Polycyclic fused ring derivative as well as preparation method and application thereof

Abstract

The invention discloses a polycyclic fused ring derivative as well as a preparation method and application thereof. In particular, the invention discloses a compound shown as a general formula (I-2-1), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a regulator in treatment of cancer-related diseases, and substituents in the general formula (I-2-1) are as defined in the specification. # imgabs0 #

Description

Polycyclic fused ring derivatives, preparation methods and applications thereof Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a polycyclic cyclic derivative, a preparation method and application thereof. Background Art

[0002] The phosphatidylinositol 3-kinase (PI3K) family of proteins is divided into four major classes: I, II, III, and IV. They are involved in regulating various cellular functions, including cell growth, proliferation, differentiation, survival, and energy metabolism. The four PI3K classes differ in structure and function, with class I being the most extensively studied. This class of PI3K is further divided into four subtypes: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. PI3Kα undergoes activating mutations and amplification in various tumors, closely implicated in tumor development and progression. Reports have demonstrated that PI3Kβ can activate platelets and play a crucial role in the development and progression of diseases such as thrombosis. PI3Kδ and PI3Kγ are primarily expressed in the blood system and are closely associated with the immune system and inflammation. PI3Kγ is also closely linked to blood pressure regulation and smooth muscle contraction.

[0003] PI3Kα consists of the p110α catalytic subunit and the p85 regulatory subunit, encoded by the PIK3CA gene. When activated by upstream receptor tyrosine kinases (such as the insulin receptor and platelet-derived growth factor receptor) and Ras proteins, PI3Kα catalyzes the conversion of phosphatidylinositol 2-phosphate (PIP2) to phosphatidylinositol 3-phosphate (PIP3). PIP3 further activates protein kinase B (AKT) and its downstream signaling pathways, thereby regulating cell differentiation, migration, and metabolic homeostasis. PI3Kα mutations or amplifications can lead to persistent activation of the AKT pathway, rapid cell proliferation, and the development of tumors. PI3Kα is also a key protein in the insulin / insulin receptor pathway, regulating glucose homeostasis in tissues such as the liver and skeletal muscle. Inhibition of PI3Kα can reduce hepatic glycogen synthesis, increase blood sugar levels, and increase insulin levels.

[0004] PI3Kα is one of the kinases with the highest mutation rate in cancer, with a total mutation rate of 14% in all cancers. It is widely distributed, such as in 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, but are not selective for PI3Kα wild-type inhibition. They have some inhibition against PI3Kβ / γ / δ, resulting in clinical trials with severe hyperglycemia mediated by PI3Kα wild-type and side effects such as rash and diarrhea involving the PI3K / AKT pathway. In addition, due to the increase in insulin in the body, the insulin receptor pathway is activated, leading to 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 in combination with Fulvestrant for the treatment of ER with PIK3CA mutations. + HER2 - Breast cancer, the efficacy is good, but the clinical side effect of hyperglycemia is more serious. In addition, HER2 + Clinical trials for indications such as breast cancer, triple-negative breast cancer, and ovarian cancer. Roche's PI3Kα inhibitor GDC-0077 is in Phase III clinical trials and is indicated for combined treatment of ER-positive patients with PIK3CA mutations. + HER2 - For breast cancer, the early clinical effect is good, but it also causes more serious side effects of hyperglycemia.

[0005] In summary, PI3Kα inhibitors have significant therapeutic effects in indications such as breast cancer and have promising market prospects. Existing PI3Kα inhibitors lack selectivity for wild-type PI3Kα, leading to severe hyperglycemia as a side effect, limiting clinical dosage and efficacy. Therefore, the development of mutant-specific allosteric inhibitors of PI3Kα is of great significance.

[0006] Summary of the Invention

[0007] The object of the present invention is to provide a compound represented by the general formula (I'-1):

[0008] in:

[0009] X1, X2, X3 are each independently selected from a bond, O, S, S=O, C=O, C, CR A1 , CR A1 R A2 , N or NR A1 ;

[0010] M is selected from a bond, S, S=O, S(O)2, N, NH, C=O, CH, CH2, C or O;

[0011] M1 is selected from C, CR A1 or N;

[0012] M2 is selected from a bond, O, S, S=O, C=O, C, CR A1 , CR A1 R A2 , N or NR A1 ;

[0013] M 1 Selected from C, CR A1 or N;

[0014] M 2 is selected from a bond, S, S=O, S(O)2, N, NH, C=O, CH, CH2, C or O;

[0015] M 3 is selected from a bond, S, S=O, S(O)2, N, NH, C=O, CH, CH2, C or O;

[0016] Ring G is present or absent. When present, it is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and may be further substituted.

[0017] R1 is each independently selected from hydrogen, deuterium, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, haloalkyl, halogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, membered heterocyclyl, aryl or heteroaryl;

[0018] R2 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 , cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, membered heterocyclyl, aryl or heteroaryl;

[0019] R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , which may be further substituted with one or more substituents selected from hydrogen, deuterium, halogen, oxo, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0020] Alternatively, any two R3 and the atoms to which they are connected form a cycloalkyl, heterocyclic, aryl or heteroaryl group, which may optionally be selected from hydrogen, deuterium, halogen, oxo, amino, aminocarbonyl, carbonylamino, carboxyl, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkyl substituted with cyano, oxo, cycloalkyl, heterocyclic, aryl, heteroaryl, -alkenyl R 22 , -alkynyl R 22 , -alkenyl R 33 , -alkynyl R 33 , -alkenyl R 22 R 33 , -alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) nO(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 (CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 44、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O) n (CH2) n1 R 22 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0021] Alternatively, R2 and R3 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which may optionally be selected from hydrogen, deuterium, halogen, oxo, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkyl substituted with cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0022] R 11are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, or hydroxyalkyl;

[0023] R 22 each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl, and optionally further substituted with deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkylsulfonyl, alkylsulfinyl, aminosulfonyl, aminosulfinyl, alkylaminocarbonyl, alkylcarbonylamino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, aminocarbonyl, carbonylamino, carboxyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0024] R 33 each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally further substituted with deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, alkylsulfonyl, alkylsulfinyl, alkylaminocarbonyl, alkylcarbonylamino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, aminocarbonyl, carbonylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0025] R 44 each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, aminocarbonyl, carbonylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0026] R A1 or R A2 each independently selected from hydrogen, deuterium, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, haloalkyl, halogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, membered heterocyclyl, aryl or heteroaryl;

[0027] x, y and z are each independently 0, 1, 2, 3 or 4;

[0028] n, n1 and m1 are each independently 0, 1, 2, 3 or 4.

[0029] In a further preferred embodiment of the present invention, the compound is further represented by general formula (I-1):

[0030] in:

[0031] M is selected from S, S=O, S(O)2, N, NH, C=O, CH, CH2, C or O;

[0032] M1 is selected from C;

[0033] M2 is selected from N, C or CH;

[0034] M 1 is selected from N, C or CH;

[0035] M 2 is selected from N, NH, C, CH or CH2;

[0036] M 3 is selected from N, NH, C, CH or CH2;

[0037] is a single bond or a double bond; I

[0038] Ring G is present or absent. When ring G is present, it is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and may be further substituted.

[0039] R1 is each independently selected from hydrogen, deuterium, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, haloalkyl, halogen, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, membered heterocyclyl, aryl or heteroaryl;

[0040] R2 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 , cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, membered heterocyclyl, aryl or heteroaryl;

[0041] R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , which may be further substituted with one or more substituents selected from hydrogen, deuterium, halogen, oxo, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0042] Alternatively, any two R3 and the atoms to which they are connected form a cycloalkyl, heterocyclic, aryl or heteroaryl group, which may optionally be selected from hydrogen, deuterium, halogen, oxo, amino, aminocarbonyl, carbonylamino, carboxyl, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkyl substituted with cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -alkenyl R 22 , -alkynyl R 22 , -alkenyl R 33 , -alkynyl R 33 , -alkenyl R 22 R 33 , -alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2)n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 44 、-(CH2)n S(O)(CH2) n1 R 33 、-(CH2) n S(O) n (CH2) n1 R 22 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or - (CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0043] Alternatively, R2 and R3 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which may optionally be selected from hydrogen, deuterium, halogen, oxo, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkyl substituted with cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0044] R 11are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, or hydroxyalkyl;

[0045] R 22 each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, or hydroxyalkyl, and optionally further substituted with deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, alkylsulfonyl, alkylsulfinyl, aminosulfonyl, aminosulfinyl, alkylaminocarbonyl, alkylcarbonylamino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, aminocarbonyl, carbonylamino, carboxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0046] R 33 each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally further substituted with deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, alkylsulfonyl, alkylsulfinyl, alkylaminocarbonyl, alkylcarbonylamino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, aminocarbonyl, carbonylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0047] R 44 each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, aminocarbonyl, carbonylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0048] x, y and z are each independently 0, 1, 2, 3 or 4;

[0049] n, n1 and m1 are each independently 0, 1, 2, 3 or 4.

[0050] In certain embodiments of the present invention,

[0051] M is selected from S, S=O, S(O)2, N, NH, C=O, CH, CH2, C or O;

[0052] M1 is selected from C;

[0053] M2 is selected from N, C or CH;

[0054] M 1 is selected from N, C or CH;

[0055] M 2 is selected from N, NH, C, CH or CH2;

[0056] M 3 is selected from N, NH, C, CH or CH2;

[0057] is a single bond or a double bond;

[0058] Ring G is present or absent. When present, it is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and may be further substituted.

[0059] R1 is each independently selected from hydrogen, deuterium, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, haloalkyl, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, and optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, membered heterocyclyl, aryl, or heteroaryl;

[0060] R2 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 , cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, membered heterocyclyl, aryl or heteroaryl;

[0061] R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) nS(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , which may be further substituted with one or more substituents selected from hydrogen, deuterium, halogen, oxo, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0062] Alternatively, any two R3 and the atoms to which they are connected form a cycloalkyl, heterocyclic, aryl or heteroaryl group, which may optionally be selected from hydrogen, deuterium, halogen, oxo, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -alkenyl R 22 , -alkynyl R 22 , -alkenyl R 33 , -alkynyl R 33 , -alkenyl R 22 R 33 , -alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2)n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、- (CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 44 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0063] Alternatively, R2 and R3 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which may optionally be selected from hydrogen, deuterium, halogen, oxo, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkyl substituted with cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0064] R 11 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, or hydroxyalkyl;

[0065] R 22 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, or hydroxyalkyl;

[0066] R 33 each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkylsulfonyl, alkylsulfinyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, aminocarbonyl, carbonylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0067] R 44each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, aminocarbonyl, carbonylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0068] x, y and z are each independently 0, 1, 2, 3 or 4;

[0069] n, n1 and m1 are each independently 0, 1, 2, 3 or 4.

[0070] In certain embodiments of the present invention,

[0071] M is selected from S, S=O, S(O)2, N, NH, C=O, CH, CH2, C or O;

[0072] M1 is selected from C;

[0073] M2 is selected from N, C or CH;

[0074] M 1 is selected from N, C or CH;

[0075] M 2 is selected from N, NH, C, CH or CH2;

[0076] M 3 is selected from N, NH, C, CH or CH2;

[0077] is a single bond or a double bond;

[0078] Ring G is present or absent. When present, it is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and may be further substituted.

[0079] R1 is each independently selected from hydrogen, deuterium, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, haloalkyl, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, and optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, membered heterocyclyl, aryl, or heteroaryl;

[0080] R2 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, -(CH2) n NR 22 C(O)(CH2)n1 R 33 , cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, membered heterocyclyl, aryl or heteroaryl;

[0081] R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , which may optionally be further substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, membered heterocyclyl, aryl or heteroaryl;

[0082] Alternatively, two R3 are linked to the atoms to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n C(O)(CH2) n1 R 33 、-(CH2)n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0083] Alternatively, R2 and R3 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which may optionally be selected from hydrogen, deuterium, halogen, oxo, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkyl substituted with cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0084] R 22selected from hydrogen, deuterium, or halogen;

[0085] R 33 each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0086] x, y and z are each independently 0, 1, 2, 3 or 4;

[0087] n, n1 and m1 are each independently 0, 1, 2, 3 or 4.

[0088] In a further preferred embodiment of the present invention, the compound is further represented by the general formula (I-2-1):

[0089] in:

[0090] when When it is a single bond, there is hydrogen on the N connected to it;

[0091] M2 is selected from N, CR A1 , or C;

[0092] Ring D is present or absent; Ring E is present or absent; and at least one of Ring D and Ring E is present;

[0093] Ring D and Ring E are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally, may be selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, oxo, cycloalkyl, heterocyclyl, aryl, heteroaryl, -alkenyl R 22 , -alkynyl R 22 , -alkenyl R 33 , -alkynyl R 33 , -alkenyl R 22 R 33 , -alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) nNR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n R 33 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2)n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 Preferably, ring D and ring E are each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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, -C 2-6 Alkenyl R 22 、-C 2-6 Alkynyl R 22 、-C 2-6 Alkenyl R 33 、-C 2-6 Alkynyl R 33 、-C 2-6 Alkenyl R 22 R 33 、-C 2-6 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 More preferably, ring D and ring E are each independently selected from C 6-10aryl, 3-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur, or 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C6-10 aryl, 5-8 membered heteroaryl, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0094] In a further preferred embodiment of the present invention, wherein:

[0095] when When it is a single bond, there is hydrogen on the N connected to it;

[0096] M2 is selected from N or C;

[0097] Ring D is present or absent; Ring E is present or absent; and at least one of Ring D and Ring E is present;

[0098] Ring D and Ring E are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally, may be selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -alkenyl R 22 , -alkynyl R 22 , -alkenyl R 33 , -alkynyl R 33 , -alkenyl R 22 R 33 , -alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n R 33 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 More preferably, ring D and ring E are each independently selected from C 6-10 aryl, 3-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur, or 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-8 membered heteroaryl, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R33 ,-C 2-3 alkynyl R 33 ,-C 2-3 alkenyl R 22 R 33 ,-C 2-3 alkynyl R 22 R 33 ,-(CH2) n O(CH2) n1 R 22 ,-(CH2) n O(CH2) n1 R 33 ,-(CH2) n NR 11 (CH2) n1 R 22 ,-(CH2) n NR 11 (CH2) n1 R 33 ,-(CH2) n NR 22 R 33 , -(CH2) n C(O)NR 22 R 33 ,-(CH2) n R 33 ,-(CH2) n R 22 ,-(CH2) n R 22 R 33 ,-(CH2) n NR 11 C(O)(CH2) n1 R 22 ,-(CH2) n NR 11 C(O)O(CH2) n1 R 22 ,-(CH2) n NR 11 C(O)O(CH2) n1 R 33 ,-(CH2) n O(CH2) n1 C(O)R 22 ,-(CH2) n NR 11 S(O)2(CH2) n1 R 22 ,-(CH2) n C(O)(CH2) n1 [[ID=33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0099] z is 0, 1, or 2;

[0100] M, M1, R2, R3, R 22 、R 33 , n, n1 and m1 are as defined in the general formula (I-1).

[0101] In certain embodiments of the present invention, M2 is selected from N or C;

[0102] Ring D is present or absent; Ring E is present or absent; and at least one of Ring D and Ring E is present;

[0103] Ring D and Ring E are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally, may be selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n R 33 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) nS(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、- (CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 Preferably, ring D and ring E are each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33More preferably, ring D and ring E are each independently selected from a 3-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms or a 5-10 membered heteroaryl group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 substituted by one or more substituents selected from cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-8 membered heteroaryl; further preferably, ring D and ring E are each independently selected from a 3-6 membered heterocyclyl containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms or a 5-8 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, and optionally substituted by one or more substituents selected from hydrogen, deuterium, hydroxyl, fluorine, chlorine, bromine, oxo, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, cyclopropyl or cyclobutyl;

[0104] z is 0, 1, or 2;

[0105] M, M1, R2, R3, R 22 、R 33 , n, n1 and m1 are as defined in the general formula (I-1).

[0106] In a further preferred embodiment of this method, the compound of formula (I-2-1) is not:

[0107] In a further preferred embodiment of this method,

[0108] It is a single bond, and there is hydrogen on the N connected to it;

[0109] M is C=O;

[0110] M1 is selected from C;

[0111] Ring D is present or absent; Ring E is present or absent; and at least one of Ring D and Ring E is present;

[0112] Ring D or Ring E are each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12Aryl or 5-12 membered heteroaryl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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, -C 2-6 Alkenyl R 22 、-C 2-6 Alkynyl R 22 、-C 2-6 Alkenyl R 33 、-C 2-6 Alkynyl R 33 、-C 2-6 Alkenyl R 22 R 33 、-C 2-6 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0113] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n NR 22C(O)(CH2) n1 R 33 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, said R2 optionally can be selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 substituted by one or more substituents in aryl or 5-12 membered heteroaryl;

[0114] R3 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 44 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) nS(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , said R3 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 substituted by one or more substituents in aryl or 5-12 membered heteroaryl;

[0115] R 22 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 1-6 hydroxyalkyl;

[0116] R 33 Each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-6 Alkyl S(O)2-, C 1-6 Alkyl S(O)-, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, aminocarbonyl, carbonylamino, C 1-6 Alkylaminocarbonyl, C 1-6 Alkylcarbonylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions of aryl or 5-10 membered heteroaryl;

[0117] m1 is 0.

[0118] In a further preferred embodiment of the present invention, the compound is further represented by the general formula (IA-1):

[0119] in:

[0120] M2 is selected from N or C;

[0121] Ring D is present or absent; Ring E is present or absent; and at least one of Ring D and Ring E is present;

[0122] Ring D and Ring E are each independently selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, preferably a 3-10-membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms or a 5-10-membered heteroaryl group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, more preferably a 3-6-membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms or a 5-8-membered heteroaryl group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, further preferably a phenyl group, a naphthyl group, a 3-, 4-, 5- or 6-membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms or a 5-, 6-, 7- or 8-membered heteroaryl group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, and further preferably

[0123] M, M1, R1, R2, R3, m1, y and z are as defined in the general formula (I-2-1).

[0124] In a further preferred embodiment of the present invention, the compound is further represented by the general formula (IBI):

[0125] Ring D is selected from C 6-10 Aryl, 3-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms or 5-10 membered heteroaryl group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, preferably phenyl, naphthyl, 3-6 membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms or 5-8 membered heteroaryl group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, more preferably phenyl, pyridyl, Further optimization

[0126] R4 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 Halogenated alkyl, 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, -C 2-3 Alkenyl-R 22 、-C 2-3 Alkynyl-R 22 、-C 2-3 Alkenyl-R 33 、-C 2-3 Alkynyl-R 33 、-C 2- 3-Alkenyl-R 22 R 33 、-C 2-3 Alkynyl-R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally substituted by hydrogen, hydroxy, 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, and R4 is preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2- 3 alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、- (CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally substituted by hydroxy, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 R4 is preferably substituted by one or more substituents of deuterated alkyl, and R4 is more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitrile, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, -C 2-3 Alkenyl-R 22 、-C 2-3 Alkynyl-R 22 、-C 2-3 Alkenyl-R 33 、-C 2-3 Alkynyl-R 33 、-C 2-3 Alkenyl-R 22 R 33 、-C 2-3 Alkynyl-R 22 R 33 、-(CH2) n O(CH2) n1 R 22、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 ;

[0127] u are each independently 1, 2, 3 or 4;

[0128] R2, R3, y, and z are as defined in the general formula (I-1).

[0129] In certain embodiments of the present invention,

[0130] Ring D is selected from a 3-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms or a 5-10 membered heteroaryl group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, more preferably a 3-6 membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms or a 5-8 membered heteroaryl group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, further preferably

[0131] R4 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 Halogenated alkyl, 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 The deuterated alkyl group is substituted with one or more substituents, and R4 is preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, optionally substituted by hydrogen, hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 R4 is substituted by one or more substituents of deuterated alkyl, and R4 is more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitrile, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl or trichloromethyl;

[0132] u are each independently 1, 2, 3 or 4;

[0133] R2, R3, x, and y are as defined in the general formula (I-1).

[0134] In certain embodiments of the present invention, ring D is selected from phenyl, pyridyl,

[0135] In a further preferred embodiment of the present invention, the compound is further represented by the general formula (IC-II):

[0136] M6, M7, M8, and M9 are each independently selected from C, CH, CH2, N, NH, O, S, C=O, or S=O;

[0137] R2 are each independently selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 3-8 membered heteroaryl, preferably 3-8 membered heteroaryl or C containing 1-3 N, O or S atoms 6-10 Aryl, said R2 may optionally be substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl or alkynyl; R2 is more preferably a 5-6 membered heteroaryl containing 1-3 N, O or S atoms or C 6-10 Aryl, optionally substituted by hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 2-3 Alkenyl or C 2-3Alkynyl substituted; R2 is further preferably phenyl, which may be optionally substituted with one or more substituents of hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl or trichloromethyl;

[0138] R3 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 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、、-(CH2) n NR 22 C(O)(CH2) n1 R 44 、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 and C 1-6 The alkyl group is substituted by one or more substituents, preferably hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl or -(CH2) n NR 22 C(O)(CH2) n1 R 33 ;

[0139] R4 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 Halogenated alkyl, 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, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、- (CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally substituted by hydrogen, hydroxy, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 R4 is preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2- 3 alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally substituted by hydroxy, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 R4 is more preferably substituted by one or more substituents of deuterated alkyl; R4 is more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitrile, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2)n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 .

[0140] In certain embodiments of the present invention,

[0141] M6, M7, M8, and M9 are each independently selected from CH, CH2, N, NH, O, S, C=O, or S=O;

[0142] R2 are each independently selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 3-8 membered heteroaryl; preferably 3-8 membered heteroaryl or C containing 1-3 N, O or S atoms 6-10 Aryl, wherein R2 may be optionally substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl; R2 is preferably a 5-6 membered heteroaryl containing 1-3 N, O or S atoms or C 6-10 Aryl, optionally substituted by hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl substitution; R2 is more preferably phenyl, which may be optionally substituted with one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl or trichloromethyl;

[0143] R3 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 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、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 and C 1-6 The alkyl group is substituted by one or more substituents, preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, deuterated alkyl or -(CH2) n NR 22 C(O)(CH2) n1 R 33 ;

[0144] R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6Alkyl, C 2- 6 alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 The deuterated alkyl group is substituted by one or more substituents, preferably hydrogen, halogen, amino, 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 The deuterated alkyl group is substituted with one or more substituents.

[0145] In a further preferred embodiment of the present invention, the compound is further represented by the general formula (ID-IV):

[0146] R 44 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 3-12 membered heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aryl or 3-12 heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; preferably, R 44 Selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 3-10 Aryl or 3-10 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted with hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 3-6 membered heteroaryl.

[0147] In a further preferred embodiment of the present invention, the compound is further represented by the general formula (ID-IV-1), (ID-IV-2), (ID-IV-3), (ID-IV-4), (ID-IV-5) or (ID-IV-6):

[0148] R2 is selected from 5-6 membered heteroaryl containing 1-3 N, O or S atoms or C 6-10 Aryl, optionally substituted by hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, oxo, C 1-3 Alkyl, C 1- 3-deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 2-3 Alkenyl or C 2-3 Alkynyl substituted; R2 is preferably phenyl, optionally substituted by one or more substituents of hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl or trichloromethyl;

[0149] R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2- 3 alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R33 、 -C 2-3 Alkynyl R 22 R 33 、 -(CH2) n O(CH2) n1 R 22 、 -(CH2) n O(CH2) n1 R 33 、 -(CH2) n NR 11 (CH2) n1 R 22 、 -(CH2) n NR 11 (CH2) n1 R 33 、 -(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、 -(CH2) n R 33 、 -(CH2) n R 22 、 -(CH2) n R 22 R 33 、 -(CH2) n NR 11 C(O)(CH2) n1 R 22 、 -(CH2) n NR 11 C(O)O(CH2) n1 R 22 、 -(CH2) n NR 11 C(O)O(CH2) n1 R 33 、 -(CH2) n O(CH2) n1 C(O)R 22 、 - (CH2) n NR 11 S(O)2(CH2) n1 R 22 、 -(CH2) n C(O)(CH2) n1 R 33 、 -(CH2) n OC(O)(CH2) n1 R 33 、 -(CH2)n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally substituted by hydroxy, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 R4 is preferably substituted by one or more substituents of deuterated alkyl, and R4 is preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitrile, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2)n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 ;

[0150] R 44 Each independently selected from C 3-12Cycloalkyl, 3-12 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6 haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 3-6 membered heteroaryl substituted; preferably, R 44 Each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1- 3 haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 3-6 membered heteroaryl; more preferably, R 44 Selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, Optionally substituted with one or more substituents selected from deuterium, hydroxyl, fluorine, chlorine, bromine, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloromethyl, 1,2-difluoroethyl or 1,2-dichloroethyl; further preferably, R 44 Selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, optionally substituted with one or more of deuterium, hydroxy, fluorine, chlorine, bromine, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloromethyl, 1,2-difluoroethyl or 1,2-dichloroethyl;

[0151] u is 1, 2, 3, or 4.

[0152] In certain embodiments of the present invention,

[0153] R 44 Selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, Optionally substituted with one or more of deuterium, hydroxy, fluorine, chlorine, bromine, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloromethyl, 1,2-difluoroethyl or 1,2-dichloroethyl.

[0154] In certain embodiments of the present invention,

[0155] R2 is selected from 5-6 membered heteroaryl containing 1-3 N, O or S atoms or C6-10 aryl, optionally substituted by hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl substitution; R2 is more preferably phenyl, which may be optionally substituted with one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl or trichloromethyl;

[0156] R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2- 3 alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C2-3 Alkenyl R 22 R 33 、 -C 2-3 Alkynyl R 22 R 33 、 -(CH2) n O(CH2) n1 R 22 、 -(CH2) n O(CH2) n1 R 33 、 -(CH2) n NR 11 (CH2) n1 R 22 、 -(CH2) n NR 11 (CH2) n1 R 33 、 -(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、 -(CH2) n r R 33 、 -(CH2) n R 22 、 -(CH2) n R 22 R 33 、 -(CH2) n NR 11 C(O)(CH2) n1 R 22 、 -(CH2) n NR 11 C(O)O(CH2) n1 R 22 、 -(CH2) n NR 11 C(O)O(CH2) n1 R 33 、 -(CH2) n O(CH2) n1 C(O)R 22 、 -(CH2) n NR 11 S(O)2(CH2) n1 R 22 、 -(CH2) n C(O)(CH2) n1 R 33 、 -(CH2) n OC(O)(CH2) n1R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally substituted by hydroxy, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 R4 is preferably substituted by one or more substituents of deuterated alkyl, and R4 is more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitrile, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 ;

[0157] R 44 Each independently selected from C3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 3-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1- 3 haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 3-6 membered heteroaryl substituted; preferably, R 44 Selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, optionally substituted with one or more of hydroxy, fluoro, chloro, bromo, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloromethyl, 1,2-difluoroethyl or 1,2-dichloroethyl;

[0158] u is 1, 2, 3, or 4.

[0159] In certain embodiments of the present invention,

[0160] R2 is selected from 5-6 membered heteroaryl containing 1-3 N, O or S atoms or C6-10 aryl, optionally substituted by hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl substitution; R2 is more preferably phenyl, which may be optionally substituted with one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl or trichloromethyl;

[0161] R4 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2- 3 alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, optionally substituted by hydroxyl, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 R4 is substituted by one or more substituents of deuterated alkyl, and R4 is more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitrile, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl or trichloromethyl;

[0162] R 44 Each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 3-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1- 3 haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted with aryl or 3-6 membered heteroaryl;

[0163] u is 1, 2, 3, or 4.

[0164] In certain embodiments of the present invention, in the general formulas,

[0165] R1 are each independently selected from hydrogen, deuterium,

[0166] R2 and R3 are each independently selected from hydrogen, deuterium, fluorine, chlorine, amino, cyano, ethoxy, propoxy, methylamino, dimethylamino, formamido, difluoromethyl, trifluoromethyl, cyanomethyl,

[0167] In certain embodiments of the present invention, the compound is further represented by formula (ID-IV-11) or (ID-IV-41):

[0168] R2 is selected from 5-6 membered heteroaryl containing 1-3 N, O or S atoms or C 6-10 Aryl, optionally substituted by hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, oxo, C 1-3 Alkyl, C 1- 3-deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 2-3 Alkenyl or C 2-3 Alkynyl substituted; R2 is preferably phenyl, optionally substituted by one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl or trichloromethyl;

[0169] R 44 Each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6 haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 3-6 membered heteroaryl substituted; preferably, R 44 Each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1- 3 haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 3-6 membered heteroaryl; more preferably, R 44 Each independently selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, Optionally substituted with one or more substituents selected from deuterium, hydroxyl, fluorine, chlorine, bromine, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloromethyl, 1,2-difluoroethyl or 1,2-dichloroethyl; further preferably, R 44 Selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, optionally substituted with one or more of deuterium, hydroxy, fluorine, chlorine, bromine, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloromethyl, 1,2-difluoroethyl or 1,2-dichloroethyl;

[0170] L is selected from a bond, C 2-3 Alkenylene, C 2-3 Alkynylidene, C 1-3 Alkylene, O, S, -NH(CH2) w -, -C(O)-, -C(O)NH-, -NHC(O)-, -S(O)-, -S(O)2-, -S(O)2NH- or -NHS(O)2-;

[0171] Ring A1 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms, more preferably C 3-6 Monocyclic alkyl, C 5-10 Spiroalkyl, C 5-10 Bridged cycloalkyl, C 5-10 fused cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, 5-10 membered spiro heterocyclic group containing 1-3 N, O or S atoms, 5-10 membered bridged heterocyclic group containing 1-3 N, O or S atoms, 5-10 membered fused heterocyclic group containing 1-3 N, O or S atoms, C 6-8 Monocyclic aromatic group, C 8-10 A fused ring aryl group, a 5-6 membered monocyclic heteroaryl group containing 1-3 N, O or S atoms, or a 5-10 membered fused ring heteroaryl group containing 1-3 N, O or S atoms, further preferably a cyclopropyl group, a cyclobutyl group,

[0172] R 331 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-3 Alkylamino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkyl S(O)2-, C 1-3 Alkyl S(O)-, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkylaminosulfonyl, C 1-3 Alkylaminocarbonyl, C 1-3 Alkylcarbonylamino, aminocarbonyl, carbonylamino, C 1-3 Alkylcarbonyl, C 1-3 Deuterated alkylcarbonyl, C 1-3 Haloalkylcarbonyl, C 1-4 Hydroxyalkylcarbonyl, C 1- 3 alkoxycarbonyl, C 1-3 Deuterated alkoxycarbonyl, C 1-3 Haloalkoxycarbonyl, C 3-6 Cycloalkylcarbonyl, 3-6 membered heterocyclylcarbonyl, C 6-10 Arylcarbonyl, 5-8 membered heteroarylcarbonyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-8 membered heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2- 3 alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-8 membered heteroaryl, optionally further substituted by one or more substituents selected from hydrogen, deuterium, halogen, nitro, hydroxyl, thiol, cyano, and amino; preferably, R 331are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkyl S(O)2-, C 1-3 Alkyl S(O)-, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylaminocarbonyl, C 1-3 Alkylcarbonylamino, aminocarbonyl, carbonylamino, C 3-6 Cycloalkylcarbonyl, 3-6 membered heterocyclic carbonyl containing 1-3 N, O or S atoms, C 6-10 Arylcarbonyl, 5-8 membered heteroarylcarbonyl containing 1-3 N, O or S atoms, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms, more preferably, R 331 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl, chloroethyl, aminocarbonyl, carbonylamino, cyclopropyl, cyclobutyl, cyclohexyl, carboxyl, aminosulfonyl, aminosulfinyl, methylaminocarbonyl, methylcarbonylamino, methyl S(O)2-, methyl S(O)-, cyclopropyl, cyclobutyl,

[0173] w is 0, 1, 2, 3, or 4;

[0174] u1 is 0, 1, 2, 3, or 4.

[0175] In a preferred embodiment of the present invention, R2 is selected from a 5-6 membered heteroaryl group containing 1-3 N, O or S atoms or a C 6-10 Aryl, optionally substituted by hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 2-3Alkenyl, C 2-3 Alkynyl substitution; R2 is more preferably phenyl, which may be optionally substituted with one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl or trichloromethyl;

[0176] R 44 Each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group containing 1-3 N, O or S atoms, C 3-12 Aryl or 5-12 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1- 6 haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 3-6 membered heteroaryl substituted; preferably, R 44 Each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 3-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted by hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1- 3 haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 3-6 membered heteroaryl substituted; preferably, R 44 Selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, optionally substituted with one or more of deuterium, hydroxy, fluorine, chlorine, bromine, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloromethyl, 1,2-difluoroethyl or 1,2-dichloroethyl;

[0177] L is selected from a bond, C1-3 Alkenylene, C 1-3 Alkynylidene, C 1-3 Alkylene, O, S, -C(O)-, -C(O)NH-, -NHC(O)-, -S(O)-, -S(O)2-, -S(O)2NH-, or -NHS(O)2-;

[0178] Ring A1 is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-9 membered heteroaryl, preferably C 3- 8-membered cycloalkyl, 3-8-membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-9 membered heteroaryl containing 1-3 N, O or S atoms, more preferably cyclopropyl, cyclobutyl,

[0179] R 331 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-3 Alkylamino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkyl S(O)2-, C 1-3 Alkyl S(O)-, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkylaminosulfonyl, C 1-3 Alkylaminocarbonyl, C 1-3 Alkylcarbonylamino, aminocarbonyl, carbonylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-8 membered heteroaryl, preferably hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkyl S(O)2-, C 1-3 Alkyl S(O)-, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylaminocarbonyl, C 1-3 Alkylcarbonylamino, aminocarbonyl, carbonylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or a 5-8 membered heteroaryl containing 1-3 N, O or S atoms, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl, chloroethyl, aminocarbonyl, carbonylamino, cyclopropyl, cyclobutyl, cyclohexyl, carboxyl, aminosulfonyl, aminosulfinyl, methylaminocarbonyl, methylcarbonylamino, methyl S(O)2-, methyl S(O)-, cyclopropyl, cyclobutyl,

[0180] u1 is 0, 1, 2, 3, or 4.

[0181] In certain embodiments of the present invention, in the general formulas,

[0182] R1 is independently selected from hydrogen, deuterium, C 1-6 Alkyl, halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 12 Aryl or 5-12 membered heteroaryl, said R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, 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 is substituted with one or more substituents;

[0183] Preferably, R1 is independently selected from hydrogen, deuterium, C 1-3 Alkyl, halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12aryl or 5-12 membered heteroaryl containing 1-3 N, O or S atoms, wherein R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 3 alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 5-10 membered heteroaryl;

[0184] More preferably, R1 is independently selected from hydrogen, deuterium, C 1-3 Alkyl, halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 aryl or 5-12 membered heteroaryl containing 1-3 N, O or S atoms, wherein R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 5-10 membered heteroaryl;

[0185] Further preferably, R1 is independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, phenyl, pyridyl, pyrimidinyl or naphthyl, and R1 may be optionally substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, thiol, cyano, amino, oxo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, trifluoromethyl, chloromethyl, chloroethyl or trichloromethyl.

[0186] In certain embodiments of the present invention, in the general formulas,

[0187] R2 is 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 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, said R2 optionally can be selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 is substituted with one or more substituents;

[0188] Preferably, R2 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10Aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms, wherein R2 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, 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 substituted by one or more substituents selected from cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-8 membered heteroaryl;

[0189] More preferably, R2 is each independently selected from hydrogen, deuterium, phenyl, naphthyl, pyridyl or pyrimidinyl, optionally substituted with one or more substituents selected from hydroxy, fluorine, chlorine or bromine;

[0190] Further preferably, R2 is each independently selected from phenyl substituted by halogen;

[0191] More preferably, R2 is independently selected from phenyl groups substituted with 1 to 3 atoms selected from fluorine, chlorine and bromine.

[0192] In certain embodiments of the present invention, in the general formulas,

[0193] R3 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2)n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 44 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , said R3 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 is substituted with one or more substituents;

[0194] Preferably, R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl, 5-8 membered heteroaryl containing 1-3 N, O or S atoms or -NHC(O)R 33 , said R3 may optionally be selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 5-8 membered heteroaryl;

[0195] More preferably, R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 3 alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl, 5-8 membered heteroaryl containing 1-3 N, O or S atoms or -NHC(O)R 33 , said R3 may be optionally substituted by one or more substituents selected from hydrogen, hydroxy, fluorine, chlorine, bromine, oxo, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, cyclopropyl or cyclobutyl;

[0196] Alternatively, any two R3 atoms form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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, -C 2-3 Alkenyl R 22 、-C2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0197] Preferably, any two R3 and the atoms to which they are connected form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 membered heteroaryl containing 1-3 N, O or S atoms, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O, S atoms, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents.

[0198] In certain embodiments of the present invention, in the general formulas,

[0199] R 44 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 is substituted with one or more substituents;

[0200] Preferably, R 44 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 membered heteroaryl containing 1-3 N, O or S atoms, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C1-3 Halogenated alkyl, 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 containing 1-3 N, O or S atoms, C 6-10 substituted by one or more substituents in aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms;

[0201] More preferably, R 44 Selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, Optionally substituted with one or more of deuterium, hydroxy, fluorine, chlorine, bromine, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloromethyl, 1,2-difluoroethyl or 1,2-dichloroethyl.

[0202] In certain embodiments of the present invention, in the general formulas,

[0203] R1 is independently selected from hydrogen, deuterium, C 1-6 Alkyl, halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 12 Aryl, 5-12 membered heteroaryl, said R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, 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; preferably, R1 is independently selected from hydrogen, deuterium, C 1-3 Alkyl, halogen, 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 containing 1-3 N, O or S atoms, wherein R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; more preferably, R1 is independently selected from hydrogen, deuterium, C 1-3 Alkyl, halogen, 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 containing 1-3 N, O or S atoms, wherein R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl is substituted with one or more substituents; further preferably, R1 is each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, phenyl, pyridyl, pyrimidinyl or naphthyl, and R1 may optionally be substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, oxo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, trifluoromethyl, chloromethyl, chloroethyl, trichloromethyl;

[0204] R2 is 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 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C1-6 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, said R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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; preferably, R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms, wherein R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8substituted by one or more substituents selected from cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-8 membered heteroaryl; more preferably, R2 is each independently selected from hydrogen, deuterium, phenyl, naphthyl, pyridyl or pyrimidinyl, optionally substituted by one or more substituents selected from hydroxy, fluorine, chlorine or bromine; further preferably, R2 is each independently selected from phenyl substituted by halogen; further preferably, it is phenyl substituted by 1 to 3 atoms selected from fluorine, chlorine and bromine;

[0205] R3 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 44 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally may be selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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; preferably, R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C6-10 aryl, 5-8 membered heteroaryl containing 1-3 N, O or S atoms, or -NHC(O)R 33 , said R3 may optionally be selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1- 3-hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 substituted by one or more substituents selected from cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-8 membered heteroaryl; more preferably, R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C6-10 aryl, 5-8 membered heteroaryl containing 1-3 N, O or S atoms, or -NHC(O)R 33 , said R3 may be optionally substituted by one or more substituents selected from hydrogen, hydroxy, fluorine, chlorine, bromine, oxo, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, cyclopropyl or cyclobutyl;

[0206] Alternatively, any two R3 atoms form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0207] R 44 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 is substituted with one or more substituents; preferably, R 44 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 membered heteroaryl containing 1-3 N, O or S atoms, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 containing 1-3 N, O or S atoms, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms; more preferably, R 44 Selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, Optionally substituted with one or more of deuterium, hydroxy, fluorine, chlorine, bromine, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloromethyl, 1,2-difluoroethyl or 1,2-dichloroethyl.

[0208] In certain embodiments of the present invention, in the general formulas,

[0209] R1 is independently selected from hydrogen, deuterium, C 1-6 Alkyl, halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 12 Aryl, 5-12 membered heteroaryl, said R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, 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; preferably, R1 is independently selected from hydrogen, deuterium, C 1-3 Alkyl, halogen, 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 containing 1-3 N, O or S atoms, wherein R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; more preferably, R1 is independently selected from hydrogen, deuterium, C 1-3 Alkyl, halogen, 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 containing 1-3 N, O or S atoms, wherein R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl is substituted with one or more substituents; further preferably, R1 is each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, phenyl, pyridyl, pyrimidinyl or naphthyl, and R1 may optionally be substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, oxo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, trifluoromethyl, chloromethyl, chloroethyl, trichloromethyl;

[0210] R2 is 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 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, said R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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; preferably, R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms, wherein R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 substituted by one or more substituents selected from cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-8 membered heteroaryl; more preferably, R2 is each independently selected from hydrogen, deuterium, phenyl, naphthyl, pyridyl or pyrimidinyl, optionally substituted by one or more substituents selected from hydroxy, fluorine, chlorine or bromine; further preferably, R2 is each independently selected from phenyl substituted by halogen; further preferably, it is phenyl substituted by 1 to 3 atoms selected from fluorine, chlorine and bromine;

[0211] R3 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 44 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally may be selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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; preferably, R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C6-10 aryl, 5-8 membered heteroaryl containing 1-3 N, O or S atoms, or -NHC(O)R 33 , said R3 may optionally be selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1- 3-hydroxyalkyl, cyano-substituted C 1-3 Alkyl, C 3-8 substituted by one or more substituents selected from cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-8 membered heteroaryl; more preferably, R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C6-10 aryl, 5-8 membered heteroaryl containing 1-3 N, O or S atoms, or -NHC(O)R 33 , said R3 may be optionally substituted by one or more substituents selected from hydrogen, hydroxy, fluorine, chlorine, bromine, oxo, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, cyclopropyl or cyclobutyl;

[0212] Alternatively, any two R3 atoms form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl, 5-12 membered heteroaryl, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0213] R 44 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 is substituted with one or more substituents; preferably, R 44 Selected from C 3-12Cycloalkyl, 3-12 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 membered heteroaryl containing 1-3 N, O or S atoms, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 containing 1-3 N, O or S atoms, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms; more preferably, R 44 Selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, Optionally substituted with one or more of hydroxy, fluoro, chloro, bromo, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloromethyl, 1,2-difluoroethyl or 1,2-dichloroethyl.

[0214] In certain embodiments of the present invention, in the general formulas,

[0215] R1 is independently selected from hydrogen, deuterium, C 1-6 Alkyl, halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 12 Aryl, 5-12 membered heteroaryl, said R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, 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; preferably, R1 is independently selected from hydrogen, deuterium, C 1-3 Alkyl, halogen, C3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 Aryl, 5-12 membered heteroaryl containing 1-3 N, O or S atoms, wherein R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; more preferably, R1 is independently selected from hydrogen, deuterium, C 1-3 Alkyl, halogen, 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 containing 1-3 N, O or S atoms, wherein R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl is substituted with one or more substituents; further preferably, R1 is each independently selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, phenyl, pyridyl, pyrimidinyl or naphthyl, and R1 may optionally be substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, oxo, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, fluoromethyl, fluoroethyl, trifluoromethyl, chloromethyl, chloroethyl, trichloromethyl;

[0216] R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2- 6 alkenyl, C2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, said R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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; preferably, R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms, wherein R1 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 substituted by one or more substituents selected from cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-8 membered heteroaryl; more preferably, R2 is each independently selected from hydrogen, deuterium, phenyl, naphthyl, pyridyl or pyrimidinyl, optionally substituted by one or more substituents selected from hydroxy, fluorine, chlorine or bromine; further preferably, R2 is each independently selected from phenyl substituted by halogen; further preferably, it is phenyl substituted by 1 to 3 atoms selected from fluorine, chlorine and bromine;

[0217] R3 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33, optionally may be selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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; preferably, R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C6-10 aryl, 5-8 membered heteroaryl containing 1-3 N, O or S atoms, or -NHC(O)R 33 , said R3 may optionally be selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, 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 substituted by one or more substituents selected from cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-8 membered heteroaryl; more preferably, R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 3 alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C6-10 aryl, 5-8 membered heteroaryl containing 1-3 N, O or S atoms, or -NHC(O)R 33 , said R3 may be optionally substituted by one or more substituents selected from hydrogen, hydroxy, fluorine, chlorine, bromine, oxo, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, cyclopropyl or cyclobutyl;

[0218] Alternatively, two R3 atoms are linked to form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents;

[0219] R 44 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 is substituted with one or more substituents; preferably, R 33 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 membered heteroaryl containing 1-3 N, O or S atoms, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 containing 1-3 N, O or S atoms, C 6-10 aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms; more preferably, R 33 Selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, Optionally substituted with one or more of hydroxy, fluoro, chloro, bromo, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloromethyl, 1,2-difluoroethyl or 1,2-dichloroethyl.

[0220] In certain embodiments of the present invention, in the general formulas,

[0221] R1 is independently selected from phenyl substituted by halogen; preferably phenyl substituted by 1 to 3 atoms selected from fluorine, chlorine and bromine, more preferably More preferably

[0222] R2 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl, -NHC(O)R 33 ; Preferably, R2 are each independently selected from hydrogen, methyl,

[0223] R3 are each independently selected from hydrogen, deuterium, C 6-10 Aryl or 5-10 membered heteroaryl, the C 6-10 Aryl or 5-10 membered heteroaryl is replaced by hydrogen, hydroxy, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 The phenyl or 5-10 membered heteroaryl group is substituted with one or more substituents of a deuterated alkyl group; preferably hydrogen, deuterium, phenyl or 5-10 membered heteroaryl, wherein the phenyl or 5-10 membered heteroaryl group is substituted with one or more substituents of hydrogen, hydroxyl, fluorine, chlorine, bromine or trifluoromethyl; more preferably hydrogen, deuterium,

[0224] “*” represents the attachment site.

[0225] In certain embodiments of the present invention, in the general formulas,

[0226] Ring D and Ring E are each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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, -C 2-6 Alkenyl R 22 、-C 2-6 Alkynyl R 22、-C 2-6 Alkenyl R 33 、-C 2-6 Alkynyl R 33 、-C 2-6 Alkenyl R 22 R 33 、-C 2-6 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2)n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 Preferably, ring D and ring E are each independently selected from C 6-10 Aryl, 3-6 membered heterocyclic radical containing 1-3 atoms selected from nitrogen, oxygen or sulfur, or 5-8 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, optionally selected from hydrogen, deuterium, hydroxyl, fluorine, chlorine, bromine, oxo, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, propoxy, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2- 3 alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11(CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 22 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 、、-(CH2) n NR 22S(O)2(CH2) n1 R 33、 is substituted by one or more substituents.

[0227] In certain embodiments of the present invention, in the general formulas,

[0228] Ring D is selected from C 6-10 Aryl, 3-10 membered heterocyclic groups containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, or 5-10 membered heteroaryl groups containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, preferably phenyl, naphthyl, 3-6 membered heterocyclic groups containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, or 5-8 membered heteroaryl groups containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, more preferably phenyl, naphthyl, 3, 4, 5 or 6 membered heterocyclic groups containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, or 5, 6, 7 or 8 membered heteroaryl groups containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, further preferably phenyl, pyridyl, Further optimization

[0229] Ring E is selected from a 3-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms or a 5-10 membered heteroaryl group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, preferably a 3-6 membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms or a 5-8 membered heteroaryl group containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, more preferably

[0230] In certain embodiments of the present invention, in the general formulas,

[0231] R 11 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy or C 1-6 Hydroxyalkyl, preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 3 alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C1-3 hydroxyalkyl, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl or chloroethyl;

[0232] R 22 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy or C 1-6 Hydroxyalkyl, preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 3 alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 hydroxyalkyl, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl or chloroethyl;

[0233] R 33 Each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-6 Alkyl S(O)2-, C 1-6 Alkyl S(O)-, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6Alkenyl, C 2-6 Alkynyl, aminocarbonyl, carbonylamino, C 1-6 Alkylaminocarbonyl, C 1-6 Alkylcarbonylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; preferably, R 33 Each independently selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-9 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkyl S(O)2-, C 1-3 Alkyl S(O)-, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkylaminocarbonyl, C 1-3 Alkylcarbonylamino, aminocarbonyl, carbonylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 5-8 membered heteroaryl; more preferably, R 33 Each independently selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-9 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkyl S(O)2-, C 1-3 Alkyl S(O)-, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylaminocarbonyl, C 1-3 Alkylcarbonylamino, aminocarbonyl, carbonylamino, C 3-6-membered cycloalkyl, 3-6-membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms; further preferably, R 33 Each independently selected from cyclopropyl, cyclobutyl, Optionally, the alkyl radicals may be further substituted with deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl, chloroethyl, aminocarbonyl, carbonylamino, cyclopropyl, cyclobutyl, cyclohexyl, carboxyl, aminosulfonyl, aminosulfinyl, methylaminocarbonyl, methylcarbonylamino, methyl S(O)2-, methyl S(O)-, cyclopropyl, cyclobutyl, is substituted by one or more substituents.

[0234] In certain embodiments of the present invention,

[0235] R 11 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy or C 1-6 Hydroxyalkyl, preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 3 alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 hydroxyalkyl, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl or chloroethyl;

[0236] R22 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy or C 1-6 Hydroxyalkyl, preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 3 alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 hydroxyalkyl, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl or chloroethyl;

[0237] R 33 Each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, aminocarbonyl, carbonylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-10 membered heteroaryl; preferably, R 33 Each independently selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-9 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-3 Alkyl, C 1-3Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, aminocarbonyl, carbonylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 5-8 membered heteroaryl; more preferably, R 33 Each independently selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-9 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, aminocarbonyl, carbonylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms; further preferably, R 33 Each independently selected from cyclopropyl, cyclobutyl, Optionally, it may be further substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl, chloroethyl, aminocarbonyl, carbonylamino, cyclopropyl, cyclobutyl or cyclohexyl.

[0238] The present invention also provides a method for preparing the compound represented by the aforementioned general formula (ID-IV), its stereoisomers or pharmaceutically acceptable salts thereof, comprising the following steps:

[0239] The compound of formula (ID-IV-a), its stereoisomer or a pharmaceutically acceptable salt thereof, is subjected to cyclization, dehydroxylation, reduction, amidation and deprotection to obtain the compound of formula (IC-II), its stereoisomer or a pharmaceutically acceptable salt thereof;

[0240] in,

[0241] R d2 or R d3 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl or -(CH2) n C(O)NR e2 (CH2) n1 R e1 , the R d2 or R d3 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 substituted by one or more substituents in aryl or 5-12 membered heteroaryl;

[0242] Or, R d2 and R d3 Together they form an oxo group or a thio group;

[0243] Preferably, R d2 or R d3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylamino, C 1-3Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl or -(CH2) n C(O)NR e2 (CH2) n1 R e1 , the R d2 or R d3 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 One or more substituents in the alkyl group;

[0244] Or, R d2 and R d3 Together they form an oxo group or a thio group;

[0245] R e1 or R e2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms, wherein R e1 or R e2 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 5-8 membered heteroaryl;

[0246] Preferably, R e1 or R e2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, cyano substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms, wherein R e1 or R e2 Optionally, it may be selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 5-8 membered heteroaryl;

[0247] P G is a leaving group, preferably a hydroxyl group or an ester group;

[0248] R d is an amino protecting group; preferably tert-butyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyl, tert-butyloxycarbonyl, Troc, 9-fluorenylmethoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, toluenesulfonyl or nitrobenzenesulfonyl.

[0249] In a further preferred embodiment of the present invention,

[0250] The cyclization reaction is carried out under alkaline conditions. Preferably, the base is selected from an organic base or an inorganic base. The organic base is selected from trimethylamine, triethylamine, pyridine, piperidine, morpholine, diisopropylethylamine, lithium diisopropylamide, lithium diethylamide, lithium bis(trimethylsilyl)amide, lithium isopropylcyclohexylamide, LiHMDS or a mixture thereof, preferably triethylamine, pyridine, N,N-diisopropylethylamine, lithium diisopropylamide, lithium diethylamide, lithium bis(trimethylsilyl)amide, lithium isopropylcyclohexylamide or a mixture thereof; the inorganic base is selected from potassium phosphate, potassium phosphate trihydrate, potassium phosphate dihydrate, potassium phosphate monohydrate, potassium acetate, sodium acetate, sodium bicarbonate, potassium bicarbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium hydride, sodium hydride, lithium hydroxide or 2-tert-butyl-1,1,3,3-tetramethylguanidine and a mixture thereof;

[0251] The dehydroxylation reaction is carried out in the presence of triethylsilane, trifluoroacetic acid, triethylsilyl hydrochloride or boron trifluoride etherate;

[0252] The reduction reaction is carried out under the action of a reducing agent and a catalyst, wherein the catalyst is preferably palladium acetate, tetrakistriphenylphosphine palladium, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; the reducing agent is preferably iron powder, cesium carbonate, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, sodium acetate borohydride, sodium borohydride or sodium cyanoborohydride and a mixture thereof, preferably sodium acetate borohydride;

[0253] Amidation is carried out under methylimidazole or tetramethylchlorouronium hexafluorophosphate conditions;

[0254] The deprotection is carried out in the presence of an organic acid or an inorganic acid, preferably hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, formic acid, acetic acid, p-toluenesulfonic acid, maleic acid, trifluoromethanesulfonic acid, trifluoroacetic acid and mixtures thereof.

[0255] The present invention also provides a compound represented by general formula (II) or (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0256] in,

[0257] X1, X2, X3, X4 are each independently selected from CR4 or N;

[0258] R4 are each independently selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C1- 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, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally substituted by hydroxy, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted with one or more substituents of a deuterated alkyl group;

[0259] R 11 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy or C 1-6 hydroxyalkyl;

[0260] R 22 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2- 6 alkenyl, C 2-6Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy or C 1-6 hydroxyalkyl;

[0261] R 33 Each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-6 Alkyl S(O)2-, C 1-6 Alkyl S(O)-, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, aminocarbonyl, carbonylamino, C 1-6 Alkylaminocarbonyl, C 1-6 Alkylcarbonylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted with aryl or 5-10 membered heteroaryl;

[0262] R a 、R b or R c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or cyano substituted C 1-6 Alkyl, the R a 、R b or R c Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 One or more substituents in the alkyl group;

[0263] R d is an amino protecting group;

[0264] R d2 or R d3 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl or -(CH2) n C(O)NR e2 (CH2) n1 R e1 , the R d2 or R d3 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 is substituted with one or more substituents;

[0265] Or, R d2 and R d3 Together they form an oxo group or a thio group;

[0266] R e1 or R e2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms, wherein R e1 or R e2 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 5-8 membered heteroaryl;

[0267] R d4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or cyano substituted C 1-6 Alkyl, the R d4 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 One or more substituents in the alkyl group;

[0268] n is an integer from 0 to 3; and

[0269] n1 is an integer from 0 to 3.

[0270] In a further preferred embodiment of the present invention,

[0271] R4 are each independently selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, -C 2- 3 alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2- 3 alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2)n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally substituted by hydroxy, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 substituted by one or more substituents in a deuterated alkyl group;

[0272] Preferably, R4 is each independently selected from deuterium, fluorine, chlorine, bromine, amino, nitrile, hydroxyl, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2)n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 ;

[0273] R 11 each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl or chloroethyl;

[0274] R 22 each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl or chloroethyl;

[0275] R 33 Each independently selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl or 5-9 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkyl S(O)2-, C 1-3 Alkyl S(O)-, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkylaminocarbonyl, C 1- 3-alkylcarbonylamino, aminocarbonyl, carbonylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 5-8 membered heteroaryl; preferably, R 33 Each independently selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-9 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkyl S(O)2-, C 1-3 Alkyl S(O)-, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylaminocarbonyl, C 1-3 Alkylcarbonylamino, aminocarbonyl, carbonylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms; more preferably, R 33 Each independently selected from cyclopropyl, cyclobutyl, Optionally, the alkyl radicals may be further substituted with deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl, chloroethyl, aminocarbonyl, carbonylamino, cyclopropyl, cyclobutyl, cyclohexyl, carboxyl, aminosulfonyl, aminosulfinyl, methylaminocarbonyl, methylcarbonylamino, methyl S(O)2-, methyl S(O)-, cyclopropyl, cyclobutyl, is substituted by one or more substituents;

[0276] Or, R a 、R b or R c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl, the R a 、R b or R c Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 One or more substituents in the alkyl group;

[0277] Or, R d is selected from tert-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyl, tert-butoxycarbonyl, Troc, 9-fluorenylmethoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, toluenesulfonyl or nitrobenzenesulfonyl;

[0278] Or, R d2 or R d3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl or -(CH2) n C(O)NR e2 (CH2) n1 R e1 , the R d2 or R d3 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 One or more substituents in the alkyl group;

[0279] Or, R d2 and R d3 Together they form an oxo group or a thio group;

[0280] Or, R e1 or R e2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms, wherein R e1 or R e2 Optionally, it may be selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 5-8 membered heteroaryl;

[0281] Or, R d4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl, the R d4 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1- 3. One or more substituents in the alkyl group;

[0282] n is an integer from 0 to 3; and

[0283] n1 is an integer from 0 to 3.

[0284] In a further preferred embodiment of the present invention, the compound structure is as follows:

[0285] 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.

[0286] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, has a weight percentage of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof of 0.1% to 95%, preferably 5-70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%.

[0287] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, and preferably further comprises a filler, optionally a disintegrant, or further comprises one or more of a glidant or a lubricant.

[0288] In certain embodiments of the present invention, the pharmaceutical composition is a rapid-release formulation or a sustained-release formulation.

[0289] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, the unit dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is 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.

[0290] In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, can 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.

[0291] In certain embodiments of the present invention, the compound, its stereoisomers or pharmaceutically acceptable salts thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0292] The present invention further relates to the use of any compound 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.

[0293] The present invention further relates to the use of a compound represented by the general formula, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating cancer, PROS (PIK3CA-related overgrowth spectrum), an immune disorder, or an inflammatory disorder, wherein 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.

[0294] The present invention further relates to a compound of the general formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the preparation of a pharmaceutical composition for treating proliferative diseases; benign or malignant tumors; cancer selected from sarcoma; lung cancer; bronchial cancer; prostate cancer; breast cancer (including sporadic breast cancer and Cowden's disease); pancreatic and gastrointestinal cancer; colon cancer; colorectal adenoma; thyroid cancer; liver cancer; intrahepatic bile duct cancer; hepatocellular carcinoma; adrenal cancer; gastric cancer; glioma; glioblastoma; endometrial cancer; melanoma; kidney cancer; bladder cancer; bladder cancer; endometrial cancer; cervical cancer; vaginal cancer; ovarian cancer; multiple myeloma; esophageal leukemia; acute myeloid leukemia; chronic myeloid leukemia; lymphocytic leukemia; myeloid leukemia; brain cancer; oral cavity and pharyngeal cancer; laryngeal cancer; non-Hodgkin lymphoma; melanoma; villous colon adenoma; epithelial tumors; lymphoma; breast cancer; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstrom's disease.

[0295] The present invention further relates to a method for using the compound represented by the general formula, its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in the preparation of drugs for treating PI3Kα-related diseases.

[0296] 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.

[0297] 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.

[0298] The present invention also relates to a method for treating a PI3Kα-related disease 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.

[0299] Detailed Description of the Invention

[0300] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0301] 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 containing 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 point of attachment. 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

[0302] The term "alkylene" refers to an alkyl group in which one hydrogen atom is 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, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted. 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0303] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0304] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiral atom) shared 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 the rings, the spiroalkyl is divided into a single spiroalkyl, a double spiroalkyl or a multi-spiroalkyl, preferably a single spiroalkyl and a double spiroalkyl. 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 of single spiroalkyl. Non-limiting examples of spiroalkyl include:

[0305] wait;

[0306] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0307] wait.

[0308] The term "fused 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 the 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. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0309] wait.

[0310] The term "bridged cycloalkyl" refers to a 5-20 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 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0311] 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 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0312] 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, excluding the ring portion of -OO-, -OS- or -SS-, and 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 is a 3-8 membered heterocyclic group containing 1-3 nitrogen atoms, optionally substituted with 1-2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups, or nitrogen-containing fused heterocyclic groups.

[0313] Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 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, fused and bridged heterocyclic groups; wherein the spirocyclic, fused and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0314] The term "spiroheterocyclyl" 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 ring atoms are 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. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between the rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiral heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably 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 group. Non-limiting examples of spiral heterocyclic groups include: wait.

[0315] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein 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, the remaining ring atoms being carbon. 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 bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include: wait.

[0316] 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 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, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include: wait.

[0317] 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:

[0318] wait.

[0319] The heterocyclyl group may be optionally substituted or unsubstituted. 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0320] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings 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- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl, and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl, and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

[0321] Wherein the ring connecting to the parent structure is an aryl ring, non-limiting examples of which include: wait.

[0322] The aryl group may be substituted or unsubstituted. 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0323] 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 group 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, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include: wait.

[0324] 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0325] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. The 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 following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0326] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0327] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0328] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0329] "Alkenyl" refers to an alkenyl group, also known as an alkene group, which refers to a straight-chain 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 (C2-8 ), 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 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0330] "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 within the alkynyl group, which contains at least one carbon-carbon double bond and the carbon-carbon double bond can be located at any position within 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.

[0331] 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, the substituent is preferably one or more of the following groups 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.

[0332] "Hydroxy" refers to an -OH group.

[0333] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0334] "Amino" refers to -NH2.

[0335] "Cyano" refers to -CN.

[0336] "Nitro" refers to -NO2.

[0337] "Carbonyl" refers to -C(O)-.

[0338] "Carboxyl" refers to -C(O)OH.

[0339] 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”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0340] The hydrogen atoms described in the present invention can all 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.

[0341] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that 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.

[0342] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0343] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with 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, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0344] "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

[0345] Example

[0346] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0347] MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

[0348] 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).

[0349] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0350] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0351] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0352] 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, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0353] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0354] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0355] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0356] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0357] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0358] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0359] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0360] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0361] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent systems used in the reactions were: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, and D: acetone. The volume ratio of the solvents was adjusted according to the polarity of the compounds.

[0362] The eluent system for column chromatography and the developing solvent system for thin-layer chromatography used to purify the compound 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.

[0363] Intermediate A

[0364] first step

[0365] 5-Fluoro-3-hydroxy-3-(trifluoromethyl)indol-2-one

[0366] 5-Fluoroindole-2,3-dione (1.0 g, 6.06 mmol) was dissolved in 20 mL of tetrahydrofuran at -78°C. Trimethyltrifluoromethylsilane (2.58 g, 18.14 mmol, 2.84 mL) and potassium tert-butoxide (1.0 M, 18.17 mL) were added sequentially to the reaction system. The reaction was stirred at 20°C for 2 hours. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with eluent System B to obtain Example 5-fluoro-3-hydroxy-3-(trifluoromethyl)indole-2-one 2 (450 mg, yellow solid) in a 31.6% yield. MS m / z (ESI): 236.0 [M+1].

[0367] Step 2

[0368] 5-Fluoro-3-(trifluoromethyl)indole-2,2-d2-3-ol

[0369] 5-Fluoro-3-hydroxy-3-(trifluoromethyl)indole-2-one 2 (1.5 g, 6.38 mmol) was dissolved in 10 mL of tetrahydrofuran, and BD3 / THF (1.0 M, 19.14 mL) was added to the reaction system. The reaction was heated at 70°C for 3 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent System B to obtain Example 5-Fluoro-3-(trifluoromethyl)indole-2,2-d2-3-ol A (1.1 g, yellow solid) in a yield of 77.3%.

[0370] Compound A was separated using a chiral column (CHIRALCEL AD-H 4.6*250 mm, 5 μm; detection wavelength (nm): 214; temperature: 35°C; flow rate (mL / min): 30; mobile phase: Hexane:IPA:DEA = 80:20:0.1%; run time (min): 12; linear mode: isocratic) to give Example A-P1 (390 mg, RT (retention time) = 8.756 min, yield: 78.0%); and Example A-P2 (395 mg, RT (retention time) = 10.114 min, yield: 79.0%). MS m / z (ESI): 224.0 [M+1]

[0371] Intermediate B

[0372] Intermediate B was obtained by referring to the synthesis method of intermediate A, MS m / z (ESI): 206.1[M+1]

[0373] Intermediate C

[0374] Refer to the synthesis method of intermediate A to obtain intermediate C, MS m / z (ESI): 222.1 [M+1]

[0375] Compound C was separated using a chiral column (chromatographic column: CHIRALCEL AD-H 4.6*250 mm, 5 μm; detection wavelength (nm): 214; temperature (°C): 35; flow rate (mL / min): 30; mobile phase: Hexane:IPA:DEA=85:15:0.1%; run time (min): 18; linear mode: isocratic) to obtain Example C-P1 (350 mg, RT (retention time) = 11.62 min, yield: 40.1%); Example C-P2 (360 mg, RT (retention time) = 13.92 min, yield: 40.8%).

[0376] Intermediate D

[0377] Intermediate D was obtained by referring to the synthesis method of intermediate A, MS m / z (ESI): 204.1[M+1]

[0378] Compound D was separated using a chiral column (chromatographic column: CHIRALCEL OD-H 4.6*150 mm, 5 μm; detection wavelength (nm): 214; temperature (°C): 35; flow rate (mL / min): 30; mobile phase: Hexane:EtOH:MeOH=70:15:15%; run time (min): 8; linear mode: isocratic) to give Example D-P1 (148 mg, RT (retention time) = 2.423 min, yield: 41.1%); Example D-P2 (150 mg, RT (retention time) = 2.570 min, yield: 41.7%).

[0379] Intermediate E

[0380] Refer to the synthesis method of intermediate A to obtain intermediate C, MS m / z (ESI): 222.1 [M+1]

[0381] Compound E (450 mg, 2 mmol) was separated using a chiral column (chromatographic column: CHIRALCEL OJ-H 4.6*150 mm, 5 μm; detection wavelength (nm): 214; temperature (°C): 35; flow rate (mL / min): 1; mobile phase: Hexane:CH3OH:DEA = 70:30:0.1%; running time (min): 12; linear mode: isocratic) to give Example E-P1 (200 mg, RT (retention time) = 4.177 min, yield: 44%); Example E-P2 (200 mg, RT (retention time) = 4.897 min, yield: 44%).

[0382] Intermediate F

[0383] first step

[0384] 2-Bromo-N-cyclobutylaniline

[0385] 2-Bromoaniline (3.0 g, 17.44 mmol), cyclobutanone (1.2 g, 16.57 mmol), sodium triacetoxyborohydride (5.5 g, 26.16 mmol), and glacial acetic acid (1.1 g, 17.44 mmol) were dissolved in THF (50 mL), replaced with nitrogen, and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane, washed once with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain Example F-1 (2.8 g, yield: 71.0%).

[0386] MS m / z(ESI):226.0[M+1]

[0387] Step 2

[0388] Benzyl (2-bromophenyl) (cyclobutyl) carbamate

[0389] 2-Bromo-N-cyclobutylaniline (800 mg, 3.54 mmol) was dissolved in benzyl chloroformate (5 mL). The reaction mixture was heated to 70°C and stirred for 5 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography to obtain Example F-2 (1.1 g, yield: 86.3%). MS m / z (ESI): 360.1 [M+1]

[0390] Step 3

[0391] 1,2,2a,7b-Tetrahydro-3H-cyclobutane[b]indole-3-carboxylic acid benzyl ester

[0392] Benzyl (2-bromophenyl) (cyclobutyl) carbamate (900 mg, 2.50 mmol), palladium acetate (28 mg, 0.13 mmol), tricyclohexylphosphine tetrafluoroborate (92 mg, 0.25 mmol), cesium carbonate (1.2 g, 3.75 mmol), and trimethylacetic acid (77 mg, 0.75 mmol) were dispersed in mesitylene (5 mL). The atmosphere was replaced with nitrogen. The reaction mixture was heated to 140°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, filtered through celite, and purified by silica gel column chromatography to obtain Example F-3 (496 mg, yield: 73.0%). MS m / z (ESI): 280.1 [M+1]

[0393] Step 4

[0394] 2,2a,3,7b-Tetrahydro-1H-cyclobutane[b]indole

[0395] Benzyl 1,2,2a,7b-tetrahydro-3H-cyclobutane[b]indole-3-carboxylate (426 mg, 1.53 mmol) and Pd (43 mg, 0.40 mmol) were dispersed in ethyl acetate (10 mL). The atmosphere was replaced with hydrogen and the mixture was stirred at room temperature under a hydrogen balloon for 4 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain a crude yellow oil. This crude product was purified by silica gel column chromatography to obtain Intermediate F (218 mg, 98.5% yield).

[0396] MS m / z(ESI):146.1[M+1]

[0397] Intermediate F was separated by chiral column (chromatographic column: CHIRALPAK IC 4.6*250mm, 5μm; detection wavelength (nm): 214; temperature (℃): 35; flow rate (mL / min): 1; mobile phase: Hexane:iPrOH:DEA=70:30:0.1%; running time (min): 12; linear mode: isocratic) to obtain Example F-P1 (96 mg, RT (retention time) = 3.990 min, yield: 88.0%); Example F-P2 (98 mg, RT (retention time) = 4.367 min, yield: 90.0%).

[0398] Intermediate G

[0399] first step

[0400] Compound G-1 (20 g) was dissolved in THF (10 V), cooled to 0°C, and NaH (1.2 eq) was added. Ethyl formate (1.1 eq) was added dropwise under N2 protection. After the addition was complete, the mixture was warmed to room temperature and stirred overnight. LC-MS showed that the starting material was completely reacted. The reaction solution was quenched by adding ice water, allowed to stand and separate into layers. The aqueous phase was extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Column chromatography (PE:EA = 15:1) gave compound 2 (21 g, 90.3% yield).

[0401] Step 2

[0402] Compound G-2 (21 g) was dissolved in dry THF (10 V), cooled to 0°C, and NaH (1.85 eq) was added under N2 protection. The mixture was heated to room temperature and stirred for 0.5 h. The temperature was then lowered to -78°C, and a THF solution of nBuLi (1.25 eq) was slowly added dropwise. The mixture was stirred for 0.5 h. A THF solution of cyclobutanone (1.1 eq) was slowly added dropwise. After the addition was complete, the mixture was stirred for 2 h. LC-MS showed that the reaction of the starting materials was complete. The reaction solution was quenched with saturated ammonium chloride solution, allowed to stand for separation, and the aqueous phase was extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product. Column chromatography (PE:EA = 3:1) gave compound G-3 (6.3 g, 31.5% yield).

[0403] Step 3

[0404] Compound G-3 (21 g) was dissolved in dioxane (6 V), and a 5 mol / L aqueous KOH solution (3 eq) was added. The mixture was heated to 100°C and stirred for 3 h. LC-MS indicated complete reaction. The mixture was cooled to room temperature, extracted with EA and water, and the aqueous phase was washed with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford the crude product. Column chromatography (PE:EA = 5:1) afforded compound G-4 (3.1 g, 57.7% yield).

[0405] Step 4

[0406] Compound G-4 (3.1 g) was dissolved in acetonitrile (10 V), cooled to 0°C, and isoamyl nitrite and TMSN3 were added dropwise sequentially. The mixture was stirred at room temperature for 1.5 h. LC-MS indicated complete reaction. The crude product was concentrated to dryness and purified by column chromatography (PE:EA = 15:1) to afford compound G-5 (1.5 g, 20.5% yield).

[0407] Step 5

[0408] Compound G-5 (1.5 g) was dissolved in toluene (10 V). Rh(esp) was added under N2 protection and stirred at 120°C overnight. LC-MS indicated complete reaction. The crude product was concentrated and purified by column chromatography (PE:EA = 4:1) to afford Intermediate G (170 mg, 13.3% yield).

[0409] Intermediate H

[0410] Refer to the synthesis method of intermediate A to obtain intermediate H, MS m / z (ESI): 206.1 [M+1]

[0411] Intermediate I

[0412] first step

[0413] N-(4-methoxybenzyl)-7-nitroquinoline-5-carboxamide

[0414] 7-Nitroquinoline-5-carboxylic acid I-1 (5.0 g, 23 mmol) was dissolved in 80 mL of dichloromethane, and N,N'-carbonyldiimidazole (5.61 g, 34 mmol) and 4-dimethylaminopyridine (0.28 g, 2.3 mmol) were added. The reaction mixture was stirred at 25°C for 2 hours. 4-Methoxybenzylamine (3.14 g, 23 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 25°C for 1 hour. 50 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using eluent System B to obtain Example N-(4-methoxybenzyl)-7-nitroquinoline-5-carboxamide I-2 (6.30 g) in an 81.5% yield.

[0415] MS m / z(ESI):338.2[M+1]

[0416] Step 2

[0417] N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-7-nitroquinoline-5-carboxamide

[0418] Dissolve N-(4-methoxybenzyl)-7-nitroquinoline-5-carboxamide I-2 (6.30 g, 19 mmol) in 80 mL of tetrahydrofuran and add sodium hydroxide (1.49 g, 37 mmol). Stir and react at 25°C for 2 hours. Add a solution of 2-chloro-5-fluorobenzoyl chloride (5.39 g, 28 mmol) in tetrahydrofuran (10 mL) to the reaction mixture. Continue stirring at 25°C for 2 hours. 100 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System B to obtain Example N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-7-nitroquinoline-5-carboxamide I-3 (6.80 g) in a yield of 73.8%. MS m / z (ESI): 494.2 [M+1].

[0419] Step 3

[0420] 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitro-2,3-dihydro-1H-pyrrolo[3,4]quinolin-1-one

[0421] At -50°C, N-(2-chloro-5-fluorobenzoyl)-N-(4-methoxybenzyl)-7-nitroquinoline-5-carboxamide I-3 (6.80 g, 14 mmol) was dissolved in 80 mL of tetrahydrofuran, and LiHMDS (1.0 M, 20.9 mL, 21 mmol) was added. The mixture was stirred at -50°C for 3 hours. 100 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System B to obtain Example 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitro-2,3-dihydro-1H-pyrrolo[3,4]quinolin-1-one I-4 (1.20 g) in a yield of 17.6%. MS m / z (ESI): 494.2 [M+1].

[0422] Step 4

[0423] 3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitro-2,3-dihydro-1H-pyrrolo[3,4]quinolin-1-one

[0424] 3-(2-chloro-5-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)-4-nitro-2,3-dihydro-1H-pyrrolo[3,4]quinolin-1-one I-4 (1.20 g, 2.4 mmol) was dissolved in 30 mL of dichloromethane, and triethylsilane (2.79 g, 24 mmol) and boron trifluoride etherate (0.99 g, 7.3 mmol) were added, and the reaction was heated at 40°C for 15 hours. The reaction mixture was adjusted to a pH greater than 7 by adding saturated sodium bicarbonate solution, and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System B to obtain Example 3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitro-2,3-dihydro-1H-pyrrolo[3,4]quinolin-1-one I-5 (0.95 g) in an 81.9% yield. MS m / z (ESI): 478.2 [M+1].

[0425] Step 5

[0426] 4-Amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-1-one

[0427] Dissolve 3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-4-nitro-2,3-dihydro-1H-pyrrolo[3,4]quinolin-1-one I-5 (0.43 g, 1.2 mmol) in a mixture of 10 mL of ethanol and 1 mL of glacial acetic acid. Add ammonium chloride (0.64 g, 12 mmol). Raise the temperature to 50°C, and add reduced iron powder (0.67 g, 52 mmol). Heat at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and 30 mL of water was added to the resulting residue. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent System A to obtain Example 4-amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-1-one I-6 (0.31 g) in a yield of 77.5%. MS m / z (ESI): 448.9 [M+1].

[0428] Step 6

[0429] N-(3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0430] 4-Amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-1-one I-6 (50 mg, 0.15 mmol) was dissolved in 5 mL of dichloromethane, and 3-fluoro-5-(trifluoromethyl)benzoic acid (38 mg, 0.18 mmol), 1-methylimidazole (38 mg, 0.46 mmol) and tetramethylchlorouronium hexafluorophosphate (64 mg, 0.23 mmol) were added, and the reaction was stirred at 25 ° C for 1 hour. 10 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to give Example N-(3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxo-4-nitropropene)-2-nitropropene)-3 ...

[0431] 2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide I (26 mg), yield: 36.5%. MS m / z (ESI): 639.0 [M+1]

[0432] Example 1

[0433] N-(7-Chloro-3-(2-chloro-5-fluorophenyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0434] first step

[0435] N-(7-Chloro-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0436] Intermediate I (1.0 g, 1.6 mmol) was dissolved in 20 mL of anhydrous dichloromethane, cooled to 0°C, and m-chloroperbenzoic acid (0.3 g, 1.7 mmol) was added. The reaction was stirred at 25°C for 18 hours. The reaction mixture was poured into 100 mL of sodium carbonate and extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude nitroxide. 30 mL of phosphorus oxychloride was added, and the reaction was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature and slowly poured into 100 mL of ice water. Extraction was performed with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to obtain Example 1b (0.6 g, 57% yield). MS m / z(ESI):672.2[M+1]

[0437] Step 2

[0438] N-(7-Chloro-3-(2-chloro-5-fluorophenyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0439] 1b (50 mg, 0.075 mmol) was dissolved in 5 mL of trifluoroacetic acid and 1 mL of methanesulfonic acid was added. The reaction was stirred at 85°C for 1 hour. The solvent was dried by rotary evaporation, and 30 mL of saturated sodium carbonate solution was added. The mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain Example 1 (25 mg, yield: 60.4%). MS m / z (ESI): 552.2 [M+1]

[0440] 1 H NMR(400MHz,DMSO-d6)δ10.82(s,1H),9.52-9.44(m,2H),8.07(s,1H),7.99(d,1H),7.82-7.74 (m,2H),7.68(s,1H),7.35-7.32(m,1H),7.14-7.10(m,1H),6.55-6.50(m,1H),6.28(brs,1H).

[0441] Example 1 was subjected to chiral separation: chromatographic column: CHIRALCEL OD-H 4.6*150 mm, 5 μm; detection wavelength (nm): 214; temperature (°C): 35; flow rate (mL / min): 1; mobile phase: Hexane:EtOH:MeOH = 70:15:15; run time (min): 12; linear mode: isocratic), Example 1-P1 (RT (retention time) = 3.167 min), Example 1-P2 (RT (retention time) = 3.530 min).

[0442] Example 2

[0443] N-(7-Amino-3-(2-chloro-5-fluorophenyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0444] Example 1 (30 mg, 0.054 mmol) was dissolved in 5 mL of 7 M amine / methanol solution and the reaction was stirred at 100°C in a sealed tube for 1 hour. The solvent was evaporated to dryness, and the resulting residue was purified by HPLC to obtain Example 2 (4 mg, yield: 13.8%). MS m / z (ESI): 533.2 [M+1]

[0445] Example 3

[0446] N-(3-(2-chloro-5-fluorophenyl)-7-(cyclopropylamino)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0447] Example 1 (30 mg, 0.054 mmol) was dissolved in 3 mL of N,N-dimethylformamide, and cesium carbonate (53 mg, 0.16 mmol) and cyclopropylamine (9 mg, 0.16 mmol) were added. The reaction was stirred at 110°C for 5 hours. The reaction solution was filtered, and the filtrate was purified by HPLC to obtain Example 3 (12 mg, yield: 38.7%). MS m / z (ESI): 573.2 [M+1]

[0448] Example 5

[0449] N-(3-(2-chloro-5-fluorophenyl)-7-methyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0450] Example 1 (30 mg, 0.054 mmol) and trimethylboroxine (8.0 mg, 0.065 mmol) were dissolved in 2 mL of dioxane and 0.4 mL of water. Cesium carbonate (53 mg, 0.16 mmol) and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride (7.3 mg, 0.01 mmol) were added. The nitrogen atmosphere was replaced, and the reaction was stirred in a microwave at 90°C for 1 hour. The reaction solution was poured into 10 mL of water and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC to obtain Example 5 (9.0 mg, 31% yield). MS m / z (ESI): 532.2 [M+1]

[0451] Example 7

[0452] N-(3-(2-chloro-5-fluorophenyl)-7-cyano-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0453] Example 1 (30 mg, 0.054 mmol) was dissolved in 2 mL of acetonitrile, and hexanedichloronickel (2.4 mg, 0.01 mmol), 1,1'-bis(diphenylphosphino)ferrocene (5.5 mg, 0.01 mmol), zinc powder (6.5 mg, 0.1 mmol), dimethylaminopyridine (6.6 mg, 0.054 mmol), and zinc cyanide (7.0 mg, 0.06 mmol) were added. The atmosphere was replaced with nitrogen, and the reaction was stirred in a microwave at 80°C for 1 hour. The reaction solution was poured into 10 mL of water and extracted with dichloromethane (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography to obtain Example 7 (5.0 mg, 20.3% yield).

[0454] 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H), 9.65(d,1H), 9.58(brs,1H), 8.25-8.22(m,2H), 7.99(d,1H), 7.76(d,1H),7.67(s,1H),7.36-7.32(m,1H),7.15-7.10(m,1H),6.66-6.58(m,1H),6.28(brs,1H).

[0455] MS m / z(ESI):543.2[M+1]

[0456] Example 8

[0457] N-(7-Chloro-3-(2-chloro-5-fluorophenyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)indoline-1-carboxamide

[0458] first step

[0459] N-(3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)indoline-1-carboxamide

[0460] I-6 (200 mg, 0.45 mmol) was dissolved in 5 mL of anhydrous dichloromethane and cooled to 0°C. Diisopropylethylamine (289 mg, 2.2 mmol) was added, followed by a dichloromethane solution of triphosgene (160 mg, 0.54 mmol). The reaction was stirred at 25°C for 1 hour. The solvent was dried by rotary evaporation, and indoline (70 mg, 0.6 mmol) and diisopropylethylamine (289 mg, 2.2 mmol) were added. The reaction was stirred at 25°C for 1 hour. 30 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford Example 8a (50 mg, 18.9% yield). MS m / z (ESI): 593.2 [M+1].

[0461] Step 2

[0462] N-(7-Chloro-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)indoline-1-carboxamide

[0463] Referring to the synthesis method of the first step in Example 1, product 8b was obtained using 8a as the starting material.

[0464] MS m / z(ESI):627.2[M+1]

[0465] Step 3

[0466] N-(7-Chloro-3-(2-chloro-5-fluorophenyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)indoline-1-carboxamide

[0467] Referring to the synthesis method of the second step of Example 1, product 8 was obtained using 8b as the starting material.

[0468] MS m / z(ESI):507.2[M+1]

[0469] Example 15

[0470] N-(7-Chloro-3-(2-chloro-5-fluorophenyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-5-(trifluoromethyl)bicyclo[3.1.1]heptane-1-carboxamide

[0471] first step

[0472] 1-(3-chloropropyl)cyclopropan-1-ol

[0473] Ethyl 4-chlorobutyrate 15a (20.0 g, 0.13 mol) was dissolved in 300 mL of anhydrous tetrahydrofuran, and tetraisopropyl titanate (37.8 g, 0.13 mmol) was added. The mixture was cooled to 0°C, and ethyl Grignard reagent (162 mL, 0.33 mmol) was slowly added dropwise. The reaction was stirred at 25°C for 18 hours. The reaction mixture was poured into 200 mL of water and extracted with ethyl acetate (200 mL x 2). The organic phases were combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to obtain Example 15b (15 g, 84% yield).

[0474] 1 H NMR (400MHz, CDCl3-d) δ3.65 (t, J = 8.0Hz, 2H), 2.08-2.01 (m, 2H), 1.69- 1.65 (m, 2H), 0.78-0.75 (m, 2H), 0.5-0.47 (m, 2H).

[0475] Step 2

[0476] 1-(3-chloropropyl)cyclopropyl methanesulfonate

[0477] 15b (15.0 g, 0.11 mol) was dissolved in 200 mL of anhydrous dichloromethane, and triethylamine (33.9 g, 0.33 mol) was added. The mixture was cooled to 0°C, and methanesulfonyl chloride (15 g, 0.13 mol) was slowly added. The reaction was stirred at 25°C for 18 hours. The reaction solution was poured into 200 mL of water and extracted with dichloromethane (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to provide Example 15c (12 g, 50.6% yield). 1H NMR (400MHz, CDCl3-d) δ3.64 (t, J = 8.0Hz, 2H), 3.00 (s, 3H), 2.09-2.00 (m, 4H), 1.28-1.27 (m, 2H), 0.78-0.74 (m, 2H).

[0478] Step 3

[0479] 5-Chloro-2-(chloromethyl)pent-1-ene

[0480] 15c (5.0 g, 23.5 mmol) was dissolved in 50 mL of anhydrous dichloromethane and cooled to 0°C. A dichloromethane solution of titanium tetrachloride (6.7 g, 35.3 mmol) was slowly added, and the reaction was stirred at 25°C for 18 hours. The reaction solution was poured into 50 mL of water and extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude Example 15d (3.2 g, 89% yield).

[0481] 1 H NMR (400MHz, CDCl3-d) δ5.19-5.18(m,1H),5.01-5.00(m,1H),4.05-4.04(m,2H),3.60-3.55(m,2H),2.37-2.33(m,2H),2.05-1.95(m,2H).

[0482] Step 4

[0483] 1,1-Dibromo-2-(chloromethyl)-2-(3-chloropropyl)cyclopropane

[0484] 15d (3.2 g, 21.1 mmol) was dissolved in 100 mL of dichloromethane and 1 mL of ethanol, and benzyltriethylammonium chloride (143 mg, 0.63 mmol) and bromoform (21 g, 83.6 mmol) were added. 55 mL of 50% aqueous sodium hydroxide solution was then added, and the reaction was stirred at 25°C for 18 hours. The reaction solution was poured into 100 mL of water and extracted with dichloromethane (100 mL x 2). The organic phases were combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford Example 15e (1.8 g, 26% yield).

[0485] 1 H NMR (400MHz, CDCl3-d) δ3.77(s,2H),3.61-3.57(m,2H),2.06-1.98(m,4H),1,68-1.62(m,2H).

[0486] Step 5

[0487] tricyclo[3.1.1.01,5]heptane

[0488] 15e (1.0 g, 3.1 mmol) was dissolved in 5 mL of diethyl ether, cooled to -40°C, and phenyllithium (4 mL, 7.8 mmol, 1.9 M in BuO) was added. The reaction was stirred at -40°C to 0°C for 5 hours. The reaction solution was poured into 10 mL of water and extracted with diethyl ether (10 mL). The organic phases were combined, washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate to provide Example 15f (0.29 g, crude yield: 100%), which was stored at -20°C and used directly in the next reaction.

[0489] Step 6

[0490] 1-iodo-5-(trifluoromethyl)bicyclo[3.1.1]heptane

[0491] To a solution of 15f (0.29 g, 3.1 mmol) in diethyl ether was added triethylborane (0.3 mL, 0.3 mmol, 1 M in hexane), and trifluoroiodomethane gas was slowly bubbled through the reaction mixture. The reaction was stirred at 25°C for 1 hour. The reaction mixture was poured into 20 mL of water and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent System B to afford Example 15g (180 mg, 20.2% yield).

[0492] Step 7

[0493] 5-(Trifluoromethyl)bicyclo[3.1.1]heptane-1-carboxylic acid

[0494] 15 g (0.18 g, 0.6 mmol) was dissolved in anhydrous tetrahydrofuran and cooled to -78°C. n-Butyl lithium (0.48 mL, 1.2 mmol, 2.5 M) was added and the reaction was stirred at this temperature for half an hour. Carbon dioxide gas was then slowly introduced into the reaction mixture and the reaction was stirred at this temperature for 1 hour. The reaction mixture was poured into 20 mL of water and the pH was adjusted to 1. The mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford Example 15h (40 mg, 31% yield).

[0495] Step 8

[0496] N-(3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-5-(trifluoromethyl)bicyclo[3.1.1]heptane-1-carboxamide

[0497] 8c (86 mg, 0.19 mmol) and 15h (40 mg, 0.19 mmol) were dissolved in pyridine (5 mL) and phosphorus oxychloride (88 mg, 0.57 mmol) was added. The reaction was stirred at 25°C for 18 hours. 30 mL of water was added and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent System B to afford Example 15i (50 mg, 41% yield). MS m / z (ESI): 638.2 [M+1]

[0498] Step 9

[0499] N-(7-chloro-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-5-(trifluoromethyl)bicyclo[3.1.1]heptane-1-carboxamide

[0500] Referring to the synthesis method of the first step in Example 1, product 15j was obtained using 15i as the starting material.

[0501] MS m / z(ESI):672.2[M+1]

[0502] Step 10

[0503] N-(7-Chloro-3-(2-chloro-5-fluorophenyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-5-(trifluoromethyl)bicyclo[3.1.1]heptane-1-carboxamide

[0504] Referring to the synthesis method of the second step of Example 1, product 15 was obtained using 15j as the starting material.

[0505] MS m / z(ESI):552.2[M+1]

[0506] Example 22

[0507] N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0508] first step

[0509] Methyl 2-fluoro-5-formyl-3-nitrobenzoate

[0510] Methyl 5-bromo-2-fluoro-3-nitrobenzoate (1 g, 3.6 mmol) was dissolved in 20 mL of tetrahydrofuran at -78°C, and n-BuLi (4 mL, 4 mmol, 1 M) was added. The reaction mixture was stirred at -78°C for 0.5 hour. DMF (0.53 g, 7.2 mmol) was added to the reaction mixture, and the reaction was stirred at 0°C for 1 hour. 30 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent System B to obtain Example 2-fluoro-5-formyl-3-nitrobenzoic acid methyl ester 22b (0.6 g, 73% yield). MS m / z (ESI): 228.2 [M+1]

[0511] Step 2

[0512] Methyl (Z)-5-((2,2-dimethoxyethyl)imino)methyl)-2-fluoro-3-nitrobenzoate

[0513] 22b (1 g, 4.4 mmol) was dissolved in 20 mL of toluene, and 2,2-dimethoxyethane-1-amine (0.51 g, 4.8 mmol) was added. The reaction mixture was stirred at 100°C for 2 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using eluent System B to obtain Example 22c (1 g, yield: 72%). MS m / z (ESI): 315.2 [M+1]

[0514] Step 3

[0515] 6-Fluoro-7-nitroisoquinoline-5-carboxylic acid

[0516] 22c (1 g, 3.18 mmol) was dissolved in 10 mL of sulfuric acid and heated to 120°C with stirring for 3 hours. 20 mL of saturated sodium hydroxide was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using eluent System B to afford Example 22d (0.5 g, 67% yield). MS m / z (ESI): 237.2 [M+1]

[0517] The remaining steps of the synthesis of compound 22 start from intermediate 22d and are prepared by referring to the synthesis method of intermediate I.

[0518] Example 23

[0519] N-(3-(2-chloro-5-fluorophenyl)-6-(cyclobutylamino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0520] first step

[0521] 1-Chloro-6-fluoro-7-nitroisoquinoline-5-carbaldehyde

[0522] 23a (5.0 g, 22.07 mmol) was dissolved in 30 mL of THF and cooled in a dry ice / ethanol bath for 10 minutes. n-Butyl lithium (8.8 mL, 2.5 M in hexane) was slowly added, and the mixture was stirred for 30 minutes. DMF (1.9 g, 26.48 mmol) was then added dropwise to the reaction mixture, and the mixture was maintained at the dry ice / ethanol bath temperature for 2 hours. The reaction mixture was warmed to room temperature and quenched by addition of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to afford Example 1-chloro-6-fluoro-7-nitroisoquinoline-5-carbaldehyde 23b (4.8 g, 85.4% yield). MS m / z (ESI): 255.0 [M+1].

[0523] Step 2

[0524] 1-Chloro-6-fluoro-7-nitroisoquinoline-5-carboxylic acid

[0525] 23b (4.8 g, 18.85 mmol), CuCl (187 mg, 1.89 mmol), and TBHP (1.0 mL) were dissolved in 30 mL of MeCN. The reaction mixture was heated to 50°C and stirred for 6 hours. The reaction mixture was cooled to room temperature and quenched with saturated sodium sulfite solution. The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to afford Example 23c (4.4 g, 86.3% yield). MS m / z (ESI): 269.0 [M-1].

[0526] Steps 3 to 7 were prepared by referring to the synthesis method of Intermediate I, using 23c (4.4 g, 16.26 mmol) as starting material to obtain Example 23h (2.5 g, yield: 85.4%). MS m / z (ESI): 672.1 [M+1]

[0527] Step 8

[0528] N-(3-(2-chloro-5-fluorophenyl)-6-(cyclobutylamino)-2-(4-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0529] 23h (300 mg, 0.446 mmol), cyclobutylamine (64 mg, 0.892 mmol), and DIEA (231 mg, 1.78 mmol) were dissolved in 10 mL of DMSO. The reaction mixture was heated to 70°C and stirred for 4 hours. The reaction mixture was purified by preparative HPLC to afford Example 23i (184 mg, 70.3% yield).

[0530] MS m / z(ESI):707.2[M+1]

[0531] Step 9

[0532] N-(3-(2-chloro-5-fluorophenyl)-6-(cyclobutylamino)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]isoquinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0533] Referring to the synthesis method of Example 1, 23i (184 mg, 0.260 mmol) was used as the starting material to obtain Example 23 (110 mg, yield: 72.0%). MS m / z (ESI): 587.1 [M+1]

[0534] Example 28

[0535] N-(3-(2-chloro-5-fluorophenyl)-7-cyano-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0536] first step

[0537] 4-Amino-7-chloro-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-1-one

[0538] I-6 (1.0 g, 1.8 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperbenzoic acid (0.55 g, 2.7 mmol, purity: 85%) was added. The reaction was stirred at 25°C for 1 hour. The reaction solution was washed with 30 mL of 6M potassium hydroxide solution, washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. To this residue was added 10 mL of phosphorus oxychloride, and the reaction was stirred at 80°C for 1 hour. The reaction solution was slowly added to 100 mL of water to quench the reaction. The mixture was stirred for half an hour, and a solid precipitated. The solid was collected by filtration and dried to obtain Example 28c (0.8 g, 91.2% yield).

[0539] MS m / z(ESI):482.1[M+1]

[0540] Step 2

[0541] 4-Amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinoline-7-carbonitrile

[0542] 28c (0.5 g, 1.0 mmol) was added to 10 mL of N'N-dimethylformamide and heated to 70°C. Zinc cyanide (0.14 g, 1.2 mmol), bis(diphenylphosphinoferrocene) (0.17 g, 0.3 mmol), and tris(dibenzylideneacetone)dipalladium (0.18 g, 0.2 mmol) were added and reacted at 120°C for 18 hours. 50 mL of water was added and the mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using eluent System B to afford Example 28d (400 mg, 81.6% yield). MS m / z (ESI): 473.1 [M+1].

[0543] Step 3

[0544] 4-Amino-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinoline-7-carbonitrile

[0545] Referring to the synthesis method of Example 1, product 28e was obtained using 28d as the starting material.

[0546] MS m / z(ESI):353.1[M+1]

[0547] Step 4

[0548] N-(3-(2-chloro-5-fluorophenyl)-7-cyano-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0549] Referring to the synthetic method of intermediate I, product 28 was obtained using 28e as the starting material.

[0550] MS m / z(ESI):517.1[M+1]

[0551] Example 49

[0552] N-(3-(2-chloro-5-fluorophenyl)-7-ethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0553] first step

[0554] N-(3-(2-chloro-5-fluorophenyl)-7-vinyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0555] Example 1 (27.6 mg, 0.05 mmol), potassium ethylene trifluoroborate (10.1 mg, 0.075 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloromethane complex (10.1 mg, 0.005 mmol), and cesium carbonate (48.9 mg, 0.15 mmol) were weighed in sequence. 2 mL of dioxane aqueous solution (V / V = 4:1) was added, the atmosphere was replaced with nitrogen, and the reaction was stirred in a microwave at 100°C for 1 hour. The reaction solution was poured into 3 mL of water and extracted with ethyl acetate (3 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Example 49a (27.2 mg), which was used directly in the next step. MS m / z (ESI): 544.1 [M+1]

[0556] Step 2

[0557] N-(3-(2-chloro-5-fluorophenyl)-7-ethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0558] 49a (27.2 mg, 0.05 mmol) and 10% Pd / C (5.3 mg) were dispersed in 5 mL of tetrahydrofuran, the hydrogen atmosphere was replaced three times, and the reaction was stirred at 50°C for 3 hours. The reaction solution was filtered through a short column of celite and washed with 10 mL of ethyl acetate. The filtrate was concentrated under reduced pressure and purified by reverse phase preparative purification to give Example 49 (17.2 mg, yield: 63.0%). MS m / z (ESI): 546.1 [M+1]

[0559] Example 50

[0560] N-(3-(2-chloro-5-fluorophenyl)-7-methoxymethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0561] first step

[0562] 3-(2-chloro-5-fluorophenyl)-4-(3-fluoro-5-(trifluoromethyl)benzamido)-2-(4-methoxybenzyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolinyl)-7-carboxylic acid methyl ester

[0563] Example 1b (67.2 mg, 0.1 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (20.2 mg, 0.01 mmol) were weighed, and 10 mL of a mixed solvent of DMF and methanol (V / V = 1:1) and triethylamine (50.6 mg, 0.5 mmol) were added sequentially. After replacing the carbon monoxide gas three times, the reaction solution was stirred at 80°C for 5 hours. The methanol solvent was then dried by spin drying, and 3 mL of water was poured into the reaction solution. The mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Example 50a (69.2 mg), which was used directly in the next step. MS m / z (ESI): 696.1 [M+1]

[0564] Step 2

[0565] N-(3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-7-hydroxymethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0566] To a reaction flask containing 50a (69.2 mg, 0.1 mmol) was added 5 mL of THF. LiAlH4 (0.5 mL, 0.5 mmol, 1 M in THF) was then added under an ice bath at 0°C. The reaction solution was stirred at room temperature for half an hour, then the reaction temperature was raised to 50°C. Stirring was continued for 3 hours, and 5 mL of water was poured into the reaction solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford Example 50b (66.2 mg), which was used directly in the next step. MS m / z (ESI): 668.1 [M+1]

[0567] Step 3

[0568] N-(3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-7-methoxymethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0569] To a reaction flask containing 50b (66.2 mg, 0.1 mmol) was added 5 mL of THF. NaH (20.3 mg, 0.5 mmol, 60% dispersion in kerosene) was added under ice-bath conditions at 0°C. Methyl iodide (71.2 mg, 0.5 mmol) was then added dropwise to the reaction solution. The reaction solution was stirred at room temperature for 5 hours. 1 M hydrochloric acid solution (3 mL) was then poured into the reaction solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford Example 50c (67.6 mg), which was used directly in the next step. MS m / z (ESI): 682.2 [M+1]

[0570] Step 4

[0571] N-(3-(2-chloro-5-fluorophenyl)-7-methoxymethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0572] Referring to the synthesis method of the second step of Example 1, Example 50 was obtained using Example 50c as the starting material. MS m / z (ESI): 562.1 [M+1]

[0573] Example 51

[0574] N-(3-(2-chloro-5-fluorophenyl)-7-(2-hydroxy-2-propyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0575] first step

[0576] N-(3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-7-(2-hydroxy-2-propyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0577] To a reaction flask containing 50a (69.2 mg, 0.1 mmol) was added 5 mL of THF. After purging with nitrogen, EtMgBr (0.2 mL, 0.6 mmol, 3 M in THF) was added in an ice bath at 0°C. The reaction solution was stirred at room temperature for 1 hour. 5 mL of water was then poured into the reaction solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford Example 51a (69.1 mg), which was used directly in the next step. MS m / z (ESI): 696.2 [M+1]

[0578] Step 2

[0579] N-(3-(2-chloro-5-fluorophenyl)-7-(2-hydroxy-2-propyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0580] Referring to the synthesis method of the second step of Example 1, Example 51 was obtained using Example 51a as the starting material. MS m / z (ESI): 576.1 [M+1]

[0581] Example 52

[0582] N-(3-(2-chloro-5-fluorophenyl)-7-(1-hydroxycyclopropyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0583] first step

[0584] N-(3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-7-(1-hydroxycyclopropyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0585] Under nitrogen atmosphere, 5 mL of ether was added to a reaction flask containing Example 1b (67.2 mg, 0.1 mmol). The reaction solution was placed in a dry ice-acetone bath and stirred, and n-BuLi (0.3 mL, 0.5 mmol, 1.6 M n-hexane solution) was added dropwise. After the reaction solution was stirred for half an hour, 1,3-dichloroacetone (12.7 mg, 0.1 mmol) was added dropwise to the reaction solution. The cold bath was then removed, and the reaction solution was stirred at room temperature for 1 hour. To the reaction mixture, a solution of FeCl3 (1.6 mg, 0.01 mmol) in ether (1 mL) and EtMgBr (0.2 mL, 0.6 mmol, 3 M in THF) were added dropwise in an ice-water bath at 0°C. The reaction mixture was stirred at room temperature for 12 hours, and then quenched by the addition of ammonium chloride solution (5 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Example 52a (55.4 mg), which was used directly in the next step. MS m / z (ESI): 694.2 [M+1]

[0586] Step 2

[0587] N-(3-(2-chloro-5-fluorophenyl)-7-(1-hydroxycyclopropyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0588] Referring to the synthesis method of the second step of Example 1, Example 52 was obtained using Example 52a as the starting material. MS m / z (ESI): 574.1 [M+1]

[0589] Example 53

[0590] N-(3-(2-chloro-5-fluorophenyl)-7-hydroxyethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0591] first step

[0592] (E)-N-(3-(2-chloro-5-fluorophenyl)-7-benzyloxyvinyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0593] Example 1 (27.6 mg, 0.05 mmol), 2-benzyloxyvinyl-1-boronic acid pinacol ester (19.5 mg, 0.075 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (10.1 mg, 0.005 mmol), and cesium carbonate (48.9 mg, 0.15 mmol) were weighed in sequence. 2 mL of dioxane aqueous solution (V / V = 4:1) was added, the atmosphere was replaced with nitrogen, and the reaction was stirred in a microwave at 100°C for 1 hour. 3 mL of water was poured into the reaction solution, and the mixture was extracted with ethyl acetate (3 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Example 53a (30.4 mg), which was used directly in the next step. MS m / z (ESI): 650.1 [M+1]

[0594] Step 2

[0595] N-(3-(2-chloro-5-fluorophenyl)-7-hydroxyethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0596] 53a (30.4 mg) and 10% Pd / C (5.3 mg) were dispersed in 5 mL of methanol, the hydrogen atmosphere was replaced three times, and the reaction was stirred at room temperature for 10 hours. The reaction solution was filtered through a short column of celite and washed with 10 mL of ethyl acetate. The filtrate was concentrated under reduced pressure and purified by reverse phase preparative purification to give Example 53 (12.4 mg, 44.1% yield).

[0597] MS m / z(ESI):562.1[M+1]

[0598] Example 55

[0599] N-(3-(2-chloro-5-fluorophenyl)-7-cyanomethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0600] Example 1 (27.6 mg, 0.05 mmol), (tributyltinyl)acetonitrile (24.8 mg, 0.075 mmol), and bistriphenylphosphine palladium dichloride (3.5 mg, 0.005 mmol) were weighed in sequence. 2 mL of dioxane was added, the nitrogen atmosphere was replaced, and the reaction was stirred in a microwave at 100°C for 1 hour. 3 mL of water was poured into the reaction solution, and the mixture was extracted with ethyl acetate (3 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by reverse phase preparative purification afforded Example 55 (12.4 mg, 44.6% yield). MS m / z (ESI): 557.1 [M+1].

[0601] Example 57

[0602] N-(3-(2-chloro-5-fluorophenyl)-7-(methoxyethynyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0603] Example 1 (27.6 mg, 0.05 mmol), methoxyacetylene (5.6 mg, 0.1 mmol), bistriphenylphosphine palladium dichloride (3.5 mg, 0.005 mmol), and cuprous iodide (1.9 mg, 0.01 mmol) were weighed in sequence. 2 mL of triethylamine was added, the nitrogen atmosphere was replaced, and the reaction was stirred at 90°C for 2 hours. 3 mL of water was poured into the reaction solution, and the mixture was extracted with ethyl acetate (3 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by reverse phase preparative chromatography afforded Example 57 (10.4 mg, 36.4% yield).

[0604] MS m / z(ESI):572.1[M+1]

[0605] Example 60

[0606] N-(3-(2-chloro-5-fluorophenyl)-7-aminomethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0607] first step

[0608] 3-(2-chloro-5-fluorophenyl)-4-(3-fluoro-5-(trifluoromethyl)benzamido)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-7-carboxamide

[0609] Example 1 (27.6 mg, 0.05 mmol), methoxyamine hydrochloride (5.0 mg, 0.06 mmol), triethylenediamine (11.2 mg, 0.1 mmol), palladium dichloride (1.8 mg, 0.01 mmol), and sodium iodide (2.2 mg, 0.015 mmol) were weighed in sequence. 5 mL of acetonitrile was added, and the carbon monoxide atmosphere was replaced three times. The reaction solution was stirred at 100°C for 8 hours. Most of the organic solvent was removed by vortexing, and 3 mL of water was poured into the reaction solution. The mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Example 60a (27.6 mg), which was used directly in the next step. MS m / z (ESI): 561.1 [M+1]

[0610] Step 2

[0611] N-(3-(2-chloro-5-fluorophenyl)-7-aminomethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0612] Example 60a (27.6 mg) was dissolved in 5 mL of dichloromethane. The reaction solution was stirred in an ice-water bath at 0°C, followed by the dropwise addition of 1 M diisobutylaluminum hydride in n-hexane (0.5 mL, 0.5 mmol). The reaction solution was stirred at room temperature for 12 hours, and then quenched by the addition of 5 mL of potassium sodium tartrate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by reverse phase preparative purification afforded Example 60 (9.8 mg, yield: 35.9%). MS m / z (ESI): 547.1 [M+1].

[0613] Example 61

[0614] N-(3-(2-chloro-5-fluorophenyl)-7-(1-aminocyclopropyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0615] first step

[0616] tert-Butyl (1-(3-(2-chloro-5-fluorophenyl)-4-(3-fluoro-5-(trifluoromethyl)benzamido)-7-(1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)cyclopropyl)carbamate

[0617] Referring to the synthesis method of the first step of Example 49, Example 61a was obtained using Example 1 and (1-Boc aminocyclopropyl)boronic acid pinacol ester as starting materials. MS m / z (ESI): 673.2 [M+1]

[0618] Step 2

[0619] N-(3-(2-chloro-5-fluorophenyl)-7-(1-aminocyclopropyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0620] Example 61a (33.6 mg, 0.05 mmol) was dissolved in 2 mL of dioxane, followed by the dropwise addition of 1 M hydrochloric acid solution in dioxane (0.5 mL, 0.5 mmol). The reaction mixture was stirred at room temperature for 1 hour, quenched with 5 mL of water, and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by reverse phase preparative chromatography afforded Example 61 (14.1 mg, 49.3% yield). MS m / z (ESI): 573.1 [M+1].

[0621] Example 62

[0622] N-(7-((azetidine-3-sulfonylimino)methyl)-3-(2-chloro-5-fluorophenyl)-7-(1-aminocyclopropyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0623] first step

[0624] 3-(2-chloro-5-fluorophenyl)-4-(3-fluoro-5-(trifluoromethyl)benzamido)-2-(4-methoxybenzyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-7-carboxylic acid

[0625] Example 50a (34.8 mg, 0.05 mmol) was dissolved in 4 mL of THF, and a solution of LiOH (6.0 mg, 0.25 mmol) in water (1 mL) was added dropwise to the reaction solution. The reaction solution was stirred at 50°C for 1 hour, and then quenched by adding 1 M HCl (3 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (3 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Example 62a (33.7 mg), which was used directly in the next step. MS m / z (ESI): 680.1 [M-1]

[0626] Step 2

[0627] tert-Butyl 3-((3-(2-chloro-5-fluorophenyl)-4-(3-fluoro-5-(trifluoromethyl)benzamido)-2-(4-methoxybenzyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-7-carboxylate)thio)azetidine-1-carboxylate

[0628] Example 62a (33.7 mg, 0.05 mmol) was dissolved in 1 mL of N,N-dimethylacetamide, and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (28.5 mg, 0.075 mmol), N,N-diisopropylethylamine (19.4 mg, 0.15 mmol), and tert-butyl 3-mercaptoazetidine-1-carboxylate (14.2 mg, 0.075 mmol) were added to the reaction system in sequence. After the reaction solution was reacted at room temperature for 12 hours, 5 mL of ammonium chloride solution was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Example 62b (41.4 mg), which was used directly in the next step. MS m / z (ESI): 853.2 [M+1]

[0629] Step 3

[0630] tert-Butyl 3-((7-(3-(2-chloro-5-fluorophenyl)-4-(3-fluoro-5-(trifluoromethyl)benzamido)-2-(4-methoxybenzyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)methyl)thio)azetidine-1-carboxylate

[0631] Example 62b (41.4 mg) was dissolved in 5 mL of diethyl ether. The reaction solution was stirred in an ice-water bath at 0°C, followed by the dropwise addition of 1 M diisobutylaluminum hydride in n-hexane (0.5 mL, 0.5 mmol). The reaction solution was stirred at room temperature for 12 hours, and then quenched by the addition of 5 mL of potassium sodium tartrate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford Example 62c (40.2 mg), which was used directly in the next step. MS m / z (ESI): 839.2 [M+1]

[0632] Step 4

[0633] tert-Butyl 3-((7-(3-(2-chloro-5-fluorophenyl)-4-(3-fluoro-5-(trifluoromethyl)benzamido)-2-(4-methoxybenzyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)methyl)sulfoxide)azetidine-1-carboxylate

[0634] Example 62c (40.2 mg) was dissolved in dichloromethane (5 mL) and cooled to -20°C in a dry ice / ethyl acetate bath. m-Chloroperbenzoic acid (10.4 mg, 0.06 mmol) was added. After the addition, the ice bath was removed and the mixture was allowed to warm to room temperature. The mixture was stirred for 30 minutes. LC-MS confirmed the reaction was complete. Saturated sodium carbonate solution (5 mL) was added to the reaction solution, followed by extraction with ethyl acetate (5 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (5 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford Example 62d (38.7 mg), which was used directly in the next step.

[0635] MS m / z(ESI):855.2[M+1]

[0636] Step 5

[0637] tert-Butyl 3-((7-(3-(2-chloro-5-fluorophenyl)-4-(3-fluoro-5-(trifluoromethyl)benzamido)-2-(4-methoxybenzyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)methyl)sulfonimide)azetidine-1-carboxylate

[0638] Example 62d (38.7 mg) was dissolved in methanol (5 mL), and ammonium carbamate (15.6 mg, 0.2 mmol) and iodobenzene diacetate (48.3 mg, 0.15 mmol) were added sequentially. The mixture was stirred at room temperature for 1 hour. The reaction was stopped and quenched by adding water (5 mL). The mixture was extracted with ethyl acetate (5 mL x 2), and the organic phases were combined. The organic phases were washed with saturated sodium chloride (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford Example 62e (41.7 mg), which was used directly in the next step. MS m / z (ESI): 870.2 [M+1]

[0639] Step 6

[0640] N-(7-((azetidine-3-sulfonylimino)methyl)-3-(2-chloro-5-fluorophenyl)-7-(1-aminocyclopropyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0641] Referring to the synthesis method of the second step of Example 1, Example 62 was obtained using Example 62e as the starting material. MS m / z (ESI): 650.1 [M+1]

[0642] Example 63

[0643] N-(3-(2-chloro-5-fluorophenyl)-7-(3-azetidinyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0644] Example 1 (27.6 mg, 0.05 mmol), 3-azetidinecarboxylic acid (7.6 mg, 0.075 mmol), di(tri-tert-butylphosphine)palladium (2.6 mg, 0.005 mmol), cesium carbonate (48.9 mg, 0.15 mmol), and tetrabutylammonium chloride (27.8 mg, 0.1 mmol) were weighed in sequence. 2 mL of DMF was added, the atmosphere was replaced with nitrogen, and the reaction was stirred in a microwave oven at 170°C for 0.5 hour. 3 mL of water was poured into the reaction solution, and the mixture was extracted with ethyl acetate (3 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by reverse phase preparative purification afforded Example 63 (9.8 mg, 34.3% yield). MS m / z (ESI): 573.1 [M+1]

[0645] Example 67

[0646] 3-(2-chloro-5-fluorophenyl)-N-cyclobutyl-4-(3-fluoro-5-trifluoromethylbenzamido)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-7-carboxamide

[0647] first step

[0648] 3-(2-chloro-5-fluorophenyl)-N-cyclobutyl-4-(3-fluoro-5-(trifluoromethyl)benzamido)-2-(4-methoxybenzyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-7-carboxamide

[0649] Example 62a (34.1 mg, 0.05 mmol) was dissolved in 1 mL of N,N-dimethylacetamide. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (28.5 mg, 0.075 mmol), N,N-diisopropylethylamine (19.4 mg, 0.15 mmol), and cyclobutylamine (5.3 mg, 0.075 mmol) were added to the reaction system in that order. The reaction solution was reacted at room temperature for 12 hours, and then 5 mL of ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford Example 67a (32.4 mg), which was used directly in the next step.

[0650] MS m / z(ESI):735.2[M+1]

[0651] Step 2

[0652] 3-(2-chloro-5-fluorophenyl)-N-cyclobutyl-4-(3-fluoro-5-trifluoromethylbenzamido)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-7-carboxamide

[0653] Referring to the synthesis method of the second step of Example 1, Example 67 was obtained using Example 67a as the starting material. MS m / z (ESI): 615.1 [M+1]

[0654] Example 68

[0655] N-[3-(2-chloro-5-fluorophenyl)-1-oxyidene-7-[(2-oxyidenepropyl)oxy]-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0656] first step

[0657] N-[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-1-oxo-7-[(2-oxopropylidene)oxy]-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0658] Compound 1b (50 mg, 74.36 μmol) and 1-hydroxypropan-2-one (16 mg, 223.08 μmol) were dissolved in 1 mL of N,N-dimethylformamide. The atmosphere was replaced with nitrogen bubbling for 1 minute. Potassium tert-butoxide (25 mg, 223.08 μmol), cuprous iodide (2.8 mg, 14.88 μmol), and N,N,N',N'-tetramethylethylenediamine (1.7 mg, 14.88 μmol) were added all at once and stirred in a microwave oven at 130°C for 1 hour. The reaction solution was cooled to room temperature, 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography using solvent System B to afford Example 68a (20 mg, 37.9% yield). MS: m / z(ESI):710.1[M+1]

[0659] Step 2

[0660] N-[3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-1-oxo-7-[(2-oxopropylidene)oxy]-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0661] Compound 68a (20 mg, 28.17 μmol) was dissolved in 1 mL of trifluoroacetic acid, and 0.2 mL of trifluoromethanesulfonic acid was added. The mixture was stirred at 80°C for 1 hour. The reaction solution was concentrated, and the resulting residue was purified by preparative HPLC to afford Example 68 (10 mg, yield: 60.2%). MS: m / z (ESI): 590.1 [M+1]

[0662] Example 75

[0663] N-[3-(2-chloro-5-fluorophenyl)-7-[(2-hydroxyethyl)amino]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0664] first step

[0665] N-[3-(2-chloro-5-fluorophenyl)-7-[(2-hydroxyethyl)amino]-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0666] Compound 1b (50 mg, 74.36 μmol) and 2-aminoethan-1-ol (14 mg, 223.08 μmol) were dissolved in 1 mL of dimethyl sulfoxide and stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, and 10 mL of water was added. The mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography using solvent System B to obtain Example 75a (20 mg, 38.6% yield).

[0667] MS: m / z(ESI):697.2[M+1]

[0668] Step 2

[0669] N-[3-(2-chloro-5-fluorophenyl)-7-[(2-hydroxyethyl)amino]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-3-(trifluoromethyl)benzamide

[0670] Compound 75a (20 mg, 34.67 μmol) was dissolved in 1 mL of trifluoroacetic acid, and 0.2 mL of trifluoromethanesulfonic acid was added. The mixture was stirred at 80°C for 1 hour. The reaction solution was concentrated, and the resulting residue was purified by preparative HPLC to afford Example 75 (10 mg, 60.4% yield). MS: m / z (ESI): 577.1 [M+1]

[0671] Example 82

[0672] 7-(1,3,4-oxadiazol-2-ylamino)-3-chloro-5-fluorophenyl-1-oxo-2,3-dihydropyrrolopyrrolyl-3-fluoro-5-benzamide

[0673] first step

[0674] 7-(1,3,4-oxadiazol-2-ylamino)-3-chloro-5-fluorophenyl-2-methoxybenzyl-1-oxo-2,3-dihydropyrrolopyrrolopyrrolidine-3-fluoro-5-trifluoromethylbenzamide

[0675] Under N₂, Intermediate 82a (40 mg, 59.49 μmol), Cs₂CO₃ (39.02 mg, 118.97 μmol), Pd₂(dba)₃ (4.83 mg, 5.95 μmol), and xantsphos (6.69 mg, 11.90 μmol) were added to dioxane (3 mL). 1,3,4-Oxadiazol-2-amine (10.12 mg, 118.97 μmol) was then added. The reaction solution was stirred in a microwave at 100°C for 1 hour. 1 M hydrochloric acid (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined extracts were dried over Na₂SO₄ and spin-dried to afford Example 82b (35 mg) in an 81.6% yield. MS m / z (ESI): 721.1 [M+1].

[0676] Step 2

[0677] 7-(1,3,4-oxadiazol-2-ylamino)-3-chloro-5-fluorophenyl-1-oxo-2,3-dihydropyrrolopyrrolyl-3-fluoro-5-benzamide

[0678] Under N₂, 82b (35 mg, 48.54 μmol) was added to TFA (2 mL) and CF₃SO₃H (0.5 mL). The reaction solution was stirred at 75°C for 1 hour, 1 M Na₂CO₃ (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined extracts were dried over Na₂SO₄ and spin-dried. The crude product was purified by p-HPLC (FA) to afford Example 82 (8 mg) in a 26% yield. MS m / z (ESI): 601.2 [M+1]. 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),9.46-9.19(m,2H),8.89(s,1H),8.18-7.85(m,3H),7 .77-7.64(m,2H),7.38-7.18(m,2H),7.11(td,J=8.4,3.0Hz,1H),6.67(s,1H),6.12(s,1H).

[0679] Example 83

[0680] 3-Chloro-5-fluorophenyl-3-chloro-2,3-dihydropyrrole-3-fluoro-4-quinoline-3-fluoro-5-benzamide

[0681] The synthesis method of Example 83 was similar to that of Example 82, and Example 83 (10 mg, 32%) was obtained using tert-butyl 4-aminopyrazole-1-carboxylate as the starting material. MS m / z (ESI): 599.2 [M+1]

[0682] 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),10.02(s,1H),9.24(s,1H),9.09(d,J=9.1Hz,1H),8.26(s,1H),7. 95(d,J=8.4Hz,1H),7.84-7.57(m,4H),7.41-7.27(m,2H),7.23-7.05(m,2H),6.84(s,1H),6.12(s,1H).

[0683] Example 84

[0684] 3-Chloro-5-fluorophenyl-7-methanesulfonamido-3-fluoro-2,3-dihydropyrrolopyrrole-3-fluoro-5-trifluoromethylbenzamide

[0685] The synthesis method of Example 84 was referred to that of Example 82, and Example 84 (32 mg, 31%) was obtained using methylsulfonamide as the starting material. MS m / z (ESI): 611.2 [M+1]

[0686] 1 H NMR (400MHz, DMSO-d6) δ10.02(s,1H),9.62(s,1H),8.78(d,J=8.3Hz,1H),8. 33(s,1H),7.89(t,J=2.2Hz,1H),7.69(dt,J=12.3,2.2Hz,1H),7.58-7.50(m, 2H),7.31-7.17(m,2H),7.05(ddd,J=10.3,7.1,2.2Hz,1H),6.12(s,1H),5.98-5.93(m,1H),2.98(s,3H).

[0687] Example 85

[0688] 3-Chloro-5-fluorophenyl-7-hydroxy-2-methylpropionamido-1-oxo-2,3-dihydropyrrolopyrrole-3-fluoro-5-trifluoromethylbenzamide

[0689] The synthesis method of Example 85 was similar to that of Example 82, and Example 85 (16 mg, 36%) was obtained using 2-hydroxy-2-methylpropionamide as the starting material. MS m / z (ESI): 619.2 [M+1]

[0690] 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),9.13(d,J=8.3Hz,1H),8.34(s,1H),7.89(t,J=2.2Hz,1H),7.83(d,J=8.2Hz,1H),7.69(dt,J=12.3,2.2Hz,1H), 7.58-7.50(m,3H),7.28(s,1H),7.20(ddd,J=12.1,2.2,0.7Hz,1H),7.05( ddd,J=10.3,7.1,2.2Hz,1H),5.98-5.93(m,1H),4.55(s,1H),1.48(s,6H).

[0691] Example 86

[0692] 3-Chloro-5-fluorophenyl-1-oxo-7-oxoxazolidin-3-yl-2,3-dihydropyrrol-3-quinolin-4-yl-3-fluoro-5-benzamide

[0693] The synthesis method of Example 86 was referred to the synthesis method of Example 82, and Example 86 (25 mg, 45%) was obtained using oxazolidin-2-one as the starting material. MS m / z (ESI): 603.2 [M+1]

[0694] 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),9.41(d,J=9.3Hz,2H),8.52(d,J=9.3Hz,1H),7.98(d,J=6.0Hz,2H),7.75(d,J=9.0Hz,1H),7.68(s,1 H),7.34(dd,J=8.9,5.1Hz,1H),7.11(td,J=8.4,3.0Hz,1H),6.57(d,J=78.0Hz,1H),6.19(s,1H),4.54(t,J=8.0Hz,2H),4.39-4.23(m,2H).

[0695] Example 87

[0696] 3-Chloro-5-fluorophenyl-7-(3-methylisoxazol-4-ylamino)-1-oxo-2,3-dihydropyrrolopyrrole-3-fluoro-5-trifluoromethylbenzamide

[0697] The synthesis method of Example 87 was similar to that of Example 82, and Example 87 (22 mg, 41%) was obtained using 3-methyl-4-isoxazolamine as the starting material. MS m / z (ESI): 614.2 [M+1]

[0698] Example 88

[0699] 3-Chloro-5-fluorophenyl-7-amino-3-oxopyrazole-3-amino-3-dihydropyrrolopyrrole-3-4-fluoro-4-ylquinoline

[0700] The synthesis method of Example 88 was similar to that of Example 82, and Example 88 (22 mg, 41%) was obtained using 3-aminomethylpyrazole as the starting material. MS m / z (ESI): 613.2 [M+1]

[0701] 1H NMR (400MHz, DMSO-d6) δ10.56(s,1H),9.97(s,1H),9.24(s,1H),9.08(d,J=9.2Hz,1H),7.95(d,J=8.5Hz,1H),7.77-7.67(m,3H),7 .59(d,J=2.2Hz,1H),7.32(dt,J=9.1,5.1Hz,2H),7.08(td,J=8.3,3.1Hz,1H),6.88(s,1H),6.66(s,1H),6.10(s,1H),3.77(s,3H).

[0702] Example 102

[0703] N-(3-(2-chloro-5-fluorophenyl)-1-oxo-7-(thiazol-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0704] first step

[0705] N-(3-(2-chloro-5-fluorophenyl)-1-oxo-7-(thiazol-2-yl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0706] N-(7-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide 1 (30 mg, 0.054 mmol) was dissolved in 1.0 mL of N,N-dimethylformamide. 2-(tributyltinyl)thiazole (31 mg, 0.081 mmol) and tetrakistriphenylphosphine palladium (6.2 mg, 0.0054 mmol) were added to the reaction system in sequence. The reaction was heated in a microwave oven at 100°C for 1 hour. After cooling to room temperature, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to afford Example 102 (14 mg) in a 42.9% yield. MS m / z(ESI):601.2[M+1]

[0707] Example 104

[0708] N-(3-(2-chloro-5-fluorophenyl)-1-oxo-7-(1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide

[0709] first step

[0710] N-(3-(2-chloro-5-fluorophenyl)-1-oxo-7-(1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl]-3-fluoro-5-(trifluoromethyl)benzamide

[0711] N-(7-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide 1 (30 mg, 0.054 mmol) was dissolved in 2.0 mL of 1,4-dioxane and water (V / V=4:1), and 1H-pyrazole-4-boronic acid (9 mg, 0.081 mmol), 1,1 ’ -bis(diphenylphosphinoferrocenepalladium dichloride) (4.6 mg, 0.0054 mmol) and cesium carbonate (53 mg, 0.16 mmol) were added. The reaction was heated in a microwave at 100°C for 1 hour. After cooling to room temperature, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain Example 104 (14 mg, yield: 43.8%).

[0712] MS m / z(ESI):584.1[M+1]

[0713] Example 126

[0714] N-(3-(2-chloro-5-fluorophenyl)-7-((4-cyano-1H-pyrazol-1-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrido[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0715] first step

[0716] 3-(2-chloro-5-fluorophenyl)-4-(3-fluoro-5-(trifluoromethyl)benzamido)-2-(4-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinoline-7-carboxylic acid methyl ester

[0717] N-(7-chloro-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide 1b (1.0 g, 1.49 mmol) was dissolved in 20 mL of dimethyl sulfoxide and methanol (V / V=1:1). 1, 1 ’ -bis(diphenylphosphinoferrocenepalladium dichloride) (125 mg, 0.15 mmol) and triethylamine (450 mg, 4.46 mmol). After carbon monoxide was replaced three times, the mixture was heated to 70°C and reacted for 15 hours. After cooling to room temperature, 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with eluent System B to obtain 0.72 g of 126a in a 69.6% yield. MS m / z (ESI): 696.2 [M+1].

[0718] Step 2

[0719] 3-(2-chloro-5-fluorophenyl)-4-(3-fluoro-5-(trifluoromethyl)benzamide)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinoline-7-carboxylic acid methyl ester

[0720] 126a (0.72 g, 1.0 mmol) was dissolved in 10 mL of a mixture of trifluoroacetic acid and trifluoromethanesulfonic acid (v / v = 4:1) and heated at 70°C for 2 hours. After cooling to room temperature, the reaction solution was slowly poured into 60 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with eluent System A to afford 0.55 g of 126b in a 92.4% yield.

[0721] MS m / z(ESI):576.1[M+1]

[0722] Step 3

[0723] N-(3-(2-chloro-5-fluorophenyl)-7-(hydroxymethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0724] 126b (0.50 g, 0.87 mmol) was dissolved in 10 mL of tetrahydrofuran, and a solution of lithium aluminum tetrahydride (1.3 mL, 1.3 mmol, 1.0 M) in tetrahydrofuran was added. After complete addition, the mixture was allowed to react at 25°C for 0.5 h. The reaction solution was slowly poured into 20 mL of saturated sodium potassium tartrate solution and stirred at room temperature for 2 h. The mixture was then extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using eluent System A to afford 0.42 g of Example 126c in an 88.2% yield. MS m / z (ESI): 548.1 [M+1].

[0725] Step 4

[0726] N-(7-(Bromomethyl)-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0727] 126c (0.20 g, 0.37 mmol) was dissolved in 5.0 mL of dichloromethane, and phosphorus tribromide (99 mg, 0.37 mmol) was added. After the addition was complete, the mixture was allowed to react at 25°C for 2 hours. The reaction solution was slowly poured into 20 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using eluent System B to afford Example 126d (145 mg, 65.0% yield).

[0728] MS m / z(ESI):610.2, 612.2[M+1]

[0729] Step 5

[0730] N-(3-(2-chloro-5-fluorophenyl)-7-((4-cyano-1H-pyrazol-1-yl)methyl)-1-oxo-2,3-dihydro-1H-pyrido[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0731] 126d (30 mg, 0.049 mmol) was dissolved in 2.0 mL of N,N-dimethylformamide, and potassium tert-butoxide (17 mg, 0.15 mmol) and 4-cyanopyrazole (7 mg, 0.074 mmol) were added. After the addition was complete, the mixture was reacted at 25°C for 1 hour. The reaction solution was slowly poured into 20 mL of water and extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to afford Example 126 (12 mg, yield: 39.2%). MS m / z (ESI): 623.1 [M+1]

[0732] Example 150

[0733] N-(3-(2-chloro-5-fluorophenyl)-1-oxo-7-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0734] To a 25 mL round-bottom flask containing Example 149 (30.00 mg, 0.05 mmol) was added 10% Pd / C (5.32 mg, 49.99 μmol) and MeOH (5 mL) in sequence. After purging the hydrogen, the reaction solution was stirred at 80°C for 10 hours. After the reaction solution was cooled, the filtrate was evaporated to dryness and purified by reverse phase preparative purification to give Example 150 (17 mg, 57% yield). MS m / z (ESI): 602.1 [M+1]

[0735] Example 167

[0736] N-(3-(2-chloro-5-fluorophenyl)-7-methoxy-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indoline-2,2-d2-1-carboxamide

[0737] first step

[0738] 4-Amino-7-chloro-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-1-one

[0739] Referring to the synthetic method of Example 1, 4-amino-7-chloro-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-1-one 28c was used as the starting material to obtain Example 4-amino-7-chloro-3-(2-chloro-5-fluorophenyl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-1-one 167a.

[0740] MS m / z(ESI):362.1[M+1]

[0741] Step 2

[0742] N-(7-chloro-3-(2-chloro-5-fluorophenyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indoline-2,2-d2-1-carboxamide

[0743] Referring to the synthesis method of step 3 in Example 8, 167a was used as the starting material to obtain Example N-(7-chloro-3-(2-chloro-5-fluorophenyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)dihydroindole-2,2-d2-1-carboxamide 167b. MS m / z (ESI): 593.1 [M+1].

[0744] Step 3

[0745] N-(3-(2-chloro-5-fluorophenyl)-7-methoxy-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indoline-2,2-d2-1-carboxamide

[0746] 167b (20 mg, 0.034 mmol) was dissolved in 2 mL of methanol, and 0.5 mL of acetic acid was added. The reaction was stirred at room temperature overnight. The solvent was concentrated under reduced pressure, and the resulting residue was purified by reverse phase preparative purification to afford Example N-(3-(2-chloro-5-fluorophenyl)-7-methoxy-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indoline-2,2-d2-1-carboxamide (2.0 mg, 10.0% yield). MS m / z (ESI): 589.1 [M+1]

[0747] Example 169

[0748] N-(3-(2-chloro-5-fluorophenyl)-7-ethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indoline-2,2-d2-1-carboxamide

[0749] first step

[0750] N-(3-(2-chloro-5-fluorophenyl)-7-vinyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indoline-2,2-d2-1-carboxamide

[0751] Referring to the synthetic method of the first step of Example 49, N-(7-chloro-3-(2-chloro-5-fluorophenyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indoline-2,2-d2-1-carboxamide 167b and potassium ethylene trifluoroborate were used as starting materials to obtain Example N-(3-(2-chloro-5-fluorophenyl)-7-vinyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indoline-2,2-d2-1-carboxamide 169a. MS m / z (ESI): 585.2 [M+1].

[0752] Step 2

[0753] N-(3-(2-chloro-5-fluorophenyl)-7-ethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indoline-2,2-d2-1-carboxamide

[0754] With reference to the synthetic method of the second step of Example 49, N-(3-(2-chloro-5-fluorophenyl)-7-vinyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indoline-2,2-d2-1-carboxamide 169a was used as a starting material to obtain Example N-(3-(2-chloro-5-fluorophenyl)-7-ethyl-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indoline-2,2-d2-1-carboxamide 169.

[0755] MS m / z(ESI):587.2[M+1]

[0756] Example 170

[0757] N-(3-(2-chloro-5-fluorophenyl)-7-(methoxymethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indole-2,2-d2-1-carboxamide

[0758] first step

[0759] 3-(2-chloro-5-fluorophenyl)-4-(3-hydroxy-3-(trifluoromethyl)indole-1-carboxamide-2,2-d2)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinoline-7-carboxylic acid methyl ester

[0760] Referring to the synthetic method of the first step in Example 126, N-(7-chloro-3-(2-chloro-5-fluorophenyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)dihydroindole-2,2-d2-1-carboxamide 167b was used as the starting material to obtain Example 3-(2-chloro-5-fluorophenyl)-4-(3-hydroxy-3-(trifluoromethyl)indole-1-carboxamide-2,2-d2)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinoline-7-carboxylic acid methyl ester 170a. MS m / z (ESI): 617.2 [M+1].

[0761] Step 2

[0762] N-(3-(2-chloro-5-fluorophenyl)-7-(hydroxymethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indole-2,2-d2-1-carboxamide

[0763] Referring to the synthesis method of step 3 in Example 126, methyl 3-(2-chloro-5-fluorophenyl)-4-(3-hydroxy-3-(trifluoromethyl)indole-1-carboxamide-2,2-d2)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinoline-7-carboxylate 170a was used as the starting material to obtain Example N-(3-(2-chloro-5-fluorophenyl)-7-(hydroxymethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indole-2,2-d2-1-carboxamide 170b. MS m / z (ESI): 589.2 [M+1].

[0764] Step 3

[0765] N-(3-(2-chloro-5-fluorophenyl)-7-(methoxymethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indole-2,2-d2-1-carboxamide

[0766] N-(3-(2-chloro-5-fluorophenyl)-7-(hydroxymethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indole-2,2-d2-1-carboxamide 170b (20 mg, 0.034 mmol) was dissolved in 2 mL of methanol, and 2 drops of methanesulfonic acid were added. The reaction was heated at 60°C for 2 hours. The solvent was concentrated under reduced pressure, and the resulting residue was purified by reverse phase preparative purification to afford Example N-(3-(2-chloro-5-fluorophenyl)-7-(methoxymethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-hydroxy-3-(trifluoromethyl)indole-2,2-d2-1-carboxamide 170 (8 mg, 39.1% yield). MS m / z(ESI):603.2[M+1]

[0767] Example 199

[0768] N-(3-(2-chloro-5-fluorophenyl)-7-methoxy-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indole-2,2-d2-1-carboxamide

[0769] The preparation of the compound of Example 199 was carried out according to Example 167. MS m / z (ESI): 607.2 [M+1]

[0770] Example 229

[0771] N-[3-(2-Chloro-5-fluorophenyl)-1-oxyylidene-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5'-fluoro-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-1'-carboxamide

[0772] first step

[0773] 5'-Fluoro-1',2'-dihydrospiro[cyclopropane-1,3'-indole]

[0774] Compound 229a (50 mg, 282.22 μmol) was dissolved in 4 mL of anhydrous tetrahydrofuran. A 1 M solution of lithium aluminum tetrahydride in tetrahydrofuran (564.41 μmol, 564 μL) was added dropwise under nitrogen at 0°C. The mixture was then slowly warmed to room temperature and stirred at 50°C for 12 hours. The reaction mixture was cooled to 0°C and quenched by the dropwise addition of 1 M sodium hydroxide solution (564 μL). Water (564 μL) was then added for further quenching. The mixture was dried over anhydrous magnesium sulfate and filtered. The filter cake was rinsed several times with tetrahydrofuran. The filtrate was concentrated under reduced pressure to afford Example 229b (60 mg). The crude product was used directly in the next reaction. MS: m / z (ESI): 164.1 [M+1].

[0775] Step 2

[0776] N-(3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-5'-fluorospiro[cyclopropane-1,3'-indoline]-1'-carboxamide

[0777] Triphosgene (18 mg, 61.02 μmol) was dissolved in 1 mL of anhydrous dichloromethane. Under a nitrogen balloon, a solution of compound I-6 (50 mg, 152.56 μmol) in anhydrous tetrahydrofuran (1 mL) and triethylamine (64 μL, 457.68 μmol) were added dropwise at 0°C. The mixture was stirred under a nitrogen balloon at 20°C for 12 hours. The reaction mixture was cooled to 0°C, and a solution of compound 229b (60 mg) in anhydrous tetrahydrofuran (1 mL) was added dropwise. The mixture was stirred under a nitrogen balloon at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by HPLC to afford Example 229c (20 mg, 10.2% yield).

[0778] MS: m / z(ESI):638.1[M+1]

[0779] Step 3

[0780] N-(3-(2-Chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-5'-fluorospiro[cyclopropane-1,3'-indoline]-1'-carboxamide

[0781] The preparation of the compound of Example 229 was carried out according to Example 1. MS m / z (ESI): 517.9 [M+1]

[0782] Example 232

[0783] N-[3-(2-Chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-1,2-dihydrospiro[indole-3,2'-oxetane]-1-carboxamide

[0784] first step

[0785] 5-Fluoro-3-hydroxy-2,3-dihydro-1H-indol-2-one

[0786] Compound 232a (1 g, 6.06 mmol) was dispersed in 50% hypophosphorous acid aqueous solution (10 mL) and stirred at 70°C for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with water (2 mL x 3) and dried under reduced pressure to give Example 232b (1 g). MS: m / z (ESI): 168.0 [M+1]

[0787] Step 2

[0788] 5-Fluoro-1,2-dihydrospiro[indole-3,2'-oxetane]-2-one

[0789] Compound 232b (1 g) was dispersed in water (20 mL), and potassium hydroxide (1.02 g, 18.18 mmol) was added portionwise at 20°C. Compound 232c (869 mg, 4.04 mmol) was then added and stirred for 2 hours. The reaction mixture was diluted with 10 mL of saturated ammonium chloride solution and extracted with dichloromethane (20 mL x 2). The combined organic phases were 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 separated and purified by column chromatography to afford Example 232d (500 mg) in a two-step total yield of 42.7%.

[0790] MS: m / z(ESI):194.1[M+1]

[0791] Step 3

[0792] 5-Fluoro-1,2-dihydrospiro[indole-3,2'-oxetane]

[0793] Compound 232d (500 mg, 2.59 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran. Under a nitrogen balloon, a 1 M solution of lithium aluminum tetrahydride in tetrahydrofuran (5.18 mmol, 5.18 mL) was added dropwise at 0°C. The mixture was then slowly warmed to room temperature and stirred at 50°C for 12 hours. The reaction solution was cooled to 0°C and quenched by the dropwise addition of 1 M sodium hydroxide solution (5.18 mL). Water (5.18 mL) was then added to further quench the reaction. The mixture was dried over anhydrous magnesium sulfate and filtered. The filter cake was rinsed several times with tetrahydrofuran. The filtrate was concentrated under reduced pressure to afford Example 232e (600 mg). The crude product was used directly in the next step. MS: m / z (ESI): 180.1 [M+1].

[0794] Step 4

[0795] N-[3-(2-Chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-1,2-dihydrospiro[indole-3,2'-oxetane]-1-carboxamide

[0796] Triphosgene (18 mg, 61.02 μmol) was dissolved in 1 mL of anhydrous dichloromethane. A solution of compound I-6 (50 mg, 152.56 μmol) in anhydrous tetrahydrofuran (1 mL) and triethylamine (64 μL, 457.68 μmol) were added dropwise under a nitrogen balloon at 0°C. The mixture was stirred at 20°C for 12 hours. The reaction mixture was cooled to 0°C and a solution of compound 232e (60 mg) in anhydrous tetrahydrofuran (1 mL) was added dropwise. The mixture was stirred at 20°C for 1 hour under a nitrogen balloon. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to obtain Example 232 (10 mg, yield: 12.3%). MS: m / z (ESI): 533.1 [M+1].

[0797] Example 234

[0798] N-(3-(2-Chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-6-fluoro-1,2,2a,7b-tetrahydro-3H-cyclobutane[b]indole-3-carboxamide

[0799] first step

[0800] 2-Bromo-N-cyclobutyl-4-fluoroaniline

[0801] 2-Bromo-4-fluoroaniline (5.0 g, 26.31 mmol), cyclobutanone (1.8 g, 26.31 mmol), sodium triacetoxyborohydride (8.4 g, 39.47 mmol), and acetic acid (1.6 g, 26.31 mmol) were dissolved in THF (70 mL). The reaction was stirred at room temperature for 14 hours. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain Example 234b (5.9 g) in a 92% yield. MS m / z (ESI): 244.0 [M+1].

[0802] Step 2

[0803] Methyl (2-bromo-4-fluorophenyl)(cyclobutyl)carbamate

[0804] 234b (5.9 g, 24.17 mmol) was dissolved in methyl chloroformate (60 mL). The reaction mixture was heated to 70°C and stirred for 14 hours. Saturated sodium carbonate solution was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to afford Example 234c (6.3 g) in 86% yield. MS m / z (ESI): 302.0 [M+1]

[0805] Step 3

[0806] 6-Fluoro-1,2,2a,7b-tetrahydro-3H-cyclobutane[b]indole-3-carboxylic acid methyl ester

[0807] 234c (6.3 g, 20.85 mmol), palladium acetate (174 mg, 1.04 mmol), tricyclohexylphosphine tetrafluoroborate (766 mg, 2.08 mmol), cesium carbonate (10.3 g, 31.28 mmol), and trimethylacetic acid (639 mg, 6.26 mmol) were dissolved in mesitylene (60 mL). The atmosphere was replaced with nitrogen and the reaction mixture was heated to 140°C with stirring for 14 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was purified by silica gel column chromatography to obtain Example 234d (2.8 g) in a 61% yield. MS m / z (ESI): 222.1 [M+1]

[0808] Step 4

[0809] 6-Fluoro-2,2a,3,7b-tetrahydro-1H-cyclobutane[b]indole

[0810] 234d (2.8 g, 12.66 mmol) and sodium hydroxide (5.07 g, 126.7 mmol) were dissolved in a mixture of methanol and water (60 mL, 2:1, V / V). The reaction mixture was heated to 60°C and stirred for 14 hours. The reaction mixture was cooled to room temperature and extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford Example 234e (1.6 g) in a 77% yield. MS m / z (ESI): 164.1 [M+1].

[0811] Step 5

[0812] N-(3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-6-fluoro-1,2,2a,7b-tetrahydro-3H-cyclobutane[b]indole-3-carboxamide

[0813] 234e (1.6 g, 9.80 mmol), 4-amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-1-one (4.4 g, 9.80 mmol), triphosgene (4.4 g, 14.70 mmol), and triethylamine (4.0 g, 39.20 mmol) were dissolved in dichloromethane (30 mL) and stirred at room temperature for 14 hours. The reaction mixture was quenched by addition of saturated ammonium chloride solution and extracted with dichloromethane (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford Example 234f (4.5 g) in a 72% yield. MS m / z (ESI): 637.2 [M+1].

[0814] Step 6

[0815] N-(3-(2-Chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-6-fluoro-1,2,2a,7b-tetrahydro-3H-cyclobutane[b]indole-3-carboxamide

[0816] 234f (200 mg, 9.80 mmol) and 4-amino-3-(2-chloro-5-fluorophenyl)-2-(4-methoxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-1-one (4.4 g, 0.31 mmol) were dissolved in a mixture of trifluoroacetic acid and trifluoromethanesulfonic acid (5 mL, 4:1, v / v). The reaction mixture was heated to 80°C and stirred for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed once with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to provide Example 234 (128 mg) in a 79% yield. MS m / z (ESI): 517.1 [M+1].

[0817] Example 314

[0818] N-[3-(2-Chloro-5-fluorophenyl)-1-oxyylidene-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-2,3-dihydro-1H-indole-1-carboxamide

[0819] first step

[0820] 3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinoline-4-carboxylic acid methyl ester

[0821] Compound 314a (1 g, 1.95 mmol) was dissolved in a mixed solvent of N,N-dimethylformamide (10 mL) and methanol (10 mL). The atmosphere was replaced with nitrogen three times, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (79 mg, 97.70 umol) and triethylamine (818 uL, 5.86 mmol) were added sequentially. The atmosphere was then replaced with a carbon monoxide balloon three times, and the reaction was stirred at 80°C under a carbon monoxide balloon atmosphere for 24 hours. The reaction solution was cooled to room temperature, 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 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 filtrate was purified by column chromatography using eluent System C to obtain Example 3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-1-oxyylidene-2,3-dihydro-1H-pyrrolo[4,3-f]quinoline-4-carboxylic acid methyl ester 314b (900 mg, yield 93.8%).

[0822] MS: m / z(ESI):491.1[M+1]

[0823] Step 2

[0824] 3-(2-Chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-1-oxo-2,3-dihydro-1H-pyrrolo[4,3-f]quinoline-4-carboxylic acid

[0825] Compound 314b (500 mg) was dissolved in 10 mL of methanol and 2 mL of water, and lithium hydroxide (73 mg, 3.06 mmol) was added. The reaction mixture was stirred at 40°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water (10 mL). The pH was then adjusted to 2-3 with 2 M hydrochloric acid in an ice bath. The mixture was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford Example 3-(2-chloro-5-fluorophenyl)-2-[(4-methoxyphenyl)methyl]-1-oxyylidene-2,3-dihydro-1H-pyrrolo[4,3-f]quinoline-4-carboxylic acid 314c (500 mg, crude). MS: m / z (ESI): 477.1 [M+1].

[0826] Step 3

[0827] 3-(2-Chloro-5-fluorophenyl)-1-oxyylidene-2,3-dihydro-1H-pyrrolo[4,3-f]quinoline-4-carboxylic acid

[0828] Compound 314c (400 mg) was dissolved in 8 mL of trifluoroacetic acid, and methanesulfonic acid (1.6 mL) was added. The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water (10 mL). The pH was then adjusted to 2-3 with 2 M sodium hydroxide solution under ice-cooling. The mixture was filtered under reduced pressure, and the filter cake was rinsed with water. The filter cake was collected and the filtrate was extracted with ethyl acetate (20 mL x 3). The organic phase and filter cake were combined and concentrated under reduced pressure to give Example 3-(2-chloro-5-fluorophenyl)-1-oxyylidene-2,3-dihydro-1H-pyrrolo[4,3-f]quinoline-4-carboxylic acid 314d (300 mg, crude product). MS: m / z (ESI): 357.1 [M+1].

[0829] Step 4

[0830] N-[3-(2-Chloro-5-fluorophenyl)-1-oxyylidene-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-2,3-dihydro-1H-indole-1-carboxamide

[0831] Compounds 314d (20 mg, 56.06 μmol) and 314e (12 mg, 84.10 μmol) were dissolved in 1 mL of toluene. Diphenylphosphoryl azide (11 mg, 44.85 μmol) and triethylamine (17 mg, 168.19 μmol) were added. The atmosphere was purged with nitrogen three times, and the mixture was stirred at 80°C for 12 hours. The reaction mixture was directly concentrated under reduced pressure, and the resulting residue was dissolved in trifluoroacetic acid (1 mL). Triethylsilane (0.1 mL) was added, and the mixture was stirred at 80°C for 1 hour. The reaction mixture was again concentrated under reduced pressure to dryness, and the product was separated and purified by HPLC to afford Example N-[3-(2-chloro-5-fluorophenyl)-1-oxyylidene-2,3-dihydro-1H-pyrrolo[4,3-f]quinolin-4-yl]-5-fluoro-2,3-dihydro-1H-indole-1-carboxamide 314 (10 mg, 36.3% yield). MS: m / z(ESI):491.1[M+1]

[0832] Example 316

[0833] N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl-3d)-3-fluoro-5-(trifluoromethyl)benzamide

[0834] first step

[0835] N-(3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0836] The synthesis of Example 316a was carried out according to Example 1. MS m / z (ESI): 518.8 [M+1]

[0837] Step 2

[0838] N-(3-(2-chloro-5-fluorophenyl)-1-carbonyl-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl-3-d)-3-fluoro-5-(trifluoromethyl)benzamide

[0839] Example 316a (50 mg, 0.097 mmol) was dissolved in 4 mL of tetrahydrofuran and cooled to -78°C. n-Butyl lithium (0.14 mL, 0.34 mmol) was added and the reaction was stirred at -78°C to room temperature for 2 hours. 0.6 mL of deuterated methanol was added to quench the reaction and stirred for 5 minutes. The solvent was dried by rotary evaporation, 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford Example 316 (45 mg, 90.0% yield). MS m / z (ESI): 519.9 [M+1]

[0840] 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),9.47-9.39(m,2H),9.07-9.05(m,1H),8.13( s,1H),7.99-7.97(m,1H),7.78-7.69(m,4H),7.36-7.32(m,1H),7.14-7.10(m,1H).

[0841] Example 316 was separated using a chiral column (chromatographic column: CHIRALCEL IB-H 4.6*150 mm, 5 μm; detection wavelength (nm): 214; temperature (°C): 35; flow rate (mL / min): 1; mobile phase: Hexane:IPA:DEA=70:30:0.1%; running time (min): 12; linear mode: isocratic) to obtain 316-P1 (11.6 mg, RT (retention time) = 3.093 min, yield: 25.7%); 316-P2 (12.2 mg, RT (retention time) = 3.647 min, yield: 27.1%).

[0842] 316-P1, MS m / z(ESI):519.1[M+1]

[0843] 316-P2, 1 H NMR (400MHz, DMSO-d6) δ10.75 (s, 1H), 9.48-9.38 (m, 2H), 9.00 (d, 1H), 9.07-9.05 (m, 1H), 8.13 (s ,1H),7.98(d,1H),7.78-7.69(m,2H),7.35-7.32(m,1H),7.13-7.09(m,1H),6.67-6.47(m,1H).MS m / z(ESI):519.1[M+1]

[0844] Example 405

[0845] N-(3-(2-chloro-5-fluorophenyl)-7-mercapto-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0846] N-(7-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide 1 (50 mg, 90.53 μmol) and Na2S (21 mg, 0.27 mmol) were dissolved in 3 mL of DMSO, and the reaction solution was heated to 100°C and stirred for 16 hours. The reaction solution was cooled to room temperature and quenched by adding saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (3 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain Example N-(3-(2-chloro-5-fluorophenyl)-7-mercapto-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide 405 (32 mg, yield: 64.3%). MS m / z (ESI): 550.1 [M+1].

[0847] Example 406

[0848] N-(3-(2-chloro-5-fluorophenyl)-7-mercapto-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0849] first step

[0850] N-(3-(2-chloro-5-fluorophenyl)-7-(methylthio)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0851] Disperse N-(7-chloro-3-(2-chloro-5-fluorophenyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-f]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide (1.0 g, 1.81 mmol), sodium thiomethoxide (381 mg, 5.43 mmol), potassium carbonate (750 mg, 5.43 mmol), cuprous iodide (34 mg, 0.18 mmol), and L-Proline (41 mg, 0.36 mmol) in 15 mL of DMSO, replace the atmosphere with nitrogen, and heat the reaction solution to 80°C with stirring for 16 hours. The reaction mixture was cooled to room temperature and quenched by adding saturated ammonium chloride solution. The mixture was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain Example 406a (840 mg, yield: 82.3%). MS m / z (ESI): 564.1 [M+1]

[0852] Step 2

[0853] N-(3-(2-chloro-5-fluorophenyl)-7-...

Claims

1. A compound represented by general formula (I-2-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in: when When it is a single bond, there is hydrogen on the N connected to it; M is selected from S, S=O, S(O)2, N, NH, C=O, CH, CH2, C or O; M1 is C; M2 is selected from N, CR A1 , or C; R2 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 , cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally substituted with one or more substituents selected from deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , which may be further substituted with one or more substituents selected from deuterium, halogen, oxo, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; Alternatively, any two R3 and the atoms to which they are connected form a cycloalkyl, heterocyclic, aryl or heteroaryl group, which may optionally be selected from deuterium, halogen, oxo, amino, aminocarbonyl, carbonylamino, carboxyl, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkyl substituted with cyano, oxo, cycloalkyl, heterocyclic, aryl, heteroaryl, -alkenyl R 22 , -alkynyl R 22 , -alkenyl R 33 , -alkynyl R 33 , -alkenyl R 22 R 33 , -alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 - (CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 44 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O) n (CH2) n1 R 22 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents; Alternatively, R2 and R3 together with the atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which may optionally be selected from deuterium, halogen, oxo, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkyl substituted with cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents; Ring D is present or absent; Ring E is present or absent; and at least one of ring D and ring E exists; Ring D or Ring E is each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally, may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, oxo, cycloalkyl, heterocyclyl, aryl, heteroaryl, -alkenyl R 22 , -alkynyl R 22 , -alkenyl R 33 , -alkynyl R 33 , -alkenyl R 22 R 33 , -alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R[[ID= 57]] 22 、-(CH2) n R 33 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-C(O)(CH2) n1 OR 22 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R[[ID= 97]] 33 、-(CH2) n OS(O)2(CH2) n1 R 33 或-(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents; Preferably, ring D or ring E are each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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, -C 2-6 Alkenyl R 22 、-C 2-6 Alkynyl R 22 、-C 2-6 Alkenyl R 33 、-C 2-6 Alkynyl R 33 、-C 2-6 Alkenyl R 22 R 33 、-C 2-6 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-C(O)(CH2) n1 OR 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents; More preferably, ring D or ring E are each independently selected from C 6-10 aryl, 3-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen, oxygen or sulfur, or 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, optionally selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1- 3-hydroxyalkyl, cyano-substituted C 1-3 Alkyl, oxo, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-8 membered heteroaryl, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2- 3 alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-C(O)(CH2) n1 OR 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents; R 11 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, or hydroxyalkyl; R 22 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl, and optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkylsulfonyl, alkylene substituted with one or more substituents selected from the group consisting of sulfonyl, aminosulfonyl, aminosulfinyl, alkylaminocarbonyl, alkylcarbonylamino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, aminocarbonyl, carbonylamino, carboxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 33 each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally further substituted with one or more substituents selected from deuterium, halogen, nitro, hydroxy, thiol, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, alkylsulfonyl, alkylsulfinyl, alkylaminocarbonyl, alkylcarbonylamino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, aminocarbonyl, carbonylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 44 each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, aminocarbonyl, carbonylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl; R A1 is selected from hydrogen, deuterium, amino, cyano, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, haloalkyl, halogen, cycloalkyl, heterocyclyl, aryl, heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkylamino, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, membered heterocyclyl, aryl or heteroaryl; z is 0, 1, or 2; n, n1 and m1 are each independently 0, 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: Formula (I-2-1) is not the following compound, 3. The compound according to claim 2, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: It is a single bond, and there is hydrogen on the N connected to it; M is C=O; M1 is selected from C; Ring D is present or absent; Ring E is present or absent; and at least one of Ring D and Ring E is present; Ring D or Ring E are each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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, -C 2-6 Alkenyl R 22 、-C 2-6 Alkynyl R 22 、-C 2-6 Alkenyl R 33 、-C 2-6 Alkynyl R 33 、-C 2-6 Alkenyl R 22 R 33 、-C 2-6 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、- (CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents; R2 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, said R2 optionally can be selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 substituted by one or more substituents in aryl or 5-12 membered heteroaryl; R3 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 44 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , said R3 can be optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 substituted by one or more substituents in aryl or 5-12 membered heteroaryl; R 22 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 1-6 hydroxyalkyl; R 33 Each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-6 Alkyl S(O)2-, C 1-6 Alkyl S(O)-, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, aminocarbonyl, carbonylamino, C 1-6 Alkylaminocarbonyl, C 1-6 Alkylcarbonylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 one or more substitutions of aryl or 5-10 membered heteroaryl; m1 is 0.

4. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (IBI): Ring D is selected from C 6-10 Aryl, 3-10 membered heterocyclic groups containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, or 5-10 membered heteroaryl groups containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, preferably phenyl, naphthyl, 3-6 membered heterocyclic groups containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, or 5-8 membered heteroaryl groups containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, more preferably phenyl, naphthyl, 3, 4, 5 or 6 membered heterocyclic groups containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, or 5, 6, 7 or 8 membered heteroaryl groups containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, further preferably phenyl, pyridyl, Further optimization R4 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 Halogenated alkyl, 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, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、- (CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally substituted by hydroxy, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted with one or more substituents of a deuterated alkyl group; R4 is preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2- 3 alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally substituted by hydroxy, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 substituted by one or more substituents in a deuterated alkyl group; R4 is more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitrile, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 ; y is 1, 2, 3, or 4 u is 1, 2, 3, or 4.

5. The compound according to claim 4, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (IC-II): M6, M7, M8, and M9 are each independently selected from C, CH, CH2, N, NH, O, S, C=O, or S=O; R2 are each independently selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 3-8 membered heteroaryl, preferably 3-8 membered heteroaryl or C 6-10 Aryl, said R2 optionally being substituted by deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl or alkynyl; R2 is more preferably a 5-6 membered heteroaryl group containing 1-3 N, O or S atoms or a C 6-10 Aryl, optionally substituted by hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, oxo, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 2-3 Alkenyl or C 2-3 Alkynyl substitution; R2 is further preferably phenyl, which may be optionally substituted with one or more substituents selected from hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, methyl, ethyl, isopropyl, trifluoromethyl or trichloromethyl; R3 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 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 44 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered hetero Aryl, optionally substituted by hydrogen, hydroxy, halogen, cyano, amino and C 1-6 The alkyl group is substituted with one or more substituents; R3 is preferably hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Deuterated alkyl or -(CH2) n NR 22 C(O)(CH2) n1 R 33 ; R4 is preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2- 3 alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 containing 1-3 atoms selected from nitrogen, oxygen or sulfur atoms, C 6-10 Aryl, 5-10 membered heteroaryl containing 1-3 atoms selected from nitrogen, oxygen or sulfur, -C 2-3 Alkenyl-R 22 、-C 2-3 Alkynyl-R 22 、-C 2-3 Alkenyl-R 33 、-C 2-3 Alkynyl-R 33 、-C 2-3 Alkenyl-R 22 R 33 、-C 2-3 Alkynyl-R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally substituted by hydroxy, halogen, cyano, amino, C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 substituted with one or more substituents of a deuterated alkyl group; R4 is more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitrile, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, -C 2-3 Alkenyl-R 22 、-C 2-3 Alkynyl-R 22 、-C 2-3- Alkenyl R 33 、-C 2-3 Alkynyl-R 33 、-C 2-3 Alkenyl-R 22 R 33 、-C 2-3 Alkynyl-R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 。 6. The compound according to claim 5, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (ID-IV): R 44 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, the C 3-12 Cycloalkyl, 5-12 membered heterocyclic group, C 6-12 The aryl or 3-12 heteroaryl groups may be further substituted with one or more of deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, deuterated alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups.

7. The compound according to claim 6, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (ID-IV-1), (ID-IV-2), (ID-IV-3), (ID-IV-4), (ID-IV-5) or (ID-IV-6): R2 is selected from 5-6 membered heteroaryl containing 1-3 N, O or S atoms or C 6-10 Aryl, optionally substituted by deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, oxo, C 1-3 Alkyl, C 1-3 Deuterium Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 2-3 Alkenyl or C 2-3 Alkynyl is substituted with one or more substituents; R4 is each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, nitrile, hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2)​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ R 44 Each independently selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 3-6 membered heteroaryl; u is 1, 2, 3, or 4.

8. The compound according to claim 7, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by the general formula (ID-IV-11) or (ID-IV-41): R2 is selected from 5-6 membered heteroaryl containing 1-3 N, O or S atoms or C 6-10 Aryl, optionally substituted by hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, oxo, C 1-3 Alkyl, C 1- 3-deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 2-3 Alkenyl or C 2-3 Alkynyl substitution; R 44 Each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 3-6 membered heteroaryl; L is selected from a bond, C 2-3 Alkenylene, C 2-3 Alkynylidene, C 1-3 Alkylene, O, S, -NH(CH2) w , -C(O)-, -C(O)NH-, -NHC(O)-, -S(O)-, -S(O)2-, -S(O)2NH- or -NHS(O)2-; Ring A1 is selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, preferably C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms, more preferably C 3-6 Monocyclic alkyl, C 5-10 Spiroalkyl, C 5-10 Bridged cycloalkyl, C 5-10 Condensed cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, 5-10 membered spiro heterocyclic group containing 1-3 N, O or S atoms, 5-10 membered bridged heterocyclic group containing 1-3 N, O or S atoms, 5-10 membered fused heterocyclic group containing 1-3 N, O or S atoms, C 6-8 Monocyclic aromatic group, C 8-10 Condensed ring aryl, 5-6 membered monocyclic heteroaryl containing 1-3 N, O or S atoms or 5-10 membered condensed ring heteroaryl containing 1-3 N, O or S atoms, more preferably cyclopropyl, cyclobutyl, R 331 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, C 1-3 Alkylamino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkyl S(O)2-, C 1-3 Alkyl S(O)-, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkylaminosulfonyl, C 1-3 Alkylaminocarbonyl, C 1-3 Alkylcarbonylamino, aminocarbonyl, carbonylamino, C 1-3 Alkylcarbonyl, C 1-3 Deuterated alkylcarbonyl, C 1-3 Haloalkylcarbonyl, C 1-4 Hydroxyalkylcarbonyl, C 1- 3 alkoxycarbonyl, C 1-3 Deuterated alkoxycarbonyl, C 1-3 Haloalkoxycarbonyl, C 3-6 Cycloalkylcarbonyl, 3-6 membered heterocyclylcarbonyl, C 6-10 Arylcarbonyl, 5-8 membered heteroarylcarbonyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-8 membered heteroaryl, wherein the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2- 3 alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-8 membered heteroaryl, optionally further substituted by one or more substituents selected from deuterium, halogen, nitro, hydroxyl, mercapto, cyano or amino; Preferably, R 331 are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkyl S(O)2-, C 1-3 Alkyl S(O)-, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylaminocarbonyl, C 1-3 Alkylcarbonylamino, aminocarbonyl, carbonylamino, C 3-6 Cycloalkylcarbonyl, 3-6 membered heterocyclic ring containing 1-3 N, O or S atoms alkylcarbonyl, C 6-10 Arylcarbonyl, 5-8 membered heteroarylcarbonyl containing 1-3 N, O or S atoms, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms; More preferably, R 331 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl, chloroethyl, aminocarbonyl, carbonylamino, cyclopropyl, cyclobutyl, cyclohexyl, carboxyl, aminosulfonyl, aminosulfinyl, methylaminocarbonyl, methylcarbonylamino, methyl S(O)2-, methyl S(O)-, cyclopropyl, cyclobutyl, w is 0, 1, 2, 3, or 4; u1 is 0, 1, 2, 3, or 4.

9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R2 is 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 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, said R2 optionally can be selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 substituted by one or more substituents in aryl or 5-12 membered heteroaryl; Preferably, R2 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, -(CH2) n NR 22 C(O)(CH2) n1 R 33 、C 3-10 Cycloalkyl, 3-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms, wherein R2 can be optionally selected from deuterium, halogen, amino, hydroxyl, cyano Base, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 5-8 membered heteroaryl; More preferably, R2 is each independently selected from hydrogen, deuterium, phenyl, naphthyl, pyridyl or pyrimidinyl, optionally substituted with one or more substituents selected from hydroxy, fluorine, chlorine or bromine; Further preferably, R2 is each independently selected from phenyl substituted by halogen; More preferably, R2 is independently selected from phenyl groups substituted with 1 to 3 atoms selected from fluorine, chlorine and bromine.

10. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R3 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 44 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , said R3 can be optionally selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 substituted by one or more substituents in aryl or 5-12 membered heteroaryl; Preferably, R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl, 5-8 membered heteroaryl containing 1-3 N, O or S atoms or -NHC(O)R 33 , said R3 can be optionally selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 5-8 membered heteroaryl; More preferably, R3 is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 3 alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl, 5-8 membered heteroaryl containing 1-3 N, O or S atoms or -NHC(O)R 33 , wherein R3 can be optionally selected from one of hydroxy, fluorine, chlorine, bromine, oxo, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, cyclopropyl or cyclobutyl. substituted with multiple substituents; Alternatively, any two R3 atoms form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents; Preferably, any two R3 and the atoms to which they are connected form a C 3-12 Cycloalkyl, 3-12 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 membered heteroaryl containing 1-3 N, O or S atoms, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 N, O, S atoms, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 is substituted with one or more substituents.

11. The compound according to any one of claims 6 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 44 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-12 Aryl or 5-12 membered heteroaryl, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 substituted by one or more substituents in aryl or 5-12 membered heteroaryl; Preferably, R 44 Selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-12 Aryl or 5-12 membered heteroaryl containing 1-3 N, O or S atoms, optionally selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, 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 containing 1-3 N, O or S atoms, C 6-10 substituted by one or more substituents in aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms; More preferably, R 44 Selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, optionally substituted with one or more of deuterium, hydroxy, fluorine, chlorine, bromine, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloromethyl, 1,2-difluoroethyl or 1,2-dichloroethyl; More preferably, R 44 Selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, Optionally substituted with one or more of deuterium, hydroxy, fluorine, chlorine, bromine, cyano, amino, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, 1-fluoromethyl, 1-chloromethyl, 1,2-difluoroethyl or 1,2-dichloroethyl.

12. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R 11 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy or C 1-6 Hydroxyalkyl, preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 3 alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 hydroxyalkyl, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl or chloroethyl; R 22 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy or C 1-6 Hydroxyalkyl, preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 3 alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or C 1-3 hydroxyalkyl, more preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl or chloroethyl; R 33 Each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-6 Alkyl S(O)2-, C 1-6 Alkyl S(O)-, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, aminocarbonyl, carbonylamino, C 1-6 Alkylaminocarbonyl, C 1-6 Alkylcarbonylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted with aryl or 5-10 membered heteroaryl; Preferably, R 33 Each independently selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-9 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkyl S(O)2-, C 1-3 Alkyl S(O)-, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkylaminocarbonyl Base, C 1-3 Alkylcarbonylamino, aminocarbonyl, carbonylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 substituted with aryl or 5-8 membered heteroaryl; More preferably, R 33 Each independently selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-9 membered heteroaryl containing 1-3 N, O or S atoms, optionally further substituted by deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-3 Alkyl S(O)2-, C 1-3 Alkyl S(O)-, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Halogenated alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylaminocarbonyl, C 1-3 Alkylcarbonylamino, aminocarbonyl, carbonylamino, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 substituted with aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms; More preferably, R 33 Each independently selected from cyclopropyl, cyclobutyl, Optionally, the alkyl radicals may be further substituted with deuterium, fluorine, chlorine, bromine, nitro, hydroxyl, mercapto, cyano, amino, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, fluoromethyl, fluoroethyl, chloromethyl, chloroethyl, aminocarbonyl, carbonylamino, cyclopropyl, cyclobutyl, cyclohexyl, carboxyl, aminosulfonyl, aminosulfinyl, methylaminocarbonyl, methylcarbonylamino, methyl S(O)2-, methyl S(O)-, cyclopropyl, cyclobutyl, is substituted by one or more substituents.

13. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound structure is as follows:

14. A method for preparing the compound of formula (ID-IV) according to claim 6, its stereoisomers or pharmaceutically acceptable salts thereof, comprising the following steps: The compound of formula (ID-IV-a), its stereoisomer or a pharmaceutically acceptable salt thereof, is subjected to cyclization, dehydroxylation, reduction, amidation and deprotection to obtain the compound of formula (IC-II), its stereoisomer or a pharmaceutically acceptable salt thereof; in, R d2 or R d3 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl or -(CH2) n C(O)NR e2 (CH2) n1 R e1 , the R d2 or R d3 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 deuterium alkyl, C 1-6 Halogenated alkyl, 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 substituted by one or more substituents in aryl or 5-12 membered heteroaryl; Or, R d2 and R d3 Together they form an oxo group or a thio group; Preferably, R d2 or R d3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl or -(CH2) n C(O)NR e2 (CH2) n1 R e1 , the R d2 or R d3 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 One or more substituents in the alkyl group; Or, R d2 and R d3 Together they form an oxo group or a thio group; R e1 or R e2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms, wherein R e1 or R e2 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 5-8 membered heteroaryl; Preferably, R e1 or R e2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, cyano substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms, wherein R e1 or R e2 Optionally, it may be selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 5-8 membered heteroaryl; P G is a leaving group, preferably a hydroxyl group or an ester group; R d is an amino protecting group; preferably tert-butyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyl, tert-butyloxycarbonyl, Troc, 9-fluorenylmethoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, toluenesulfonyl or nitrobenzenesulfonyl.

15. A compound represented by general formula (II) or (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, X1, X2, X3, X4 are each independently selected from CR4 or N; R4 are each independently selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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, -C 2-3 Alkenyl R 22 、-C 2-3 Alkynyl R 22 、-C 2-3 Alkenyl R 33 、-C 2-3 Alkynyl R 33 、-C 2-3 Alkenyl R 22 R 33 、-C 2-3 Alkynyl R 22 R 33 、-(CH2) n O(CH2) n1 R 22 、-(CH2) n O(CH2) n1 R 33 、-(CH2) n NR 11 (CH2) n1 R 22 、-(CH2) n NR 11 (CH2) n1 R 33 、-(CH2) n NR 22 R 33 、 -(CH2) n C(O)NR 22 R 33 、-(CH2) n R 33 、-(CH2) n R 22 、-(CH2) n R 22 R 33 、-(CH2) n NR 11 C(O)(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 22 、-(CH2) n NR 11 C(O)O(CH2) n1 R 33 、-(CH2) n O(CH2) n1 C(O)R 22 、-(CH2) n NR 11 S(O)2(CH2) n1 R 22 、-(CH2) n C(O)(CH2) n1 R 33 、-(CH2) n OC(O)(CH2) n1 R 33 、-(CH2) n NR 22 C(O)(CH2) n1 R 33 、-(CH2) n S(O)(CH2) n1 R 33 、-(CH2) n S(O)2(CH2) n1 R 33 、-(CH2) n OS(O)2(CH2) n1 R 33 or -(CH2) n NR 22 S(O)2(CH2) n1 R 33 , optionally substituted by hydroxy, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 substituted with one or more substituents of a deuterated alkyl group; R 11 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy or C 1-6 hydroxyalkyl; R 22 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1- 6-halogenated alkoxy or C 1-6 hydroxyalkyl; R 33 Each independently selected from C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with deuterium, halogen, nitro, hydroxyl, mercapto, cyano, amino, carboxyl, aminosulfonyl, aminosulfinyl, C 1-6 Alkyl S(O)2-, C 1-6 Alkyl S(O)-, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, aminocarbonyl, carbonylamino, C 1-6 Alkylaminocarbonyl, C 1-6 Alkylcarbonylamino, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted with aryl or 5-10 membered heteroaryl; R a 、R b or R c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or cyano substituted C 1-6 Alkyl, the R a 、R b or R c Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 One or more substituents in the alkyl group; R d is an amino protecting group; R d2 or R d3 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 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl or -(CH2) n C(O)NR e2 (CH2) n1 R e1 , the R d2 or R d3 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 substituted by one or more substituents in aryl or 5-12 membered heteroaryl; Or, R d2 and R d3 Together they form an oxo group or a thio group; R e1 or R e2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, cyano substituted C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms, wherein R e1 or R e2 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 5-8 membered heteroaryl; R d4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkylamino, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl or cyano substituted C 1-6 Alkyl, the R d4 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 One or more substituents in the alkyl group; n is an integer from 0 to 3; and n1 is an integer from 0 to 3.

16. The compound according to claim 15, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R a 、R b or R c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl, the R a 、R b or R c Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 One or more substituents in the alkyl group; Or, R d is selected from tert-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyl, tert-butoxycarbonyl, Troc, 9-fluorenylmethoxycarbonyl, acetyl, benzoyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, toluenesulfonyl or nitrobenzenesulfonyl; Or, R d2 or R d3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl or -(CH2) n C(O)NR e2 (CH2) n1 R e1 , the R d2 or R d3 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 One or more substituents in the alkyl group; Or, R d2 and R d3 Together they form an oxo group or a thio group; Or, R e1 or R e2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkylamino, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, cyano substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 aryl or 5-8 membered heteroaryl containing 1-3 N, O or S atoms, wherein R e1 or R e2 Optionally, it may be selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl or 5-8 membered heteroaryl; Or, R d4 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1-3 Alkyl, the R d4 Optionally, it may be selected from deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkylamino, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or cyano substituted C 1- 3. One or more substituents in the alkyl group; n is an integer from 0 to 3; and n1 is an integer from 0 to 3.

17. The compound according to claim 15 or 16, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound structure is as follows:

18. A pharmaceutical composition comprising a therapeutically effective dose of a compound of the general formula as shown in any one of claims 1 to 13, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

19. Use of the compound of any one of claims 1 to 13, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 18 in the preparation of a medicament for treating diseases associated with PI3Kα.

20. Use of a compound of the formula shown in any one of claims 1 to 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the preparation of a pharmaceutical composition for treating cancer, PROS, 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, and multiple myeloma; more preferably, clear cell ovarian cancer or breast cancer.

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