 mg) by silica gel column chromatography (methanol:dichloromethane volume ratio = 1:20). 1 H NMR(600MHz, CDCl3)δ8.82(s,1H),8.42(s,1H),8.08–8.11(m,1H),7.18(s, 1H),6.90–6.85(m,1H),6.70(s,1H),6.08(d,J=15.6Hz,1H),4.14–4.10(m,2 H),3.94–3.93(m,3H),3.85–3.80(m,7H),3.70–3.64(m,3H),3.49–3.39(m, 4H),3.29(d,J=6.0Hz,2H),2.60–2.54(m,8H),1.06(t,J=7.2Hz,6H).ESI-MS m / z[M+H] + =734.687.

[0246] Example 7: Synthesis of compound Z7

[0247] Step 1: Dissolve compound 6-3 (15 mg) in tetrahydrofuran (1 mL) solution, add diallylamine (249 μL) and potassium carbonate (28 mg), seal the reaction system and react at 60 °C for 2 hours, add diallylamine (50 μL) and seal the system and react at 75 °C overnight. TLC monitoring showed that the starting material was completely consumed. Concentrate the reaction system and purify by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain (E)-(5-(6-(4-((4-(diallylamino)but-2-enoyl)glycero)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z7, 12.8 mg), a pale yellow liquid. 1 HNMR (600MHz, CDCl3): δ8.83(s,1H),8.42(s,1H),7.19(s,1H),6.96(s,1H),6. 86(dt,J=15.4,6.4Hz,1H),6.09–6.00(m,2H),5.95–5.80(m,1H),5.50–5.44(m, 4H),4.18–4.09(m,2H),3.98–3.91(m,4H),3.86(s,3H),3.85–3.82(m,4H),3.72 –3.60(m,6H),,3.53–3.40(m,4H),3.33–3.30(m,2H),2.62–2.51(m,4H).ESI-MS m / z[M+H] + =758.717.

[0248] Example 8: Synthesis of compound Z8

[0249] Step 1: In a sealed tube, dissolve compound 6-3 (15 mg, 0.02023 mmol) in tetrahydrofuran (2 mL) solution, add potassium carbonate (28.0 mg, 0.2023 mmol), and then add piperidine (40 μL, 0.4046 mmol). Seal the reaction system and react at 70 °C. Monitor the reaction by TLC. After the reactants have reacted completely, cool to room temperature, transfer the reaction solution to a round-bottom flask, rinse three times with dichloromethane, transfer the entire solution to a round-bottom flask, add silica gel, and directly remove the solvent under reduced pressure. The product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1, 1% triethylamine) to obtain (E)-(5-(4-morpholino-6-(4-(4-(piperidin-1-yl)but-2-enyl)glycero)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z8, 17 mg), a pale yellow solid. 1H NMR (400MHz, CDCl3) δ8.83 (s, 1H), 8.40 (s, 1H), 7.17 (s, 1H), 6.85 (d, J = 15.4Hz, 1H), 6.6 5(d,J=3.9Hz,1H),6.02(d,J=15.5Hz,1H),4.11(d,J=4.0Hz,2H),3.96–3.89(m,4H),3.84 (d,J=7.1Hz,8H),3.79(s,2H),3.68(s,2H),3.49–3.42(m,2H),3.08(dd,J=6.2,1.6Hz,2 H),2.54(m,J=5.4,4.6Hz,4H),2.38(s,4H),1.51–1.35(m,4H),0.89–0.79(m,2H).ESI-MS m / z[M+H] + =746.705.

[0250] Example 9: Synthesis of compound Z9

[0251] Step 1: Dissolve compound 6-3 (15 mg, 0.02 mmol) in a tetrahydrofuran (4 mL) solution of Me2NH (90 mg, 2 mmol), add potassium carbonate (28 mg, 0.2 mmol), seal the reaction system and react at 60 °C for 2 h, add dimethylamine hydrochloride (33 mg, 0.4 mmol), seal the system and react at 75 °C overnight. TLC (dichloromethane:methanol = 10:1) monitoring showed that the raw material (Rf = 0.7) was completely consumed. The reaction system was concentrated and purified by silica gel column chromatography (methanol:dichloromethane volume ratio = 1:20) to obtain a white solid (E)-(5-(6-((4-(4-(dimethylamino)but-2-enoyl)glycero)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z9,6 mg). 1H NMR(400MHz, CDCl3)δ8.82(s,1H),8.40(s,1H),7.69(s,1H),7.17(s,1H),6.85(dt, J=15.4,6.1Hz,1H),6.64(s,1H),6.04(d,J=15.5Hz,1H),4.13(d,J=4.0Hz,2H),3.94 (dd,J=5.6,3.8Hz,4H),3.83(d,J=4.6Hz,4H),3.80(s,3H),3.78–3.70(m,2H),3.51– 3.43(m,3H),3.07(dd,J=6.1,1.6Hz,3H),2.55(d,J=4.9Hz,4H),2.25(s,6H).ESI-MS m / z[M+H] + =706.678.

[0252] Example 10: Synthesis of compound Z10

[0253] Step 1: Dissolve compound 6-3 (15 mg) in tetrahydrofuran (2 mL) solution, add potassium carbonate (28 mg, 0.2 mmol), then add pyrrolidine (28 mg, 0.4 mmol), and react the system at 75 °C. Monitor by TLC. After the starting material disappears, concentrate the reaction system and purify by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound (E)-(5-(4-morpholino-6-(4-(4-(pyrrolidine-1-yl)but-2-enyl)glycero)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z10, Z10, 4 mg), an orange-yellow solid. 1 H NMR (600MHz, CDCl3) δ8.83(s,1H),8.41(s,1H),7.21(s,1H),7.10(s,1H),6. 82(dt,J=14.6,7.0Hz,2H),6.34(d,J=15.3Hz,1H),4.12(t,J=5.9Hz,4H),4. 01–3.91(m,5H),3.85(s,3H),3.70(s,3H),3.49(t,J=5.0Hz,3H),2.60(d,J= 14.4Hz,6H)2.03–1.96(m,3H),1.66–1.58(m,2H),1.27–1.23(m,4H).ESI-MS m / z[M+H] + =732.68.

[0254] Example 11: Synthesis of compound Z11

[0255] Step 1: In a sealed tube, compound 6-3 (15 mg, 0.02023 mmol) was dissolved in tetrahydrofuran (2 mL) solution, followed by potassium carbonate (28.0 mg, 0.2023 mmol) and then piperazine (40 μL, 0.4046 mmol). The reaction system was sealed and incubated at 70 °C under TLC monitoring. After the reactants had completely reacted, the mixture was cooled to room temperature and transferred to a round-bottom flask. The flask was washed three times with dichloromethane, and the entire solution was transferred to the round-bottom flask. Silica gel was added, and the solvent was removed under reduced pressure. The solution was then subjected to silica gel column chromatography (tetrahydrofuran:ethyl acetate = 2:1, 10% Et2NH, R). f =0.26) Purification yielded a white solid (E)-(5-(6-(4-((4-(azacycloheptane-1-yl)but-2-enyl)glyceryl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z11, 6.8 mg). 1 H NMR (400MHz, CDCl3) δ8.84(s,1H),8.40(s,1H),7.54(s,1H),6.97(dt,J=14.6,7.1Hz,1H),6.38(d,J=15.4Hz,1H),4.11(t,J=5.0Hz,2 H),3.91(t,J=4.8Hz,5H),3.84–3.75(m,12H),3.68–3.60(m,5H),3.45(d,J=8.3Hz,3H),2.57–2.50(m,4H),1.74–1.56(m,8H).ESI-MS m / z[M+H] + =760.733.

[0256] Example 12: Synthesis of compound Z12

[0257] Step 1: Compound 2 (30 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (0.3 mL) and methacryloyl chloride (30 μL, 0.3 mmol) were added at 0 °C, and the mixture was stirred at room temperature until the reactants were completely consumed. The reaction mixture was quenched with saturated sodium bicarbonate solution, separated, and the aqueous phase was extracted five times with dichloromethane. All organic phases were combined, dried over Na₂SO₄, and concentrated. The organic phase was purified by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 1:20) to obtain compound (5-(6-((4-(methacryloylglycol)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z12, 14 mg), a white solid. ESI-MS: m / z [M+H] + =663.3. 1 H NMR (600MHz, CDCl3) δ8.82(s,1H),8.40(s,1H),7.62(s,1H),7.18(s,1H),6.94(s,1H),5.81(s,1H),5.38(d,J=2.0Hz,1H),4.11(d,J=3.9Hz,2H), 3.95–3.93(m,4H),3.85(s,3H),3.84(d,J=4.6Hz,4H),3.80(s,2H),3.70 (s,2H),3.49–3.47(m,2H),2.56(d,J=5.1Hz,4H),2.00(t,J=1.2Hz,3H).

[0258] Example 13: Synthesis of compound Z13

[0259] Step 1: Compound 2 (30 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL). Triethylamine (0.3 mL) and 3-methylbut-2-enoyl chloride (35 mg, 0.3 mmol) were added at 0 °C, and the mixture was stirred at room temperature until the reactants were completely consumed. The reaction mixture was quenched with saturated sodium bicarbonate solution, separated, and the aqueous phase was extracted five times with dichloromethane. All organic phases were combined, dried over Na₂SO₄, and concentrated. The organic phase was purified by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 1:20) to obtain compound (5-(6-((4-(3-methylbut-2-enoyl)glycero)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z13, 13 mg), a white solid. ESI-MS: m / z [M+H] + =677.3141,[M+Na] + =699.2972.1 H NMR(400MHz, CDCl3)δ8.84(s,1H),8.41(s,1H),8.11(s,1H),7.17(s,1H),6.44(t,J =4.0Hz,1H),5.67(q,J=1.3Hz,1H),4.10(d,J=4.1Hz,2H),3.94(dd,J=5.7,3.8Hz,4 H),3.86(s,3H),3.84(dd,J=5.7,3.7Hz,4H),3.79(s,2H),3.69(t,J=4.9Hz,2H),3. 49–3.44(m,2H),2.55(t,J=4.8Hz,4H),2.15(d,J=1.2Hz,3H),1.85(d,J=1.3Hz,3H).

[0260] Example 14: Synthesis of compounds Z14, Z16, Z18, and Z19

[0261] Step 1: Dissolve 2-fluoroacrylic acid (18 mg, 0.2 mmol) in dichloromethane (4 mL), add triethylamine (40 mg, 0.4 mmol) and tervapotranol chloride (38 mg, 0.32 mmol) at 0 °C, and stir at room temperature for 2 hours. While stirring, add the above mixture to an acetonitrile (2 mL) solution of compound intermediate 2 (60 mg, 0.1 mmol), and continue the reaction until the starting material disappears. The reaction system was quenched with saturated sodium bicarbonate aqueous solution, separated, and the aqueous phase was extracted five times with dichloromethane (10 mL). All organic phases were combined, dried over Na₂SO₄, concentrated, and purified by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 1:50 to 1:20) to obtain compound (5-(6-((4-(((2-fluoroacryloyl)glycero)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z14, 8 mg), white solid. ESI-MS m / z [M+H] + =667.3. 1H NMR (600MHz, CDCl3) δ8.82(s,1H),8.40(s,1H),7.64(s,1H),7.38(s,1H),7.18(s,1H),5.64(d,J=3.3Hz,1H),5.16–5.13(m,1H),4.13(d, J=4.2Hz,2H),3.94(t,J=4.8Hz,4H),3.86–3.83(m,7H),3.81(s,2H),3.71(t,J=5.2Hz,2H),3.47(t,J=5.1Hz,2H),2.57(q,J=5.6Hz,4H).

[0262] The compound N-(2-(4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-oxoethyl)neopentamide (Z19, 10 mg) was given as a white solid. ESI-MS m / z [M+H] + =621.3393. 1 H NMR (600MHz, CDCl3) δ8.75(d,J=1.4Hz,1H),8.41(d,J=5.2Hz,1H),7.93(s,1H),7.19–7.07(m,1H),7.04(s,1H),6.81(t,J=3.9Hz,1H) ,4.02(d,J=3.9Hz,2H),3.94–3.80(m,8H),3.73(s,2H),3.68(d,J=5.1Hz,2H),3.45(t,J=5.1Hz,2H),2.57-2.48(m,4H),1.22(s,9H).

[0263] The compound N-(2-(4-(2-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-oxoethyl)-2-fluoroacrylamide (Z16, 4 mg) was given as a white solid. ESI-MS m / z [M+H] + =609.3. 1H NMR (600MHz, CDCl3) δ8.76(s,1H),8.40(d,J=5.1Hz,1H),7.83(s,1H),7.39(s,1H),7.09(d,J=5.2Hz,1H),7.04(s,1H),5.72(d,J=3.3Hz, 1H),5.14(d,J=11.6Hz,1H),4.13(d,J=4.2Hz,2H),3.87(dt,J=7.3,4.5Hz,8H),3.74(s,2H),3.70(s,2H),3.46(s,2H),2.57–2.51(m,4H).

[0264] The compound (5-(4-morpholino-6-((4-(neovalerylglycerol)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z18, 16 mg) was obtained as a white solid. ESI-MS m / z [M+H] + =679.3484. 1 H NMR (600MHz, CDCl3) δ8.85(s,1H),8.41(s,1H),8.16(s,1H),7.17(s,1H),6.81(t,J=3.9Hz,1H),4.03(d,J= 3.9Hz,2H),3.96–3.90(m,4H),3.88–3.82(m,7H),3.69(s,2H),3.46(s,2H),2.60–2.42(m,4H),1.23(s,9H).

[0265] Example 15: Synthesis of compound Z15

[0266] Step 1: Dissolve intermediate 2 (30 mg, 0.05 mmol) in dichloromethane (2 mL), add triethylamine (0.3 mL) and 3-methylbutynyl chloride (31 mg, 0.3 mmol) at 0 °C, and stir at room temperature until the reactants are completely consumed. Quench the reaction mixture with saturated sodium bicarbonate solution, separate the layers, extract the aqueous phase five times with dichloromethane, combine all organic phases, dry with Na2SO4, concentrate the organic phase, and purify by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 1:20) to obtain compound (5-(6-((4-(but-2-ynylglycerol)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z15, 12 mg), a gray solid. ESI-MS m / z [M+H] + =661.28. 1H NMR (600MHz, CDCl3) δ8.82(s,1H),8.40(s,1H),7.62(s,1H),7.17(s,1H),6.86(s,1H),4.09(d,J=4.1Hz,2H),3.96–3.90(m ,4H),3.85(s,3H),3.83-3.84(m,4H),3.80(s,2H),3.69(s,2H),3.43(t,J=5.1Hz,2H),2.55(d,J=5.6Hz,4H),1.96(s,3H).

[0267] Example 16: Synthesis of compound Z17

[0268] Step 1: Dissolve intermediate 2 (30 mg, 0.05 mmol) in dichloromethane (2 mL), add triethylamine (0.3 mL) and (E)-but-2-enoyl chloride (31 mg, 0.3 mmol) at 0 °C, and stir at room temperature until the reactants are completely consumed. Quench the reaction system with saturated sodium bicarbonate aqueous solution, separate the layers, extract the aqueous phase five times with dichloromethane, combine all organic phases, dry with Na2SO4, concentrate the organic phase, and purify by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 1:20) to obtain compound (E)-(5-(6-((4-(but-2-enoylglycerol)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z17, 13 mg), a light yellow solid. ESI-MS m / z[M+H] + =663.5. 1 H NMR (400MHz, CDCl3) δ8.83(s,1H),8.41(s,1H),7.87(s,1H),7.18(s,1H),6.92–6.79(m,1H),6.56(s,1H),5.90(dd,J=15.2,1.8Hz,1H),4.12 (d,J=4.0Hz,2H),3.99-3.91(m,4H),3.90–3.76(m,9H),3.74–3.66(m,2H),3.51–3.42(m,2H),2.62–2.49(m,4H),1.87(dd,J=6.9,1.7Hz,3H).

[0269] Example 17: Synthesis of compound Z20

[0270] Step 1: Dissolve intermediate 2 (30 mg, 0.05 mmol) in dichloromethane (2 mL), add triethylamine (0.3 mL) and acryloyl chloride (27 mg, 0.3 mmol) at 0 °C, and stir at room temperature until the reactants are completely consumed. Quench the reaction system with saturated sodium bicarbonate aqueous solution, separate the layers, extract the aqueous phase five times with dichloromethane, combine all organic phases, dry with Na2SO4, concentrate the organic phase, and purify by preparative thin-layer chromatography (methanol:dichloromethane volume ratio = 1:20) to obtain compound (5-(6-((4-(acryloylglycyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z20, 9 mg), a light gray powder. 1 H NMR(400MHz, CDCl3)δ8.90(s,1H),8.47(s,1H),8.34(s,1H),7.18(s,1H),6.7 4(d,J=4.0Hz,1H),6.32(d,J=12.0Hz,1H),6.20(dd,J=8.0,12.0Hz,1H),5.68 (d,J=4.0Hz,1H),4.14(t,J=4.0Hz,2H),3.92-3.95(m,5H),3.84-3.86(m,7H) ,3.75(s,2H),3.69-3.72(m,2H),3.47-3.49(m,2H),2.52-2.58(m,3H).ESI-MS m / z[M+H] + =649.2.

[0271] Example 18: Synthesis of compound Z21

[0272] Step 1: Intermediate 3 (48 mg, 0.1 mmol), compound 1-e (38 mg, 0.14 mmol), tetra(triphenylphosphine)palladium (51 mg, 0.044 mmol), and potassium carbonate (46 mg, 0.33 mmol) were placed in a reaction tube. Toluene / ethanol / water (50 μL / 20 μL / 10 μL) was added, and the tube was sealed. The reaction was carried out at 100 °C for 12 h. After the reaction was complete, the reaction solution was evaporated to dryness and subjected to silica gel column chromatography (dichloromethane / ethanol = 50:1) to obtain compound 21-1 (50 mg), a yellow solid. 1HNMR(400MHz, CDCl3)δ8.48(s,1H),8.41(d,J=1.6Hz,1H),7.58(s,1H),7.48(s,1H),4.29- 4.31(m,4H),3.85(m,7H),3.72(s,2H),3.45-3.47(m,4H),2.52-2.54(m,4H),1.45(s,9H).

[0273] Step 2: Compound 21-1 (50 mg, 0.08 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added with stirring. The reaction was carried out for 2 hours, and then diluted with dichloromethane (50 mL). The mixture was washed with saturated sodium bicarbonate and saturated brine. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 21-2 (38 mg), a gray solid, which was used directly in the next step of the reaction without purification.

[0274] Step 3: Under an argon atmosphere, compound 21-2 (38 mg, 0.073 mmol), 1-hydroxybenzotriazine (2 mg, 0.015 mmol), and N-Boc glycine (17 mg, 0.073 mmol) were placed in a reaction flask. Then, dichloromethane (2 mL), EDC (2 mg, 0.007 mmol), and N-methylmorpholine (22 mg, 0.22 mmol) were slowly added. After the addition was complete, the mixture was stirred at room temperature for 12 h. After the reaction was completed, the mixture was evaporated to dryness, diluted with dichloromethane, and the organic phase was washed successively with saturated sodium bicarbonate solution and saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10:1) to obtain compound 21-3 (41 mg), a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.45(s,1H),8.40(s,1H),7.76(s,1H),7.58(s,1H),7.47(s,1H),5.51(s,1H),4.30(t,J=4.7Hz ,4H),3.95(d,J=4.3Hz,2H),3.85(d,J=4.1Hz,8H),3.74(s,2H),3.67(s,3H),3.42(s,2H),2.59(s,5H),1.45(s,11H).

[0275] Step 4: Compound 21-3 (30 mg, 0.044 mmol) was dissolved in dichloromethane (2 mL). A solution of trifluoroacetic acid (40 mg, 0.35 mmol) in dichloromethane (5 mL) was added dropwise under ice-water bath cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 9–10 with saturated potassium carbonate solution. The solution was extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 21-4 (21 mg), a yellow solid, which was used directly in the next reaction without further purification.

[0276] Step 5: Dissolve the above yellow solid (21 mg, 0.036 mmol) in dichloromethane (3 mL), add triethylamine (18 mg, 0.182 mmol), and stir until homogeneous. While cooling in an ice-water bath, add a solution of acryloyl chloride (12 mg, 0.132 mmol) in dichloromethane (1 mL) dropwise to the reaction mixture. After the addition is complete, continue the reaction at room temperature for 1 hour. The reaction solution was diluted with dichloromethane, and the organic phase was washed successively with 1.0M dilute hydrochloric acid, saturated sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10:1) to obtain compound (5-(2-((4-(acryloylglycyl)piperazin-1-yl)methyl)-8-morpholinoimidazo[1,2-a]pyrazin-6-yl)-4-(trifluoromethyl)pyridin-2-yl)carbamate (Z21, 9 mg), a gray solid. 1 H NMR(600MHz, CDCl3)δ8.45(s,1H),8.41(s,1H),8.01(s,1H),7.58(s,1H),7.48(s,1 H),6.75(t,J=4.0Hz,1H),6.31(dd,J=17.0,1.4Hz,1H),6.19(dd,J=17.0,10.3Hz,1H ),5.67(dd,J=10.2,1.4Hz,1H),4.30(t,J=4.8Hz,4H),4.13(d,J=4.1Hz,2H),3.85(s ,5H),3.74(s,2H),3.70(t,J=5.1Hz,2H),3.48(d,J=10.4Hz,4H),2.62–2.59(m,4H). 13C NMR (151MHz, CDCl3) δ166.34,165.52,153.55,152.12,150.58,147.87,141.84,134.54,132.70,130. 51,127.23,127.00,113.37,109.96,109.23,67.24,56.26,51.04,46.75,44.53,42.23,41.38.ESI-MS m / z[M+H] + =632.2.

[0277] The compounds listed in Table A below were synthesized by modifying some of the raw materials and / or combining them with known synthetic methods, referring to the methods in the above embodiments:

[0278] Table A

[0279] Test Example 1: Anti-cell proliferation inhibition experiment

[0280] 1. Reagents and raw materials

[0281] 2. Experimental Methods

[0282] 2.1 Preparatory work

[0283] Cell culture: Cells were cultured at 37°C in a 5% CO2 incubator, passaged 2-3 times per week at a passage ratio of 1:3 to 1:10. Specifically, T-47D cells (purchased from SIBS, TCU 87) were cultured in DMEM complete medium containing a mixture of 10% fetal bovine serum and 1% penicillin / streptomycin; MCF7 cells (purchased from ATCC, HTB-22) were cultured in MEM complete medium containing a mixture of 10% fetal bovine serum, 1% streptomycin, and 0.01 mg / mL insulin; HCC70 cells (purchased from ATCC, CRL-2315) were cultured in RPMI-1640 complete medium containing a mixture of 10% fetal bovine serum and 1% penicillin / streptomycin; and SK-BR-3 cells (purchased from ATCC, CRL-2315) were cultured in McCoy's 5a complete medium containing a mixture of 10% fetal bovine serum and 1% penicillin / streptomycin.

[0284] Preparation of 1000× storage blister packs: Dissolve the compound powder in DMSO to prepare a 10 mM storage solution. Dilute the 10 mM compound storage solution with DMSO in 9 concentration gradients, including a 3.162-fold dilution. Use DMSO as a control. Seal the compound storage blister packs with sealing film and store them at -20°C for later use.

[0285] 2.2 Experimental Procedure

[0286] Cell seeding: T-47D, MCF7, HCC70, and SK-BR-3 cells in logarithmic growth phase were collected by trypsin digestion, resuspended in fresh complete culture medium, and counted. Cell densities were adjusted as follows: T-47D cells at 600 cells / 40 μL per well, MCF7 cells at 600 cells / 40 μL per well, HCC70 cells at 800 cells / 40 μL per well, and SK-BR-3 cells at 1000 cells / 40 μL per well. These were seeded into 384-well clear flat-bottom cell culture microplates and incubated overnight at 37°C in a 5% CO2 incubator.

[0287] Compound preparation: Remove the 1000× storage plate and thaw it at room temperature in the dark. Prepare 5× intermediate plates using fresh complete culture medium and mix thoroughly. Transfer 10 μL of drug-containing culture medium from the 5× intermediate plates to 384 microplates. Then incubate at 37°C in a 5% CO2 incubator for 5 days.

[0288] CellTiter-Glo assay: After incubation of the compound for 5 days, remove the CellTiter-Glo assay reagent and thaw it in water at room temperature or 25°C in the dark. Remove the cell culture plate, add 30 μL of CellTiter-Glo assay reagent to each well, and shake in a shaker at room temperature in the dark for 2 minutes, then place it at room temperature in the dark for 10 minutes. Finally, read the luminescence value using a microplate reader.

[0289] Data analysis and processing: Calculate the inhibition rate using the following formula: Inhibition rate % = [1 - (OD)] Compound -OD Blank control ) / (OD DMSO control –OD Blank control )]×100%. Where OD Compound The readings for the cell compound treatment wells, OD Blank control The reading from the blank control hole, OD DMSO control The readings are for the DMSO control wells. The drug efficacy inhibition rate curves were fitted using the "Fit Models(205)" model in XLfit v5.5.0.5 software, and the IC50 of the drug was calculated. 50 value.

[0290] The test results for some compounds are shown in Table 1 below.

[0291] Table 1

[0292] Test Example 2: Pharmacokinetic Evaluation Experiment in Mice

[0293] 1. Experimental Objective

[0294] Male CD-1 mice were used as test animals. The plasma drug concentrations at different time points after intravenous (IV) and oral (PO) administration of the test compound were determined using LC-MS / MS. The pharmacokinetic behavior of the test compound in mice was investigated to evaluate its pharmacokinetic characteristics.

[0295] 2. Experimental Design

[0296] Experimental animals: 24 healthy adult male CD-1 mice were divided into 4 groups: Group IV (two groups, 6 mice per group) and Group PO (two groups, 6 mice per group). The animals were purchased from Zhejiang Vital River Laboratory Animal Technology Co., Ltd., and were 6-8 weeks old, weighing approximately 30g.

[0297] Drug preparation:

[0298] Group IV: Taking a 10 mL drug solution as an example, weigh 2 mg of sample, add 0.5 mL of DMSO, 1 mL of Solutol HS15, and then add 8.5 mL of 6% HP-β-CD. After vortex sonication, a clear drug solution of 0.2 mg / mL is obtained.

[0299] PO group: Taking a 10mL drug solution as an example, weigh 10mg of sample, add 0.5mL of DMSO, 1mL of Solutol HS15, and then add 8.5mL of 6% HP-β-CD. After vortex sonication, a clear drug solution of 1mg / mL is obtained.

[0300] Administration: After overnight fasting, IV group: administration volume 5 mL / kg, dose 1 mg / kg; PO group: administration volume 5 mL / kg, dose 5 mg / kg;

[0301] 3. Experimental Procedure

[0302] Male CD1 mice were administered the test compounds, and approximately 50 μL of blood was collected at 0.0833 (IV group only), 0.25, 0.5, 1, 2, 4, 7, and 24 hours in K2EDTA anticoagulant tubes. Plasma was separated by centrifugation at 8000 rpm for 15 min at 4 °C, temporarily stored on dry ice, and then stored at -80 °C. Animals were re-fed 4 hours after administration. After protein precipitation with acetonitrile, the concentration of the test compounds was determined by LC-MS / MS. The linear range of the LC-MS / MS method was 1–4000 ng / mL.

[0303] The experimental results for group IV and group PO are shown in Table 2 and Table 3, respectively.

[0304] Table 2 Note: CL represents clearance rate, and AUC represents the area under the curve after oral administration.

[0305] Table 3 Note: AUC represents the area under the curve after oral administration.

[0306] The structure of the comparative compound is as follows: (i.e., compound 1-102 of WO2021055747).

[0307] Experimental conclusion: In the pharmacokinetic evaluation experiment in mice, the Z20 series of compounds of this invention showed lower in vivo clearance and higher in vivo drug exposure than the control compounds.

[0308] Test Example 3: In vivo drug efficacy experiment

[0309] 1. Experimental Objective

[0310] To evaluate the in vivo efficacy of the test compound in a human breast cancer HCC1954 subcutaneous allogeneic tumor model.

[0311] 2. Experimental Procedure

[0312] Female BALB / c nude mice, 6-8 weeks old, weighing 18-20 grams, were used. HCC1954 cells were cultured in DMEM 10 medium supplemented with 10% FBS, 2.5% HS, and 1% penicillin-streptomycin at 37°C in a 5% CO2 incubator. Cells were collected and subcutaneously seeded with 2.0 x 10⁻⁶ HCC1954 cells (human breast cancer cells) via the right dorsal side of each animal. 6 1 cell per tumor (0.1 mL per tumor). When the tumor grows to 190-311 mm... 3 Mice with suitable tumor size were selected and divided into groups for drug administration. The dosage was 10 mg / kg from Day 0 to Day 3, and 20 mg / kg from Day 4 to Day 14, administered via gavage once daily. Animals were weighed daily using an electronic balance, and tumor volume was measured twice weekly using calipers. The tumor volume was calculated using the formula: V = 0.5axb 2 , a and b represent the long and short diameters of the tumor, respectively. Tumor volume is used to calculate the tumor growth inhibition rate (TGI), and the percentage TGI is used to indicate the antitumor activity of the drug. The TGI formula is as follows: TGI(%) = [1 - (avTi-0 / avCi-0)] x 100; where avTi-0 is the average tumor volume of the drug-treated group on a specific day, minus the average tumor volume of the drug-treated group on the grouping day; where avCi-0 is the average tumor volume of the solvent control group on a specific day, minus the average tumor volume of the solvent control group on the grouping day. Tumor volume data are displayed as mean ± standard error (SEM). Experimental results are shown in Table 4 below.

[0313] Table 4

[0314] The structure of the comparative compound is as follows: (i.e., compound 1-102 of WO2021055747).

[0315] Experimental conclusion: Compound Z20 of this invention exhibited good in vivo efficacy in a human breast cancer HCC1954 subcutaneous allogeneic tumor model. At 14 days after the start of administration, the compound of this invention showed superior tumor-inhibiting activity compared to the comparative compound.

[0316] Although specific embodiments of this disclosure have been described in detail, those skilled in the art can make various modifications and substitutions to the details of the technical solutions disclosed, based on all the teachings already disclosed, and all such modifications and substitutions are within the scope of protection of this disclosure. The full scope of this disclosure is given by the appended claims and any equivalents.

Claims

1. The compound of formula (I), or its stable deuterated derivatives, stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs: In the formula, X1 is O, N, NH, CH or S; X2 is either N or CH; X3 is either N or C; X4 can be O, N, NH, CH or S; X5 is either N or CH; X6 is either N or C; Furthermore, X2, X3, and X5 are not all N at the same time; This indicates that the connection between any two adjacent atoms within a ring can be a single bond or a double bond; L1 is selected from the following group: L2 is -(CR) 2 R 3 ) 1-4 -、-(CR 2 R 3 ) 1-4 -NR 4 -、-C 6-10 Aryl-NR 4 -、-(CR 2 R 3 ) 1-4 -C 6-10 Aryl-NR 4 -; R 2 R 3 R 4 Each is defined independently as follows: R 2 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl; R 3 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl; R 4 C is hydrogen or substituted or unsubstituted. 1-6 alkyl; or R 2 and R 3 They connect to form -(CH2)n-; n is 2, 3, 4 or 5; R 4 C is hydrogen or substituted or unsubstituted. 1-6 alkyl; or R 2 C is hydrogen, halogen, or substituted or unsubstituted. 1-6 alkyl; R 3 and R 4 They connect to form -(CH2)n-; n is 2, 3, 4 or 5; R 1 For substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl or substituted or unsubstituted C 2-6 alkynyl group; R 5 Selected from the following group: In each of the above groups, the substitution refers to each group being independently replaced by 1, 2, 3, 4, 5, or 6 groups selected from group S1; the groups in group S1 are each independently selected from the following group: -SF5, deuterium, oxo (=O), thio (=S), =CR e R f =NR e Halogen, cyano, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-20 Cycloalkyl, 3 to 20-membered heterocyclic groups, C 6-14 Aryl, 5- or 6-membered monocyclic heteroaryl, 8- to 10-membered bicyclic heteroaryl, -OC 3-20 Cycloalkyl, -O-3 to 20-membered heterocyclic groups, -OC 6-14 Aryl, -O-5 or 6-membered monocyclic heteroaryl, -O-8 to 10-membered bicyclic heteroaryl, -C≡CC 3-20 Cycloalkyl, -C≡C-3 to 20-membered heterocyclic groups, -C≡CC 6-14 Aryl, -C≡C-5 or 6-membered monocyclic heteroaryl, -C≡C-8 to 10-membered bicyclic heteroaryl, -C≡CC 1-4 Alkyl-C 3-20 cycloalkyl, -C≡CC 1-4 Alkyl-3 to 20-membered heterocyclic groups, -C≡CC 1-4 Alkyl-C 6-14 Aryl, -C≡CC 1-4 Alkyl-5 or 6-membered monocyclic heteroaryl, -C≡CC 1-4 Alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-C 1-6 Alkyl, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-C 3-20 cycloalkyl, -C 1-4 Alkyl-OC 3-20 cycloalkyl, -C 1-4 Alkyl-3 to 20-membered heterocyclic groups, -C 1-4 Alkyl-O-3 to 20-membered heterocyclic groups, -C 1-4 Alkyl-C 6-14 Aryl, -C 1-4 Alkyl-OC 6-14 Aryl, -C 1-4 Alkyl-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-O-5 or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkyl-O-8 to 10-membered bicyclic heteroaryl, -OC 1- 4-alkyl-hydroxyl, -OC 1-4 Alkyl-cyano, -OC 1-4 Alkyl-C 1-6 Alkyl, -OC 1-4 Alkyl-C 1-6 Alkoxy, -OC 1-4 Alkyl-C 3-20 cycloalkyl, -OC 1-4 Alkyl-OC 3-20 cycloalkyl, -OC 1-4 Alkyl-3 to 20-membered heterocyclic groups, -OC 1-4 Alkyl-O-3 to 20-membered heterocyclic groups, -OC 1-4 Alkyl-C 6-14 Aryl, -OC 1-4 Alkyl-OC 6-14 Aryl, -OC 1-4 Alkyl-5 or 6-membered monocyclic heteroaryl, -OC 1-4 Alkyl-O-5 or 6-membered monocyclic heteroaryl, -OC 1-4 Alkyl-8 to 10-membered bicyclic heteroaryl, -OC 1-4 Alkyl-O-8 to 10-membered bicyclic heteroaryl, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-20 Cycloalkyl, -S(=O)2-3 to 20-membered heterocyclic groups, -C(=O)OC 1-6 Alkyl group, -C(=O)OC 3-20 Cycloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-20 Cycloalkyl, -C(=O)-C 6-14 Aryl, -NR a1 R b1 -C(=O)-NR a1 R b1 -C(=O)-NR d1 -C 1-4 Alkyl-R c1 -OR c1 -C 1-4 Alkyl-S(=O)2-C 1-6 Alkyl, -C 1-4 Alkyl-S(=O)2-C 3-20 cycloalkyl, -C 1-4 Alkyl-S(=O)2-3 to 20-membered heterocyclic groups, -C 1-4 Alkyl-C(=O)OC 1-6 Alkyl, -C 1-4 Alkyl-C(=O)OC 3-20 cycloalkyl, -C 1-4 Alkyl-C(=O)-C 1-6 Alkyl, -C 1-4 Alkyl-C(=O)-C 3-20 cycloalkyl, -C 1-4 Alkyl-C(=O)-C 6-14 Aryl, -C(=O)-5 or 6-membered monocyclic heteroaryl, -C(=O)-8 to 10-membered bicyclic heteroaryl, -C(=O)-C 1-6 Alkyl-C 3-20 Cycloalkyl, -C(=O)-C 1-6 Alkyl-3 to 20-membered heterocyclic groups, -C(=O)-C 1-6 Alkyl-C 6-14 Aryl, -C(=O)-C 1-6 Alkyl-5 or 6-membered monocyclic heteroaryl, -C(=O)-C 1-6 Alkyl-8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkyl-NR a1 R b1 -C 1-4 Alkyl-C(=O)-NR a1 R b1 -C≡CC(=O)-NR a1 R b1 -C≡CC 1-4 Alkyl-C(=O)-NR a1 R b1 -C 1-4 Alkyl-OR c1 -C 1-4 Alkyl-P(=O)-(C 1-6 Alkyl)2、-P(=O)-(C 1-6 Alkyl)2, -C 1-4 Alkyl-NR d1 -C(=O)-R c1 -C 1-4 Alkyl-NR d1 -C(=O)-NR a1 R b1 -C 1-4 Alkyl-NR d1 -S(=O)2-R c1 -C 1-4 Alkyl-S(=O)2-NR a1 R b1 -C 1-4 Alkyl-NR d1 -S(=O)2-NR a1 R b1 -NR d1 -C(=O)-R c1 -NR d1 -C(=O)-C 1-4 Alkyl-R c1 -NR d1 -C(=O)-NR a1 R b1 -NR d1 -S(=O)2-R c1 -S(=O)2-NR a1 R b1 -NR d1 -S(=O)2-NR a1 R b1 and -P(=O)-(C 1-6 Alkyl)2; wherein, The C 1-6 Alkyl, the C 1-6 Alkoxy, the C 2-6 alkenyl, the C 2-6 Each alkynyl group is independently and optionally replaced by one, two, or three groups selected from halogens, deuterium, cyano, or hydroxyl groups; the C 3-20 cycloalkyl groups, the 3- to 20-membered heterocyclic groups, the C 6-14 The aryl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are each optionally substituted by 1, 2, 3, or 4 groups selected from group S2. In the above groups, each R a1 R b1 Each independently represents H and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 2-6 alkenyl, deuterated C 2-6 alkenyl, halogenated C 2-6 alkynyl, halogenated C 2-6 alkynyl group, -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-cyano, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-deuterated C 1-6 Alkyl, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C 1-4 Alkyl-deuterated C 1-6 Alkoxy, C 3-6 cycloalkyl, -C 1-4 Alkyl-C 3-6 cycloalkyl, -C 1-4 Alkyl-OC 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C 1-4 Alkyl-3 to 6-membered heterocyclic groups, -C 1- 4-alkyl-O-3 to 6-membered heterocyclic groups, phenyl, -C 1-4 Alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-5 or 6-membered monocyclic heteroaryl, 8 to 10-membered bicyclic heteroaryl, -C 1-4 Alkyl-8 to 10-membered bicyclic heteroaryl, -S(=O)2-C 1-6 Alkyl group, -S(=O)2-C 3-6 Cycloalkyl, -S(=O)2-3 to 6-membered heterocyclic groups, -C 1-4 Alkyl-S(=O)2-C 1-6 Alkyl, -C 1-4 Alkyl-S(=O)2-C 3-6 cycloalkyl, -C 1-4 Alkyl-S(=O)2-3 to 6-membered heterocyclic groups, -C(=O)-C 1-6 Alkyl, -C(=O)-C 3-6 Cycloalkyl or -C(=O)-3 to 6-membered heterocyclic groups; wherein, the C 3-6 The cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by one or two groups selected from the group consisting of: halogen, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-4 Alkyl-P(=O)-(C 1-6 alkyl)2 and -P(=O)-(C 1-6 Alkyl)2; or Each R a1 and R b1 Together with the nitrogen atoms attached to them, they form 3 to 20-membered heterocyclic groups; wherein each of the 3 to 20-membered heterocyclic groups is independently and optionally substituted by one or two groups selected from the group consisting of: halogen, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1- 6-alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-4 Alkyl-P(=O)-(C 1-6 alkyl)2 and -P(=O)-(C 1-6 Alkyl)2; In the above groups, each R d1 Each independently represents H and C. 1-6 Alkyl or deuterated C 1-6 alkyl; In the above groups, each R c1 Each independently represents H and C. 1-6 Alkyl, -C 1-4 Alkyl-hydroxyl, -C 1-4 Alkyl-NR a1 R b1 Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkyl, -C 1-4 Alkyl-deuterated C 1-6 Alkyl, -C 1-4 Alkyl-C 1-6 Alkoxy, -C 1-4 Alkyl-halogenated C 1-6 Alkoxy, -C 1-4 Alkyl-deuterated C 1-6 Alkoxy, C 3-6 cycloalkyl, -C 1-4 Alkyl-C 3-6 cycloalkyl, -C 1-4 Alkyl-OC 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C 1-4 Alkyl-3 to 6-membered heterocyclic groups, -C 1-4 Alkyl-O-3 to 6-membered heterocyclic groups, phenyl, -C 1-4 Alkyl-phenyl, 5- or 6-membered monocyclic heteroaryl, -C 1-4 Alkyl-5 or 6-membered monocyclic heteroaryl, 8 to 10-membered bicyclic heteroaryl, or -C 1-4 alkyl-8 to 10-membered bicyclic heteroaryl groups; the C 3-6 The cycloalkyl group, the 3- to 6-membered heterocyclic group, the phenyl group, the 5- or 6-membered monocyclic heteroaryl group, and the 8- to 10-membered bicyclic heteroaryl group are optionally substituted by one or two groups selected from the group consisting of: halogen, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, -C 1-4 Alkyl-P(=O)-(C 1-6 alkyl)2 or -P(=O)-(C 1-6 Alkyl)2; Among the above groups, each group of S2 is independently selected from the following group: deuterium, oxo (=O), thio (=S), =CR e R f =NR e Halogen, hydroxyl, carboxyl, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-(C=O)-NHC 1-6 Alkyl, -(C=O)-N(C 1-6 Alkyl)2, -C 1-4 Alkyl-P(=O)-(C 1-6 Alkyl)2、-P(=O)-(C 1-6 Alkyl)2、-(C=O)C 1-6 Alkyl groups and -SF5; Of the above groups, the -C 1-4 Alkyl group - is unsubstituted; or -C 1-4 The 1, 2, 3, or 4 hydrogen atoms on the alkyl group are each independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, -CH2-hydroxy, -CH2-cyano, phenyl, C 3-6 Substituted with cycloalkyl groups; or C 1-4 Two hydrogen atoms on the same carbon atom of an alkyl group are simultaneously converted to -(CH2). j - Substitution further forms a cycloalkyl group, wherein j is 2, 3, 4, 5 or 6; or C 1-4 Two hydrogen atoms on the same carbon atom of an alkyl group are simultaneously converted to CR. e R f replace; Of the above groups, R e Each is independently H, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl; Of the above groups, R f Each is independently H, halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl or deuterated C 1-6 alkyl; In each of the above-mentioned groups, one or more (e.g., 1, 2, 3, or 4) ring atoms of the 3- to 6-membered heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 3- to 20-membered heterocyclic group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; one or more (e.g., 1, 2, 3, or 4) ring atoms of the 5- or 6-membered monocyclic heteroaryl group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus; and one or more (e.g., 1, 2, 3, 4, or 5) ring atoms of the 8- to 10-membered bicyclic heteroaryl group are heteroatoms selected from nitrogen, oxygen, sulfur, or phosphorus. When the ring atom is a sulfur atom, the sulfur atom is optionally replaced by one or two atoms selected from oxo and =NR. e Group substitution; R e Definitions are the same as before; When the ring atom is a phosphorus atom, the phosphorus atom is optionally surrounded by one or two atoms selected from oxo and =NR. e Group substitution; R e The definition is the same as before.

2. The compound of claim 1, or its stable deuterated derivatives, stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, wherein, The compound represented by formula (I) is as shown in formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX): In the formula, L1, L2, R 1 R 5 The definition is the same as in claim 1.

3. The compound of claim 1, or its stable deuterated derivatives, stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, wherein, The compound represented by formula (I) is shown as that represented by formula (IIA): In the formula, L1 and R 1 R 2 R 3 R 4 R 5 The definition is the same as in claim 1.

4. The compound of claim 1, or its stable deuterated derivatives, stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, wherein, The compound represented by formula (I) is shown as that represented by formula (IIIA): In the formula, L1 and R 1 R 2 R 3 R 4 R 5 The definition is the same as in claim 1.

5. The compound of claim 1, or a stable deuterated derivative, stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, The compound represented by formula (I) is shown as shown by formula (IVA): In the formula, L1 and R 1 R 2 R 3 R 4 R 5 The definition is the same as in claim 1.

6. The compound of claim 1, or a stable deuterated derivative, stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, The compound represented by formula (I) is shown as shown by formula (VA): In the formula, L1 and R 1 R 2 R 3 R 4 R 5 The definition is the same as in claim 1.

7. The compound of claim 1, or a stable deuterated derivative, stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein, The compound represented by formula (I) is shown as shown by formula (VIA): In the formula, L1 and R 1 R 2 R 3 R 4 R 5 The definition is the same as above.

8. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-7, or a stable deuterated derivative, stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug thereof; and a pharmaceutically acceptable carrier.

9. Use of the compound of any one of claims 1-7, or a stable deuterated derivative, stereoisomer, pharmaceutically acceptable salt, solvate, or prodrug, or the pharmaceutical composition of claim 8, in the preparation of a medicament for the prevention and / or treatment of a disease or condition; wherein the disease or condition is a PI3K-related disease or condition.

10. The use as described in claim 9, wherein the PI3K-related diseases or conditions are tumors, Alzheimer's disease, aging, diabetes, cardiovascular disease, CNS-related diseases, immune diseases, allergies, Parkinson's disease, asthma, rheumatoid arthritis, or chronic obstructive pulmonary disease; Preferably, the PI3K-related disease or condition is cancer; Preferably, the cancer is selected from: lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal adenoma, thyroid cancer, liver cancer, adrenal cancer, gastric cancer, glioma, glioblastoma, neuroblastoma, endometrial cancer, melanoma, kidney cancer, bladder cancer, uterine cancer, cervical cancer, vaginal cancer, ovarian cancer, esophageal cancer, brain cancer, oral cancer, pharyngeal cancer, laryngeal cancer, small intestinal cancer, head and neck tumors, sarcoma, leukemia, lymphoma, and myeloma; Preferably, the cancer is selected from: lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, thyroid cancer, adrenal cancer, gastric cancer, glioma, glioblastoma, neuroblastoma, endometrial cancer, melanoma, intrahepatic bile duct cancer, hepatocellular carcinoma, bladder cancer, endometrial cancer, cervical cancer, vaginal cancer, ovarian cancer, esophageal cancer, brain cancer, oral cancer, pharyngeal cancer, laryngeal cancer, small intestinal cancer, renal cell carcinoma, renal pelvis cancer, head and neck squamous cell carcinoma, villous colonic adenoma, sarcoma, leukemia, lymphoma, and myeloma.

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