Carboxyl fused ring derivative regulator as well as preparation method and application thereof

Abstract

The invention relates to a carboxyl fused ring derivative regulator as well as a preparation method and application thereof. Particularly, the invention relates to a compound as shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a regulator in preparation of drugs for treating cancer-related diseases, and substituents in the general formula (I) are as defined in the specification. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of biomedicine, and specifically relates to a carboxyl fused ring derivative regulator, a preparation method and application thereof. Background Art

[0002] The phosphatidylinositol 3-kinase (PI3K) protein family is divided into four major categories: I, II, III, and IV, and is involved in the regulation of various cell functions such as cell growth, proliferation, differentiation, survival, and energy metabolism. The four types of PI3K proteins have different structures and functions. The most widely studied is the type I PI3K, which is further divided into four subtypes: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. Among them, PI3Kα undergoes activation mutations and amplification in many tumors, which is closely related to the occurrence and development of tumors. There are reports that PI3Kβ can activate platelets and play an important role in the occurrence and development of diseases such as thrombosis. PI3Kδ and PI3Kγ are mainly expressed in the blood system and are closely related to the occurrence of the immune system and inflammation. In addition, PI3Kγ is also closely related to blood pressure stability and smooth muscle contraction.

[0003] PI3Kα is composed of the p110α catalytic subunit and the p85 regulatory subunit. The p110α subunit is encoded by the PIK3CA gene. When PI3Kα is regulated by upstream receptor tyrosine kinases (such as insulin receptors, platelet-derived growth factor receptors, etc.) and Ras proteins, it catalyzes phosphatidylinositol 2-phosphate (PIP2) to generate phosphatidylinositol 3-phosphate (PIP3) after activation. PIP3 can further activate protein kinase B (also known as AKT) and its downstream signaling pathways, thereby regulating cell differentiation, migration, and metabolic homeostasis. PI3Kα mutation or amplification can lead to continuous activation of the AKT pathway, rapid cell proliferation, and the occurrence of tumors. PI3Kα is also a key protein in the insulin / insulin receptor pathway, which can regulate the balance of sugar metabolism in tissues such as the liver and skeletal muscle. Inhibition of PI3Kα can lead to reduced liver glycogen synthesis, increased blood sugar, and increased insulin levels in the body.

[0004] PI3Kα is one of the kinases with the highest mutation rate in cancer, with a total mutation rate of 14% in all cancers, and is widely distributed, such as breast cancer, head and neck cancer, ovarian cancer, gastric cancer, head and neck cancer and other cancers. There are various types of PIK3CA gene mutations, among which the three most common hotspot mutations are H1047R mutation (kinase region), E542K (helical region) and E545K (helical region). Currently, clinical PI3Kα inhibitors have strong inhibitory activity against PI3Kα mutants, non-selective inhibition of PI3Kα wild-type, and certain inhibition of PI3Kβ / γ / δ, resulting in the occurrence of severe hyperglycemia side effects mediated by PI3Kα wild-type and side effects such as rash and diarrhea involving the PI3K / AKT pathway in clinical trials. In addition, due to the increase of insulin in the body, the insulin receptor pathway is activated, resulting in enhanced activation of the PI3K pathway, which in turn affects the efficacy of PI3Kα inhibitors. Novartis' Alpelisib (BYL-719) is the fastest-progressing PI3Kα inhibitor and has been approved for combination with Fulvestrant for the treatment of ER with PIK3CA mutations. + HER2 - Breast cancer: The efficacy is good, but the side effect of clinical hyperglycemia is more serious. In addition, HER2 + Clinical trials for breast cancer, triple-negative breast cancer, ovarian cancer, etc. Roche's PI3Kα inhibitor GDC-0077 is in Phase III clinical trials and is indicated for combined treatment of ER with PIK3CA mutations. + HER2 - For breast cancer, the early clinical effect is good, but there are also more serious side effects of hyperglycemia.

[0005] In summary, PI3Kα inhibitors have significant therapeutic effects in indications such as breast cancer and have good market prospects. Existing PI3Kα inhibitors have no selectivity for wild-type PI3Kα, which leads to serious side effects of hyperglycemia and limits clinical dosage and efficacy. Therefore, the development of PI3Kα mutation-specific allosteric inhibitors is of great significance. At present, there are two PI3Kα mutant allosteric inhibitors in the preclinical development stage abroad, namely Relay's RLY-2608 and Eli Lilly's LOXO-783. Both inhibitors have improved the selectivity for wild-type PI3Kα and are very selective for PI3Kβ / γ / δ. They are expected to reduce toxicity and improve efficacy. Clinical trials will be launched in 2022 and have good development prospects. Summary of the invention

[0006] The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:

[0007]

[0008] in:

[0009] X1 or X2 are each independently selected from N, NR7, C, CR8 or O;

[0010] At least one of X1 or X2 is N;

[0011] Ring B or Ring C is each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0012] R1, R2, R3, R4, R5, R6, R7, R8, R9 or R 10 each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl or deuterated alkyl;

[0013] x is 1, 2, or 3;

[0014] y, z and m are each independently 0, 1, 2, 3 or 4.

[0015] In a preferred embodiment of the present invention, the compound is further represented by the general formula (I-1):

[0016]

[0017] X3 Selected from NR 11 , CR 12 R 13 or O;

[0018] R 11 , R 12 or R 13 each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl or deuterated alkyl;

[0019] Ring B, Ring C, X1, X2, R1, R2, R3, R4, R5, R6, x, y, z or m are as defined in the general formula (I).

[0020] In a preferred embodiment of the present invention, the compound is further represented by the general formula (I-2):

[0021]

[0022] Ring B, Ring C, X1, X2, R1, R2, R3, R4, R5, R6, x, y, z or m are as defined in the general formula (I);

[0023] X3 is as defined in the general formula (I-1).

[0024] In a further preferred embodiment of the present invention, the compound is further represented by the general formula (I-2-1) or (I-2-2):

[0025]

[0026] Ring B, Ring C, X1, X2, R1, R2, R3, R4, R5, R6, x, y, z or m are as defined in the general formula (I);

[0027] X3 is as defined in the general formula (I-1).

[0028] The present invention also provides a compound represented by general formula (II) or (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0029]

[0030] in:

[0031] represents a single bond or a double bond;

[0032] M1 or M2 are each independently selected from a bond, N, CR m1 , CR m1 R m2 -、NR m3 , O or S;

[0033] Y1 is selected from CR y1 R y2 -、NR y3 , O or S;

[0034] Y2 is selected from CR y1 or N;

[0035] Ring D, Ring E, Ring F, Ring G, Ring H or Ring K are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0036] R a , R b , R c , R d , R e , R f , R y1 , R y2 , R y3 , R A , R B , R D , R E , R m , R n , R m1 , R m2 or R m3 each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl or deuterated alkyl;

[0037] p is 1, 2, or 3;

[0038] q, t and n are each independently 0, 1, 2, 3 or 4;

[0039] u is 1, 2, or 3;

[0040] v, w and s are each independently 0, 1, 2, 3 or 4;

[0041] The conditions are:

[0042] In the general formula (II), ring D is not a benzene ring or a pyridine ring;

[0043] The general formula (II) is not the following compound:

[0044]

[0045] In a preferred embodiment of the present invention, the compound is further represented by the general formula (II-1):

[0046]

[0047] Y4 is selected from CR y4 R y5 -、NR y6 , O or S;

[0048] Y5 is selected from CR y4 or N;

[0049] R y4 , R y5or R y6 each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl or deuterated alkyl;

[0050] Ring E, Ring F, Y1, Y2, R a , R b , R c , R d , R e , R f , p, q, t or n are as defined in the general formula (II).

[0051] In a preferred embodiment of the present invention, the compound is further represented by the general formula (III-1):

[0052]

[0053] Ring H, Ring K, M1, M2, R A , R B , R D , R E , R m , R n , u, v, w or s are as defined in the general formula (III).

[0054] In a preferred embodiment of the present invention, the compound is further represented by the general formula (III-2):

[0055]

[0056] Ring H, Ring K, M2, R A , R B , R D , R E , R m , R n , u, w or s are as defined in the general formula (III).

[0057] In a preferred embodiment of the present invention, the compound is further represented by the general formula (III-3):

[0058]

[0059] Ring H, Ring K, R A , R B , R D , R E , R m , R n, w or s are as defined in the general formula (III-2).

[0060] The present invention also provides a compound represented by the general formula (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII) or (XIX), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0061]

[0062]

[0063] in,

[0064] L is selected from C 4-8 Bridged cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; preferably vinyl or ethynyl;

[0065] X4, X5, X6, X7, X8 or X9 are each independently selected from N or CR8;

[0066] Ring B or Ring C is present or absent, and when present, each is independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl;

[0067] Ring E is selected from C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-8 Monocyclic aromatic group, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents;

[0068] R a , R b , R c , R e , R f , R a1 , R a2 R1, R2, R5, R6 or R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0069] Or, R e or R f , R5 or R6 are independently linked to the connected carbon atom to form C 3-10Cycloalkyl or 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0070] R g or R3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -(CH2) m4 R g1 、-O(CH2) m4 R g1 , optionally substituted with hydrogen, deuterium, oxo, hydroxyl, halogen, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl C(O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 substituted by one or more substituents of an aryl group or a 5-10 membered heteroaryl group containing 1 to 3 atoms selected from N, O or S atoms;

[0071] R g1 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, oxo, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0072] m4 is 0, 1, 2, 3, or 4;

[0073] t is 0, 1, 2, 3, or 4;

[0074] z and m are each independently 0, 1, 2, 3 or 4;

[0075] The conditions are:

[0076] In the general formula (IV),

[0077] (1) When R a is methyl, R b When it is methyl, R e is not hydrogen, and R f Not methyl;

[0078] (2) When R a is methyl, R b is methyl, R e is not a methyl group, and R f Not hydrogen.

[0079] In the general formula (VI), (XI) or (XIV),

[0080] (1) When R a is methyl, R b When it is methyl, R e is hydrogen, R f When it is methyl, R d Not carboxyl;

[0081] (2) When R a is methyl, R b is methyl, R e is methyl, R f When it is hydrogen, R d Not carboxyl;

[0082] In the general formula (VII),

[0083] (1) When R a is methyl, R b is methyl, R eis hydrogen, R f is methyl, R d When it is a carboxyl group, ring K is not a phenyl group;

[0084] (2) When R a is methyl, R b is methyl, R e is methyl, R f is hydrogen, R d When it is a carboxyl group, ring K is not a phenyl group;

[0085] In the general formula (VIII),

[0086] R d1 , R d2 , R a1 , R a2 , R e or R f Any two of the atoms in the group are linked to form a 3-12 membered heterocyclic group containing 1-3 atoms selected from N, O or S, which may be substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0087] Preferably, R d1 With R e or R f The 5-6 membered heterocyclic group is linked to form 1-3 atoms selected from N, O or S, which are optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0088] Or, R d1 With R a2 The 5-6 membered heterocyclic group is linked to form 1-3 atoms selected from N, O or S, which are optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0089] Or, R d2 With R a1 The 8-10 membered heterocyclic group is linked to form 1-3 atoms selected from N, O or S, which are optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0090] In the general formula (IX),

[0091] (1) When R a is methyl, R b When it is methyl, R e is hydrogen, R f is methyl, R d When it is carboxyl, R c is not hydrogen, methyl, methoxy or methylaminocarbonyl;

[0092] (2) When R a is methyl, R b is methyl, R e is methyl, R f is hydrogen, R d When it is carboxyl, R c is not hydrogen, methyl, methoxy or methylaminocarbonyl;

[0093] In the general formula (XII),

[0094] When R a is methyl, R b When it is methyl, R e is hydrogen, R f When it is methyl, R g is not hydrogen, cyano, fluorine, methyl, methylsulfonyl, bromine, methoxy, carboxyl, amino, cyano or

[0095] The present invention also provides a compound represented by the general formula (XX), (XX') or (XXVII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0096]

[0097] in,

[0098] represents a single bond or a double bond;

[0099] X1 is selected from N or CR8;

[0100] X2 is selected from N, NR9, C, CR 10 or O;

[0101] X3 is selected from N, C or CR 11 ;

[0102] X4 is selected from N, C or CR 12 ;

[0103] R1, R2, R5, R6, R8, R9, R 10 , R 11 , R 12 or R a are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0104] R b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl or 5-12 membered heteroaryl group may be substituted by deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0105] R e or R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl or 5-12 membered heteroaryl group may be further substituted with deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0106] R g is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl can be further substituted with deuterium, oxo, hydroxyl, halogen, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl C(O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 substituted by one or more substituents of an aryl group or a 5-10 membered heteroaryl group containing 1 to 3 atoms selected from N, O or S atoms;

[0107] Ring M or ring C are each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl;

[0108] Alternatively, two R1 atoms are linked to form a C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 substituted by one or more substituents of aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S atoms;

[0109] R4 or R d are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 aryl, 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, or C 1-6 Alkyl S(O)(=NH), optionally substituted with hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by one or more substituents in a deuterated alkyl group;

[0110] Alternatively, R5 or R6 is linked to the carbon atom to form a C 3-10 Cycloalkyl or 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0111] x is 1, 2, or 3;

[0112] y and m are each independently 0, 1, 2, 3 or 4.

[0113] In certain embodiments of the present invention,

[0114] in,

[0115] represents a single bond or a double bond;

[0116] X1 is selected from N or CR8;

[0117] X2 is selected from N, NR9, C, CR 10 or O;

[0118] X3 is selected from N or CR 11 ;

[0119] X4 is selected from N or CR 12 ;

[0120] R8, R9, R 10 , R 11 or R 12 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0121] Ring M is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl;

[0122] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0123] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0124] R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 aryl, 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, or C 1-6 Alkyl S(O)(=NH), optionally substituted with hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by one or more substituents in a deuterated alkyl group;

[0125] R5 and R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0126] Alternatively, R5 or R6 is linked to the carbon atom to form a C3-10 Cycloalkyl or 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0127] x is 1, 2, or 3;

[0128] y and m are each independently 0, 1, 2, 3 or 4.

[0129] In a preferred embodiment of the present invention, the compound is further represented by the general formula (XX-1):

[0130]

[0131] in,

[0132] X5 is selected from N or CR 13 ;

[0133] X6 is selected from N or CR 14 ;

[0134] R 13 or R 14 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0135] X1, R1, R2, R4, R5, R6, R9, x, y or m are as defined in the general formula (XX).

[0136] The present invention also provides a compound represented by the general formula (XXI), (XXII), (XXIII), (XXIV) or (XXV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0137]

[0138] in:

[0139] X4, X5 or X6 are each independently selected from N or CR8;

[0140] In the general formula (XXI), at least one of X4, X5 or X6 is N;

[0141] Ring B or Ring C is each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0142] R1, R3, R4, R5 or R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0143] R2 or R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 NRaa C(O)CR bb =CR cc R dd , cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0144] R aa ~R dd each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl and heteroaryloxy, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl and heteroaryloxy are optionally substituted with one or more substituents of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0145] x is 1, 2, or 3;

[0146] y, z and m are each independently 0, 1, 2, 3 or 4; and

[0147] n1 and n2 are each independently 0, 1, 2, 3 or 4.

[0148] In a preferred embodiment of the present invention, the compound is further represented by the general formula (XXI-1), (XXI-2), (XXII-1) or (XXIII-1):

[0149]

[0150] R1, R2, R3, R4, R5, R6, Ring B, x, y, z and m are as defined in Formula (XXI), (XXII) or (XXIII).

[0151] The present invention also provides a compound represented by general formula (XXVI'), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0152]

[0153] in,

[0154] represents a single bond or a double bond;

[0155] X1 is selected from N or C;

[0156] X2 is selected from N or C;

[0157] X3 is selected from N or C;

[0158] X4 is selected from N, C or CR 12 ;

[0159] X5 is selected from N or C;

[0160] X6 is selected from N or C;

[0161] R 12 R1, R2, R5 or R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, deuterium, hydroxy, halogen, cyano, amino, alkyl, haloalkyl or deuterated alkyl;

[0162] Ring B is present or absent, and when present is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0163] Ring Q or Ring Q1 is each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0164] Alternatively, two R1 are linked to the atoms to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R3 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, carboxy, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, deuterium, oxo, hydroxy, halogen, cyano, amino, alkylamino, alkylC(O), alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0165] R4 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl S(O)(=NH), optionally substituted with one or more substituents of hydrogen, deuterium, hydroxy, halogen, cyano, amino, alkyl, haloalkyl or deuterated alkyl;

[0166] Alternatively, R5 or R6 is linked to the carbon atom to form a cycloalkyl or heterocyclic group, which is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, and alkyl substituted with cyano;

[0167] x, y and z are each independently 0, 1, 2 or 3; and

[0168] m is 0, 1, 2 or 3;

[0169] The conditions are:

[0170] (1) When for When R1 is methyl, one of R5 or R6 is hydrogen and the other is methyl, Not for

[0171] (2) When for When R1 is methyl, one of R5 or R6 is hydrogen and the other is methyl, Not for

[0172] (3) When for When R1 is methyl, one of R5 or R6 is hydrogen and the other is methyl, Not for

[0173] (4) When for When R1 is methyl, one of R5 or R6 is hydrogen and the other is methyl, Not for

[0174] (5) When for When R1 is methyl, R2 is hydrogen, methoxy or ethoxy, one of R5 or R6 is hydrogen and the other is methyl, Not for

[0175] Alternatively, at least one of X1, X2 and X3 is N.

[0176] In a preferred embodiment of the present invention, the compound is further represented by the general formula (XXVI) or (XXVI-a):

[0177]

[0178] X1, X2, X3, X4, X5, X6, R 12 , R1, R2, R3, R4, R5, R6, Ring B, Ring Q, x, y, z and

[0179] m is as defined in the general formula (XXVI').

[0180] In a preferred embodiment of the present invention, the compound is further represented by the general formula (XXVI-1), (XXVI-2) or (XXVI-3):

[0181]

[0182] R 12 R1, R2, R5 or R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0183] Ring B or ring Q are each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl;

[0184] Alternatively, two R1 atoms are linked to form a C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 substituted by one or more substituents of aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S atoms;

[0185] R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, oxo, hydroxyl, halogen, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl C(O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 It is substituted by one or more substituents of an aryl group or a 5-10 membered heteroaryl group containing 1 to 3 N, O or S atoms;

[0186] R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 aryl, 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, or C 1-6 Alkyl S(O)(=NH), optionally substituted with hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by one or more substituents in a deuterated alkyl group;

[0187] Alternatively, R5 or R6 is linked to the carbon atom to form a C 3-10 Cycloalkyl or 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted with one or more substituents.

[0188] In a further preferred embodiment of the present invention, the compound is further represented by the general formula (XXVI-a1), (XXVI-a2), (XXVI-a3) or (XXVI-a4):

[0189]

[0190] V1, V2 or V3 are each independently selected from C or N;

[0191] V4 or V6 are each independently selected from C or N;

[0192] V5 is selected from C, N, O or S;

[0193] V7, V8 or V9 are each independently selected from C, N, O or S;

[0194] V 10 、V 11 、V 12 or V 13 are each independently selected from C or N.

[0195] In a further preferred embodiment of the present invention, the compound is further represented by the general formula (XXVI-b1), (XXVI-b2), (XXVI-b3), (XXVI-b4) or (XXVI-b5):

[0196]

[0197] In a further preferred embodiment of the present invention, the compound is further represented by the general formula (XXVI-c1) to (XXVI-c14):

[0198]

[0199] In a preferred embodiment of the present invention, R in the general formula (XXVII) d Substitution at the ortho position of ring C.

[0200] In a preferred embodiment of the present invention, R in the general formula (XXVII) g Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-12 Aryl or 5-10 membered heteroaryl containing 1 to 3 atoms selected from N, O or S, optionally, the C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-12 The aryl group or the 5-10 membered heteroaryl group containing 1-3 atoms selected from N, O or S may be further substituted with deuterium, oxo, hydroxyl, halogen, cyano, amino, C 1-3 Alkylamino, C 1-3 Alkyl C(O), C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 The aryl group or the 5-6-membered heteroaryl group containing 1 to 3 atoms selected from N, O or S atoms is substituted by one or more substituents.

[0201] In a preferred embodiment of the present invention, ring C in the general formula (XXVII) is selected from phenyl or a 5-6 membered heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or cyano substituted C 1-6 The alkyl group is substituted with one or more substituents.

[0202] In a preferred embodiment of the present invention, R in the general formula (XXVII) a , R e or R fare each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl or C 3-6 Cycloalkyl.

[0203] In some embodiments, the compounds of the general formula (I-2-1), (I-2-2), (II-1), (III-3), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX-1), (XXI-1), (XXI-2), (XXII-1), (XXIII-1), (XXVI-c1) to (XXVI-c14) show an IC of about 1 nM to 20 nM for PI3Kα kinase activity as measured by the method of Test Example 1. 50 Value inhibition activity;

[0204] In some embodiments, the compounds of formula (I-2-1), (I-2-2), (II-1), (III-3), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX-1), (XXI-1), (XXI-2), (XXII-1), (XXIII-1), (XXVI-c1) to (XXVI-c14) show an IC of about 1 nM to 30 nM for the proliferation of PI3Kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K) and MKN1 (E545K) as measured by the method of Test Example 3. 50 Value inhibitory activity.

[0205] In the above general formulas of the present invention, wherein,

[0206] Ring B, Ring E or Ring H are each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl;

[0207] Preferably, ring B, ring E or ring H are each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0208] More preferably, Ring B, Ring E or Ring H are each independently selected from C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-8 Monocyclic aromatic group, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents;

[0209] More preferably, ring B, ring E or ring H are each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0210] In certain embodiments of the present invention, Ring B, Ring E or Ring H are each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridine, pyrimidine,

[0211] In the above general formulas of the present invention, wherein,

[0212] Ring C, Ring F or Ring K are each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl;

[0213] Preferably, ring C, ring F or ring K are each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0214] More preferably, ring C, ring F or ring K are each independently selected from C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-8 Monocyclic aromatic group, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents;

[0215] More preferably, ring C, ring F or ring K are each independently selected from phenyl, naphthyl, pyridyl,

[0216] In the above general formulas of the present invention, wherein,

[0217] Ring D is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 10-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl;

[0218] Preferably, ring D is selected from C3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 10-12 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0219] More preferably, ring D is selected from C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 10-12 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents;

[0220] More preferably, ring D is selected from

[0221] In the above general formulas of the present invention, wherein,

[0222] Ring G is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl;

[0223] Preferably, ring G is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0224] More preferably, ring G is selected from C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-8 Monocyclic aromatic group, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents;

[0225] More preferably, ring G is selected from phenyl, naphthyl, pyridyl,

[0226] In the above general formulas of the present invention, wherein,

[0227] Ring Q is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0228] Preferably, ring Q is selected from C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-8 Monocyclic aromatic group, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C1-3 More preferably, ring Q is selected from

[0229] In certain embodiments of the present invention,

[0230] Ring Q is selected from

[0231] In the above general formulas of the present invention, wherein,

[0232] R1, R a or R A are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0233] Preferably, R1, R a or R A are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0234] More preferably, R1, R a or R A are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0235] More preferably, R1, R a or R A Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl.

[0236] In a further preferred embodiment of the present invention, wherein,

[0237] R2, R b or R B are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc Rdd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0238] Preferably, R2, R b or R B are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-

[0239] (CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-

[0240] (CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-10Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0241] More preferably, R2, R b or R B are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-

[0242] (CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-

[0243] (CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0244] More preferably, R2, R b or R BEach is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -C(O)CH=CH2, -C(O)CH2Cl, -C(O)C(CH3)=CH2, -NHC(O)CH=CH2, -NHC(O)CH2Cl, -NHC(O)C(CH3)=CH2, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl.

[0245] In the above general formulas of the present invention, wherein,

[0246] R2, R b or R B are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0247] Preferably, R2, R b or R B are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0248] More preferably, R2, R b or R B are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0249] More preferably, R2, R b or R B Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl.

[0250] In the above general formulas of the present invention, wherein,

[0251] R3, R c or R D are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0252] Preferably, R3, R c or R D are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0253] More preferably, R3, R c or R D are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0254] More preferably, R3, R c or R DEach is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl.

[0255] In the above general formulas of the present invention, wherein,

[0256] R4, R d or R E are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0257] Preferably, R4, R d or R E4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0258] More preferably, R4, R d or R Eare each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0259] More preferably, R4, R d or R E Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl.

[0260] In the above general formulas of the present invention, wherein,

[0261] R5, R6, R e , R f , R m or R n are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0262] Preferably, R5, R6, R e , R f , R m or R n are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0263] More preferably, R5, R6, R e , R f , R m or R n are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0264] More preferably, R5, R6, R e , R f , R m or R nare each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl;

[0265] Or, R e or R f Linked to the carbon atom to form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0266] Preferably, R e or R f Linked to the carbon atom to form C 3-6 Cycloalkyl or 3-6 membered heterocyclic group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents;

[0267] Preferably, R e or R f Linked to the attached carbon atom to form a cyclopropyl, cyclobutyl or cyclopentyl group.

[0268] In the above general formulas of the present invention, wherein,

[0269] R7, R8, R9, R 10 , R 11 , R 12 or R 13 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0270] Preferably, R7, R8, R9, R 10 , R 11 , R 12 or R 13 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 alkyl,-

[0271] (CH2) n1 C(O)(CR cc R dd ) n2 Rbb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0272] More preferably, R7, R8, R9, R 10 , R 11 , R 12 or R 13 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl-

[0273] (CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2)n1 NR aa C(O)CR bb =CR cc R dd , a 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0274] More preferably, R7, R8, R9, R 10 , R 11 , R 12 or R 13 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -C(O)CH=CH2, -C(O)CH2Cl, -C(O)C(CH3)=CH2, -NHC(O)CH=CH2, -NHC(O)CH2Cl, -NHC(O)C(CH3)=CH2, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl.

[0275] In the above general formulas of the present invention, wherein,

[0276] R aa ~R dd are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0277] Preferably, Raa ~R dd are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0278] More preferably, R aa ~R dd are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0279] More preferably, R aa ~R dd Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, vinyl, propenyl, allyl, ethynyl, propynyl or propargyl.

[0280] In the above general formulas of the present invention, wherein,

[0281] R7, R8, R9, R 10 , R 11 , R 12 or R 13 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group;

[0282] Preferably, R7, R8, R9, R 10 , R 11 , R 12 or R 13 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0283] More preferably, R7, R8, R9, R 10 , R 11 , R 12 or R 13 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group;

[0284] More preferably, R7, R8, R9, R 10 , R 11 , R 12 or R 13 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl.

[0285] In the above general formulas of the present invention, wherein,

[0286] Ring Q1 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents;

[0287] Preferably, ring Q1 is selected from C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10a 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, a 5-10 membered bridged heterocyclic group containing 1-3 atoms selected from N, O or S, a benzene ring, a C 8-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents;

[0288] More preferably, ring Q1 is selected from a benzene ring, pyridine, pyrimidine or pyridazine.

[0289] In certain embodiments of the present invention, ring Q1 is not a pyridine ring.

[0290] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any compound of the general formula shown, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0291] In certain embodiments of the present invention, the weight percentage of the compound, its stereoisomer or pharmaceutically acceptable salt thereof in the pharmaceutical composition, calculated as the free base, is 0.1% to 95%, preferably 5-70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%.

[0292] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, preferably, further comprising a filler, optionally a disintegrant, or further comprising one or more of a glidant or a lubricant.

[0293] In certain embodiments of the present invention, the pharmaceutical composition is an immediate-release formulation or a sustained-release formulation.

[0294] In certain embodiments of the present invention, the pharmaceutical composition, calculated as a free base, has a unit dose of 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0295] In certain embodiments of the invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, may be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition adjusted accordingly.

[0296] In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0297] The present invention further relates to the use of any of the compounds of the general formula shown, its stereoisomers or pharmaceutically acceptable salts or the pharmaceutical composition in the preparation of drugs for treating diseases related to PI3Kα.

[0298] The present invention further relates to the use of a compound represented by the general formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating cancer, PROS (PIK3CA-related overgrowth spectrum), immune disorders or inflammatory disorders. Preferably, the PROS is selected from vascular malformations, lymphatic malformations and megalencephaly, and the cancer is selected from gastric cancer, breast cancer, prostate cancer, lung cancer, liver cancer, bone cancer, brain cancer, head and neck cancer, intestinal cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer, endometrial cancer or multiple myeloma; preferably clear cell ovarian cancer or breast cancer.

[0299] The present invention further relates to a method for using the compound represented by the general formula, its stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions thereof in the preparation of drugs for treating PI3Kα-related and related diseases.

[0300] The present invention also relates to a method for treating, preventing and / or treating diseases related to PI3Kα, which comprises administering to a patient a therapeutically effective dose of a compound represented by the general formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0301] The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with PI3Kα.

[0302] The present invention also relates to a method for treating a disease associated with PI3Kα in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0303] Detailed description of the invention

[0304] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0305] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include 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 the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention.

[0306] The term "alkylene" refers to an alkyl group with one hydrogen atom further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0307] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spiro rings, fused rings and bridged rings, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

[0308] The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 3 yuan / 6 yuan, 3 yuan / 5 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0309] .wait;

[0310] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0311] wait.

[0312] The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include:

[0313] wait.

[0314] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0315]

[0316] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0317] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O). m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring part of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it contains 1-3 nitrogen atoms, 3-8 membered heterocyclic groups, optionally substituted by 1-2 oxygen atoms, sulfur atoms, oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups or nitrogen-containing fused heterocyclic groups.

[0318] Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl, etc., preferably pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazepanyl and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, condensed and bridged heterocyclic groups; wherein the spirocyclic, condensed and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms on the ring.

[0319] The term "spiro heterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between rings, spiral heterocyclic groups are divided into single spiral heterocyclic groups, double spiral heterocyclic groups or multi-spiro heterocyclic groups, preferably single spiral heterocyclic groups and double spiral heterocyclic groups. More preferably, it is 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic groups. Non-limiting examples of spiral heterocyclic groups include:

[0320]

[0321] wait.

[0322] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0323]

[0324] wait.

[0325] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system, and one or more of the ring atoms is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0326]

[0327] wait.

[0328] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0329] wait.

[0330] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0331] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or further comprising a three-membered nitrogen-containing fused ring containing a benzene ring.

[0332] Wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0333]

[0334] wait.

[0335] The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0336] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5 to 12-membered, more preferably 5-membered or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0337]

[0338] wait.

[0339] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0340] The term "alkoxy" refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0341] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0342] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0343] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0344] "Alkenyl" refers to a chain alkenyl group, also known as alkene Hydrocarbon , refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond and the carbon-carbon double bond can be located at any position within the alkenyl group, the alkenyl group is a group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ), 2 to 4 (C 2-4 ) or 2 to 3 (C 2-3 ) carbon atoms. Non-limiting examples of alkenyl groups include: The alkenyl group may be further substituted by other related groups, for example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0345] "Alkynyl" refers to (CH≡C-), which contains at least one carbon-carbon triple bond and the carbon-carbon triple bond can be located at any position in the alkynyl group, which contains at least one carbon-carbon double bond and the carbon-carbon double bond can be located at any position in the alkenyl group, and the alkynyl group is a group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ), 2 to 4 (C 2-4 ) or 2 to 3 (C 2-3 ) carbon atoms. Non-limiting examples of alkynyl groups include: The alkynyl group can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0346] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein the definition of alkenyl is as described above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0347] "Hydroxy" refers to an -OH group.

[0348] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0349] "Amino" refers to -NH2.

[0350] "Cyano" refers to -CN.

[0351] "Nitro" refers to -NO2.

[0352] "Carbonyl" refers to -C(O)-.

[0353] "Carboxy" refers to -C(O)OH.

[0354] "THF" refers to tetrahydrofuran.

[0355] "EtOAc" means ethyl acetate.

[0356] "MeOH" refers to methanol.

[0357] "DMF" refers to N,N-dimethylformamide.

[0358] "DIPEA" refers to diisopropylethylamine.

[0359] "TFA" refers to trifluoroacetic acid.

[0360] "MeCN" refers to acetylene.

[0361] "DMA" refers to N,N-dimethylacetamide.

[0362] "Et2O" refers to diethyl ether.

[0363] "DCE" refers to 1,2-dichloroethane.

[0364] "DIPEA" refers to N,N-diisopropylethylamine.

[0365] "NBS" refers to N-bromosuccinimide.

[0366] "NIS" refers to N-iodosuccinimide.

[0367] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

[0368] The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0369] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0370] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0371] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0372] "Pharmaceutically acceptable salt" and "pharmaceutically usable salt" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0373] Example

[0374] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0375] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0376] HPLC analysis was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column).

[0377] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0378] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0379] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0380] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals and other companies.

[0381] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0382] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0383] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0384] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0385] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0386] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0387] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0388] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0389] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction are: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone, and the volume ratio of the solvent is adjusted according to the polarity of the compound.

[0390] The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0391] Example 1

[0392]

[0393] first step

[0394] 6-Acetyl-2,8-dimethyl-1-oxo-1,9-dihydro-2H-pyrido[1,2-a]pyrazin-3-yl methanesulfonate Under N2, 6-acetyl-3-hydroxy-2,8-dimethyl-2H-pyrido[1,2-a]pyrazin-1(9H)-one (1 g, 4.27 mmol) and TEA (1.3 g, 12.8 mmol, 1.8 mL) were added to THF (20 mL). Then methanesulfonyl chloride (0.73 g, 6.4 mmol) was added, the reaction solution was stirred at 25°C for 1 hour, water (15 ml) was added, and then extracted with ethyl acetate (30 ml*2), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a column (PE:EA=3:1) to obtain Example 1b (1 g, 75% yield). MSm / z(ESI):313.2[M+1]

[0395] Step 2

[0396] 6-acetyl-2,8-dimethyl-3-(piperidin-1-yl)-2H-pyrido[1,2-a]pyrazin-1(9H)-one 1b (1g, 3.2mmol) was added to MeCN (20mL) under N2. Then piperidine (1.36g, 16mmol) was added, the reaction solution was stirred at 80°C for 1 hour, water (15ml) was added, and then extracted with ethyl acetate (50ml*2), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a column (PE:EA=2:1) ​​to obtain Example 1c (700mg, 73% yield). MS m / z(ESI):302.2[M+1]

[0397] Step 3

[0398] 2-((1-(1-hydroxy-2,8-dimethyl-3-(piperidin-1-yl)-2H-pyrido[1,2-a]pyrazin-6-yl)ethyl)amino)

[0399] benzoic acid

[0400] Under N2, 1c (50 mg, 166 μmol) and 2-aminobenzoic acid (27 mg, 200 μmol) were added to tetrahydrofuran (5 mL). TiCl4 (35.32 mg, 187.88 μmol) was then added, and the reaction solution was stirred at 25°C for 1 hour. NaCNBH3 (11.81 mg, 187.88 μmol) and acetic acid (11.27 mg, 187.88 μmol) were further added to the reaction solution, and the reaction solution was stirred at 25°C for another hour. Water (15 ml) was added, and then extracted with ethyl acetate (30 ml*2), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a silica gel column (PE:EA=1:1) to obtain Example 1 (1 g, 75% yield). MS m / z (ESI): 423.3 [M+1]

[0401] Example 4

[0402]

[0403] first step

[0404] 6-Chloro-3-((1-(2,8-dimethyl-1-oxo-3-(piperidin-1-yl)-1,9-dihydro-2H-pyrido[1,2-a]pyrazin-6-yl)

[0405] (ethyl)amino)picolinic acid

[0406] Referring to the synthesis method of the third step in Example 1, 6-acetyl-2,8-dimethyl-3-(piperidin-1-yl)-2H-pyrido[1,2-a]pyrazin-1(9aH)-one was used as the starting material to obtain the title product 4 (21 mg, 41% yield). MS m / z (ESI): 458.2 [M+1]

[0407] Example 7

[0408]

[0409] first step

[0410] 6-Acetyl-2,8-dimethyl-1-oxo-1,2-dihydropyridazin[1,2-a][1,2,4]triazin-3-yl methanesulfonate

[0411] The synthesis method of compound 7b in Example 7 refers to the synthesis method of the first step in Example 1, using 6-acetyl-3-hydroxy-2,8-dimethylpyridazine[1,2-a][1,2,4]triazine-1(2H)-one 7a as the starting material to obtain the title product 7b.

[0412] MS m / z(ESI):314.2[M+1]

[0413] Step 2

[0414] 6-Acetyl-2,8-dimethyl-3-(piperidin-1-yl)pyridazin[1,2-a][1,2,4]triazine-1(2H)-one

[0415] The synthesis method of compound 7c in Example 7 was similar to the synthesis method in the second step of Example 1, and 6-acetyl-2,8-dimethyl-1-oxo-1,2-dihydropyridazine[1,2-a][1,2,4]triazine-3-yl methanesulfonate 7b was used as the starting material to obtain the title product 7c. MS m / z (ESI): 303.2 [M+1]

[0416] Step 3

[0417] 2-((1-(2,8-dimethyl-1-oxo-3-(piperidin-1-yl)-1,2-dihydropyridazino[1,2-a][1,2,4]triazin-6-yl)ethyl)amino)benzoic acid

[0418] Referring to the synthesis method of the third step in Example 1, 7c was used as the starting material to obtain the title product 2-((1-(2,8-dimethyl-1-oxo-3-(piperidin-1-yl)-1,2-dihydropyridazin[1,2-a][1,2,4]triazin-6-yl)ethyl)amino)benzoic acid 7. MS m / z (ESI): 424.3 [M+1]

[0419] Example 8

[0420]

[0421] first step

[0422] 6-Acetyl-3-(4,4-difluorocyclohexyl)-2,8-dimethylpyridazin[1,2-a][1,2,4]triazine-1(2H)-one

[0423] Referring to the synthesis method of the second step in Example 1, 7b was used as the starting material to obtain the title product 8a. MS m / z (ESI): 338.2 [M+1]

[0424] Step 2

[0425] 2-((1-(3-(4,4-difluorocyclohexyl)-2,8-dimethyl-1-oxo-1,2-dihydropyridazin[1,2-a][1,2,4]triazin-6-yl)

[0426] (ethyl)amino)benzoic acid

[0427] Referring to the synthesis method of the third step in Example 1, 8a was used as the starting material to obtain the title product 2-((1-(3-(4,4-difluorocyclohexyl)-2,8-dimethyl-1-oxo-1,2-dihydropyridazin[1,2-a][1,2,4]triazin-6-yl)ethyl)amino)benzoic acid 8. MS m / z (ESI): 459.3 [M+1]

[0428] Example 9

[0429]

[0430] first step

[0431] 6-Acetyl-3-(isoindolin-2-yl)-2,8-dimethylpyridazin[1,2-a][1,2,4]triazin-1(2H)-one

[0432] Referring to the synthesis method of the second step in Example 1, 7b was used as the starting material to obtain the title product 9a.

[0433] MS m / z(ESI):337.2[M+1]

[0434] Step 2

[0435] 2-((1-(2,8-dimethyl-1-oxo-3-(piperidin-1-yl)-1,2-dihydropyridazino[1,2-a][1,2,4]triazin-6-yl)ethyl)amino)benzoic acid

[0436] Referring to the synthesis method of the third step in Example 1, 9a was used as the starting material to obtain the title product 2-((1-(2,8-dimethyl-1-oxo-3-(piperidin-1-yl)-1,2-dihydropyridazin[1,2-a][1,2,4]triazin-6-yl)ethyl)amino)benzoic acid 9. MS m / z (ESI): 458.3 [M+1]

[0437] Example 10

[0438]

[0439] Referring to the synthesis method of the third step in Example 1, 7c was used as the starting material to obtain the title product 6-chloro-3-((1-(2,8-dimethyl-1-oxo-3-(piperidin-1-yl)-1,2-dihydropyridazin[1,2-a][1,2,4]triazin-6-yl)ethyl)amino)picolinic acid 10. MS m / z (ESI): 459.2 [M+1]

[0440] Embodiment 11

[0441]

[0442] Referring to the synthesis method of the third step in Example 1, 8a was used as the starting material to obtain the title product 2-((1-(3-(4,4-difluorocyclohexyl)-2,8-dimethyl-1-oxo-1,2-dihydropyridazin[1,2-a][1,2,4]triazin-6-yl)ethyl)amino)benzoic acid 11. MS m / z (ESI): 494.2 [M+1]

[0443] Example 12

[0444]

[0445] Referring to the synthesis method of the third step in Example 1, 9a was used as the starting material to obtain the title product 6-chloro-3-((1-(3-(isoindol-2-yl)-2,8-dimethyl-1-oxo-1,2-dihydropyridazin[1,2-a][1,2,4]triazin-6-yl)ethyl)amino)picolinic acid 12. MS m / z (ESI): 493.2 [M+1]

[0446] Example 13

[0447]

[0448] first step

[0449] Ethyl 3-(3-bromo-5-methylpyridin-2-yl)-2-oxyylidenepropanoate

[0450] The compound ethyl acetoacetate (3.67 g, 31.57 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and sodium hydrogen (1.58 g, 39.47 mmol, 60% dispersed in paraffin oil) was added in batches at 0°C under nitrogen protection and stirred at 0°C for 1 hour, and then a solution of compound 13-1 (5 g, 26.31 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise at 0°C, and the temperature was naturally raised to 20°C and stirred for 12 hours. The reaction solution was cooled to 0°C, and a saturated aqueous solution of ammonium chloride (5 mL) was slowly added dropwise to quench the reaction, and water (250 mL) was added to dilute it, and the aqueous phase was extracted with ethyl acetate (100 mL×2), and the organic phases were combined, washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by slurrying with a mixed solvent of petroleum ether and ethyl acetate (25 mL:5 mL) to obtain the title product 13-2 (5 g, crude yield 67%). MS: m / z(ESI):286.0[M+1]

[0451] Step 2

[0452] 3-(3-Bromo-5-methylpyridin-2-yl)-2-oxydeoxypropanoic acid

[0453] Compound 13-2 (5 g, 17.47 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and potassium trimethylsilanol (6.72 g, 52.41 mmol) was added in batches at 20°C under nitrogen protection, and then stirred at 20°C for 12 hours. The reaction solution was slowly poured into dilute hydrochloric acid (250 mL, 1 M), extracted with ethyl acetate (50 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 13-3 (5 g, crude product). MS: m / z (ESI): 258.0 [M+1]

[0454] Step 3

[0455] 5-Bromo-7-methyl-2,3-dihydro-1H-pyrido[2,1-f]pyrimidine-1,3-dione

[0456] Compound 13-3 (5 g, 19.37 mmol) was dissolved in anhydrous toluene (50 mL), triethylamine (5.87 g, 58.11 mmol, 8.08 mL) and diphenylphosphoryl azide (6.40 g, 23.24 mmol) were added in sequence at 20°C under nitrogen protection, and then stirred at 90°C for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature and directly concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography using eluent system A to obtain the title product 13-4 (2 g). MS: m / z (ESI): 255.0 [M+1]

[0457] Step 4

[0458] 5-Bromo-3-chloro-7-methyl-1H-pyrido[2,1-f]pyrimidin-1-one

[0459] Under nitrogen protection, compound 13-4 (2 g) was added to thionyl chloride (20 mL) in batches, and then stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature, directly concentrated to dryness under reduced pressure, and vortexed three times with anhydrous dichloromethane to remove residual thionyl chloride to obtain the title product 13-5 (2 g, crude product). MS: m / z (ESI): 273.0 [M+1]

[0460] Step 5

[0461] 5-Bromo-3-(hexahydropyridin-1-yl)-7-methyl-1H-pyrido[2,1-f]pyrimidin-1-one

[0462] Compound 13-5 (200 mg, 0.73 mmol) was dissolved in anhydrous dimethyl sulfoxide (2 mL), piperidine (186 mg, 2.19 mmol) and N,N-diisopropylethylamine (283 mg, 2.19 mmol) were added in sequence, and then stirred at 80°C for 12 hours. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution (20 mL) was added to dilute the reaction solution, extracted with ethyl acetate (10 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 13-6 (200 mg, crude product). MS: m / z (ESI): 322.0 [M+1]

[0463] Step 6

[0464] 5-Acetyl-3-(hexahydropyridin-1-yl)-7-methyl-1H-pyrido[2,1-f]pyrimidin-1-one

[0465] Compound 13-6 (200 mg) was dissolved in anhydrous tetrahydrofuran (4 mL), tributyl (1-ethoxyvinyl) tin (200 mg) and tetrakis triphenylphosphine palladium (20 mg) were added in sequence under nitrogen protection, and then stirred at 80°C for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, quenched and diluted with 5% potassium fluoride aqueous solution (20 mL), extracted with ethyl acetate (10 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography with eluent system A to obtain the title product 13-7 (50 mg). MS: m / z (ESI): 286.1 [M+1]

[0466] Step 7

[0467] 2-({1-[3-(Hexahydropyridin-1-yl)-7-methyl-1-oxopyrido[2,1-f]pyrimidin-5-yl]ethyl}amino)benzoic acid

[0468] Compound 13-7 (50 mg) was dissolved in anhydrous dichloromethane (2 mL), and 2-aminobenzoic acid (50 mg) and sodium acetate borohydride (50 mg) were added in sequence under nitrogen protection, and then stirred at 20°C for 12 hours under nitrogen protection. Methanol (1 mL) was added to quench the reaction, and the crude product was concentrated under reduced pressure to obtain a crude product, which was separated and purified by high performance liquid chromatography (formic acid system) to obtain the title product 13 (10 mg). MS: m / z (ESI): 407.2 [M+1]

[0469] Embodiment 19

[0470]

[0471] first step

[0472] 7-Methyl-2,3-dihydro-4H-pyrido[1,2-d][1,2,4]triazine-4-one

[0473] 2-(Chloromethyl)-5-methylpyridine 19a (20 g, 141.2 mmol) and N,N-diisopropylethylamine (75.4 mL, 423.6 mmol) were dissolved in 300 mL of acetonitrile, and phenyl hydrazinecarboxylate (22.6 g, 148.3 mmol) was added. After stirring at 25 degrees for 2 hours, the mixture was stirred at 100 degrees for 5 hours. The solvent was removed by concentration under reduced pressure, 200 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with saturated brine (300 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 19b (18.5 g) with a yield of 76.3%. MS m / z (ESI): 164.1 [M+1]

[0474] Step 2

[0475] 3,7-Dimethyl-2,3-dihydro-4H-pyrido[1,2-d][1,2,4]triazine-4-one

[0476] 19b (18.5 g, 113.4 mmol) was dissolved in 200 mL N,N-dimethylformamide, cesium carbonate (36.9 g, 113.4 mmol) was added, and after stirring at room temperature for 0.5 hours, iodomethane (14.1 mL, 226.8 mmol) was added, and the mixture was stirred at 80 degrees for 12 hours. 1 L of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (400 mL × 3). The organic phases were combined, washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 19c (9.8 g), with a yield of 45.4%. MS m / z (ESI): 178.2 [M+1]

[0477] Step 3

[0478] N-(3,7-Dimethyl-4-oxo-3,4-dihydro-2H-pyrido[1,2-d][1,2,4]triazin-2-yl)acetamide

[0479] 19c (9.8 g, 55.3 mmol) and 3-methyl-1,4,2-dioxazolone (8.4 g, 83.0 mmol) were dissolved in 200 mL of chloroform, and dichloro(pentamethylcyclopentadienyl)iridium(III) dimer (440.6 mg, 553.0 μmol) was added. The mixture was stirred at 25 degrees for 12 hours. 150 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (150 mL×3). The organic phases were combined, washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 19d (8.4 g) with a yield of 59.7%. MS m / z (ESI): 235.2 [M+1]

[0480] Step 4

[0481] 2-Amino-3,7-dimethyl-2,3-dihydro-4H-pyrido[1,2-d][1,2,4]triazine-4-one

[0482] Dissolve 19d (8.4 g, 35.9 mmol) in 75 mL of ethanol, add concentrated hydrochloric acid (15 mL, 179.3 mmol), and stir at 60 degrees for 6 hours. Remove ethanol by concentration under reduced pressure, add saturated sodium bicarbonate aqueous solution until the pH of the reaction solution is 8-9, add 80 mL of water, extract with ethyl acetate (60 mL×3), combine the organic phases, wash with saturated brine (120 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title product 19e (6.8 g), yield: 95.0%. MS m / z (ESI): 193.1 [M+1]

[0483] Step 5

[0484] 3,7-Dimethyl-2-(piperidin-1-yl)-2,3-dihydro-4H-pyrido[1,2-d][1,2,4]triazine-4-one

[0485] 19e (6.8 g, 35.4 mmol) and potassium carbonate (14.7 g, 106.2 mmol) were dissolved in 200 mL of N,N-dimethylformamide, 1,5-dichloropentane (4.7 mL, 37.1 mmol) was added, and the mixture was stirred at 100 degrees for 16 hours. 1 L of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (300 mL × 3). The organic phases were combined, washed with saturated brine (250 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 19f (2.1 g), with a yield of 20.8%. MS m / z (ESI): 261.2 [M+1]

[0486] Step 6

[0487] 9-Bromo-3,7-dimethyl-2-(piperidin-1-yl)-2,3-dihydro-4H-pyrido[1,2-d][1,2,4]triazine-4-one

[0488] 19f (2.1 g, 7.7 mmol) was dissolved in 50 mL of N,N-dimethylformamide, and dibromohydantoin (2.4 g, 8.5 mmol) was added. The reaction was stirred at room temperature for 16 hours. 500 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (400 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 19g (2.2 g), with a yield of 81.9%. MS m / z (ESI): 340.1 [M+1]

[0489] Step 7

[0490] 9-Acetyl-3,7-dimethyl-2-(piperidin-1-yl)-2,3-dihydro-4H-pyrido[1,2-d][1,2,4]triazine-4-one

[0491] Dissolve 19g (2.2g, 6.5mmol) in 16mL N,N-dimethylformamide, add bistriphenylphosphine palladium dichloride (455.2mg, 648.5μmol) and tributyl (1-ethoxyethylene) tin (3.3mL, 9.7mmol) in turn, and stir at 120 degrees for 3 hours. After cooling to room temperature, add 1N hydrochloric acid (13mL, 13.0mmol) and stir at room temperature for 1 hour. Filter the reaction solution, add saturated sodium bicarbonate aqueous solution to the filtrate to adjust pH>7, then add saturated potassium fluoride aqueous solution (150mL), extract with ethyl acetate (80mL×3), combine the organic phases, wash with saturated sodium chloride solution (200mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the title product 19h (1.3g), yield: 66.3%. MS m / z(ESI):303.1[M+1]

[0492] Step 8

[0493] 2-((1-(3,7-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydro-2H-pyrido[1,2-d][1,2,4]triazin-9-yl)ethyl)amino)

[0494] Ethyl benzoate

[0495] Under ice bath, 19h (1.3 g, 4.3 mmol), ethyl 2-aminobenzoate (1 mL, 6.8 mmol) and triethylamine (1.8 mL, 12.9 mmol) were dissolved in 30 mL of dichloromethane, titanium tetrachloride (1.4 mL, 12.9 mmol) was added, and the mixture was stirred at 25°C for 12 hours. Acetic acid (0.75 mL, 12.9 mmol), sodium cyanoborohydride (810.5 mg, 12.9 mmol) and methanol (3 mL) were added in sequence, and the mixture was stirred at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title product 19i (540 mg) with a yield of 27.8%. MS m / z (ESI): 452.2 [M+1]

[0496] Step 9

[0497] 2-((1-(3,7-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydro-2H-pyrido[1,2-d][1,2,4]triazin-9-yl)ethyl)amino)

[0498] benzoic acid

[0499] 19i (540 mg, 1.2 mmol) was dissolved in 8 mL methanol and 4 mL water, potassium carbonate (330.5 mg, 2.4 mmol) was added, and the mixture was stirred at 80°C for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title product 19 (420 mg), with a yield of 82.9%. MS m / z (ESI): 424.1 [M+1]

[0500] Embodiment 25

[0501]

[0502] first step

[0503] 2-Bromo-5-methylthiophen-3-ol

[0504] 5-Methylthiophene-3-ol 25a (10.0 g, 87.6 mmol) was dissolved in 100 mL DMF, and NBS (16.4 g, 91.9 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. 100 mL of saturated ammonium chloride solution was added to the reaction solution, and it was extracted with ethyl acetate (50 mL×4). The organic phases were combined, washed with water (200 mL) and saturated sodium chloride solution (200 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to obtain the title product 25b (12.7 g, yield: 75%). MS m / z (ESI): 192.9 [M+1]

[0505] Step 2

[0506] 2-Bromo-5-methylthiophen-3-yl acetate

[0507] 25b (12.7 g, 65.8 mmol) was dissolved in 100 mL of dichloromethane, and triethylamine (20.0 g, 197.4 mmol) and acetyl chloride (7.7 g, 98.7 mmol) were added in sequence. After the reaction solution was stirred at room temperature for 5 hours, the solvent was dried to obtain the title product 25c (15.1 g, yield: 98%). MS m / z (ESI): 234.9 [M+1]

[0508] Step 3

[0509] 1-(5-Bromo-4-hydroxy-2-methylthiophen-3-yl)ethan-1-one

[0510] 25c (15.1 g, 64.2 mmol) was dissolved in 100 mL of toluene, and the reaction solution was stirred at 130°C for 4 hours. The reaction solvent was dried by spin drying, and the residue was chromatographed on a silica gel column using eluent system A to obtain the title product 25d (12.8 g, yield: 85%). MS m / z (ESI): 234.9 [M+1]

[0511] Step 4

[0512] 7-Bromo-4-hydroxy-5-methyl-2H-thieno[3,4-b]pyran-2-thione

[0513] 25d (12.8 g, 54.5 mmol) was dissolved in 100 mL THF. After nitrogen was replaced three times, the reaction solution was stirred at -70 °C, and then LIHMDS (163.5 mL, 163.5 mmol, 1.0 M in THF) was added dropwise to the reaction solution. The reaction solution was stirred at -70 °C for 2 hours, and CS2 (4.2 g, 54.5 mmol) was added dropwise thereto. After the reaction solution was naturally warmed to room temperature and stirred for 12 hours, it was poured into ice water (500 mL), and the pH of the solution was adjusted to 4 with citric acid. After the mixed solution was stirred for 2 hours, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 25e (11.6 g, yield: 77%). MS m / z (ESI): 276.9 [M+1]

[0514] Step 5

[0515] 7-Bromo-2-(ethylthio)-5-methyl-4H-thieno[3,4-b]pyran-4-one

[0516] 25e (11.6 g, 41.9 mmol) was dissolved in 100 mL of acetone, and K2CO3 (5.8 g, 41.9 mmol) and iodoethane (7.2 g, 46.0 mmol) were added in sequence. After the reaction solution was stirred at room temperature for 3 hours, the solvent was dried by spin drying, 50 mL of water was added to the crude product, and it was extracted with CH2Cl2 (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 25f (9.7 g, yield: 76%). MS m / z (ESI): 304.9 [M+1]

[0517] Step 6

[0518] 7-Bromo-2-(ethylsulfonyl)-5-methyl-4H-thieno[3,4-b]pyran-4-one

[0519] 25f (9.7 g, 31.8 mmol) was dissolved in 150 mL of dichloromethane, and m-CPBA (13.7 g, 79.5 mmol) was added under stirring at 0°C. After the reaction solution was stirred at room temperature for 3 hours, 20 mL of saturated NaHSO3 solution was added to quench the reaction, and washed with 50 mL of water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 25g (8.4 g, yield: 78%). MS m / z (ESI): 336.9 [M+1]

[0520] Step 7

[0521] 7-Bromo-5-methyl-2-(piperidin-1-yl)-4H-thieno[3,4-b]pyran-4-one

[0522] Dissolve 25g (8.4g, 31.8mmol) in 100mL THF, add piperidine (6.4g, 74.7mmol), stir the reaction solution at room temperature for 2 hours, spin dry the reaction solvent, and use silica gel column chromatography with eluent system A to obtain the title product 25h (6.6g, yield: 81%). MS m / z (ESI): 328.0 [M+1]

[0523] Step 8

[0524] 7-Acetyl-5-methyl-2-(piperidin-1-yl)-4H-thieno[3,4-b]pyran-4-one

[0525] 25h (6.6 g, 20.1 mmol) was dissolved in 100 mL DMF, Pd(PPh3)2Cl2 (1.4 g, 2.0 mmol) was added, nitrogen was replaced three times, and tributyl(1-ethoxyethylene)tin (10.9 g, 30.2 mmol) was added. The reaction solution was heated to 120°C and stirred for 3 hours. The heating was stopped, and after cooling to room temperature, 1.0 M hydrochloric acid (50 mL) was added to the reaction solution. The reaction solution was stirred for 1 hour and extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated KF solution (50 mL) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 25i (3.5 g, yield: 60%). MS m / z (ESI): 292.1 [M+1]

[0526] Step 9

[0527] Ethyl 2-((1-(5-methyl-4-oxo-2-(piperidin-1-yl)-4H-thieno[3,4-b]pyran-7-yl)ethyl)amino)benzoate

[0528] 25i (3.5 g, 12.0 mmol) was dissolved in 100 mL of dichloromethane, and ethyl 2-aminobenzoate (4.0 g, 24.0 mmol), triethylamine (3.7 g, 36.0 mmol) and titanium tetrachloride (6.8 g, 36.0 mmol) were added in sequence. The reaction solution was stirred at room temperature for 12 hours, and AcOH (2.2 g, 36.0 mmol), sodium cyanoborohydride (2.3 g, 36.0 mmol) and MeOH (10 mL) were added. After stirring for 1 hour, the solvent was dried by spin drying, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 25j (2.8 g, yield: 53%). MS m / z (ESI): 441.2 [M+1]

[0529] Step 10

[0530] 2-((1-(5-methyl-4-oxo-2-(piperidin-1-yl)-4H-thieno[3,4-b]pyran-7-yl)ethyl)amino)benzoic acid

[0531] 25j (2.8 g, 6.4 mmol) was dissolved in 100 mL of methanol, and a solution of K2CO3 (8.8 g, 63.6 mmol) in water (50 mL) was added. The reaction solution was stirred at 50°C for 5 hours, the methanol solvent was removed by vortexing, 1 M hydrochloric acid (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and vortexed. The residue was chromatographed on a silica gel column using eluent system A to obtain the title product 25 (1.8 g, yield: 69%). MS m / z (ESI): 413.2 [M+1]

[0532] Embodiment 31

[0533]

[0534] first step

[0535] 4-Methyl-2-(3-methylureido)thiophene-3-carboxylic acid methyl ester

[0536] Dissolve methyl 2-amino-4-methylthiophene-3-carboxylate (5.0 g, 29.2 mmol) in 50 mL of dichloromethane, add triethylamine (14.8 g, 146.0 mmol) and N,N'-carbonyldiimidazole (5.7 g, 35.0 mmol) under ice bath, and stir the reaction at 25°C for 1 hour. Add methylamine hydrochloride (2.9 g, 43.8 mmol), and stir the reaction at 25°C for 18 hours. Add 100 mL of water, extract with dichloromethane (50 mL×2), combine the organic phases, wash with saturated sodium chloride solution (50 mL×2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the title product 31b (4.5 g, yield 67%). MS m / z(ESI):229.2[M+1]

[0537] Step 2

[0538] 3,5-Dimethylthieno[3,4-d]pyrimidine-2,4(1H,3H)-dione

[0539] Dissolve 4-methyl-2-(3-methylureido)thiophene-3-carboxylic acid methyl ester 31b (4.5 g, 19.7 mmol) in 40 mL of isopropanol, add sodium bicarbonate (3.3 g, 39.4 mmol) and sodium iodide (0.59 g, 3.9 mmol), and stir under reflux for 18 hours. Add 100 mL of water, extract with dichloromethane (50 mL × 2), combine the organic phases, wash with saturated sodium chloride solution (50 mL × 2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the title product 31c (0.8 g, yield 20.7%). MS m / z (ESI): 197.2 [M+1]

[0540] Step 3

[0541] 7-Bromo-3,5-dimethylthieno[3,4-d]pyrimidine-2,4(1H,3H)-dione

[0542] 31c (0.8 g, 4.1 mmol) was dissolved in 10 mL of acetonitrile, and N-bromosuccinimide (0.88 g, 4.9 mmol) was added. The reaction was stirred at 80°C for 2 hours. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 31d (0.6 g, yield 44.2%). MS m / z (ESI): 275.2, 277.2 [M+1]

[0543] Step 4

[0544] 7-Bromo-2-chloro-3,5-dimethylthieno[3,4-d]pyrimidin-4(3H)-one

[0545] 31d (0.6 g, 2.2 mmol) was dissolved in 10 mL of 1,2-dichloroethane, phosphorus oxychloride (3.4 g, 22 mmol) was added, and the reaction was stirred at 80°C for 2 hours. The reaction was quenched by adding into 200 mL of water, extracted with dichloromethane (20 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 31e (0.4 g, yield 62%). MS m / z (ESI): 293.2, 295.2 [M+1]

[0546] Step 5

[0547] 7-Bromo-3,5-dimethyl-2-(piperidin-1-yl)thieno[3,4-d]pyrimidin-4(3H)-one

[0548] Referring to the synthesis method in Example 13, 7-bromo-2-chloro-3,5-dimethylthieno[3,4-d]pyrimidin-4(3H)-one 31e was used as the starting material to obtain the title product 31f. MS m / z (ESI): 257.2 [M+1]

[0549] Step 6

[0550] 7-Acetyl-3,5-dimethyl-2-(piperidin-1-yl)thieno[3,4-d]pyrimidin-4(3H)-one

[0551] Referring to the synthesis method in Example 13, 31f was used as the starting material to obtain the title product 31g. MS m / z (ESI): 306.2 [M+1]

[0552] Step 7

[0553] 2-((1-(3,5-dimethyl-4-oxo-2-(piperidin-1-yl)-3,4-dihydrothieno[3,4-d]pyrimidin-7-yl)ethyl)amino)

[0554] benzoic acid

[0555] Referring to the synthesis method in Example 13, 31 g was used as the starting material to obtain the title product 31. MS m / z (ESI): 427.2 [M+1]

[0556] Embodiment 37

[0557]

[0558] first step

[0559] tert-Butyl 2-(3-bromo-2-fluoro-5-methylbenzoyl)-2-methylhydrazine-1-carboxylate

[0560] 3-Bromo-2-fluoro-5-methylbenzoic acid (5.0 g, 21.5 mmol) was dissolved in 50 mL of N,N-dimethylformamide, and tert-butyl 2-methylhydrazine-1-carboxylate (3.8 g, 25.8 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (9.0 g, 23.7 mmol) and triethylamine (6.5 g, 64.5 mmol) were added, and the reaction was stirred at 25°C for 18 hours. 100 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL×2), and the organic phases were combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 37c (6.0 g, yield 77%). MS m / z(ESI):361.2,363.2[M+1]

[0561] Step 2

[0562] 7-Bromo-2,5-dimethyl-1,2-dihydro-3H-indazol-3-one

[0563] 37c (6.0 g, 16.6 mmol) was dissolved in 50 mL of N,N-dimethylformamide, cooled to 0°C, sodium hydride (0.8 g, 19.9 mmol, 60%) was added, and the reaction was stirred at 25°C for 18 hours. 100 mL of water was added, extracted with ethyl acetate (50 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 37d (2.2 g, yield 55%). MS m / z (ESI): 241.2, 243.2 [M+1]

[0564] Step 3

[0565] 7-Bromo-1-(4,4-difluorocyclohexyl)-2,5-dimethyl-1,2-dihydro-3H-indazol-3-one

[0566] Referring to the synthesis method in Example 20, 37d was used as the starting material to obtain the title product 37e. MS m / z (ESI): 359.2, 361.2 [M+1]

[0567] Step 4

[0568] 7-Acetyl-1-(4,4-difluorocyclohexyl)-2,5-dimethyl-1,2-dihydro-3H-indazol-3-one

[0569] Referring to the synthesis method in Example 20, 37e was used as the starting material to obtain the title product 37f. MS m / z (ESI): 323.2 [M+1]

[0570] Step 5

[0571] 2-((1-(1-(4,4-difluorocyclohexyl)-2,5-dimethyl-3-oxo-2,3-dihydro-1H-indazol-7-yl)ethyl)amino)benzene

[0572] Formic acid

[0573] Referring to the synthesis method in Example 20, 37f was used as the starting material to obtain the title product 37. MS m / z (ESI): 444.2 [M+1]

[0574] Embodiment 39

[0575]

[0576] first step

[0577] 2-Bromo-4-methylpropionic acid phenyl ester

[0578] 2-Bromo-4-methylphenol 39a (15.0 g, 80.2 mmol) was dissolved in 100 mL of dichloromethane, and triethylamine (24.3 g, 240.6 mmol) and propionyl chloride (11.1 g, 120.3 mmol) were added in sequence. After the reaction solution was stirred at room temperature for 5 hours, the solvent was dried to obtain the title product 39b (19.1 g, yield: 98%). MS m / z (ESI): 243.0 [M+1]

[0579] Step 2

[0580] 1-(3-Bromo-2-hydroxy-5-methylphenyl)propan-1-one

[0581] A mixture of 39b (19.1 g, 78.6 mmol) and AlCl3 (36.7 g, 275.1 mmol) was stirred at 140°C for 1 hour. After the reaction was cooled to room temperature, 100 mL of water was added and extracted with ethyl acetate (50 mL×4). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain the title product 39c (13.9 g, yield: 73%). MS m / z (ESI): 243.0 [M+1]

[0582] Step 3

[0583] 8-Bromo-4-hydroxy-3,6-dimethyl-2H-methane-2-thione

[0584] 39c (13.9 g, 57.2 mmol) was dissolved in 100 mL THF. After nitrogen was replaced three times, the reaction solution was stirred at -70 °C, and then LiHMDS (171.6 mL, 171.6 mmol, 1.0 M in THF) was added dropwise to the reaction solution. The reaction solution was stirred at -70 °C for 2 hours, and CS2 (4.4 g, 57.2 mmol) was added dropwise thereto. After the reaction solution was naturally warmed to room temperature and stirred for 12 hours, it was poured into ice water (500 mL), and the pH of the solution was adjusted to 4 with citric acid. After the mixed solution was stirred for 2 hours, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 39d (11.0 g, yield: 67%). MS m / z (ESI): 285.0 [M+1]

[0585] Step 4

[0586] 8-Bromo-2-(ethylthio)-3,6-dimethyl-4H-bromo-4-one

[0587] 39d (11.0 g, 38.4 mmol) was dissolved in 100 mL of acetone, and K2CO3 (5.3 g, 38.4 mmol) and iodoethane (6.6 g, 42.2 mmol) were added in sequence. After the reaction solution was stirred at room temperature for 3 hours, the solvent was dried by spin drying, 50 mL of water was added to the crude product, and it was extracted with CH2Cl2 (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 39e (9.1 g, yield: 76%). MS m / z (ESI): 313.0 [M+1]

[0588] Step 5

[0589] Cyclopropyl(2-(ethylthio)-4-hydroxy-3,6-methyl-2H-chromen-8-yl)methanone

[0590] 39e (9.1 g, 29.2 mmol) was dissolved in 100 mL of tetrahydrofuran. After nitrogen was replaced, the reaction solution was stirred in a dry ice ethanol solution at -70 °C. Then n-butyl lithium (14 mL, 2.5 M in hexanes, 35.0 mmol) was added dropwise. The reaction solution was stirred at 0 °C for 1 hour. N-methoxy-N-methylcyclopropanecarboxamide (11.3 g, 87.6 mmol) was added. After the reaction solution was stirred at 0 °C for 3 hours, 20 mL of saturated ammonium chloride solution was added to quench the reaction, and the reaction solution was diluted with 50 mL of water. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the residue was chromatographed on a silica gel column with eluent system A to obtain the title product 39f (5.3 g, yield: 60%). MS m / z (ESI): 303.1 [M+1]

[0591] Step 6

[0592] Ethyl 2-((Cyclopropyl(2-(ethylthio)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)methyl)amino)benzoate

[0593] 39f (5.3 g, 18.3 mmol) was dissolved in 100 mL of dichloromethane, and ethyl 2-aminobenzoate (6.0 g, 36.6 mmol), triethylamine (5.6 g, 54.9 mmol) and titanium tetrachloride (10.4 g, 54.9 mmol) were added in sequence. The reaction solution was stirred at room temperature for 12 hours, and AcOH (3.3 g, 54.9 mmol), sodium cyanoborohydride (3.4 g, 54.9 mmol) and MeOH (10 mL) were added. After stirring for 1 hour, the solvent was dried by spin drying, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 39g (4.4 g, yield: 53%). MS m / z (ESI): 452.2 [M+1]

[0594] Step 7

[0595] 2-((Cyclopropyl(3,6-dimethyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-4-oxo-4H-chromene-8-

[0596] ethyl)amino)benzoate

[0597] Dissolve 39g (4.4g, 9.7mmol) in 100mL of a mixed solution of 1,4-dioxane and water (V / V=4:1), add 2-(1-methyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.1g, 14.6mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (0.7g, 1.0mmol) and cesium carbonate (9.5g, 29.1mmol) into the reaction system in sequence. Heat at 85℃ for 4 hours. After cooling to room temperature, 20 mL of saturated ammonium chloride solution was added to quench the reaction, and diluted with 50 mL of water. The aqueous phase was extracted with ethyl acetate (80 mL×3), and the organic phases were combined, washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 39h (4.2 g, yield: 78%). MS m / z (ESI): 549.2 [M+1]

[0598] Step 8

[0599] 2-((Cyclopropyl(3,6-dimethyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-4-oxo-4H-chromene-8-

[0600] 1-(4-(2-amino-3-methyl)-1 ...

[0601] 39h (4.2 g, 7.7 mmol) was dissolved in 100 mL of methanol, and a solution of K2CO3 (10.6 g, 76.6 mmol) in water (50 mL) was added. The reaction solution was stirred at 50°C for 5 hours, the methanol solvent was removed by vortexing, 1 M hydrochloric acid (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and vortexed. The residue was chromatographed on a silica gel column using eluent system A to obtain the title product 39 (2.9 g, yield: 72%). MS m / z (ESI): 521.2 [M+1]

[0602] Embodiment 40

[0603]

[0604] first step

[0605] 2-(Ethylthio)-3,6-dimethyl-4-oxo-4H-chromene-8-carbonyl-d

[0606] PdCl2 (227.0 mg, 1.3 mmol) and 4,4'-dimethoxy-2,2'-bipyridine (553.6 mg, 2.6 mmol) were dissolved in 5 mL DMF solvent and heated at 50°C for 1 hour. 39e (2.0 g, 6.4 mmol), cyclooctadienyl rhodium chloride dimer (295.8 mg, 0.6 mmol), TMEDA (1.5 g, 12.8 mmol) and deuterated water (256.4 mg, 12.8 mmol) were dissolved in 10 mL DMF, and the freshly prepared palladium catalyst was added while hot. After the CO gas was replaced three times, the reaction solution was stirred at 85°C for 16 hours. After the reaction solution was cooled, it was filtered through a short silica gel column, and the filtrate was dried by spin drying. The residue was chromatographed on a silica gel column with eluent system A to obtain the title product 40a (1.1 g, yield: 64%). MS m / z (ESI): 264.1 [M+1]

[0607] Step 2

[0608] 2-(Ethylthio)-8-(1-hydroxyethyl-1,2,2,2-d4)-3,6-dimethyl-4H-methen-4-one

[0609] Dissolve 40a (1.1 g, 4.2 mmol), triethylamine (850.0 mg, 8.4 mmol) and deuterated iodomethane (724.8 mg, 5.0 mmol) in 20 mL CH2Cl2 solvent, stir at room temperature for 5 hours, spin dry the solvent, and use silica gel column chromatography with eluent system A to obtain the title product 40b (1.1 g, yield: 91%). MS m / z (ESI): 283.1 [M+1]

[0610] Step 3

[0611] 8-(1-chloroethyl-1,2,2,2-d4)-2-(ethylthio)-3,6-dimethyl-4H-methen-4-one

[0612] 40b (1.1 g, 3.9 mmol) was dissolved in 20 mL of cyclopentylhexyl methyl ether, and cyanuric chloride (719.2 mg, 3.9 mmol) and DMF (570.1 mg, 7.8 mmol) were added in sequence. After the reaction solution was stirred at room temperature for 16 hours, 10 mL of 2M NaOH solution was added to the reaction solution, and the organic phase was separated and washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 40c (1.0 g, yield: 87%). MS m / z (ESI): 301.1 [M+1]

[0613] Step 4

[0614] 2-((1-(2-(Ethylthio)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl-1,2,2,2-d4)amino)benzoic acid ethyl

[0615] ester

[0616] 40c (1.0 g, 3.3 mmol) and ethyl 2-aminobenzoate (2.7 g, 16.5 mmol) were dissolved in 20 mL DMSO, and DIEA (2.1 g, 16.5 mmol) was added. The reaction solution was stirred at 120°C for 16 hours. After the reaction solution was cooled to room temperature, 20 mL of water was added and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 40d (964.0 mg, yield: 68%). MS m / z (ESI): 430.2 [M+1]

[0617] Step 5

[0618] 2-((1-(3,6-dimethyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-4-oxo-4H-chromen-8-yl)ethyl

[0619] -1,2,2,2-d4)amino)benzoic acid ethyl ester

[0620] Referring to the synthesis method of step 7 in Example 39, the title product 40e was obtained. MS m / z (ESI): 527.3 [M+1]

[0621] Step 6

[0622] 2-((1-(3,6-dimethyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-4-oxo-4H-chromen-8-yl)ethyl

[0623] -1,2,2,2-d4)amino)benzoic acid

[0624] Referring to the synthesis method of step 8 in Example 39, the title product 40 was obtained. MS m / z (ESI): 499.2 [M+1]

[0625] Embodiment 63

[0626]

[0627] first step

[0628] 8-Acetyl-2-(ethylthio)-3,6-dimethyl-4H-chromen-4-one

[0629] 39e (2.0 g, 6.4 mmol) was dissolved in 100 mL DMF, Pd(PPh3)2Cl2 (448.2 mg, 0.6 mmol) was added, nitrogen was replaced three times, and tributyl(1-ethoxyethylene)tin (3.5 g, 9.6 mmol) was added. The reaction solution was heated to 120°C and stirred for 3 hours. The heating was stopped, and after cooling to room temperature, 1.0 M hydrochloric acid (50 mL) was added to the reaction solution. The reaction solution was stirred for 1 hour and extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated KF solution (50 mL) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 63a (1.5 g, yield: 85%). MS m / z (ESI): 277.1 [M+1]

[0630] Step 2

[0631] Ethyl 2-((1-(2-(ethylthio)-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate

[0632] 63a (1.5 g, 5.4 mmol) was dissolved in 100 mL of dichloromethane, and ethyl 2-aminobenzoate (1.8 g, 10.8 mmol), triethylamine (1.6 g, 16.2 mmol) and titanium tetrachloride (3.1 g, 16.2 mmol) were added in sequence. The reaction solution was stirred at room temperature for 12 hours, and AcOH (972.8 mg, 16.2 mmol), sodium cyanoborohydride (1.0 g, 16.2 mmol) and MeOH (10 mL) were added. After stirring for 1 hour, the solvent was dried by spin drying, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 63b (1.6 g, yield: 70%). MS m / z (ESI): 426.2 [M+1]

[0633] Step 3

[0634] Ethyl 2-((1-(2-bromo-3,6-dimethyl-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate

[0635] 63b (1.6 g, 5.4 mmol) was dissolved in 100 mL of dichloromethane, and benzyltriethylammonium bromide (735.0 mg, 2.7 mmol) and hydrogen bromide (4.6 g, 48% wt, 27.0 mmol) were added in sequence. After the reaction solution was stirred at room temperature for 4 hours, 10 mL of saturated sodium carbonate was added to quench the reaction, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (10 mL x 2), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 63c (2.0 g, yield: 83%). MS m / z (ESI): 444.1 [M+1]

[0636] Step 4

[0637] Ethyl 2-((1-(3,6-dimethyl-2-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoate

[0638] 63c (2.0 g, 4.5 mmol), 4-ethynyl-1-methyl-1H-pyrazole (954.9 mg, 9.0 mmol), bistriphenylphosphine palladium dichloride (351.0 mg, 0.5 mmol) and cuprous iodide (171.5 mg, 0.9 mmol) were weighed in sequence, 20 mL of triethylamine was added, nitrogen was replaced, and the reaction was stirred at 90 ° C for 2 hours. 30 mL of water was poured into the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by reverse phase preparation to obtain the title product 63d (1.2 g, yield: 56%). MS m / z (ESI): 470.2 [M+1]

[0639] Step 5

[0640] 2-((1-(3,6-dimethyl-2-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-4H-chromen-8-yl)ethyl)amino)benzoic acid

[0641] Referring to the synthesis method of step 8 in Example 39, the title product 63 was obtained. MS m / z (ESI): 442.2 [M+1]

[0642] Embodiment 71

[0643]

[0644] first step

[0645] 9-Bromo-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0646] Under N2, 3-bromo-5-methylpyridin-2-amine (1 g, 5.35 mmol) was added to acetone (20 mL). Then bis(2,4,6-trichlorophenyl) 2-methylmalonate (3.06 g, 6.42 mmol) was added, the reaction solution was stirred at 65°C for 3 hours, water (15 mL) was added, and then extracted with ethyl acetate (30 mL*2), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a column (PE:EA=1:1) to obtain Example 71b (1.1 g, 76.5% yield). MS m / z(ESI):269.2[M+1]

[0647] Step 2

[0648] 9-Acetyl-2-hydroxy-3,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one

[0649] Under N2, 71b (5.16 g, 19.16 mmol) and Pd(PPh3)2Cl2 (937.90 mg, 1.15 mmol) were added to 1'4-dioxane (100 mL). Then tributyl(1-ethoxyvinyl)tin (8.99 g, 24.90 mmol) was added, the reaction solution was stirred at 100°C for 16 hours, 1M HCl (55 mL) was added, and then extracted with ethyl acetate (150 mL*2), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a column (PE:EA=3:1) to obtain Example 71c (3.5 g, 78% yield). MS m / z(ESI):233.2[M+1]

[0650] Step 3

[0651] 9-Acetyl-3,7-dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl trifluoromethanesulfonate

[0652] Under N2, 71c (1 g, 4.31 mmol) and (Tf)2O (1.82 g, 6.46 mmol) were added to tetrahydrofuran (25 mL). Then triethylamine (871 mg, 8.61 mmol) was added, the reaction solution was stirred at 25°C for 1 hour, water (15 mL) was added, and then extracted with ethyl acetate (30 mL*2), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a silica gel column (PE:EA=3:1) to obtain Example 71d (1 g, 64% yield). MS m / z (ESI): 365.3 [M+1]

[0653] Step 4

[0654] 9-acetyl-3,7-dimethyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidine-

[0655] 4-Keto

[0656] Under N2, 71d (46 mg, 126.10 μmol), Pd(dppf)Cl2 (10.24 mg, 12.61 μmol), CuTc (47.67 mg, 252.21 μmol), and Cs2CO3 (82.72 mg, 252.21 μmol) were added to dioxane (8 mL). Then 2-(1-methyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (71.92 mg, 252.21 μmol) was added, the reaction solution was stirred at 100°C for 6 hours, 1M HCl (15 mL) was added, and then extracted with ethyl acetate (50 mL*2), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a column (PE:EA=2:1) ​​to obtain Example 71e (30 mg, 64% yield). MS m / z (ESI): 374.3 [M+1]

[0657] Step 5

[0658] 2-((1-(3,7-dimethyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-4-oxo-4H-pyrido[1,2-

[0659] a]pyrimidin-9-yl)ethyl)amino)benzoic acid

[0660] Under N2, 71e (62 mg, 166 μmol) and 2-aminobenzoic acid (27 mg, 200 μmol) were added to tetrahydrofuran (5 mL). TiCl4 (35.32 mg, 187.88 μmol) was then added, and the reaction solution was stirred at 25°C for 1 hour. NaCNBH3 (11.81 mg, 187.88 μmol) and acetic acid (11.27 mg, 187.88 μmol) were further added to the reaction solution, and the reaction solution was stirred at 25°C for another 1 hour. Water (15 mL) was added, and then extracted with ethyl acetate (30 mL*2), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a silica gel column (PE:EA=1:4) to obtain Example 71 (40 mg, 49% yield). MS m / z(ESI):495.3[M+1]

[0661] Embodiment 106

[0662]

[0663] first step

[0664] 8-Acetyl-3,6-dimethyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)quinazolin-4(3H)-one

[0665] Referring to the synthesis method of step 4 in Example 71, 8-acetyl-2-chloro-3,6-dimethylquinazolin-4(3H)-one 106a was used as the starting material to obtain the title product 106b. MS m / z (ESI): 374.2 [M+1]

[0666] Step 2

[0667] 8-(1-Hydroxyethyl)-3,6-dimethyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)quinazolin-4(3H)-one

[0668] Referring to the synthesis method of the third step in Example 1, 106b was used as the starting material to obtain the title product 106. MS m / z (ESI): 495.2 [M+1]

[0669] Embodiment 133

[0670]

[0671] first step

[0672] 8-Acetyl-3,6-dimethyl-2-((1-methyl-1H-pyrazol-4-yl)ethynyl)quinazolin-4(3H)-one

[0673] 106a (200 mg, 0.80 mmol) and 4-ethynyl-1-methyl-1H-pyrazole (127 mg, 1.20 mmol) were dissolved in 2 mL DMF. Tetrakistriphenylphosphine palladium (92 mg, 0.08 mmol), cuprous iodide (15 mg, 0.08 mmol) and triethylamine (242 mg, 2.4 mmol) were added in sequence. After the addition, the reaction was heated at 80 °C for 5 hours. The solvent was concentrated under reduced pressure and the residue was purified by reverse phase preparation to obtain the title product 133a (105 mg, yield: 41.2%). MS m / z (ESI): 321.2 [M+1]

[0674] Step 2

[0675] 2-((1-(3,6-dimethyl-2-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-3,4-dihydroquinazolin-8-yl)ethyl)amino)benzoic acid

[0676] Referring to the synthesis method of the third step in Example 1, 133a was used as the starting material to obtain the title product 133.

[0677] MS m / z(ESI):442.2[M+1]

[0678] Embodiment 161

[0679]

[0680] first step

[0681] 8-Acetyl-3,6-dimethyl-2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinazolin-4(3H)-one

[0682] Referring to the synthesis method of the second step in Example 1, 8-acetyl-2-chloro-3,6-dimethylquinazolin-4(3H)-one 106a was used as the starting material to obtain the title product 161a. MS m / z (ESI): 341.2 [M+1]

[0683] Step 2

[0684] 2-((1-(3,6-dimethyl-2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-oxo-3,4-dihydroquinazoline

[0685] -8-yl)ethyl)amino)benzoic acid

[0686] Referring to the synthesis method of the third step in Example 1, 161a was used as the starting material to obtain the title product 161.

[0687] MS m / z(ESI):462.2[M+1]

[0688] Embodiment 191

[0689]

[0690] first step

[0691] 5-Acetyl-3-(isoindol-2-yl)-2,7-dimethyl-2,6-naphthyridin-1(2H)-one

[0692] Referring to the synthesis method of the second step in Example 1, 5-acetyl-3-chloro-2,7-dimethyl-2,6-naphthyridin-1(2H)-one 191a was used as the starting material to obtain the title product 191b. MS m / z (ESI): 334.2 [M+1]

[0693] Step 2

[0694] 2-((1-(7-(isoindol-2-yl)-3,6-dimethyl-5-oxo-5,6-dihydro-2,6-naphthyridin-1-yl)ethyl)amino)benzyl

[0695] acid

[0696] Referring to the synthesis method of the third step in Example 1, 191b was used as the starting material to obtain the title product 191.

[0697] MS m / z(ESI):455.2[M+1]

[0698] Embodiment 194

[0699]

[0700] first step

[0701] 5-Acetyl-2,7-dimethyl-3-phenyl-2,6-naphthyridin-1(2H)-one

[0702] Referring to the synthesis method of step 7 in Example 39, using 191a as the starting material, the title product 194a was obtained.

[0703] MS m / z(ESI):293.2[M+1]

[0704] Step 2

[0705] 2-((1-(3,6-dimethyl-5-oxo-7-phenyl-56-dihydro-2,6-naphthyridin-1-yl)ethyl)amino)benzoic acid

[0706] Referring to the synthesis method of the third step in Example 1, 194a was used as the starting material to obtain the title product 194.

[0707] MS m / z(ESI):414.2[M+1]

[0708] Embodiment 201

[0709]

[0710] first step

[0711] 4-Acetyl-6-(isoindol-2-yl)-2,7-dimethyl-1,7-naphthyridin-8(7H)-one

[0712] Referring to the synthesis method of the second step in Example 1, 4-acetyl-6-chloro-2,7-dimethyl-1,7-naphthyridin-8(7H)-one 201a was used as the starting material to obtain the title product 201b. MS m / z (ESI): 334.2 [M+1]

[0713] Step 2

[0714] 2-((1-(6-(isoindol-2-yl)-2,7-dimethyl-8-oxo-7,8-dihydro-1,7-naphthyridin-4-yl)ethyl)amino)benzoic acid

[0715] Referring to the synthesis method of the third step in Example 1, 201b was used as the starting material to obtain the title product 201. MS: m / z (ESI): 455.2 [M+1]

[0716] Embodiment 204

[0717]

[0718] first step

[0719] 4-Acetyl-2,7-dimethyl-6-phenyl-1,7-naphthyridin-8(7H)-one

[0720] Referring to the synthesis method of step 7 in Example 39, 4-acetyl-6-chloro-2,7-dimethyl-1,7-naphthyridin-8(7H)-one 201a was used as the starting material to obtain the title product 204a. MS m / z (ESI): 293.2 [M+1]

[0721] Step 2

[0722] 2-((1-(2,7-dimethyl-8-oxo-6-phenyl-7,8-dihydro-1,7-naphthyridin-4-yl)ethyl)amino)benzoic acid

[0723] Referring to the synthesis method of the third step in Example 1, 204a was used as the starting material to obtain the title product 204.

[0724] MS m / z(ESI):414.2[M+1]

[0725] Embodiment 211

[0726]

[0727] first step

[0728] 4-Acetyl-6-hydroxy-2,7-dimethyl-8H-pyrido[1,2-b]pyridazin-8-one

[0729] 211a (5.0 g, 18.6 mmol) was dissolved in 100 mL of dioxane, Pd(PPh3)2Cl2 (1.3 g, 1.9 mmol) was added, nitrogen was replaced three times, and tributyl(1-ethoxyethylene)tin (10.1 g, 27.9 mmol) was added. The reaction solution was heated to 120°C and stirred for 3 hours. The heating was stopped, and after cooling to room temperature, 1.0 M hydrochloric acid (50 mL) was added to the reaction solution. The reaction solution was stirred for 1 hour and extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated KF solution (50 mL) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 211b (3.6 g, yield: 83%). MS m / z (ESI): 233.1 [M+1]

[0730] Step 2

[0731] Ethyl 2-(6-hydroxy-2,7-dimethyl-8-oxo-8H-pyrido[1,2-b]pyridazine-4-carboxamide)benzoate

[0732] 211b (3.6 g, 15.5 mmol) was dissolved in 100 mL of dichloromethane, and ethyl 2-aminobenzoate (5.1 g, 31.0 mmol), triethylamine (4.7 g, 46.5 mmol) and titanium tetrachloride (8.8 g, 46.5 mmol) were added in sequence. The reaction solution was stirred at room temperature for 12 hours, and AcOH (2.8 g, 46.5 mmol), sodium cyanoborohydride (2.9 g, 46.5 mmol) and MeOH (10 mL) were added. After stirring for 1 hour, the solvent was dried by spin drying, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 211c (4.3 g, yield: 72%). MS m / z (ESI): 382.1 [M+1]

[0733] Step 3

[0734] Ethyl 2-(6-bromo-2,7-dimethyl-8-oxo-8H-pyrido[1,2-b]pyridazine-4-carboxamide)benzoate

[0735] 211c (4.3 g, 11.3 mmol) was dissolved in 100 mL of dichloromethane, and phosphorus tribromide (4.6 g, 17.0 mmol) was added dropwise under stirring at 0°C. After the reaction solution was stirred at room temperature for 1 hour, 1 M sodium bicarbonate solution (30 mL) was added under stirring at 0°C. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography using eluent system A to obtain the title product 211d (4.1 g, yield: 82%). MS m / z (ESI): 444.1 [M+1]

[0736] Step 4

[0737] Ethyl 2-((1-(6-(isoindolin-2-yl)-2,7-dimethyl-8-oxo-8H-pyrido[1,2-b]pyridazin-4-yl)ethyl)amino)benzoate

[0738] 211d (100 mg, 225.0 μmol) was dissolved in 3 mL DMF, and isoindoline (53.6 mg, 450.1 μmol) was added. After the reaction solution was stirred at 100 °C for 12 hours, water (5 mL) was added to quench the reaction, and it was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered and dried, and the residue was chromatographed on a silica gel column with eluent system A to obtain the title product 211e (84.7 mg, yield: 78%). MS m / z (ESI): 483.2 [M+1]

[0739] Step 5

[0740] 2-((1-(6-(isoindolin-2-yl)-2,7-dimethyl-8-oxo-8H-pyrido[1,2-b]pyridazin-4-yl)ethyl)amino)

[0741] benzoic acid

[0742] Referring to the synthesis method of step 8 in Example 39, the title product 211 was obtained. MS m / z (ESI): 455.2 [M+1]

[0743] Embodiment 221

[0744]

[0745] first step

[0746] 2-Amino-3-bromo-5-methylbenzonitrile

[0747] 221a (5.0 g, 37.8 mmol) was dissolved in 50 mL DMF, and NBS (7.1 g, 39.7 mmol) was added. The reaction solution was stirred at room temperature for 3 hours, 50 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with eluent system A to obtain the title product 221b (6.8 g, yield: 85%). MS m / z (ESI): 211.0 [M+1]

[0748] Step 2

[0749] 1-(2-Amino-3-bromo-5-methylphenyl)propan-1-one

[0750] 221b (6.8 g, 32.2 mmol) was dissolved in 100 mL THF. After nitrogen was purged, the reaction solution was stirred at 0°C, and ethylmagnesium bromide (64.4 mL, 1.0 M inTHF, 64.4 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours. 1.0 M HCl (50 mL) was added to the reaction solution at 0°C, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 221c (7.2 g, yield: 92%). MS m / z (ESI): 242.0 [M+1]

[0751] Step 3

[0752] 8-Bromo-4-hydroxy-3,6-dimethylquinoline-2(1H)-thione

[0753] 221c (7.2 g, 29.7 mmol) was dissolved in 100 mL THF. After nitrogen was replaced three times, the reaction solution was stirred at -70 °C, and then LiHMDS (89.1 mL, 1.0 M in THF, 89.1 mmol) was added dropwise to the reaction solution. The reaction solution was stirred at -70 °C for 2 hours, and CS2 (2.3 g, 29.7 mmol) was added dropwise thereto. The reaction solution was naturally warmed to room temperature and stirred for 12 hours, then poured into ice water (500 mL), and the pH of the solution was adjusted to 4 with citric acid. After the mixed solution was stirred for 2 hours, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 221d (5.8 g, yield: 69%). MS m / z (ESI): 284.0 [M+1]

[0754] Step 4

[0755] 8-Bromo-2-(ethylthio)-3,6-dimethyl-4H-bromo-4-one

[0756] 221d (5.8 g, 20.4 mmol) was dissolved in 100 mL of acetone, and K2CO3 (2.8 g, 20.4 mmol) and iodoethane (3.5 g, 22.5 mmol) were added in sequence. After the reaction solution was stirred at room temperature for 4 hours, the solvent was dried by spin drying, 50 mL of water was added to the crude product, and it was extracted with CH2Cl2 (100 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 221e (5.4 g, yield: 85%). MS m / z (ESI): 312.0 [M+1]

[0757] Step 5

[0758] 8-Acetyl-2-(ethylthio)-3,6-dimethylquinolin-4(1H)-one

[0759] 221e (5.4 g, 17.3 mmol) was dissolved in 100 mL DMF, Pd(PPh3)2Cl2 (1.2 g, 1.7 mmol) was added, nitrogen was replaced three times, and tributyl(1-ethoxyethylene)tin (9.4 g, 25.9 mmol) was added. The reaction solution was heated to 120°C and stirred for 3 hours. The heating was stopped, and after cooling to room temperature, 1.0 M hydrochloric acid (50 mL) was added to the reaction solution. The reaction solution was stirred for 1 hour and extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated KF solution (50 mL) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 221f (4.1 g, yield: 86%). MS m / z (ESI): 276.1 [M+1]

[0760] Step 6

[0761] Ethyl 2-((1-(2-(ethylthio)-3,6-dimethyl-4-oxo-1,4-dihydroquinolin-8-yl)ethyl)amino)benzoate

[0762] Under ice bath, 221f (4.1 g, 14.9 mmol), ethyl 2-aminobenzoate (3.7 g, 22.3 mmol) and triethylamine (4.5 g, 44.7 mmol) were dissolved in 30 mL of dichloromethane, titanium tetrachloride (8.5 g, 44.7 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Acetic acid (2.7 g, 44.7 mmol), sodium cyanoborohydride (2.8 g, 44.7 mmol) and methanol (5 mL) were added in sequence, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column with eluent system A to obtain the title product 221g (5.2 g, yield: 82%). MS m / z (ESI): 425.2 [M+1]

[0763] Step 7

[0764] Ethyl 2-((1-(2-(ethylsulfonyl)-3,6-dimethyl-4-oxo-1,4-dihydroquinolin-8-yl)ethyl)amino)benzoate

[0765] Dissolve 221g (5.2g, 12.3mmol) in 100mL dichloromethane, add m-CPBA (5.3g, 30.6mmol) under stirring at 0℃, stir the reaction solution at room temperature for 3 hours, add 20mL saturated NaHSO3 solution to quench the reaction, wash with 50mL water, separate the organic phase, extract the aqueous phase with dichloromethane (50mL x 2), combine the organic phases, dry over anhydrous sodium sulfate, filter and spin dry, and the residue is chromatographed on a silica gel column with eluent system A to obtain the title product 221h (4.7g, yield: 84%). MS m / z (ESI): 457.2[M+1]

[0766] Step 8

[0767] Ethyl 2-((1-(2-(isoindol-2-yl)-3,6-dimethyl-4-oxo-1,4-dihydroquinolin-8-yl)ethyl)amino)benzoate

[0768] ester

[0769] 221h (200.0 mg, 438.1 μmol) was dissolved in 5 mL THF, and isoindoline (156.6 mg, 1.3 mmol) was added. After the reaction solution was stirred at room temperature for 2 hours, the reaction solvent was dried by spin drying, and the residue was chromatographed on a silica gel column using eluent system A to obtain the title product 221i (168.4 mg, yield: 80%). MS m / z (ESI): 482.2 [M+1]

[0770] Step 9

[0771] 2-((1-(2-(isoindol-2-yl)-3,6-dimethyl-4-oxo-1,4-dihydroquinolin-8-yl)ethyl)amino)benzoic acid was synthesized by the eighth step in reference example 39 to obtain the title product 221. MS m / z (ESI): 454.2 [M+1]

[0772] Embodiment 231

[0773]

[0774] first step

[0775] 4-Bromo-2-chloro-6-methylnicotinic acid chloride

[0776] 231a (5.0 g, 20.0 mmol) was dissolved in 80 mL CH2Cl2, and oxalyl chloride (7.0 g, 60.0 mmol) and DMF (145.9 mg, 2.0 mmol) were added in sequence. The reaction solution was stirred at room temperature for 5 hours, and the solvent was dried to obtain the title product 231b (5.3 g, yield: 99%). MS m / z (ESI): 267.9 [M+1]

[0777] Step 2

[0778] 5-(4-Bromo-2-chloro-6-methylnicotinamide)-1H-pyrazole-1-carboxylic acid tert-butyl ester

[0779] 231b (5.3 g, 19.7 mmol) was dissolved in 80 mL CH2Cl2, and tert-butyl 5-amino-1H-pyrazole-1-carboxylate (5.4 g, 29.6 mmol) and triethylamine (6.0 g, 59.1 mmol) were added in sequence. The reaction solution was stirred at 50°C for 12 hours, and the solvent was dried by spin drying. The residue was chromatographed on a silica gel column with eluent system A to give the title product 231c (6.8 g, yield: 83%).

[0780] MS m / z(ESI):415.0[M+1]

[0781] Step 3

[0782] 4-Bromo-2-chloro-6-methyl-N-(1H-pyrazol-5-yl)nicotinamide

[0783] 231c (6.8 g, 16.4 mmol) was dissolved in 30 mL of 2 M hydrochloric acid-dioxane solution and stirred at room temperature for 1 hour. 20 mL of water was added to the reaction solution and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and dried to give the title product 231d (4.9 g, yield: 95%).

[0784] MS m / z(ESI):415.0[M+1]

[0785] Step 4

[0786] 6-Bromo-8-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5(4H)-one

[0787] 231d (4.9 g, 15.5 mmol) was dissolved in 20 mL DMSO, DIEA (10.0 g, 77.6 mmol) was added, and the reaction solution was stirred at 120°C for 12 hours. After the reaction solution was cooled, 30 mL of water was added to the reaction solution to precipitate solids. The solids were filtered and dried to obtain the title product 231e (3.8 g, yield: 88%). MS m / z (ESI): 279.0 [M+1]

[0788] Step 5

[0789] 6-Bromo-4-ethyl-8-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5(4H)-one

[0790] 231e (3.8 g, 13.6 mmol) was dissolved in 50 mL of acetone, and K2CO3 (2.8 g, 20.4 mmol) and iodoethane (2.3 g, 15.0 mmol) were added in sequence. After the reaction solution was stirred at room temperature for 3 hours, the solvent was dried by spin drying, 30 mL of water was added to the crude product, and it was extracted with CH2Cl2 (50 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 231f (3.4 g, yield: 81%). MS m / z (ESI): 307.0 [M+1]

[0791] Step 6

[0792] 6-Acetyl-4-ethyl-8-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-5(4H)-one

[0793] 231f (3.4 g, 11.1 mmol) was dissolved in 100 mL DMF, Pd(PPh3)2Cl2 (777.0 mg, 1.1 mmol) was added, nitrogen was replaced three times, and tributyl(1-ethoxyethylene)tin (6.0 g, 16.6 mmol) was added. The reaction solution was heated to 120°C and stirred for 3 hours. The heating was stopped, and after cooling to room temperature, 1.0 M hydrochloric acid (50 mL) was added to the reaction solution. The reaction solution was stirred for 1 hour and extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated KF solution (50 mL) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 231g (2.1 g, yield: 70%). MS m / z (ESI): 271.1 [M+1]

[0794] Step 7

[0795] Ethyl 2-((1-(4-ethyl-8-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6-yl)ethyl)amino)benzoate

[0796] The synthetic method of the second step of reference Example 63 was used to obtain the title product 231h. MS m / z (ESI): 420.2 [M+1]

[0797] Step 8

[0798] 2-((1-(4-ethyl-8-methyl-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrido[3,2-e]pyrimidin-6-yl)ethyl)amino)benzene

[0799] Formic acid

[0800] The synthetic method of step 8 of reference example 39 was used to obtain the title product 231. MS m / z (ESI): 392.2 [M+1]

[0801] Embodiment 243

[0802]

[0803] first step

[0804] 1-(4-Chloro-6-methylquinolin-8-yl)ethan-1-one

[0805] 8-Bromo-4-chloro-6-methylquinoline 243a (5.0 g, 19.5 mmol) was dissolved in 100 mL of dioxane, Pd(PPh3)4 (2.3 g, 2.0 mmol) was added, nitrogen was replaced three times, and tributyl(1-ethoxyethylene)tin (8.5 g, 23.4 mmol) was added. The reaction solution was heated to 120°C and stirred for 3 hours. The heating was stopped, and after cooling to room temperature, 1.0 M hydrochloric acid (50 mL) was added to the reaction solution. The reaction solution was stirred for 1 hour and extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated KF solution (50 mL) and saturated brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 243b (3.3 g, yield: 77%). MS m / z (ESI): 220.1 [M+1]

[0806] Step 2

[0807] 8-Acetyl-4-chloro-6-methylquinoline 1-oxide

[0808] Dissolve 243b (3.3 g, 15.0 mmol) and m-CPBA (5.2 g, 30.1 mmol) in 80 mL of dichloromethane and stir at room temperature for 2 hours. Add 30 mL of saturated sodium sulfite solution to the reaction solution, extract with dichloromethane (60 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography using eluent system A to obtain the title product 243c (3.1 g, yield: 88%). MS m / z (ESI): 236.0 [M+1]

[0809] Step 3

[0810] 1-(2,4-Dichloro-6-methylquinolin-8-yl)ethan-1-one

[0811] 243c (3.1 g, 13.2 mmol) was dissolved in 20 mL of phosphorus oxychloride, heated to 80 °C and stirred for 2 hours. After the reaction solution was cooled to room temperature, it was poured into 50 mL of water, stirred thoroughly, extracted with dichloromethane (30 mL × 3), the organic phases were combined, washed with saturated sodium bicarbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title product 243d (3.1 g, yield: 93%). MS m / z (ESI): 254.0 [M+1]

[0812] Step 4

[0813] 1-(2,4-Dichloro-6-methylquinolin-8-yl)ethan-1-ol

[0814] 243d (3.1 g, 12.2 mmol) was dissolved in 40 mL of a mixed solvent of dichloromethane and methanol (V / V=1:1), and NaBH4 (553.8 mg, 14.6 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. 50 mL of water was added, the organic phase was separated, the aqueous phase was extracted with dichloromethane (30 mL×2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title product 243e (2.8 g, yield: 90%). MS m / z (ESI): 256.0 [M+1]

[0815] Step 5

[0816] 8-(1-Bromoethyl)-2,4-dichloro-6-methylquinoline

[0817] 243e (2.8 g, 10.9 mmol) was dissolved in 40 mL of dichloromethane solvent, and phosphorus tribromide (5.9 g, 21.9 mmol) was added dropwise. The reaction solution was stirred at room temperature for 1 hour. 30 mL of saturated sodium bicarbonate was added under ice-water bath conditions, the organic phase was separated, the aqueous phase was extracted with dichloromethane (30 mL×2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title product 243f (3.1 g, yield: 89%). MS m / z (ESI): 317.9 [M+1]

[0818] Step 6

[0819] Methyl 2-((1-(2,4-dichloro-6-methylquinolin-8-yl)ethyl)amino)benzoate

[0820] 243f (3.1 g, 9.7 mmol) and methyl 2-aminobenzoate (2.9 g, 19.4 mmol) were dissolved in 20 mL of DMF solvent, and the reaction solution was stirred at 80°C for 12 hours. After the reaction solution was cooled to room temperature, 40 mL of water was added, and it was extracted with ethyl acetate (20 mL×4), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title product 243g (3.2 g, yield: 85%).

[0821] MS m / z(ESI):389.1[M+1]

[0822] Step 7

[0823] 2-((1-(4-chloro-6-methyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)quinolin-8-yl)ethyl)amino)

[0824] Methyl benzoate

[0825] 243g (3.2mg, 8.2mmol), (6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)boric acid (2.5g, 12.3mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (648.5mg, 0.8mmol) and potassium carbonate (3.4g, 24.6mmol) were weighed in sequence, 20mL of dioxane aqueous solution (V / V=4:1) was added, nitrogen was replaced, and the reaction was stirred at 80°C for 1 hour. The reaction solution was poured into 30mL of water and extracted with ethyl acetate (30mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title product 243h (3.8g, yield: 90%). MS m / z(ESI):512.2[M+1]

[0826] Step 8

[0827] Methyl 2-((1-(4-amino-6-methyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)quinolin-8-yl)ethyl)amino)benzoate

[0828] 243h (3.8 g, 7.4 mmol) was dissolved in 20 mL of ethanol, and 10 mL of ammonia solution (4 M in dioxane) was added. The reaction was stirred at 80 ° C for 12 hours in a sealed container. The reaction solution was poured into 50 mL of water, stirred and precipitated, and the title product 243i (3.1 g, yield: 85%) was obtained after suction filtration. MS m / z (ESI): 493.2 [M+1]

[0829] Step 9

[0830] Methyl 2-((1-(4-acrylamido-6-methyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)quinolin-8-yl)ethyl)amino)benzoate

[0831] 243i (100.0 mg, 0.2 mmol) was dissolved in 5 mL of dichloromethane, triethylamine (61.6 mg, 0.6 mmol) and acryloyl chloride (36.8 mg, 0.4 mmol) were added in sequence, and the reaction was stirred at room temperature for 2 hours. The reaction solvent was dried and the residue was purified by silica gel column chromatography to obtain the title product 243j (81.5 mg, yield: 73%). MS m / z (ESI): 547.2 [M+1]

[0832] Step 10

[0833] 2-((1-(4-Acrylamido-6-methyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)quinolin-8-yl)ethyl)amino)benzoic acid

[0834] 243j (81.5 mg, 0.15 mmol) was dissolved in 2 mL of methanol, and a solution of K2CO3 (41.2 mg, 0.3 mmol) in water (0.5 mL) was added. The reaction solution was stirred at 50°C for 5 hours. After cooling to room temperature, 1 M hydrochloric acid (2 mL) was added and extracted with dichloromethane (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the residue was chromatographed on a silica gel column using eluent system A to obtain the title product 243 (51.4 mg, yield: 65%). MS m / z (ESI): 533.2 [M+1]

[0835] Embodiment 267

[0836]

[0837] first step

[0838] 5-Bromo-2-(1-methyl-1H-pyrazol-4-yl)pyridine

[0839] 2,5-Dibromopyridine 267a (50 g, 211.1 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (26.6 g, 211.1 mmol) were dissolved in 1 L of 1,4-dioxane, and tetrakis(triphenylphosphine)palladium (12.2 g, 10.6 mmol) and 200 mL of 2M potassium carbonate aqueous solution were added in sequence, and the mixture was stirred at 90 degrees for 5 hours. After cooling to room temperature, 1 L of water was added to quench the mixture, and the mixture was extracted with ethyl acetate (600 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (1200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 267b (35.8 g) with a yield of 71.2%. MS m / z (ESI): 239.1 [M+1]

[0840] Step 2

[0841] 2-Hydroxy-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)acetic acid

[0842] Isopropylmagnesium chloride lithium chloride complex (2M tetrahydrofuran solution, 75.2mL, 150.4mmol) was diluted in 200mL anhydrous tetrahydrofuran, 267b (35.8g, 150.4mmol) was added under ice bath, stirred at 20 degrees for 0.5 hours, ethyl glyoxylate (29.8mL, 150.4mmol) was added, and stirred at 20 degrees for 2 hours. The reaction solution was quenched with 300mL saturated aqueous ammonium chloride solution, extracted with ethyl acetate (300mL×3), the organic phases were combined, washed with saturated brine (500mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 267c (31.7g), yield: 80.7%. MS m / z (ESI): 262.2[M+1]

[0843] Step 3

[0844] Ethyl 2-bromo-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)acetate

[0845] 267c (31.7 g, 121.3 mmol) was dissolved in 250 mL of dichloromethane, and carbon tetrabromide (44.3 g, 133.5 μmol) and triphenylphosphine (35 g, 133.5 μmol) were added in sequence, and the mixture was stirred at 25 degrees for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 267d (32.5 g), with a yield of 82.6%.

[0846] MS m / z(ESI):325.2[M+1]

[0847] Step 4

[0848] 4-Methyl-2-(2-methyl-1,3-dioxolan-2-yl)-6-nitrophenol

[0849] 1-(2-Hydroxy-5-methyl-3-nitrophenyl)ethane-1-one 267e (30 g, 153.7 mmol) and ethylene glycol (10.3 mL, 184.5 mmol) were dissolved in 300 mL of toluene, p-toluenesulfonic acid (2.65 g, 15.4 mmol) was added, and the mixture was stirred at 110 degrees for 6 hours. The mixture was concentrated under reduced pressure to remove toluene, and a saturated aqueous sodium bicarbonate solution was added dropwise until the pH of the reaction solution was 6. 100 mL of water was added, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined, washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 267f (33.2 g) with a yield of 90.3%. MS m / z (ESI): 240.1 [M+1]

[0850] Step 5

[0851] 2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-(4-methyl-2-(2-methyl-1,3-dioxolan-2-yl)-6-nitrophenoxy)

[0852] Ethyl acetate

[0853] 267f (12 g, 50.2 mmol) was dissolved in 100 mL of N,N-dimethylformamide, potassium carbonate (13.9 g, 100.3 mmol) and 267d (16.3 g, 50.2 mmol) were added in sequence, and the mixture was stirred at 25 degrees for 16 hours. 500 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 267g (18.6 g), with a yield of 76.9%. MS m / z (ESI): 483.2 [M+1]

[0854] Step 6

[0855] 6-methyl-8-(2-methyl-1,3-dioxolan-2-yl)-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2H-benzo[b][1,4]

[0856] Oxazine-3(4H)-one

[0857] Dissolve 267g (18.6g, 38.6mmol) in 200mL methanol, add 10% palladium carbon (2.1g, 1.9mmol), stir at 30 degrees for 16 hours. Filter the reaction solution, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system A to obtain the title product 267h (12.8g), yield: 81.7%. MS m / z (ESI): 407.1 [M+1]

[0858] Step 7

[0859] 6-methyl-8-(2-methyl-1,3-dioxolan-2-yl)-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-4H-benzo[b][1,4]oxathiolan

[0860] Oxazine

[0861] Sodium borohydride (3.6 g, 94.5 mmol) was suspended in 60 mL of tetrahydrofuran, and boron trifluoride ether complex (17.9 g, 126.0 mmol) was added dropwise under ice bath. After stirring at 0 degrees for 0.2 hours, 30 mL of 267h (12.8 g, 31.5 mmol) tetrahydrofuran solution was added, and the mixture was stirred at 20 degrees for 2 hours. After the reaction solution was cooled with ice water, 50 mL of water was added dropwise, and saturated sodium bicarbonate aqueous solution was added to adjust the pH>7, and the mixture was extracted with ethyl acetate (80 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 267i (8.5 g), with a yield of 69.1%. MS m / z (ESI): 391.1 [M+1]

[0862] Step 8

[0863] 1-(6-methyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-4H-benzo[b][1,4]oxazin-8-yl)ethan-1-one

[0864] Dissolve 267i (8.5 g, 21.8 mmol) in 100 mL of tetrahydrofuran, add 40 mL of 1N hydrochloric acid, and stir at 60 degrees for 2 hours. Remove tetrahydrofuran by concentration under reduced pressure, add saturated sodium bicarbonate aqueous solution until the pH of the reaction solution is 7, add 50 mL of water, extract with ethyl acetate (60 mL×3), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title product 267j (5.1 g), yield: 67.6%. MS m / z (ESI): 347.1 [M+1]

[0865] Step 9

[0866] Ethyl 2-((1-(6-methyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-4H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)benzoate

[0867] Under ice bath, 267j (600 mg, 1.7 mmol), ethyl 2-aminobenzoate (429 mg, 2.6 mmol) and triethylamine (0.72 mL, 5.2 mmol) were dissolved in 20 mL of dichloromethane, titanium tetrachloride (0.57 mL, 5.2 mmol) was added, and the mixture was stirred at 25°C for 12 hours. Acetic acid (0.3 mL, 5.2 mmol), sodium cyanoborohydride (326.6 mg, 5.2 mmol) and methanol (1.2 mL) were added in sequence, and the mixture was stirred at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title product 267k (245 mg) with a yield of 28.5%. MS m / z (ESI): 496.2 [M+1]

[0868] Step 10

[0869] 2-((1-(6-methyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-4H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)benzyl

[0870] acid

[0871] 267k (245 mg, 0.5 mmol) was dissolved in 6 mL methanol and 3 mL water, potassium carbonate (136.7 mg, 1.0 mmol) was added, and the mixture was stirred at 80 degrees for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title product 267l (184 mg), with a yield of 79.6%. MS m / z (ESI): 468.1 [M+1]

[0872] Step 11

[0873] 2-((1-(4-Acryloyl-6-methyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-4H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)benzoic acid

[0874] 267l (50 mg, 0.11 mmol) was dissolved in 10 mL of dichloromethane, triethylamine (30 μL, 0.22 mmol) and acryloyl chloride (13 μL, 0.16 mmol) were added in sequence, and the mixture was stirred at 25 degrees for 16 hours. 15 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain the title product 267 (13.2 mg), with a yield of 23.7%. MS m / z (ESI): 522.2 [M+1]

[0875] Embodiment 273

[0876] 2-((1-(4-Acryloyl-2-(isoindol-2-yl)-6-methyl-4H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)benzoic acid

[0877]

[0878] first step

[0879] 2-Amino-4-methyl-6-(2-methyl-1,3-dioxolan-2-yl)phenol

[0880] 267f (10 g, 41.8 mmol) was dissolved in 160 mL of methanol, and 10% palladium on carbon (2.2 g, 2.1 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 273a (8.1 g) with a yield of 92.6%. MS m / z (ESI): 210.1 [M+1]

[0881] Step 2

[0882] 2-Chloro-6-methyl-8-(2-methyl-1,3-dioxolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0883] 273a (8.1 g, 38.7 mmol) was dissolved in 80 mL of acetone, potassium carbonate (10.7 g, 77.4 mmol) and dichloroacetyl chloride (3.7 mL, 38.7 mmol) were added in sequence, and the mixture was stirred at 60 degrees for 16 hours. After the reaction solution was cooled, it was poured into ice water, and the solid was precipitated. The solid was filtered and the filter cake was purified by recrystallization to obtain the title product 273b (6.8 g) with a yield of 61.9%. MS m / z (ESI): 285.1 [M+1]

[0884] Step 3

[0885] 2-(Isoindolin-2-yl)-6-methyl-8-(2-methyl-1,3-dioxolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[0886] 273b (6.8 g, 24.0 mmol) was dissolved in 50 mL of toluene, triethylamine (6.7 mL, 47.9 mmol) and isoindoline (3.4 g, 28.8 mmol) were added in sequence, and the mixture was stirred at 110 degrees for 5 hours. 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 273c (4.2 g), with a yield of 47.9%. MS m / z (ESI): 367.1 [M+1]

[0887] Step 4

[0888] 2-(Isoindolin-2-yl)-6-methyl-8-(2-methyl-1,3-dioxolan-2-yl)-4H-benzo[b][1,4]oxazine

[0889] Sodium borohydride (1.3 g, 34.4 mmol) was suspended in 20 mL of tetrahydrofuran, and boron trifluoride ether complex (6.5 g, 45.9 mmol) was added dropwise under ice bath. After stirring at 0 degrees for 0.2 hours, 10 mL of 273c (4.2 g, 11.5 mmol) in tetrahydrofuran was added, and the mixture was stirred at 20 degrees for 2 hours. After the reaction solution was cooled with ice water, 20 mL of water was added dropwise, and saturated sodium bicarbonate aqueous solution was added to adjust the pH>7, and extracted with ethyl acetate (30 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 273d (2.7 g), with a yield of 67.2%. MS m / z (ESI): 351.1 [M+1]

[0890] Step 5

[0891] 1-(2-(Isoindol-2-yl)-6-methyl-4H-benzo[b][1,4]oxazin-8-yl)ethan-1-one

[0892] Dissolve 273d (2.7 g, 7.7 mmol) in 40 mL of tetrahydrofuran, add 15 mL of 1N hydrochloric acid, and stir at 60 degrees for 2 hours. Concentrate under reduced pressure to remove tetrahydrofuran, add saturated sodium bicarbonate aqueous solution until the pH of the reaction solution is 7, add 30 mL of water, extract with ethyl acetate (30 mL×3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title product 273e (1.9 g), yield: 80.5%. MS m / z (ESI): 307.1 [M+1]

[0893] Step 6

[0894] Ethyl 2-((1-(2-(isoindolin-2-yl)-6-methyl-4H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)benzoate

[0895] Under ice bath, 273e (800 mg, 2.6 mmol), ethyl 2-aminobenzoate (647 mg, 3.9 mmol) and triethylamine (1.1 mL, 7.8 mmol) were dissolved in 28 mL of dichloromethane, titanium tetrachloride (0.86 mL, 7.8 mmol) was added, and the mixture was stirred at 25°C for 12 hours. Acetic acid (0.45 mL, 7.8 mmol), sodium cyanoborohydride (492.3 mg, 7.8 mmol) and methanol (2 mL) were added in sequence, and the mixture was stirred at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title product 273f (330 mg) with a yield of 27.7%. MS m / z (ESI): 456.2 [M+1]

[0896] Step 7

[0897] 2-((1-(2-(isoindolin-2-yl)-6-methyl-4H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)benzoic acid

[0898] Dissolve 273f (330 mg, 0.7 mmol) in 8 mL methanol and 4 mL water, add potassium carbonate (200.2 mg, 1.4 mmol), and stir at 80 degrees for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title product 273g (230 mg), with a yield of 74.3%. MS m / z (ESI): 428.1 [M+1]

[0899] Step 8

[0900] 2-((1-(4-Acryloyl-2-(isoindol-2-yl)-6-methyl-4H-benzo[b][1,4]oxazin-8-yl)ethyl)amino)benzoic acid

[0901] Dissolve 273g (50mg, 0.12mmol) in 10mL dichloromethane, add triethylamine (33μL, 0.24mmol) and acryloyl chloride (14μL, 0.18mmol) in sequence, and stir at 25 degrees for 16 hours. Add 15mL of water to the reaction solution, extract with dichloromethane (10mL×3), combine the organic phases, wash with saturated brine (15mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative high performance liquid chromatography to obtain the title product 273 (15.3mg), yield: 27.2%. MS m / z (ESI): 482.2 [M+1]

[0902] Embodiment 279

[0903]

[0904] first step

[0905] tert-Butyl (8-bromo-2-(ethylthio)-6-methyl-4H-chromen-4-yl)carbamate

[0906] Under N2, (8-bromo-2-(ethylthio)-6-methyl-4H-chromen-4-yl)amino (1.5 g, 5 mmol), TEA (1.3 g, 12.8 mmol,) were added to THF (20 mL). Then (Boc)2O (1.3 g, 6 mmol) was added, the reaction solution was stirred at 25°C for 1 hour, water (15 mL) was added, and then extracted with ethyl acetate (30 mL*2), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a column (PE:EA=3:1) to obtain Example 279b (1.8 g, 90% yield).

[0907] MS m / z(ESI):400.2[M+1]

[0908] Step 2

[0909] tert-Butyl (8-acetyl-2-(ethylthio)-6-methyl-4H-chromen-4-yl)carbamate

[0910] Under N2, 279b (7.7 g, 19.2 mmol) and Pd(PPh3)2Cl2 (1.56 g, 1.92 mmol) were added to 1'4-Dioxane (100 mL). Then, tributyl(1-ethoxyvinyl)stannane (8.30 g, 22.99 mmol) was added, and the reaction solution was stirred at 100°C for 12 hours, and 1M HCl (55 mL) was added and stirred for 2 hours to remove the ethyl group, and then extracted with ethyl acetate (150 mL*2). 100 mL of an aqueous solution of about 20 g of potassium fluoride was added to the organic phase, filtered to remove the tin reagent, and then extracted with ethyl acetate (150 mL*2), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a column (PE:EA=3:1) to obtain Example 279c (5 g, 72% yield). MS m / z(ESI):364.2[M+1]

[0911] Step 3

[0912] tert-Butyl (2-(ethylthio)-8-(1-hydroxyethyl)-6-methyl-4H-chromen-4-yl)carbamate

[0913] At 0°C, 279c (5.32 g, 14.47 mmol), NaBH4 (657.12 mg, 17.37 mmol) were added to MeOH (40 mL), dichloromethane (40 mL). The reaction solution was stirred at 25°C for 0.2 hours, water (50 ml) was added, and then extracted with dichloromethane (50 mL*2), and the combined extracts were dried over Na2SO4 and spin-dried to give Example 279d (5 g, 93% yield). MS m / z (ESI): 366.3 [M+1]

[0914] Step 4

[0915] tert-Butyl (8-(1-bromoethyl)-2-(ethylthio)-6-methyl-4H-chromen-4-yl)carbamate

[0916] At 0°C, 279d (5 g, 13.65 mmol) and PBr3 (5.54 g, 20.48 mmol, 1.92 mL) were added to DCM (45 mL). The reaction solution was stirred at 25°C for 0.2 hours, 1 M sodium bicarbonate (35 mL) was added at 0°C, and then extracted with dichloromethane (50 ml*2), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a column (PE:EA=4:1) to obtain Example 279e (5 g, 85% yield). MS m / z (ESI): 428.3 [M+1]

[0917] Step 5

[0918] 2-((1-(4-(tert-Butoxycarbonyl)amino)-2-(ethylthio)-6-methyl-4H-chromen-8-yl)ethyl)amino)benzene

[0919] Formic acid

[0920] 279e (4.7 g, 11.2 mmol) was added to DMF (45 mL). Then 2-aminobenzoic acid (3.45 g, 22.4 mmol) was added, the reaction solution was stirred at 80°C for 12 hours, water (35 mL) was added, and then extracted with ethyl acetate (50 mL*2), and the combined extracts were washed several times with saturated brine to remove the amine of the raw material, and then dried over Na2SO4, spin-dried, and passed through a column (PE:EA=3:1) to obtain Example 279f (4.5 g, 83% yield). MS m / z (ESI): 485.3 [M+1]

[0921] Step 6

[0922] 2-((1-(4-((tert-butoxycarbonyl)amino)-6-methyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-

[0923] (4H-chromen-8-yl)ethyl)amino)benzoic acid

[0924] Under N2, 279f (550 mg, 1.13 mmol), Pd(dppf)Cl2 (92.16 mg, 113.49 μmol), CuTC (429.01 mg, 2.27 mmol), Cs2CO3 (744.52 mg, 2.27 mmol) were added to dioxane (12 mL). Then 2-(1-methylpyrazol-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (647.25 mg, 2.27 mmol) was added, the reaction solution was stirred at 100°C for 12 hours, water (15 mL) was added, and then extracted with ethyl acetate (50 mL*2), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a column (PE:EA=1:1) to obtain Example 279fg (0.25 g, 38% yield). MS m / z(ESI):582.3[M+1]

[0925] Step 7

[0926] 2-((1-(4-amino-6-methyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-4H-chromen-8-yl)ethyl)amino)benzoic acid

[0927] Under N2, 279g (500mg, 0.86mmol) was added to 4M hydrochloric acid / dioxane (8mL). The reaction solution was stirred at 25°C for 1 hour and dried to give Example 279h (0.4g, 97% yield). MS m / z (ESI): 482.3 [M+1]

[0928] Step 8

[0929] 2-((1-(4-Acrylamido-6-methyl-2-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-4H-chromene-8-

[0930] 1-(4-(2-ethyl)amino)benzoic acid

[0931] Under N2, 279h (500 mg, 0.42 mmol) and acryloyl chloride (45 mg, 498 μmol) were added to dichloromethane (12 mL). Then triethylamine (84 mg, 0.83 mmol) was added, the reaction solution was stirred at 25°C for 1 hour, water (15 mL) was added, and then extracted with ethyl acetate (50 mL*2), and the combined extracts were dried over Na2SO4, spin-dried, and passed through a column (PE:EA=1:1) to obtain Example 279 (0.15 g, 67% yield). MS m / z (ESI): 536.3 [M+1]

[0932] Embodiment 315

[0933]

[0934] first step

[0935] 1-(7-Methoxynaphthalen-1-yl)ethan-1-one

[0936] 1-Bromo-7-methoxynaphthalene 315a (5.0 g, 21.1 mmol) was dissolved in 100 mL of dioxane, and Pd(dppf)Cl2.CH2Cl2 (1.7 g, 2.1 mmol) was added. After nitrogen was replaced three times, tributyl(1-ethoxyethylene)tin (9.1 g, 25.3 mmol) was added. The reaction solution was heated to 110°C and stirred for 6 hours. The heating was stopped. After cooling to room temperature, 1.0 M hydrochloric acid (50 mL) was added to the reaction solution, and the mixture was stirred for 0.5 hours. 2.0 M KF solution (50 mL) was added and stirred for 0.5 hours. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and dried, and the residue was chromatographed on a silica gel column using eluent system A to obtain the title product 315b (3.8 g, yield: 90%). MS m / z (ESI): 201.1 [M+1]

[0937] Step 2

[0938] 1-(6-Bromo-7-methoxynaphthalen-1-yl)ethan-1-one

[0939] 315b (3.8 g, 19.0 mmol) was dissolved in 100 mL of dichloromethane, and NBS (3.6 g, 20.0 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The solvent was dried, followed by 50 mL of water, and the mixture was filtered after vigorous stirring and washed with 50 mL of water to obtain the title product 315c (5.1 g, yield: 96%). MS m / z (ESI): 279.0 [M+1]

[0940] Step 3

[0941] 1-(6-Hydrazino-7-methoxynaphthalen-1-yl)ethan-1-one

[0942] 315c (5.1 g, 18.3 mmol) was dissolved in 50 mL of ethylene glycol methyl ether, 5 mL of hydrazine hydrate was added, and the mixture was heated to 120°C and stirred for 5 hours. After the reaction solution was cooled to room temperature, it was filtered and washed with 30 mL of ethanol. The filter cake was dried to obtain the title product 315d (4.1 g, yield: 97%). MS m / z (ESI): 231.1 [M+1]

[0943] Step 4

[0944] 7-Acetyl-5-methoxybenzo[f]cinnolin-2(3H)-one

[0945] 315d (4.1 g, 17.8 mmol) was dissolved in 50 mL of dichloromethane, and then diethoxyacetyl chloride (3.0 g, 17.8 mmol) and triethylamine (3.6 g, 35.6 mmol) were added to the mixed solvent. After the reaction solution was stirred at room temperature for 16 hours, saturated ammonium chloride (10 mL) was added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was stirred at 0 ° C, and 20 mL of concentrated sulfuric acid was added dropwise. The reaction solution was naturally heated to room temperature and stirred for 12 hours. Saturated sodium bicarbonate (50 mL) was added to quench the reaction, and extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and dried, and the residue was chromatographed on a silica gel column with eluent system A to obtain the title product 315e (1.8 g, yield: 38%). MS m / z (ESI): 269.1 [M+1]

[0946] Step 5

[0947] Methyl 2-((1-(5-methoxy-2-oxo-2,3-dihydrobenzo[f]cinnolin-7-yl)ethyl)amino)benzoate was prepared by the synthesis method of step 7 of reference Example 13 to obtain the title product 315f. MS m / z (ESI): 404.2 [M+1]

[0948] Step 6

[0949] Methyl 2-((1-(5-hydroxy-2-oxo-2,3-dihydrobenzo[f]cinnolin-7-yl)ethyl)amino)benzoate

[0950] 315f (1.5 g, 3.7 mmol) was dissolved in 30 mL of dichloromethane. The reaction solution was stirred in a dry ice acetone bath at -70°C, and 15 mL of a 1.0 M dichloromethane solution of boron tribromide was added dropwise. The reaction solution was naturally warmed to room temperature and stirred for 2 hours. 10 mL of saturated sodium bicarbonate was added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title product 315g (1.2 g, yield: 83%). MS m / z (ESI): 390.1 [M+1]

[0951] Step 7

[0952] Methyl 2-((1-(5-bromo-2-oxo-2,3-dihydrobenzo[f]cinnolin-7-yl)ethyl)amino)benzoate

[0953] At 0°C, 315g (1.2g, 3.1mmol) was added to DCM (30mL), followed by PBr3 (1.3g, 4.6mmol). The reaction solution was naturally warmed to room temperature and stirred for 2 hours. At 0°C, 1M sodium bicarbonate (30mL) was added, and then extracted with dichloromethane (30mL x 3), and the combined extracts were dried over Na2SO4, spin-dried, and the resulting residue was purified by silica gel column chromatography to obtain Example 315h (1.1g, 79% yield). MS m / z (ESI): 452.1 [M+1]

[0954] Step 8

[0955] Methyl 2-((1-(5-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-oxo-2,3-dihydrobenzo[f]cinnolin-7-yl)ethyl)amino)benzoate

[0956] Referring to the synthesis method of step 7 of Example 243, the title product 315i was obtained. MS m / z (ESI): 531.2 [M+1]

[0957] Step 9

[0958] 2-((1-(5-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2-oxo-2,3-dihydrobenzo[f]cinnolin-7-yl)ethyl)amino)benzoic acid

[0959] 315i (100 mg, 0.19 mmol) was dissolved in 5 mL methanol, and a solution of K2CO3 (52.1 mg, 0.4 mmol) in water (1 mL) was added. The reaction solution was stirred at 50°C for 5 hours. After cooling to room temperature, 1 M hydrochloric acid (2 mL) was added and extracted with dichloromethane (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and the residue was chromatographed on a silica gel column using eluent system A to obtain the title product 315 (58 mg, yield: 60%). MS m / z (ESI): 517.2 [M+1]

[0960] Embodiment 354

[0961]

[0962] first step

[0963] 6-Methylpyridone[3,4-d]pyrimidine-2,4(1H,3H)-dione

[0964] 5-Amino-2-methyl-4-carboxypyridine 354a (5.0 g, 32.9 mmol) was dissolved in 100 mL of acetic acid, and urea (19.7 g, 328.6 mmol) was added. The reaction solution was stirred at 110°C for 5 hours, cooled to room temperature, and the solvent was dried by spin drying. 100 mL of water was added to the crude product, stirred, filtered, and washed with 50 mL of water. The solid was drained to obtain the title product 354b (4.2 g, yield: 72%). MS m / z (ESI): 178.1 [M+1]

[0965] Step 2

[0966] 2,4-Dichloro-6-methylpyridone[3,4-d]pyrimidine

[0967] The synthetic method of the fourth step of reference Example 31 was used to obtain the title product 354c. MS m / z (ESI): 214.0 [M+1]

[0968] Step 3

[0969] 2-Chloro-4-hydrazino-6-methylpyrido[3,4-d]pyrimidine

[0970] 354c (4.0 g, 18.7 mmol) was dissolved in 50 mL of ethanol, hydrazine hydrate (1.1 g, 80%, 28.1 mmol) was added, and the reaction solution was stirred at 100°C for 2 hours. After the reaction solution was cooled to room temperature, the solvent was dried to obtain the title product 354d (4.0 g, yield: 100%). MS m / z (ESI): 210.1 [M+1]

[0971] Step 4

[0972] 5-Chloro-9-methylpyridone[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine

[0973] Dissolve 354d (3.8 g, 18.1 mmol) in 100 mL of dichloromethane, add trimethyl orthoformate (19.2 g, 181.3 mmol) and trifluoroacetic acid (2.1 g, 18.1 mmol). Stir the reaction mixture at room temperature for 2 hours. The solvent was dried and the residue was purified by silica gel column chromatography using eluent system B to obtain the title product 354e (3.5 g, yield: 88%). MS m / z (ESI): 220.0 [M+1]

[0974] Step 5

[0975] 9-Methyl-5-vinylpyrido[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine

[0976] 354e (3.0 g, 13.7 mmol), vinylboronic acid (1.5 g, 20.5 mmol), potassium carbonate (5.7 g, 41.0 mmol), Pd(dppf)Cl2 (1.0 g, 1.4 mmol) were dispersed in 50 mL of a mixed solvent of dioxane and water (V / V=4:1), heated to 80°C and stirred for 4 hours. After cooling to room temperature, the mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title product 354f (2.4 g, yield: 83%). MS m / z (ESI): 212.1 [M+1]

[0977] Step 6

[0978] 5-Ethyl-9-methylpyridone[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine

[0979] 354f (2.4 g, 11.4 mmol) and 10% Pd / C (120 mg) were dispersed in 50 mL of tetrahydrofuran, and the hydrogen was replaced three times. The reaction was stirred at 50°C for 3 hours. The reaction solution was filtered through a short column of diatomaceous earth and washed with 50 mL of ethyl acetate. After the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title product 354g (2.1 g, yield: 87%). MS m / z (ESI): 214.1 [M+1]

[0980] Step 7

[0981] 5-Ethyl-9-methylpyrido[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine 8-oxide was synthesized by the second step of reference Example 243 to obtain the title product 354h. MS m / z (ESI): 230.1 [M+1]

[0982] Step 8

[0983] 7-Bromo-5-ethyl-9-methylpyridone[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine was synthesized by referring to the third step of Example 243 to obtain the title product 354i. MS m / z (ESI): 292.0 [M+1]

[0984] Step 9

[0985] 1-(5-ethyl-9-methylpyridone[4,3-e][1,2,4]triazol[4,3-c]pyrimidin-7-yl)ethan-1-one was prepared by the synthesis method of step 6 of reference Example 13 to obtain the title product 354j. MS m / z (ESI): 256.1 [M+1]

[0986] Step 10

[0987] 2-((1-(5-ethyl-9-methylpyrido[4,3-e][1,2,4]triazolo[4,3-c]pyrimidin-7-yl)ethyl)amino)benzoic acid was prepared by the synthesis method of step 7 of reference Example 13 to obtain the title product 354. MS m / z (ESI): 377.2 [M+1]

[0988] Embodiment 374

[0989]

[0990] first step

[0991] 1-(3-Nitropyridin-2-yl)ethane-1-amine

[0992] 3-Nitro-2-cyanopyridine 374a (10.0 g, 67.1 mmol) was dissolved in 100 mL of tetrahydrofuran. After nitrogen was replaced three times, the reaction solution was stirred in a dry ice-ethanol bath at -70 °C, and then methylmagnesium bromide (3.0 M in ) was added dropwise. 2-methyl-THF, 26.8mL, 80.5mmol), the reaction solution was stirred at -70℃ for 0.5 hours, and then continued to stir at room temperature for 1 hour. Then, MeOH (30mL) was slowly added dropwise to the reaction solution under 0℃ ice bath conditions. After stirring at 0℃ for 0.5 hours, NaBH4 (1.5g, 40.2mmol) was slowly added. The reaction solution was stirred at room temperature for 2 hours. Ice water (10mL) was added to the reaction solution, stirred for 0.5 hours, and the solvent was dried by spin drying. Dichloromethane (50mL) was added to the obtained crude product, and after sufficient stirring, it was filtered through a short diatomaceous earth column and washed with 200mL of dichloromethane. The filtrate was dried by spin drying. The residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 374b (5.8g, yield: 52%). MS m / z (ESI): 168.1[M+1]

[0993] Step 2

[0994] N-(1-(3-Nitropyridin-2-yl)ethyl)formamide

[0995] 374b (5.5 g, 19.0 mmol) was dissolved in 50 mL of methanol, and ethyl formate (10 mL) was added. The reaction solution was stirred at room temperature for 16 hours. The solvent was dried to give the title product 374c (6.4 g, yield: 100%). MS m / z (ESI): 196.1 [M+1]

[0996] Step 3

[0997] 1-Methyl-8-nitroimidazo[1,5-a]pyridine

[0998] 374c (5.1 g, 30.7 mmol) was dissolved in 100 mL of toluene, heated to 100 °C and stirred, then phosphorus oxychloride (7.1 g, 46.1 mmol) was added, and the reaction solution was stirred at 100 °C for 2 hours. After the reaction solution was cooled to room temperature, the reaction solution was slowly poured into 30 mL of saturated sodium carbonate solution and extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 374d (4.2 g, yield: 91%). MS m / z (ESI): 178.1 [M+1]

[0999] Step 4

[1000] 1-Methylimidazo[1,5-a]pyridin-8-amine

[1001] 374d (4.0 g, 22.6 mmol) was dissolved in a mixed solution of 50 mL ethanol and 5 mL glacial acetic acid, and ammonium chloride (6.0 g, 112.9 mmol) was added. The temperature was raised to 50°C, and reduced iron powder (6.3 g, 112.9 mmol) was added in batches at this temperature. The reaction mixture was heated at 80°C for 1 hour. The reaction solution was concentrated under reduced pressure, 100 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 374e (2.8 g, yield: 84%). MS m / z(ESI):148.1[M+1]

[1002] Step 5

[1003] 5-Bromo-1-methylimidazo[1,5-a]pyridin-8-amine

[1004] Referring to the synthesis method of the first step of Example 25, the title product 374f was obtained. MS m / z (ESI): 226.0 [M+1]

[1005] Step 6

[1006] 6-Bromo-2,10-dimethylimidazo[1,5-h][1,7]naphthyridin-4-ol

[1007] Polyphosphoric acid (10 g) was added to 374f (3.5 g, 15.5 mmol) and ethyl acetoacetate (3.0 g, 23.2 mmol), and the reaction solution was stirred at 130°C for 2 hours. After cooling to room temperature, the reaction solution was poured into 50 mL of ice water and stirred vigorously, and the pH was adjusted to 6-8 with 4 M sodium hydroxide solution. After the reaction solution was filtered, the title product 374g (3.5 g, yield: 77%) was obtained. MS m / z (ESI): 292.0 [M+1]

[1008] Step 7

[1009] 6-Ethyl-2,10-dimethylimidazo[1,5-h][1,7]naphthyridin-4-ol

[1010] 374g (2.0g, 6.9mmol) was added to THF (50mL), followed by cesium carbonate (6.7g, 20.5mmol), Pd(dppf)Cl2.CH2Cl2 (571.6mg, 0.7mmol) and triethylboron (20.5mL, 1.0M in THF, 20.5mmol). After nitrogen was replaced three times, the reaction solution was heated and stirred at 70°C for 2 hours. After cooling to room temperature, 20mL of saturated ammonium chloride solution was added to quench the reaction and diluted with 50mL of water. The aqueous phase was extracted with ethyl acetate (80mL×3), the organic phases were combined, washed with saturated sodium chloride solution (50mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 374h (1.2g, yield: 73%). MS m / z (ESI): 242.1 [M+1]

[1011] Step 8

[1012] 4-Bromo-6-ethyl-2,10-dimethylimidazo[1,5-h][1,7]naphthyridine

[1013] 374h (1.0 g, 4.1 mmol) was dissolved in 20 mL DMF, and phosphorus tribromide (1.7 g, 6.2 mmol) was added dropwise under stirring. The reaction solution was heated and stirred at 65°C for 5 hours, and after cooling to room temperature, the reaction was quenched with 30 mL of water, and the pH was adjusted to 8-10 with saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL×3), and the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 374i (1.1 g, yield: 87%). MS m / z (ESI): 304.0 [M+1]

[1014] Step 9

[1015] 1-(6-ethyl-2,10-dimethylimidazo[1,5-h][1,7]naphthyridin-4-yl)ethan-1-one was prepared by the synthesis method of step 6 of reference Example 13 to obtain the title product 374j. MS m / z (ESI): 268.1 [M+1]

[1016] Step 10

[1017] 2-((1-(6-ethyl-2,10-dimethylimidazo[1,5-h][1,7]naphthyridin-4-yl)ethyl)amino)benzoic acid was synthesized by the seventh step of reference Example 13 to obtain the title product 374. MS m / z (ESI): 389.2 [M+1]

[1018] Embodiment 382

[1019]

[1020] first step

[1021] 3-Amino-6-chloro-2-iodoisonicotinic acid

[1022] 382a (5.0 g, 29.0 mmol) was dissolved in 50 mL DMF, and NIS (6.8 g, 30.4 mmol) was added. The reaction solution was stirred at 100 °C for 16 hours. After the reaction solution was cooled to room temperature, 100 mL of saturated ammonium chloride solution was added, and it was extracted with ethyl acetate (50 mL×4). The organic phases were combined, washed with water (100 mL) and saturated sodium chloride solution (100 mL) in turn, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title product 382b (6.6 g, yield: 76%). MS m / z (ESI): 298.9 [M+1]

[1023] Step 2

[1024] 3-Amino-6-chloro-2-iodoisonicotinamide

[1025] 382b (6.0 g, 20.1 mmol) was dissolved in 50 mL THF, and ammonia methanol solution (10 mL, 7.0 M) was added. The reaction bottle was sealed with a rubber stopper and stirred at 50 ° C for 16 hours. After the reaction solution was cooled to room temperature, the solvent was dried to obtain the title product 382c (6.0 g, yield: 100%). MS m / z (ESI): 297.9 [M+1]

[1026] Step 3

[1027] 6-Chloro-8-iodo-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

[1028] 382c (6.0 g, 20.1 mmol) was dissolved in 50 mL of ethanol, acetylacetone (3.0 g, 30.2 mmol) and phosphoric acid (196.0 mg, 2.0 mmol) were added, and the reaction solution was stirred at 100°C for 16 hours. After the reaction solution was cooled to room temperature, the solvent was dried by spin drying, and the residue was chromatographed on a silica gel column using eluent system A to obtain the title product 382d (6.1 g, yield: 94%).

[1029] MS m / z(ESI):321.9[M+1]

[1030] Step 4

[1031] 8-Acetyl-6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one was synthesized by the method of step 6 of reference Example 13 to obtain the title product 382e. MS m / z (ESI): 238.0 [M+1]

[1032] Step 5

[1033] 8-(1-Aminoethyl)-6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

[1034] 382e (6.0 g, 16.0 mmol) was dissolved in 100 mL of methanol, and hydroxylamine hydrochloride (3.0 g, 19.2 mmol) and potassium carbonate (6.6 g, 48.0 mmol) were added. After the reaction solution was stirred at room temperature for 5 hours, the solid was filtered out, and zinc powder (5.2 g, 80.0 mmol) and ammonium chloride (4.3 g, 80.0 mmol) were added to the filtrate. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was filtered through a short diatomaceous earth column, and the filtrate was dried by rotary evaporation. The residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 382f (2.8 g, yield: 73%). MS m / z (ESI): 239.1 [M+1]

[1035] Step 6

[1036] N-(1-(6-chloro-2-methyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)ethyl)formamide The synthetic method of the second step of Reference Example 374 was used to obtain 382 g of the title product. MS m / z (ESI): 267.1 [M+1]

[1037] Step 7

[1038] 6-Chloro-2,10-dimethylimidazo[1',5':1,2]pyrido[3,4-d]pyrimidin-4(3H)-one was synthesized by the third step of reference Example 374 to obtain the title product 382h. MS m / z (ESI): 249.1 [M+1]

[1039] Step 8

[1040] 6-ethyl-2,10-dimethylimidazo[1',5':1,2]pyrido[3,4-d]pyrimidin-4(3H)-one was synthesized by the seventh step of reference Example 374 to obtain the title product 382i. MS m / z (ESI): 243.1 [M+1]

[1041] Step 9

[1042] 4-Bromo-6-ethyl-2,10-dimethylimidazo[1',5':1,2]pyrido[3,4-d]pyrimidine was synthesized according to the eighth step of Example 374 to obtain the title product 382j. MS m / z (ESI): 305.0 [M+1]

[1043] Step 10

[1044] 1-(6-ethyl-2,10-dimethylimidazo[1',5':1,2]pyrido[3,4-d]pyrimidin-4-yl)ethan-1-one was prepared by the synthesis method of step 6 of reference Example 13 to obtain the title product 382k. MS m / z (ESI): 269.1 [M+1]

[1045] Step 11

[1046] 2-((1-(6-ethyl-2,10-dimethylimidazo[1',5':1,2]pyrido[3,4-d]pyrimidin-4-yl)ethyl)amino)benzoic acid was prepared by the synthesis method of step 7 of reference Example 13 to obtain the title product 382. MS m / z (ESI): 390.2 [M+1]

[1047] Embodiment 384

[1048]

[1049] first step

[1050] Quinazolin-8-ylcarbamic acid tert-butyl ester

[1051] 384a (5.0 g, 23.9 mmol) was dissolved in 50 mL of 1,4-dioxane, and tert-butyl carbamate (8.4 g, 71.8 mmol), tris(dibenzylideneacetone)dipalladium (1.1 g, 1.2 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (1.0 g, 1.8 mmol) and cesium carbonate (23.4 g, 71.8 mmol) were added to the reaction system in sequence. The reaction was heated at 110°C for 5 hours. After cooling to room temperature, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 384b (4.8 g, yield: 82%). MS m / z(ESI):246.1[M+1]

[1052] Step 2

[1053] tert-Butyl (5-bromoquinazolin-8-yl)carbamate

[1054] Referring to the synthesis method of the first step of Example 25, the title product 384c was obtained. MS m / z (ESI): 324.0 [M+1]

[1055] Step 3

[1056] tert-Butyl (5-ethylquinazolin-8-yl)carbamate

[1057] The synthetic method of step 7 of reference example 374 was used to obtain the title product 384d. MS m / z (ESI): 274.2 [M+1]

[1058] Step 4

[1059] 5-Ethylquinazolin-8-amine

[1060] 384d (2.8 g, 10.2 mmol) was dissolved in 20 mL of anhydrous dichloromethane, trifluoroacetic acid (10 mL) was added, and the reaction was stirred at room temperature for 1 hour. The solvent was dried by rotary evaporation, 50 mL of sodium carbonate aqueous solution was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title product 384e (1.7 g, yield 96%). MS m / z (ESI): 174.1 [M+1]

[1061] Step 5

[1062] 5-Ethyl-9-methylpyrido[3,2-h]quinazolin-7(10H)-one was synthesized in the sixth step of Reference Example 374 to obtain the title product 384f. MS m / z (ESI): 240.1 [M+1]

[1063] Step 6

[1064] 7-Bromo-5-ethyl-9-methylpyridone[3,2-h]quinazoline

[1065] Referring to the synthesis method of step 8 of Example 374, 384 g of the title product was obtained. MS m / z (ESI): 302.0 [M+1]

[1066] Step 7

[1067] 1-(5-ethyl-9-methylpyridone[3,2-h]quinazolin-7-yl)ethan-1-one was synthesized by the sixth step of reference Example 13 to obtain the title product 384h. MS m / z (ESI): 266.1 [M+1]

[1068] Step 8

[1069] 2-((1-(5-ethyl-9-methylpyrido[3,2-h]quinazolin-7-yl)ethyl)amino)benzoic acid was synthesized by the seventh step of reference Example 13 to obtain the title product 384. MS m / z (ESI): 387.2 [M+1]

[1070] Embodiment 420

[1071]

[1072] first step

[1073] 9-Bromo-2-ethyl-3,7-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one

[1074] 4-Bromo-6-methylpyridazine-3-amine 420a (5.0 g, 26.6 mmol) and methyl 2-methyl-3-oxopentanoate (4.6 g, 31.9 mmol) were dissolved in 10 mL of polyphosphoric acid. The reaction solution was stirred in an oil bath at 120°C for 3 hours. After the reaction solution was cooled to room temperature, water (100 mL) was slowly added to the reaction solution, and it was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and dried, and the residue was subjected to silica gel column chromatography with eluent system A to obtain the title product 420b (3.2 g, yield: 43%). MS m / z (ESI): 282.0 [M+1]

[1075] Step 2

[1076] 9-Acetyl-2-ethyl-3,7-dimethyl-4H-pyrimido[1,2-b]pyridazin-4-one was synthesized by the sixth step of reference Example 13 to obtain the title product 420c. MS m / z (ESI): 246.1 [M+1]

[1077] Step 3

[1078] Ethyl 2-((1-(2-ethyl-3,7-dimethyl-4-oxo-4H-pyrimido[1,2-b]pyridazin-9-yl)ethyl)amino)benzoate was prepared by the synthesis method of step 8 of reference Example 19 to obtain the title product 420d. MS m / z (ESI): 395.2 [M+1]

[1079] Step 4

[1080] 2-((1-(2-ethyl-3,7-dimethyl-4-oxo-4H-pyrimido[1,2-b]pyridazin-9-yl)ethyl)amino)benzoic acid was prepared by the synthesis method of the ninth step of Reference Example 19 to obtain the title product 420. MS m / z (ESI): 367.2 [M+1]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086]

[1087]

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103]

[1104]

[1105]

[1106] Biological test evaluation

[1107] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[1108] Test Example 1: Experiment on the inhibitory activity of the compounds of the present invention on PI3Kα mutant and wild-type kinases.

[1109] Purpose of the experiment: The purpose of this test case is to test the inhibitory activity of the compound against PI3Kα mutant and wild-type kinases.

[1110] Experimental instruments: Centrifuge (5810R) was purchased from Eppendorf, pipettes were purchased from Eppendorf or Rainin, and microplate reader was purchased from BioTek, USA, model SynergyH1 full-function microplate reader.

[1111] Experimental method: This experiment uses Promega's ADP-Glo ​​lipid kinase assay (Promega # V9102). The lipid kinase PI3Kα catalyzes the reaction in the presence of substrate PIP2:3PS and ATP. ATP generates ADP. The activity of lipid kinase is characterized by measuring the content of ADP in the reaction, and the half inhibitory concentration IC of the compound on the inhibition of PI3Kα kinase activity is obtained. 50 .

[1112] The specific experimental operations are as follows:

[1113] Kinase reaction was performed in a white 384-well plate (Perkin Elmer #6007299). 2 μL of different concentrations of compounds diluted with 1% DMSO in ddH2O were added to each well. 2 μL of 1% DMSO in ddH2O was added to the positive control wells. Then, 2 μL of 0.01-1 μg / mL PI3Kα mutant (H1047R, E545K, E542K) and wild-type kinase solutions diluted with 5× kinase buffer (HEPES 250 mM, MgCl2 15 mM, NaCl 250 mM, BSA 0.05%) were added to each well. 2 μL of 5× kinase buffer was added to the negative control wells. 4 μL of 50 μM substrate PIP2:3PS (Promega #V1701) prepared with 10× Dilution buffer and ddH2O was added to all wells. Finally, 2 μL of 50-100 μM PI3Kα diluted with water was added. The reaction was initiated with ATP solution. After reacting at room temperature for 90 to 120 minutes, 10 μL ADP-Glo ​​Reagent (containing 10 mM MgCl2) was added to each well and reacted at room temperature for 60 minutes to remove excess ATP in the reaction. Then 20 μL Kinase Detection Reagent was added to each well. After reacting at room temperature in the dark for 20 minutes, the chemiluminescence value was detected using a BioTek Synergy H1 microplate reader.

[1114]

[1115] Experimental data processing method:

[1116] The percentage inhibition data of the wells treated with the compound were calculated by the positive control wells (DMSO control wells) and the negative control wells (no kinase added) on the plate {% inhibition rate = 100-[(test compound value-negative control value)] / (positive control value-negative control value)×100}. GraphPad prism was used to fit the different concentrations and the corresponding percentage inhibition rate data to a 4-parameter nonlinear logistic formula to calculate the IC 50 value.

[1117] Experimental conclusion:

[1118] The above scheme shows that the compounds of the present invention show about 0.001nM to 100nM (IC 50 )'s biological activity.

[1119] In some embodiments, the IC values ​​of the compounds of the invention for PI3Kα kinase activity are 50The IC values ​​of the compounds listed in the present invention are less than about 100 nM, the preferred compounds are less than about 50 nM, the more preferred compounds are less than about 10 nM, the further preferred compounds are less than about 1 nM, and the further preferred compounds among the compounds listed in the present invention are less than 10 nM or even less than about 1 nM. 50 Value inhibitory activity.

[1120] Test Example 2: Determination of the inhibitory activity of the compounds of the present invention on PI3Kβ / γ / δ kinases

[1121] Experimental purpose: The purpose of this test case is to test the inhibitory activity of the compound on PI3Kβ / γ / δ kinase.

[1122] Experimental instruments: Centrifuge (5810R) was purchased from Eppendorf, pipettes were purchased from Eppendorf or Rainin, and microplate reader was purchased from BioTek, USA, model SynergyH1 full-function microplate reader.

[1123] Experimental method: This experiment uses Promega's ADP-Glo ​​lipid kinase assay (Promega # V9102). Lipid kinase PI3Kβ / γ / δ undergoes a catalytic reaction in the presence of substrate PIP2:3PS and ATP. ATP generates ADP. The activity of lipid kinase is characterized by measuring the content of ADP in the reaction, and the half inhibitory concentration IC of the compound on the inhibition of PI3Kβ / γ / δ kinase activity is obtained. 50 .

[1124] The specific experimental operations are as follows:

[1125] Kinase reaction was carried out in a white 384-well plate (Perkin Elmer #6007299). 2 μL of different concentrations of compounds diluted with 1% DMSO in ddH2O were added to each well. 2 μL of 1% DMSO in ddH2O was added to the positive control wells. Then, 2 μL of 0.25-1 μg / mL PI3K kinase solution diluted with 5× kinase buffer (HEPES 250 mM, MgCl2 15 mM, NaCl 250 mM, BSA 0.05%) was added to each well. 2 μL of 5× kinase buffer was added to the negative control wells. 4 μL of 50 μM substrate PIP2:3PS (Promega #V1701) prepared with 10× Dilution buffer and ddH2O was added to all wells. Finally, 2 μL of 50-100 μM ATP solution diluted with water was added to start the reaction. After reacting at room temperature for 90-120 minutes, 10 μL of ADP-GloReagent (containing 10 mM MgCl2) at room temperature for 60 minutes to remove excess ATP in the reaction, then add 20 μL Kinase Detection Reagent to each well, react at room temperature in the dark for 20 minutes, and then use BioTek Synergy H1 microplate reader to detect chemiluminescence value.

[1126] Enzyme name Part Number Enzyme reaction concentration Enzyme reaction time ATP concentration PI3Kβ Carna#11-102 1 μg / mL 90min 100μM PI3Kγ Thermofisher#PV4786 0.5 μg / mL 120min 50μM PI3Kδ Carna#11-103 0.25 μg / mL 90min 100μM

[1127] Experimental data processing method:

[1128] The percentage inhibition data of the wells treated with the compound were calculated by the positive control wells (DMSO control wells) and the negative control wells (no kinase added) on the plate {% inhibition rate = 100-[(test compound value-negative control value)] / (positive control value-negative control value)×100}. GraphPad prism was used to fit the different concentrations and the corresponding percentage inhibition rate data to a 4-parameter nonlinear logistic formula to calculate the IC 50 value.

[1129] Experimental conclusion:

[1130] The above scheme shows that the compounds of the present invention show about 1nM to 10000nM (IC 50 )'s biological activity.

[1131] In some embodiments, the IC values ​​of the compounds of the invention for PI3K kinase activity are 50The IC values ​​of the compounds listed in the present invention are greater than about 10 nM, the preferred compounds are greater than about 100 nM, the more preferred compounds are greater than about 1000 nM, the further preferred compounds are greater than about 1000 nM, or even greater than about 10000 nM. 50 Value suppression.

[1132] Test Example 3: Determination of the Proliferation Inhibitory Effect of the Compounds of the Invention on PI3Kα Mutant Cancer Cells

[1133] Experimental purpose: The purpose of this test example is to test the activity of the compound in inhibiting the proliferation of PI3Kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K) and MKN1 (E545K).

[1134] Experimental instruments: Centrifuge (5702R) was purchased from Eppendorf, CO2 incubator was purchased from Thermo, biosafety cabinet was purchased from Shanghai Boxun, pipette was purchased from Eppendorf or Rainin, and microplate reader was purchased from BioTek, USA, model SynergyH1 full-function microplate reader.

[1135] Experimental methods: The Cell Titer-Glo method was used to detect the inhibitory effect of the compounds on the proliferation of PI3Kα mutant cancer cell lines HCC1954, HGC-27 and MKN1. The cell lines were cultured in RPMI 1640 medium (Gibco #22400089) containing 10% FBS (Gibco #10091148) and 1% P / S (Hyclone #SV30010) at 37°C and 5% CO2. When the cells grow to a certain degree of confluence, the cells are collected and the cell density is adjusted after counting. The cells are seeded at a density of 1000-10000 cells / well in a white 96-well plate (Corning#3610), placed in a 37°C, 5% CO2 incubator for overnight culture, and the prepared compound solutions of different concentrations are added. At the same time, corresponding solvent controls are set up. After continuing to be cultured in a 37°C, 5% CO2 incubator for 72 to 144 hours, the cell plate and its contents are equilibrated to room temperature, 20-100 μL Cell Titer-Glo solution (Promega#G7573) is added to each well, and after oscillation mixing, the plates are incubated at room temperature in the dark for 10 minutes, and the chemiluminescence value is detected using BioTek's SynergyH1 microplate reader.

[1136] Experimental data processing method:

[1137] The percentage inhibition data of the wells treated with the compound were calculated by the vehicle control wells on the plate {% inhibition rate = 100-(test compound value / vehicle control value) × 100}. GraphPad prism was used to fit the different concentrations and the corresponding percentage inhibition rate data to a 4-parameter nonlinear logistic formula to calculate the IC 50 value.

[1138] Experimental conclusion:

[1139] The above schemes show that the compounds of the present invention have an inhibitory activity against the proliferation of PI3Kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K) and MKN1 (E545K) of about 10 nM to 10000 nM (IC 50 )'s biological activity.

[1140] In some embodiments, the IC values ​​of the compounds prepared by the present invention for the inhibitory activity of the test compounds on the proliferation of PI3Kα mutant cancer cells HCC1954 (H1047R), HGC-27 (E542K) and MKN1 (E545K) are 50 The IC values ​​of the compounds are less than about 10000 nM, preferably less than about 5000 nM, more preferably less than about 1000 nM, more preferably less than about 500 nM, and even more preferably less than 100 nM. 50 Value inhibitory activity.

Claims

1. A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: in: X1 is selected from N, NR7, C, CR8 or O; X2 is selected from N, NR9, C, CR 10 or O; At least one of X1 or X2 is N; Ring B or Ring C is each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Ring B or ring C is preferably C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl; Ring B or ring C is each independently more preferably C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; Ring B or ring C is each independently preferably C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-8 Monocyclic aromatic group, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents; Ring B is further preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridine, pyrimidine, Ring C is further preferably phenyl, naphthyl, pyridyl, R1, R2, R3, R4, R5, R6, R7, R8, R9 or R 10 each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl or deuterated alkyl; R1, R3, R4, R5 or R6 are each independently preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R1, R3, R4, R5 or R6 are each independently more preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R1, R3, R4, R5 or R6 are each independently preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R1, R3, R4, R5 or R6 are each independently further preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl; R2, R7, R8, R9 or R 10 Preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R2, R7, R8, R9 or R 10 More preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R2, R7, R8, R9 or R 10 Each of them is further preferably independently hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R2, R7, R8, R9 or R 10 Each independently is further preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -C(O)CH=CH2, -C(O)CH2Cl, -C(O)C(CH3)=CH2, -NHC(O)CH=CH2, -NHC(O)CH2Cl, -NHC(O)C(CH3)=CH2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl; x is 1, 2, or 3; y, z and m are each independently 0, 1, 2, 3 or 4; Preferably, the compound is further represented by general formula (I-1): X3 Selected from NR 11 , CR 12 R 13 or O; R 11 , R 12 or R 13 each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl or deuterated alkyl; R 11 , R 12 or R 13 Preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R 11 , R 12 or R 13 More preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R 11 , R 12 or R 13 Each of them is further preferably independently hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl-(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 NR aa C(O)CR bb =CR cc R dd , a 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R 11 , R 12 or R 13 Each independently is further preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -C(O)CH=CH2, -C(O)CH2Cl, -C(O)C(CH3)=CH2, -NHC(O)CH=CH2, -NHC(O)CH2Cl, -NHC(O)C(CH3)=CH2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl; More preferably, the compound is further represented by general formula (I-2): More preferably, the compound is further represented by the general formula (I-2-1) or (I-2-2):

2. A compound represented by general formula (II) or (III), its stereoisomer or a pharmaceutically acceptable salt thereof: in: represents a single bond or a double bond; M1 or M2 are each independently selected from a bond, N, CR m1 , CR m1 R m2 -、NR m3 , O or S; Y1 is selected from CR y1 R y2 -、NR y3 , O or S; Y2 is selected from CR y1 or N; Ring D, Ring E, Ring F, Ring G, Ring H or Ring K are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Ring D is preferably C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 10-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl; Ring D is more preferably C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 10-12 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; Ring D is further preferably C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 10-12 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents; Ring D is further preferred Ring E, Ring F, Ring G, Ring H or Ring K are each independently preferably C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl; Ring E, Ring F, Ring G, Ring H or Ring K are each independently more preferably C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; Ring E, Ring F, Ring G, Ring H or Ring K are each independently preferably C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-8 Monocyclic aromatic group, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents; Ring E or ring H is further preferably independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridine, pyrimidine, Ring F or ring K is further preferably independently phenyl, naphthyl, pyridyl, Ring G is further preferably phenyl, naphthyl, pyridyl, R a , R b , R c , R d , R e , R f , R y1 , R y2 , R y3 , R A , R B , R D , R E , R m , R n , R m1 , R m2 or R m3 each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl or deuterated alkyl; R a , R A , R c , R D , R d , R E , R e , R f , R m or R n Preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R a , R A , R c , R D , R d , R E , R e , R f , R m or R n More preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R a , R A , R c , R D , R d , R E , R e , R f , R m or R n Each of them is further preferably independently hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R a , R A , R c , R D , R d , R E , R e , R f , R m or R n Each independently is further preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl; R b or R B Preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R b or R B More preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R b or R B Each of them is further preferably independently hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R b or R B Each independently is further preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -C(O)CH=CH2, -C(O)CH2Cl, -C(O)C(CH3)=CH2, -NHC(O)CH=CH2, -NHC(O)CH2Cl, -NHC(O)C(CH3)=CH2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl; p is 1, 2, or 3; q, t and n are each independently 0, 1, 2, 3 or 4; u is 1, 2, or 3; v, w and s are each independently 0, 1, 2, 3 or 4; The conditions are: In the general formula (II), ring D is not a benzene ring or a pyridine ring; The general formula (II) is not the following compound: Preferably, the compound is further represented by the general formula (II-1) or (III-1): Y4 is selected from CR y4 R y5 -、NR y6 , O or S; Y5 is selected from CR y4 or N; R y4 , R y5 or R y6 each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, hydroxyl, halogen, cyano, amino, alkyl, haloalkyl or deuterated alkyl; More preferably, the compound is further represented by general formula (III-2): More preferably, the compound is further represented by general formula (III-3):

3. A compound represented by the general formula (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII) or (XIX), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in, L is selected from C 4-8 Bridged cycloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; preferably vinyl or ethynyl; X4, X5, X6, X7, X8 or X9 are each independently selected from N or CR8; Ring B or Ring C is present or absent, and when present, each is independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl; Ring E is selected from C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-8 Monocyclic aromatic group, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents; Ring B or ring C is preferably C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; Ring B or ring C is each independently more preferably C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-8 Monocyclic aromatic group, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents; Ring B or ring E is further preferably independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridine, pyrimidine, Ring C is further preferably independently phenyl, naphthyl, pyridyl, Ring K is selected from C 4-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 4-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, phenyl, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents; Preferably, ring K is selected from cyclohexyl or R a , R b , R c , R e , R f , R a1 , R a2 R1, R2, R5, R6 or R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R a , R c , R e , R f R5 or R6 are each independently preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R a , R c , R e , R f R5 or R6 are each independently more preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R a , R c , R e , R f R5 or R6 are each independently preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R a , R c , R e , R f , R5 or R6 are each independently further preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl; R2, R b or R8 are each independently preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R2, R b or R8 are each independently more preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R2, R b or R8 are each independently preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R2, R b or R8 are each independently further preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -C(O)CH=CH2, -C(O)CH2Cl, -C(O)C(CH3)=CH2, -NHC(O)CH=CH2, -NHC(O)CH2Cl, -NHC(O)C(CH3)=CH2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl; R d , R d1 , R d2 or R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 aryl, 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, or C 1-6 Alkyl S(O)(=NH), optionally substituted with hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by one or more substituents in a deuterated alkyl group; Or, R e or R f , R5 or R6 are independently linked to the connected carbon atom to form C 3-10 Cycloalkyl or 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; R e or R f , R5 or R6 are independently linked to the connected carbon atom to form a C 3-8 Cycloalkyl or 3-8 membered heterocyclic group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; R e or R f , R5 or R6 are independently linked to the connected carbon atom to form a C 3-6 Cycloalkyl or 3-6 membered heterocyclic group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents; R e or R f , R5 or R6 are independently further linked to the connected carbon atom to form a cyclopropyl, cyclobutyl or cyclopentyl group; R g or R3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -(CH2) m4 R g1 、-O(CH2) m4 R g1 , optionally substituted with hydrogen, deuterium, oxo, hydroxyl, halogen, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl C(O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 substituted by one or more substituents of an aryl group or a 5-10 membered heteroaryl group containing 1 to 3 atoms selected from N, O or S atoms; R3 is each independently preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R3 is each independently more preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R3 is each independently preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R3 is further preferably each independently hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl. R g1 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 Aryl, 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, oxo, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; m4 is 0, 1, 2, 3, or 4; t is 0, 1, 2, 3, or 4; z and m are each independently 0, 1, 2, 3 or 4; The conditions are: In the general formula (IV), (1) When R a is methyl, R b When it is methyl, R e is not hydrogen, and R f Not methyl; (2) When R a is methyl, R b is methyl, R e is not a methyl group, and R f Not hydrogen; In the general formula (VI), (XI) or (XIV), (1) When R a is methyl, R b When it is methyl, R e is hydrogen, R f When it is methyl, R d Not carboxyl; (2) When R a is methyl, R b is methyl, R e is methyl, R f When it is hydrogen, R d Not carboxyl; In the general formula (VII), (1) When R a is methyl, R b is methyl, R e is hydrogen, R f is methyl, R d When it is a carboxyl group, ring K is not a phenyl group; (2) When R a is methyl, R b is methyl, R e is methyl, R f is hydrogen, R d When it is a carboxyl group, ring K is not a phenyl group; In the general formula (VIII), R d1 , R d2 , R a1 , R a2 , R e or R f Any two of the atoms in the group are linked to form a 3-12 membered heterocyclic group containing 1-3 atoms selected from N, O or S, which may be substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; Preferably, R d1 With R e or R f The 5-6 membered heterocyclic group is linked to form 1-3 atoms selected from N, O or S, which are optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; Or, R d1 With R a2 The 5-6 membered heterocyclic group is linked to form 1-3 atoms selected from N, O or S, which are optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; Or, R d2 With R a1 The 8-10 membered heterocyclic group is linked to form 1-3 atoms selected from N, O or S, which are optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; In the general formula (IX), (1) When R a is methyl, R b When it is methyl, R e is hydrogen, R f is methyl, R d When it is carboxyl, R c is not hydrogen, methyl, methoxy or methylaminocarbonyl; (2) When R a is methyl, R b is methyl, R e is methyl, R f is hydrogen, R d When it is carboxyl, R c is not hydrogen, methyl, methoxy or methylaminocarbonyl; In the general formula (XII), When R a is methyl, R b When it is methyl, R e is hydrogen, R f When it is methyl, R g is not hydrogen, cyano, fluorine, methyl, methylsulfonyl, bromine, methoxy, carboxyl, amino, cyano or 4. A compound represented by the general formula (XX), (XX') or (XXVII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in, represents a single bond or a double bond; X1 is selected from N or CR8; X2 is selected from N, NR9, C, CR 10 or O; X3 is selected from N, C or CR 11 ; X4 is selected from N, C or CR 12 ; R1, R2, R5, R6, R8, R9, R 10 , R 11 , R 12 or R a are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R a R1, R5, and R6 are each independently preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R a R1, R5, and R6 are each independently more preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R a , R1, R5, and R6 are each independently further preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, or piperazinyl; R2, R8, R9, R 10 , R 11 or R 12 Preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R2, R8, R9, R 10 , R 11 or R 12 More preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R2, R8, R9, R 10 , R 11 or R 12 Each of them is further preferably independently hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R2, R8, R9, R 10 , R 11 or R 12 Each independently further preferably is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -C(O)CH=CH2, -C(O)CH2Cl, -C(O)C(CH3)=CH2, -NHC(O)CH=CH2, -NHC(O)CH2Cl, -NHC(O)C(CH3)=CH2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl; R b is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl or 5-12 membered heteroaryl group may be substituted by deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R b Preferred are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 atoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally, the C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group containing 1-3 atoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 atoms selected from N, O or S may be substituted by deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R e or R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 The aryl or 5-12 membered heteroaryl group may be further substituted with deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R e or R f Preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R e or R f More preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R e or R f Further preferred are each independently hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl; R g is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl can be further substituted with deuterium, oxo, hydroxyl, halogen, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl C(O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 substituted by one or more substituents of an aryl group or a 5-10 membered heteroaryl group containing 1 to 3 atoms selected from N, O or S atoms; R g Preferred are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-12 Aryl or 5-10 membered heteroaryl containing 1 to 3 atoms selected from N, O or S, optionally, the C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-12 The aryl group or the 5-10 membered heteroaryl group containing 1-3 atoms selected from N, O or S may be further substituted with deuterium, oxo, hydroxyl, halogen, cyano, amino, C 1-3 Alkylamino, C 1-3 Alkyl C(O), C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Deuterated alkyl, C 3-8 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 substituted by one or more substituents of an aryl group or a 5-6-membered heteroaryl group containing 1 to 3 atoms selected from N, O or S atoms; Ring M or ring C are each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl; Ring C is preferably independently C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; Ring C is each independently more preferably C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-8 Monocyclic aromatic group, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents; Ring C is further preferably phenyl or a 5-6 membered heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; Ring C is further preferably independently phenyl, naphthyl, pyridyl, Alternatively, two R1 atoms are linked to form a C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 substituted by one or more substituents of aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S atoms; R4 or R d are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 aryl, 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, or C 1-6 Alkyl S(O)(=NH), optionally substituted with hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by one or more substituents in a deuterated alkyl group; R4 or R d Preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R4 or R d More preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R4 or R d Each of them is further preferably independently hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R4 or R d Each independently is further preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl; R d Each independently further preferably is a carboxyl group; Alternatively, R5 or R6 is linked to the carbon atom to form a C 3-10 Cycloalkyl or 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; x is 1, 2, or 3; y and m are each independently 0, 1, 2, 3 or 4; Preferably, the compound is further represented by the general formula (XX-1): in, X5 is selected from N or CR 13 ; X6 is selected from N or CR 14 ; R 13 or R 14 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 The deuterated alkyl group is substituted with one or more substituents.

5. A compound represented by the general formula (XXI), (XXII), (XXIII), (XXIV) or (XXV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in: X4, X5 or X6 are each independently selected from N or CR8; In the general formula (XXI), at least one of X4, X5 or X6 is N; Ring B or Ring C is each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Ring B or ring C is preferably C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl; Ring B or ring C is each independently more preferably C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; Ring B or ring C is each independently preferably C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-8 Monocyclic aromatic group, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents; Ring B is further preferably independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridine, pyrimidine, Ring C is further preferably independently phenyl, naphthyl, pyridyl, R1, R3, R4, R5 or R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R2 or R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 NR aa C(O)CR bb =CR cc R dd , cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R2 or R8 are each independently preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R2 or R8 are each independently more preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、-(CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R2 or R8 are each independently preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n1 C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 C(O)CR bb =CR cc R dd 、-(CH2) n1 NR aa C(O)(CR cc R dd ) n2 R bb 、- (CH2) n1 NR aa C(O)CR bb =CR cc R dd , C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R2 or R8 are each independently preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, -C(O)CH=CH2, -C(O)CH2Cl, -C(O)C(CH3)=CH2, -NHC(O)CH=CH2, -NHC(O)CH2Cl, -NHC(O)C(CH3)=CH2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl; R aa ~R dd each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl and heteroaryloxy, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl and heteroaryloxy are optionally substituted with one or more substituents of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R1, R3, R4, R5, R6, R aa ~R dd Preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; R1, R3, R4, R5, R6, R aa ~R dd More preferably, each independently is hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R1, R3, R4, R5, R6, R aa ~R dd Each of them is further preferably independently hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-9 Cycloalkyl, 3-9 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 is substituted with one or more substituents of a deuterated alkyl group; R1, R3, R4, R5 or R6 are each independently further preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or piperazinyl; R aa ~R dd Each independently further preferably is hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, propyl, fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, vinyl, propenyl, allyl, ethynyl, propynyl or propargyl; x is 1, 2, or 3; y, z and m are each independently 0, 1, 2, 3 or 4; and n1 or n2 are each independently 0, 1, 2, 3 or 4; Preferably, the compound is further represented by the general formula (XXI-1), (XXI-2), (XXII-1) or (XXIII-1):

6. A compound represented by the general formula (XXVI'), its stereoisomer or a pharmaceutically acceptable salt thereof: in, represents a single bond or a double bond; X1 is selected from N or C; X2 is selected from N or C; X3 is selected from N or C; X4 is selected from N, C or CR 12 ; X5 is selected from N or C; X6 is selected from N or C; R 12 R1, R2, R5 or R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, deuterium, hydroxy, halogen, cyano, amino, alkyl, haloalkyl or deuterated alkyl; Ring B is present or absent, and when present is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Ring Q or Ring Q1 is each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Ring B is preferably C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl; Ring B is more preferably C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; Ring B is further preferably C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-8 Monocyclic aromatic group, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents; Ring B is further preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridine, pyrimidine, Ring Q or ring Q1 is each independently preferably C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; Ring Q or ring Q1 is each independently more preferably C 5-6 Monocyclic cycloalkyl, C 5-10 Spirocyclic cycloalkyl, C 5-10 Fused ring cycloalkyl, C 5-10 bridged ring cycloalkyl, 5-6 membered monocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered spirocyclic heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered fused ring heterocyclic group containing 1-3 atoms selected from N, O or S, 5-10 membered bridged ring heterocyclic group containing 1-3 atoms selected from N, O or S, phenyl, C 6-10 A fused ring aryl group, a 5-8 membered monocyclic heteroaryl group containing 1-3 atoms selected from N, O or S, or a 5-10 membered fused ring heteroaryl group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 The alkyl group is substituted by one or more substituents; Ring Q is further preferably Ring Q1 is further preferably a benzene ring, pyridine, pyrimidine or pyridazine; Alternatively, two R1 are linked to the atoms to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which is optionally substituted by one or more substituents of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents of hydrogen, deuterium, oxo, hydroxy, halogen, cyano, amino, alkylamino, alkyl C(O), alkyl, haloalkyl, deuterated alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R4 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl S(O)(=NH), optionally substituted with one or more substituents of hydrogen, deuterium, hydroxy, halogen, cyano, amino, alkyl, haloalkyl or deuterated alkyl; Alternatively, R5 or R6 is linked to the carbon atom to form a cycloalkyl or heterocyclic group, which is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, and alkyl substituted with cyano; x, y and z are each independently 0, 1, 2 or 3; and m is 0, 1, 2 or 3; The conditions are: (1) When for When R1 is methyl, one of R5 or R6 is hydrogen and the other is methyl, Not for (2) When for When R1 is methyl, one of R5 or R6 is hydrogen and the other is methyl, Not for (3) When for When R1 is methyl, one of R5 or R6 is hydrogen and the other is methyl, Not for (4) When for When R1 is methyl, one of R5 or R6 is hydrogen and the other is methyl, Not for (5) When for When R1 is methyl, R2 is hydrogen, methoxy or ethoxy, one of R5 or R6 is hydrogen and the other is methyl, Not for Or, at least one of X1, X2 and X3 is N; Preferably, the compound is further represented by the general formula (XXVI) or (XXVI-a): More preferably, the compound is further represented by the general formula (XXVI-1), (XXVI-2) or (XXVI-3): R 12 R1, R2, R5 or R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is substituted with one or more substituents of a deuterated alkyl group; Ring Q is independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, oxo, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 is substituted by one or more substituents of aryl or 5-12 membered heteroaryl; Alternatively, two R1 atoms are linked to form a C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 substituted by one or more substituents of aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S atoms; R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, oxo, hydroxyl, halogen, cyano, amino, C 1-6 Alkylamino, C 1-6 Alkyl C(O), C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 It is substituted by one or more substituents of an aryl group or a 5-10 membered heteroaryl group containing 1 to 3 N, O or S atoms; R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, C 6-10 aryl, 5-10 membered heteroaryl containing 1-3 atoms selected from N, O or S, or C 1-6 Alkyl S(O)(=NH), optionally substituted with hydrogen, deuterium, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted by one or more substituents in a deuterated alkyl group; Alternatively, R5 or R6 is linked to the carbon atom to form a C 3-10 Cycloalkyl or 3-10 membered heterocyclic group containing 1-3 atoms selected from N, O or S, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 The alkyl group is substituted by one or more substituents; Further preferably, the compound is further represented by the general formula (XXVI-a1), (XXVI-a2), (XXVI-a3) or (XXVI-a4): V1, V2 or V3 are each independently selected from C or N; V4 or V6 are each independently selected from C or N; V5 is selected from C, N, O or S; V7, V8 or V9 are each independently selected from C, N, O or S; V 10 、V 11 、V 12 or V 13 are each independently selected from C or N; More preferably, the compound is further represented by the general formula (XXVI-b1), (XXVI-b2), (XXVI-b3), (XXVI-b4) or (XXVI-b5): Still more preferably, the compound is further represented by general formula (XXVI-c1) to (XXVI-c14):

7. The compound shown below, its stereoisomer or a pharmaceutically acceptable salt thereof, the compound structure is as follows:

8. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 7, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients.

9. Use of the compound according to any one of claims 1 to 7, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating diseases associated with PI3Kα.

10. Use of the compound according to any one of claims 1 to 7, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating cancer, PROS, immune disorders or inflammatory disorders; preferably, PROS is selected from vascular malformations, lymphatic malformations and megalencephaly, and cancer is selected from gastric cancer, breast cancer, prostate cancer, lung cancer, liver cancer, bone cancer, brain cancer, head and neck cancer, intestinal cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer, endometrial cancer and multiple myeloma; more preferably, cancer is selected from clear cell ovarian cancer or breast cancer.

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