Heterocyclic derivatives, preparation methods thereof and medical uses thereof

Abstract

The present invention relates to heterocyclic derivatives, methods for preparing the same, and their use in medicine. Specifically, the present invention relates to a heterocyclic derivative represented by the general formula (A-I) or (A-II), a method for preparing the same, and their use as therapeutic agents, particularly as KRas G12D inhibitors. The definitions of the substituents in the general formula (A-I) or (A-II) are the same as those in the specification.

Description

Technical Field

[0001] The present invention relates to a heterocyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and use of the derivative as a therapeutic agent, in particular as a K-Ras GTPase inhibitor. Background Art

[0002] RAS represents a group of closely related monomeric globular proteins (21kDa molecular weight) with 189 amino acids and is attached to the plasma membrane and binds GDP or GTP. Under normal development or physiological conditions, RAS receives growth factors and various other extracellular signals and is activated, responsible for regulating functions such as cell growth, survival, migration and differentiation. RAS acts as a molecular switch, and the on / off state of the RAS protein is determined by nucleotide binding, with the active signaling conformation binding GTP and the inactive conformation binding GDP. When RAS contains bound GDP, it is in a dormant or static or closed state and is "inactive". When cells are exposed to certain growth-promoting stimuli and respond, RAS is induced to convert the bound GDP into GTP. With GTP bound, RAS is "on" and can interact with other proteins and activate other proteins (its "downstream targets"). The RAS protein itself has a very low inherent ability to hydrolyze GTP back to GDP and thereby turn itself into a closed state. Switching RAS off requires exogenous proteins called GTPase-activating proteins (GAPs), which interact with RAS and greatly enhance the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAPs or convert GTP back to GDP will result in prolonged activation of the protein and, therefore, prolonged signals to the cell telling it to continue growing and dividing. These signals then cause cells to grow and divide, and overactive RAS signaling may ultimately lead to cancer.

[0003] Structurally, the RAS protein contains a G domain that is responsible for the enzymatic activity of RAS - guanine nucleotide binding and hydrolysis (GTPase reaction), which also includes a C-terminal extension region called the "CAAX box", which can be post-translationally modified and targets the protein to the membrane. The G domain is approximately 21-25 kDa in size and contains a phosphate binding loop (P-loop). The P-loop represents the pocket in the protein that binds nucleotides, and this is a rigid part of the domain with conserved amino acid residues that are necessary for nucleotide binding and hydrolysis (glycine-12, threonine-26, and lysine-16). The G domain also contains the so-called switch I region (residues 30-40) and switch II region (residues 60-76), both of which are dynamic parts of the protein and are often referred to as a "spring-loaded" mechanism due to the ability of this dynamic part to switch between resting and loaded states. The main interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the γ-phosphate of GTP, which allows the switch I region and switch II region, respectively, to maintain their active conformations. Following hydrolysis of GTP and release of phosphate, both relax into the inactive GDP conformation.

[0004] Among RAS family members, oncogenic mutations are most common in KRAS (85%), while NRAS (12%) and HRAS (3%) are less common. KRAS mutations are prevalent in the three most lethal cancer types in the United States: pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (25%). KRAS mutations are also found in other cancer types, including multiple myeloma, uterine cancer, bile duct cancer, gastric cancer, bladder cancer, diffuse large B-cell lymphoma, rhabdomyosarcoma, squamous cell carcinoma of the skin, cervical cancer, and testicular germ cell cancer. They are rarely found in breast cancer, ovarian cancer, and brain cancer (<2%). In non-small cell lung cancer (NSCLC), KRAS G12C is the most common mutation, accounting for nearly half of all KRAS mutations, followed by G12V and G12D. In non-small cell lung cancer, the increased frequency of specific allele mutations mostly comes from classic smoking-induced mutations (G:C to T:A substitutions), resulting in KRAS G12C (GGT to TGT) and G12V (GGT to GTT) mutations.

[0005] Large-scale genomic studies have shown that lung cancer KRAS mutations, including G12C, are mutually exclusive with other known driver oncogenic mutations in NSCLC, including EGFR, ALK, ROS1, RET, and BRAF, indicating the uniqueness of KRAS mutations in lung cancer. At the same time, KRAS mutations often occur together with certain co-mutations, such as STK11, KEAP1, and TP53, which cooperate with mutant RAS to transform cells into highly malignant and invasive tumor cells.

[0006] The three RAS oncogenes constitute the most frequently mutated gene family in human cancers. Disappointingly, despite more than three decades of research efforts, there are still no effective anti-RAS therapies available clinically, and targeting these genes with small molecules is challenging. Therefore, there is an urgent need in the art for small molecules that target RAS (e.g., K-RAS, H-RAS, and / or N-RAS) and utilize them to treat a variety of diseases, such as cancer.

[0007] Currently, there is intense competition for the clinical development of KRas G12D inhibitors both domestically and internationally. Among them, MRTX-1133, a KRas G12D inhibitor developed by Mirati Therapeutics Inc., has entered the preclinical stage for the treatment of colorectal cancer, non-small cell lung cancer, and pancreatic cancer. Currently, there are only a few publicly available patent applications for KRas G12D inhibitors, including WO2021041671 from Mirati Therapeutics Inc. While some progress has been made in the research and application of KRas G12D inhibitors, significant room for improvement remains, and continued research and development of new KRas G12D inhibitors is necessary. Summary of the Invention

[0008] The object of the present invention is to provide a compound represented by the general formula (AI) or (A-II), or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0009]

[0010] in:

[0011] Select from single or double bonds as needed so that each atom connected thereto assumes a normal valence state;

[0012] Ring A is independently selected from a 5- to 6-membered heteroaryl group or a 5- to 10-membered monocyclic heterocyclic group; preferably a 6- to 7-membered monocyclic heterocyclic group; wherein the heteroaryl group or the monocyclic heterocyclic group contains one or more N or O atoms;

[0013] Ring B is each independently selected from an aryl group, a heteroaryl group or a fused ring;

[0014] Ring C is independently selected from a 6- to 8-membered heterocyclic group containing 2 nitrogen atoms;

[0015] Q 1 Select N or CR a ;Q 1 Preferably N;

[0016] Q 2 Each independently selected from N, C or CR a ;

[0017] Y is each independently selected from a bond, O or NR b ;

[0018] X 1 、X 2 Each independently selected from N, C=O, CR c or CR d R e ;

[0019] E is independently selected from hydrogen atom or

[0020] R a are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl, an alkoxy or a cyano group; wherein the alkyl or alkoxy group is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl, a cyano group, an alkyl or an alkoxy group;

[0021] R b is selected from a hydrogen atom or an alkyl group;

[0022] R c is selected from hydrogen, halogen, cyano, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; R c Preferably halogen, more preferably fluorine or chlorine;

[0023] R d and R e are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group or an alkoxy group; wherein the alkyl group or alkoxy group is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl group, a cyano group, an alkyl group or an alkoxy group;

[0024] Or, R d and R e Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group; preferably a cyclopropyl group;

[0025] R f is selected from a hydrogen atom or a cycloalkyl group, wherein the cycloalkyl group is preferably a cyclopropyl group;

[0026] R 1 Each independently selected from hydrogen, -L-alkyl, -L-halogen, -L-OR 5 、-L-NR 6 R 7 、-LC(O)OR 5 、-LC(O)NR 6 R 7, -L-cycloalkyl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-fused ring or wherein the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or fused ring is optionally further substituted with one or more selected from R g substituted by a substituent;

[0027] R g the same or different, each independently selected from alkyl, halogen, benzyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NHC(O)NR 6 R 7 、-NHC(=NH)NR 6 R 7 、-OC(O)NR 6 R 7 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5 wherein the alkyl, benzyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more groups selected from alkyl, halogen, haloalkyl, hydroxyalkyl, benzyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 5 、-OSi(R 5 )3, -C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NHC(O)NR 6 R 7 、-NHC(=NH)NR 6 R 7 、-OC(O)NR 6 R 7 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R7 、-NHS(O) r R 5 or -S(O) r R 5 substituted by a substituent;

[0028] L is independently selected from a bond or C1-C6 alkylene, wherein the alkylene is optionally further substituted by one or more R D replaced by;

[0029] R D are each independently selected from a hydrogen atom, a halogen, a hydroxyl group or a hydroxymethyl group;

[0030] Alternatively, two R attached to the same carbon atom D Together with the carbon atom to which it is attached, it forms a cycloalkyl group; preferably a cyclopropyl group;

[0031] R 2 are the same or different, each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group or an alkoxy group, preferably a hydrogen atom or an alkyl group;

[0032] Or, any two R 2 together with the atoms to which they are attached, form a cycloalkyl or heterocyclyl group;

[0033] R 3 are the same or different and are independently selected from hydrogen, halogen, alkyl, alkoxy or =O; wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; R 3 Preferably, it is a hydrogen atom, a methyl group or =O;

[0034] R 4 are each independently selected from hydrogen, alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more groups selected from alkyl, halogen, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5 substituted by a substituent;

[0035] R 5 Each is independently selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2R 8 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0036] R 6 and R 7 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from R h substituted by a substituent;

[0037] R h the same or different, each independently selected from hydroxy, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 8 、-C(O)R 8、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 wherein the alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally further substituted by one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0038] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(O) r , and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-CH2NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0039] R 8 、R 9 and R 10Each is independently selected from hydrogen, halogen, alkyl, amino, cycloalkyl, heterocyclyl, benzyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, benzyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, amino, cyano, alkyl, aminoalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate;

[0040] m is each independently selected from 0, 1, 2, 3 or 4;

[0041] n is each independently selected from 0, 1, 2 or 3;

[0042] k is each independently selected from 0, 1 or 2;

[0043] r is each independently selected from 0, 1 or 2.

[0044] The present invention provides a compound represented by the general formula (AI) or (A-II), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (I) or (II), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof:

[0045]

[0046] Among them: Ring A, Ring B, X 1 、X 2 , Y, Q 1 , Q 2 、R 1 、R 2 、R 3 、R 4 , m, n and k are as defined in the general formula (AI) or (A-II).

[0047] The present invention provides a compound represented by general formula (I) or (II), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III), (IV), (V), or (VI), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof:

[0048]

[0049]

[0050] Among them: Ring B, X 1 、X 2 , Y, Q 1 , Q 2 、R 1 、R 2 、R 3 、R 4, m and n are as defined in the general formula (AI) or (A-II).

[0051] The present invention provides a compound represented by the general formula (AI) or (A-II), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VII), (VIII), or (IX), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof:

[0052]

[0053] Among them: Ring B, X 1 、X 2 , Y, Q 1 , Q 2 、R 1 、R 2 、R 3 、R 4 , m and n are as defined in the general formula (AI) or (A-II).

[0054] The present invention provides a compound represented by the general formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0055] are all selected from double bonds;

[0056] Q 1 Selected from N;

[0057] Q 2 Selected from C;

[0058] X 1 、X 2 Each independently selected from N or CR c ;

[0059] R c It is selected from a hydrogen atom or a halogen, preferably a halogen, more preferably fluorine or chlorine.

[0060] The present invention provides a compound represented by the general formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0061] are all selected from double bonds;

[0062] Q 1 Selected from N;

[0063] Q 2 Selected from C;

[0064] X 1 Selected from CR c ;

[0065] X 2 Selected from N;

[0066] R c is selected from halogen, preferably fluorine or chlorine, more preferably fluorine.

[0067] The present invention provides a compound represented by the general formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0068] are all selected from single bonds;

[0069] X 1 、X 2 Each independently selected from CR d R e ;

[0070] R d and R e selected from hydrogen atoms;

[0071] Or, R d and R e Together with the carbon atom to which it is attached, it forms a 3-5 membered monocyclic cycloalkyl or a 3-5 membered monocyclic heterocyclic group; preferably a cyclopropyl group.

[0072] The present invention provides a compound represented by the general formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0073] X 2 Connected selected from double bonds;

[0074] X 1 and Q 2 between is selected from single bonds;

[0075] X 1 Selected from C=O;

[0076] X 2 Selected from N;

[0077] Q 2Selected from N.

[0078] The present invention provides a compound represented by the general formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0079] R 1 -L-heterocyclyl; wherein the heterocyclyl is optionally further substituted by one or more substituents selected from alkyl, halogen, alkoxy or =O; wherein the halogen is preferably fluorine;

[0080] L is selected from a bond or C1-C3 alkylene, wherein said alkylene is optionally further substituted by one or more R D replaced by;

[0081] R D are each independently selected from a hydrogen atom, a halogen, a hydroxyl group or a hydroxymethyl group;

[0082] Alternatively, two R attached to the same carbon atom D Together with the carbon atom to which it is attached, it forms a cycloalkyl group; preferably a cyclopropyl group.

[0083] The present invention provides a compound represented by the general formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0084] L is selected from a bond, -CH2-, -CH2CH2- or

[0085] The present invention provides a compound represented by the general formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from:

[0086]

[0087]

[0088]

[0089]

[0090]

[0091] The present invention provides a compound represented by the general formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy or =O; R 3 Preferred is a hydrogen atom, a methyl group or =O.

[0092] The present invention provides a compound represented by the general formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 4 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a halogen, an alkoxy group, an alkynyl group, a hydroxyl group, an amino group, a hydroxyalkyl group, a haloalkyl group or a haloalkoxy group; R 4 Preferred are hydrogen atom, methyl group, fluorine, chlorine, bromine, iodine, hydroxyl group, amino group, hydroxymethyl group or ethynyl group.

[0093] The present invention provides a compound represented by the general formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0094] Ring B is selected from phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, indolyl, indazolyl, benzothiazolyl, tetrahydronaphthyl,

[0095] Ring B is preferably naphthyl or benzothiazolyl.

[0096] The present invention provides a compound represented by the general formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0097] Selected from the following groups:

[0098]

[0099] The present invention provides a compound represented by general formula (I) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein:

[0100] Selected from the following groups:

[0101]

[0102] The present invention provides a compound represented by general formula (II), (IV), (V) or (VI) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein:

[0103] Selected from the following groups:

[0104]

[0105] The present invention provides a compound represented by general formula (VII), (VIII) or (IX) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein:

[0106] Selected from the following groups:

[0107]

[0108] Typical compounds of the present invention include, but are not limited to:

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0116] Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0117] In another aspect, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of Formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0118] In another aspect, the present invention provides a method for inhibiting KRas G12D enzyme, wherein the method comprises administering to a patient a pharmaceutical composition comprising an effective dose of a compound of Formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0119] The present invention also provides a use of a compound of formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., the pharmaceutical composition described in the aforementioned technical solution) in the preparation of a medicament for treating a disease mediated by a KRas G12D mutation, wherein the disease mediated by a KRas G12D mutation is selected from cancer, wherein the cancer is selected from cardiac myxoma, lung cancer, gastric cancer, colorectal cancer, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, bile duct cancer, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenal neuroblastoma, myeloid leukemia, acute lymphoblastic leukemia or glioblastoma, preferably pancreatic cancer, colorectal cancer, rectal cancer and lung cancer; wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

[0120] In another aspect, the present invention provides a compound of Formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition described in the aforementioned technical solution) for use in the preparation of a KRas G12D inhibitor.

[0121] Another aspect of the present invention relates to a method for preventing and / or treating a disease mediated by KRas G12D mutation, comprising administering to a patient a therapeutically effective dose of a compound of Formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same (e.g., the pharmaceutical composition described in the aforementioned technical solution). The disease mediated by KRas G12D mutation is selected from cancer, wherein the cancer is selected from cardiac myxoma, lung cancer, gastric cancer, colorectal cancer, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, bile duct cancer, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenal neuroblastoma, myeloid leukemia, acute lymphoblastic leukemia or glioblastoma, preferably pancreatic cancer, colorectal cancer, rectal cancer and lung cancer; wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

[0122] The present invention also provides a use of a compound of formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., the pharmaceutical composition described in the aforementioned technical solution) in the preparation of a medicament for treating cancer, wherein the cancer is selected from cardiac myxoma, lung cancer, gastric cancer, colorectal cancer, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, bile duct cancer, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenal neuroblastoma, myeloid leukemia, acute lymphoblastic leukemia or glioblastoma, preferably pancreatic cancer, colorectal cancer, rectal cancer and lung cancer; wherein the lung cancer is preferably non-small cell lung cancer or small cell lung cancer.

[0123] The present invention also provides a method for preventing and / or treating cancer, comprising administering to a patient a therapeutically effective dose of a compound of formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof (e.g., a pharmaceutical composition described in the aforementioned technical solution). The cancer is selected from cardiac myxoma, lung cancer, gastric cancer, colorectal cancer, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, bile duct cancer, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenal neuroblastoma, myeloid leukemia, acute lymphoblastic leukemia or glioblastoma, preferably pancreatic cancer, colorectal cancer, rectal cancer and lung cancer; wherein the lung cancer is preferably non-small cell lung cancer.

[0124] The pharmaceutical preparations of the present invention can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsules, intradermally, intraperitoneally, subcutaneously, subcutaneously, or by inhalation. The pharmaceutical compositions containing the active ingredient can be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Tablets contain the active ingredient and a nontoxic, pharmaceutically acceptable excipient suitable for tablet preparation in admixture.

[0125] The formulations of the present invention are suitably presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form can vary depending on the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form generally refers to the amount of compound that is capable of producing a therapeutic effect.

[0126] Dosage forms for topical or transdermal administration of the compounds of this invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0127] When the compounds of the present invention are administered to humans and animals in the form of medicines, the compounds can be provided alone or in the form of pharmaceutical compositions containing the active ingredient in combination with a pharmaceutically acceptable carrier, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient.

[0128] Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution. solution); (19) ethanol; (20) phosphate buffer solution; (21) cyclodextrins, such as targeting ligands attached to nanoparticles, such as Accurins™; and (22) other non-toxic compatible substances used in pharmaceutical formulations, such as polymer-based compositions.

[0129] Examples of pharmaceutically acceptable antioxidants include, but are not limited to: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and the like; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules, and the like) may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as Such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) dissolution retardants, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuran methanol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0130] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum oxide hydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0131] Ointments, pastes, creams and gels may contain, in addition to the active compounds, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0132] In addition to the active compound, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. The sprays may contain other customary propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, for example butane and propane.

[0133] Detailed Description of the Invention

[0134] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0135] "Bond" means that the indicated substituent does not exist and the two end portions of the substituent are directly linked to form a bond.

[0136] "Alkyl" when used as a group or a part of a group refers to a group comprising C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted.

[0137] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples of which include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl groups may be optionally substituted or unsubstituted.

[0138] "Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight chain or branched. 10 The alkynyl group of the present invention is substituted or unsubstituted. The alkynyl group of the present invention is substituted or unsubstituted.

[0139] "Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused, bridged, or spirocyclic carbon ring. 12Cycloalkyl, more preferably C3-C8 cycloalkyl, most preferably C3-C6 cycloalkyl. Examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl can be optionally substituted or unsubstituted.

[0140] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into single spiro, double spiro or multiple spiroalkyl groups, preferably single spiro and double spiroalkyl groups, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spiroalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0141] "Fused cycloalkyl" refers to an aromatic system with 5 to 18 members, containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but no ring has completely conjugated π electrons. It is preferably 6 to 12 members, and more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl or tetradecahydrophenanthrenyl.

[0142] "Bridged cycloalkyl" refers to an all-carbon polycyclic group with 5 to 18 members, containing two or more cyclic structures that share two non-directly connected carbon atoms. One or more rings may contain one or more double bonds, but none of the rings have completely conjugated π electrons. It is an aromatic system with preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, and (1r,5r)-bicyclo[3.3.2]decyl.

[0143] "Heterocyclyl," "heterocycle," or "heterocyclic" are used interchangeably herein and refer to non-aromatic heterocyclic groups in which one or more of the ring atoms is a heteroatom, such as oxygen, nitrogen, or sulfur, and include monocyclic, fused, bridged, and spirocyclic rings. Preferably, the ring has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bi- or tricyclic ring, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, piperidinyl, 2-oxopiperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, and piperazinyl. Heterocyclyl groups may be substituted or unsubstituted.

[0144] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between rings, spirocycloalkyl is divided into single spiro heterocyclyl, double spiro heterocyclyl or multiple spiro heterocyclyl, preferably single spiro heterocyclyl and double spiro heterocyclyl. More preferably, it is 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered single spiro heterocyclyl. Non-limiting examples of "spiro heterocyclyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.

[0145] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are 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, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin or

[0146] "Bridged heterocyclic group" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more ring structures that share two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl.

[0147] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, aryl is C6-C 10 The aryl group is more preferably phenyl and naphthyl, and most preferably naphthyl. The aryl group may be substituted or unsubstituted.

[0148] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Preferably, it is a bicyclic heteroaryl. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl,

[0149]

[0150] Heteroaryl groups can be substituted or unsubstituted.

[0151] "Fused ring" refers to a polycyclic group in which two or more ring structures share a pair of atoms, one or more rings may contain one or more double bonds, but at least one ring does not have a completely conjugated π-electron aromatic system, wherein the ring atoms are selected from 0, one or more selected from nitrogen, oxygen or S(O) r(wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl and a monocyclic heterocyclyl or monocyclic cycloalkyl. Preferably, it includes 7 to 14 members, more preferably 8 to 10 members. Examples of "fused rings" include but are not limited to:

[0152]

[0153] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0154] "Haloalkyl" refers to an alkyl group optionally further substituted with one or more halogens, wherein alkyl is as defined herein.

[0155] "Hydroxyalkyl" refers to an alkyl group optionally further substituted with one or more hydroxy groups, wherein alkyl is as defined herein.

[0156] "Aminoalkyl" refers to an alkyl group optionally further substituted with one or more amino groups, wherein alkyl is as defined herein.

[0157] "Hydroxymethyl" refers to a methyl group optionally further substituted with one or more hydroxy groups.

[0158] "Haloalkoxy" refers to an alkyl group (alkyl-O-) optionally further substituted with one or more halogens, wherein alkoxy is as defined herein.

[0159] "Hydroxy" refers to an -OH group.

[0160] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0161] "Amino" refers to -NH2.

[0162] "Cyano" refers to -CN.

[0163] "Nitro" refers to -NO2.

[0164] "Benzyl" refers to -CH2-phenyl.

[0165] "Carboxyl" refers to -C(O)OH.

[0166] "Carboxylate" refers to a -C(O)O-alkyl group or a -C(O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

[0167] "DMSO" refers to dimethyl sulfoxide.

[0168] "BOC" refers to tert-butoxycarbonyl.

[0169] "Ts" refers to p-toluenesulfonyl.

[0170] "T3P" refers to propylphosphonic anhydride.

[0171] "DPPA" refers to diphenylphosphoryl azide.

[0172] "DEA" refers to diethylamine.

[0173] "X-PHOS Pd G2" chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0174] "MOM" refers to methoxymethyl.

[0175] "TBS" refers to tert-butyldimethylsilyl.

[0176] "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.

[0177] As used herein, "substituted" or "substituted", unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5 substituted by a substituent;

[0178] R 5is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0179] R 6 and R 7 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0180] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(O) r , and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0181] R 8 、R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0182] r is 0, 1, or 2.

[0183] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0184] Unless otherwise indicated, structures depicted herein also encompass all isomers (e.g., diastereoisomers, enantiomers, and atropisomers, and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the present compounds are within the scope of the invention.

[0185] "Pharmaceutically acceptable salts" refer to salts of the compounds described above that retain their biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by Formula (AI), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX) may include metal salts or amine salts formed with suitable acids.

[0186] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0187] Synthesis method of the compound of the present invention

[0188] In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0189] The method for preparing the compound of general formula (I) of the present invention or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof comprises the following steps:

[0190]

[0191] The compound of general formula (IA) and the compound of general formula (IB) undergo Suzuki coupling reaction in the presence of a palladium catalyst and an alkaline reagent to obtain a compound of general formula (IC); the compound of general formula (IC) is further deprotected to obtain a compound of general formula (I);

[0192] in:

[0193] X is a leaving group, preferably chlorine;

[0194] PG is a protecting group, preferably tert-butoxycarbonyl;

[0195] M is selected from -B(OH)2, -BF3K or

[0196] Ring A, Ring B, R 1 ~R 4 、X 1 、X 2 , Q 1 , Q 2 , Y, k, m and n are as defined in the general formula (I).

[0197] The method for preparing the compound of general formula (II) of the present invention or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof comprises the following steps:

[0198]

[0199] The compound of general formula (IIA) and the compound of general formula (IB) undergo Suzuki coupling reaction in the presence of a palladium catalyst and an alkaline reagent to obtain a compound of general formula (IIC); the compound of general formula (IIC) is further deprotected to obtain a compound of general formula (II);

[0200] in:

[0201] X is a leaving group, preferably chlorine;

[0202] PG is a protecting group, preferably tert-butoxycarbonyl;

[0203] M is selected from -B(OH)2, -BF3K or

[0204] Ring A, Ring B, R 1 ~R4 、X 1 、X 2 , Q 2 , Y, k, m and n are as defined in the general formula (II). DETAILED DESCRIPTION

[0205] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0206] Example

[0207] The examples provide the preparation of representative compounds represented by general formula (I) and (II) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 HNMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0208] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0209] 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.

[0210] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0211] In the following examples, unless otherwise specified, all temperatures are in degrees Celsius. Unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification, unless otherwise specified. Commercial manufacturers include but are not limited to Shanghai Haohong Biotechnology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd., San Chemical Technology (Shanghai) Co., Ltd. and Shanghai Lingkai Pharmaceutical Technology Co., Ltd.

[0212] CD3OD: deuterated methanol.

[0213] CDCl3: deuterated chloroform.

[0214] DMSO-d6: deuterated dimethyl sulfoxide.

[0215] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0216] The compound is purified using an eluent system for column chromatography and thin-layer chromatography, wherein the system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate system; D: dichloromethane and ethanol system, wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, may also be added to adjust the conditions.

[0217] Room temperature: 20℃~30℃.

[0218] Example 1

[0219] 4-(2-chloro-4-fluoro-8,9,10,11-tetrahydropyrazino[1',2':1,2]imidazo[4,5-c]quinolin-3-yl)-5,7-difluorobenzo[d]thiazol-2-amine

[0220] 4-(2-chloro-4-fluoro-8,9,10,11-tetrahydropyrazino[1',2':1,2]imidazo[4,5-c]quinolin-3-yl)-5,7-difluorobenzo[d]thiazol-2-amine

[0221]

[0222]

[0223] first step

[0224] tert-butyl(2-((7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-yl)amino)ethyl)carbamate

[0225] tert-Butyl (2-((7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-yl)amino)ethyl)carbamate

[0226] 7-Bromo-4,6-dichloro-8-fluoro-3-nitroquinoline 1a (500 mg, 1.47 mmol, prepared according to patent publication WO2019110751A1) and tert-butyl (2-aminoethyl)carbamate 1b (282.79 mg, 1.77 mmol) were added to acetonitrile (8.54 mL), cooled to 0°C, N,N-diisopropylethylamine (570.29 mg, 4.41 mmol, 729.27 μL) was added, and the reaction was allowed to react at room temperature overnight. The reaction solution was extracted with ethyl acetate (100 mL × 1), and the organic phase was washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give tert-butyl (2-((7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-yl)amino)ethyl)carbamate 1c (680 mg, 1.47 mmol) with a yield of 99.70%. The product was directly used for the next reaction without purification.

[0227] LCMS:463.0[M+1] +

[0228] Step 2

[0229] tert-butyl(2-((3-amino-7-bromo-6-chloro-8-fluoroquinolin-4-yl)amino)ethyl)carbamate

[0230] Tert-butyl (2-((7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-yl)amino)ethyl)carbamate 1c (680 mg, 1.47 mmol), iron powder (409.52 mg, 7.33 mmol) and ammonium chloride (392.22 mg, 7.33 mmol) were added to a mixed solvent of methanol (10 mL) and water (2 mL) and heated under reflux for 4 hours. The reaction solution was filtered while hot, and the filter cake was washed with methanol (20 mL). The filtrate was vortexed to remove methanol and then extracted with ethyl acetate (100 mL × 1). The organic phase was washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give tert-butyl (2-((3-amino-7-bromo-6-chloro-8-fluoroquinolin-4-yl)amino)ethyl)carbamate 1d (636 mg, 1.47 mmol) with a yield of 100.00%. The product was directly used for the next step without purification.

[0231] LCMS:433.0[M+1] +

[0232] Step 3

[0233] tert-butyl (2-(7-bromo-8-chloro-2-(chloromethyl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate

[0234] tert-Butyl (2-(7-bromo-8-chloro-2-(chloromethyl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate

[0235] Tert-butyl (2-((3-amino-7-bromo-6-chloro-8-fluoroquinolin-4-yl)amino)ethyl)carbamate 1d (300 mg, 691.72 μmol) was added to dichloromethane (5 mL), and triethylamine (139.99 mg, 1.38 mmol) was added dropwise. A dichloromethane solution (2 mL) of 2-chloroacetyl chloride (156.25 mg, 1.38 mmol) was added dropwise at room temperature. The reaction was continued at room temperature overnight. LCMS analysis showed that many intermediates had not been ring-closed. The reaction solution was extracted with dichloromethane (50 mL × 1), and the organic phase was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and concentrated. The obtained residue was added to acetic acid (5 mL), heated to 50°C for 2 hours, and the reaction solution was cooled to room temperature. The system was adjusted to alkaline with saturated sodium carbonate solution, extracted with ethyl acetate (100 mL×1), and the organic phase was washed with saturated brine (100 mL×1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain the product (tert-butyl 2-(7-bromo-8-chloro-2-(chloromethyl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate 1e (190 mg, 386.05 μmol) with a yield of 57.58%.

[0236] LCMS:492.7[M+1] +

[0237] Step 4

[0238] 2-(7-bromo-8-chloro-2-(chloromethyl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)ethan-1-amine

[0239] 2-(7-Bromo-8-chloro-2-(chloromethyl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)ethan-1-amine

[0240] Tert-butyl (2-(7-bromo-8-chloro-2-(chloromethyl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl)carbamate 1e (190 mg, 386.05 μmol) was added to dichloromethane (4 mL), followed by a 4M solution of hydrogen chloride in dioxane (2 mL). The mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to afford 2-(7-bromo-8-chloro-2-(chloromethyl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)ethan-1-amine 1f (151 mg, 385.15 μmol) in a 99.77% yield. The product was directly used in the next step without purification.

[0241] LCMS: 393.0[M+1] +

[0242] Step 5

[0243] 3-bromo-2-chloro-4-fluoro-8,9,10,11-tetrahydropyrazino[1',2':1,2]imidazo[4,5-c]quinolone

[0244] 3-Bromo-2-chloro-4-fluoro-8,9,10,11-tetrahydropyrazino[1',2':1,2]imidazo[4,5-c]quinoline

[0245] 2-(7-Bromo-8-chloro-2-(chloromethyl)-6-fluoro-1H-imidazo[4,5-c]quinolin-1-yl)ethan-1-amine 1f (151 mg, 385.15 μmol), potassium iodide (6.39 mg, 38.52 μmol) and potassium carbonate (106.46 mg, 770.30 μmol) were added to acetonitrile (5 mL) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (100 mL × 1), and the organic phase was washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g (136 mg, 382.46 μmol) of 3-bromo-2-chloro-4-fluoro-8,9,10,11-tetrahydropyrazino[1',2':1,2]imidazo[4,5-c]quinoline with a yield of 99.30%. The product was directly used for the next reaction without purification.

[0246] LCMS: 355.0[M+1] +

[0247] Step 6

[0248] tert-butyl 3-bromo-2-chloro-4-fluoro-10,11-dihydropyrazino[1',2':1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate

[0249] tert-Butyl 3-bromo-2-chloro-4-fluoro-10,11-dihydropyrazino[1',2':1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate

[0250] 3-Bromo-2-chloro-4-fluoro-8,9,10,11-tetrahydropyrazino[1',2':1,2]imidazo[4,5-c]quinoline 1g (136 mg, 382.46 μmol), triethylamine (77.40 mg, 764.92 μmol), and di-tert-butyl dicarbonate (100.17 mg, 458.95 μmol) were added to dichloromethane (5 mL) and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain the product, tert-butyl 3-bromo-2-chloro-4-fluoro-10,11-dihydropyrazino[1',2':1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate 1h (140 mg, 307.21 μmol), in a yield of 80.33%.

[0251] LCMS:456.8[M+1] +

[0252] Step 7

[0253] tert-butyl 3-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)-2-chloro-4-fluoro-10,11-dihydropyrazino[1',2':1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate

[0254] tert-Butyl 3-(2-((tert-Butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)-2-chloro-4-fluoro-10,11-dihydropyrazino[1',2':1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate

[0255] (2-((tert-Butyloxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)boronic acid 1i (152.12 mg, 460.82 μmol, prepared according to patent US20200115375A1), tert-butyl 3-bromo-2-chloro-4-fluoro-10,11-dihydropyrazino[1',2':1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate 1h (140 mg, 307.21 μmol), sodium carbonate (65.13 mg, 614.43 μmol) and tetrakistriphenylphosphine palladium (35.50 mg, 30.72 μmol) were added to a mixed solution of dioxane (4 mL) and water (1 mL), protected by argon, and heated to 110 ° C for overnight reaction. The reaction solution was cooled and extracted with ethyl acetate (100 mL × 1). The organic phase was washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give the product 3-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)-2-chloro-4-fluoro-10,11-dihydropyrazino[1',2':1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylic acid tert-butyl ester 1j (100 mg, 151.26 μmol) in a yield of 49.24%.

[0256] LCMS: 660.8[M+1] +

[0257] Step 8

[0258] 4-(2-chloro-4-fluoro-8,9,10,11-tetrahydropyrazino[1',2':1,2]imidazo[4,5-c]quinolin-3-yl)-5,7-difluorobenzo[d]thiazol-2-amine

[0259] 4-(2-chloro-4-fluoro-8,9,10,11-tetrahydropyrazino[1',2':1,2]imidazo[4,5-c]quinolin-3-yl)-5,7-difluorobenzo[d]thiazol-2-amine

[0260] Tert-butyl 3-(2-((tert-Butyloxycarbonyl)amino)-5,7-difluorobenzo[d]thiazol-4-yl)-2-chloro-4-fluoro-10,11-dihydropyrazino[1',2':1,2]imidazo[4,5-c]quinoline-9(8H)-carboxylate 1j (100 mg, 151.26 μmol) was added to dichloromethane (5 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 M, 3 mL) was added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the system was adjusted to alkaline with saturated sodium carbonate solution, extracted with ethyl acetate (100 mL × 1), the organic phase was washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product 4-(2-chloro-4-fluoro-8,9,10,11-tetrahydropyrazino[1',2':1,2]imidazo[4,5-c]quinolin-3-yl)-5,7-difluorobenzo[d]thiazol-2-amine (45 mg, 88.66 μmol) with a yield of 58.61%.

[0261] LCMS:461.0[M+1]

[0262] Example 2

[0263] 5-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,1 1,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl)naphthalen-2-ol

[0264] 5-Fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl)naphthalen-2-ol

[0265]

[0266]

[0267] first step

[0268] 2-amino-4-bromo-6-fluorobenzamide

[0269] 2-Amino-4-bromo-6-fluorobenzamide

[0270] 2-Amino-4-bromo-6-fluoro-benzonitrile 2a (4 g, 18.60 mmol, commercially available) was added to concentrated sulfuric acid (10 mL) and heated to 65°C for 3 hours. The reaction solution was cooled to room temperature and poured into ice water (100 mL). The pH was adjusted to alkaline with saturated aqueous sodium carbonate solution and extracted with ethyl acetate (100 mL × 1). The organic phase was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product 2-amino-4-bromo-6-fluorobenzamide 2b (4 g, 17.16 mmol) in a yield of 92.27%. The product was directly used in the next reaction without purification.

[0271] LCMS: 233.0[M+1] +

[0272] Step 2

[0273] 7-bromo-5-fluoroquinazoline-2,4-diol

[0274] 7-Bromo-5-fluoroquinazoline-2,4-diol

[0275] 2-Amino-4-bromo-6-fluorobenzamide 2b (1 g, 4.29 mmol) was added to acetonitrile (5 mL), followed by 4-dimethylaminopyridine (1.05 g, 8.58 mmol) and triphosgene (636.70 mg, 2.15 mmol). The reaction was allowed to react at room temperature for 4 hours, and the reaction was monitored for completion by LCMS. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to afford 7-bromo-5-fluoroquinazoline-2,4-diol 2c (400 mg, 1.54 mmol) in a 35.99% yield.

[0276] LCMS: 259.0[M+1] +

[0277] Step 3

[0278] 7-bromo-2,4-dichloro-5-fluoroquinazoline

[0279] 7-Bromo-2,4-dichloro-5-fluoroquinazoline

[0280] 7-Bromo-5-fluoroquinazoline-2,4-diol 2c (300 mg, 1.16 mmol) was added to acetonitrile (6 mL). Phosphorus oxychloride (4.43 g, 28.95 mmol) and N,N-diisopropylethylamine (1.50 g, 11.58 mmol) were added sequentially with stirring at room temperature. The reaction was heated to 80°C for 2 hours, and the reaction was complete after monitoring by LCMS. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product 7-bromo-2,4-dichloro-5-fluoroquinazoline 2d, which was directly used in the next reaction without purification.

[0281] Step 4

[0282] tert-butyl 4-(7-bromo-2-chloro-5-fluoroquinazolin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate

[0283] tert-Butyl 4-(7-bromo-2-chloro-5-fluoroquinazolin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate

[0284] Tert-butyl 3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate 2e (111.70 mg, 337.93 μmol, prepared according to patent WO2003051797) was added to dichloromethane (2 mL) and cooled to -40°C under argon protection. N,N-diisopropylethylamine (436.73 mg, 3.38 mmol) was added dropwise. The reaction solution was warmed to room temperature and stirred overnight. The next day, the reaction solution was cooled to -40°C again, N,N-diisopropylethylamine (436.73 mg, 3.38 mmol) was added dropwise, and then a fresh solution of 7-bromo-2,4-dichloro-5-fluoroquinazoline 2d (100 mg, 337.93 μmol) in dichloromethane (2 mL) was added dropwise. The reaction solution was warmed to room temperature and reacted overnight. The reaction was monitored for completion by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(7-bromo-2-chloro-5-fluoroquinazolin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate 2f (40 mg, 67.80 μmol) in a yield of 20.06%.

[0285] LCMS:589.0[M+1] +

[0286] Step 5

[0287] tert-butyl 4-(7-bromo-5-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate

[0288] tert-Butyl 4-(7-bromo-5-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate

[0289] 2 g (16.19 mg, 101.70 μmol, prepared according to patent WO2020146613) of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol was added to tetrahydrofuran (5 mL) under argon protection. Sodium hydride (4.07 mg, 169.49 μmol) was added and the temperature was lowered to 0 ° C for 30 minutes. Then, tert-butyl 4-(7-bromo-2-chloro-5-fluoroquinazolin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate 2f (40 mg, 67.80 μmol) was added and the temperature was raised to 70 ° C for overnight. The reaction was monitored by LCMS. The reaction solution was cooled to room temperature, and water (5 mL) was added to quench the reaction. The product was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(7-bromo-5-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate 2h (30 mg, 42.09 μmol) in a yield of 62.08%.

[0290] LCMS:713.0[M+1] +

[0291] Step 6

[0292] tert-butyl 5-bromo-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-carboxylate

[0293] tert-Butyl 5-bromo-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-carboxylate

[0294] Tert-butyl 4-(7-bromo-5-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylate 2h (55 mg, 77.17 μmol) was added to tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (40.35 mg, 154.33 μmol) was added, and the mixture was reacted at room temperature overnight. Water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give the product tert-butyl 5-bromo-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-carboxylate 2i (30 mg, 51.86 μmol) in a yield of 67.21%.

[0295] LCMS:578.0[M+1] +

[0296] Step 7

[0297] tert-butyl 5-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-carboxylate

[0298] tert-Butyl 5-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-carboxylate

[0299] 5-Bromo-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-carboxylic acid tert-butyl ester 2i (18 mg, 31.12 μmol) was added to a mixed solvent of 1,4-dioxane (1 mL) and water (0.2 mL) according to the reaction mixture. 2-(8-fluoro-3-methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2j (12.40 mg, 37.34 μmol, prepared according to patent WO2021041671A1), sodium carbonate (9.90 mg, 93.35 μmol) and tetrakis(triphenylphosphine)palladium (3.60 mg, 3.11 μmol) were added sequentially, protected by argon, and heated to 80 ° C for 2 hours. The reaction solution was cooled to room temperature, water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to give tert-butyl 5-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-carboxylate 2k (15 mg, 21.31 μmol) in a yield of 68.48%.

[0300] LCMS: 704.0[M+1]+

[0301] Step 8

[0302] 5-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,1 1,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl)naphthalen-2-ol

[0303] 5-Fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl)naphthalen-2-ol

[0304] tert-Butyl 5-(8-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8a,9,11,12-tetrahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazoline-10(8H)-carboxylate 2k (15 mg, 21.31 μmol) was added to acetonitrile (1 mL) and stirred. A solution of hydrogen chloride in 1,4-dioxane (4 M, 0.5 mL) was added and the mixture was reacted at room temperature for 3 hours. The reaction was monitored to completion by LCMS. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 5-fluoro-4-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-8,8a,9,10,11,12-hexahydropyrazino[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl)naphthalen-2-ol 2 (1 mg, 1.78 μmol) in a yield of 8.38%.

[0305] LCMS: 560.0[M+1] +

[0306] Biological evaluation

[0307] Test Example 1: Determination of the inhibitory activity of the compounds of the present invention on p-ERK1 / 2 in AGS cells

[0308] The following method was used to determine the inhibitory activity of the compounds of this invention against p-ERK1 / 2 in AGS (human gastric adenocarcinoma) cells. This method utilizes the Cisbio Advanced Phospho-ERK1 / 2 (Thr202 / Tyr204) Kit (Cat. No. 64AERPEH). For detailed experimental procedures, refer to the kit instructions. AGS cells (harboring the KRAS G12D mutation) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

[0309] The experimental procedure is briefly described as follows: AGS cells were cultured in F12K complete medium supplemented with 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. 40,000 AGS cells were plated per well in a 96-well plate in complete medium and incubated overnight at 37°C in a 5% CO2 incubator. The test compound was dissolved in DMSO to prepare a 10 mM stock solution and subsequently diluted in F12K complete medium. 100 μL of F12K complete medium containing the corresponding test compound concentration was added to each well. The final concentration of the test compound in the reaction system ranged from 1000 nM to 0.015 nM. After incubation for 3 hours in a cell culture incubator, the cell supernatant was discarded and the cells were washed with ice-cold PBS. 50 μL of 1× cell phospho / total protein lysis buffer (a component of the Advanced phospho-ERK1 / 2 kit) was added to each well for lysis. The 96-well plate was incubated on ice for half an hour. The lysate was then detected according to the instructions of the Advanced phospho-ERK1 / 2 (Thr202 / tyr204) kit. Finally, the fluorescence intensity of each well at 620 nm and 665 nm was measured on a microplate reader in TF-FRET mode under an excitation wavelength of 304 nm. The fluorescence intensity ratio of 665 / 620 was calculated for each well. The percentage inhibition rate of the test compound at each concentration was calculated by comparing the fluorescence intensity ratio with that of the control group (0.1% DMSO), and the IC value of the compound was obtained by nonlinear regression analysis using the test compound concentration logarithm-inhibition rate using GraphPad Prism5 software. 50 value.

[0310] The compounds of the present invention have a significant inhibitory effect on the activity of p-ERK1 / 2 in AGS cells. Preferably, the IC 50 <500 nM, more preferably, the IC 50 <200nM.

[0311] Test Example 2: Determination of the Inhibitory Effect of the Compounds of the Invention on AsPC-1 Cell Proliferation

[0312] The following method was used to determine the effects of the compounds of the present invention on the proliferation of AsPC-1 (human metastatic pancreatic adenocarcinoma) cells. AsPC-1 cells (containing the KRAS G12D mutation) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U penicillin, 100 μg / mL streptomycin, and 1 mM sodium pyruvate. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573).

[0313] The experimental method was performed according to the steps in the kit instructions, which are briefly described as follows: the test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample. The final concentration of the compound ranged from 1000nM to 0.015nM. Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 800 cells per well, cultured overnight in a 37°C, 5% CO2 incubator, and then the test compound was added and cultured for 120 hours. After the culture was completed, 50μL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes and then allowed to stand for 10 minutes. The luminescence value of each well of the sample was then read using the Luminescence mode on the microplate reader. The percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.3% DMSO). The nonlinear regression analysis of the compound concentration logarithm-inhibition rate was then performed in GraphPad Prism 5 software to obtain the IC value of the compound for inhibiting cell proliferation. 50 value.

[0314] The compounds of the present invention have a significant inhibitory effect on the proliferation of AsPC-1 cells. Preferably, the IC 50 <500 nM, more preferably, the IC 50 <200nM.

[0315] Test Example 3: Determination of the inhibitory ability of the compounds of the present invention on the interaction between KRAS G12D and RAF1 proteins

[0316] The following method is used to determine the ability of the compounds of the present invention to block the KRAS G12D:RAF1 protein interaction in vitro. This method uses the KRAS-G12C / SOS1 BINDING ASSAY KITS kit (63ADK000CB21PEG) from Cisbio. For detailed experimental procedures, refer to the kit instructions.

[0317] The experimental process is briefly described as follows: Use diluent buffer (product number 62DLBDDF) to prepare Tag1-RAF1 and Tag2-KRAS-G12D proteins at a working concentration of 5X for later use. The test compound is dissolved in DMSO to prepare a 10mM stock solution, and then diluted with diluent buffer for later use. First, add 2μL of the test compound to the well (the final concentration of the reaction system is 10000nM-0.1nM), followed by adding 4μL of Tag1-RAF1 5X working solution and 4μL of Tag2-KRAS-G12D 5X working solution, centrifuge and mix, and let stand for 15 minutes; then add 10μL of pre-mixed anti-Tag1-Eu 3+ The cells were incubated with anti-Tag2-XL665 at room temperature for 4 hours. Finally, the fluorescence intensity of each well at 620 nm and 665 nm was measured using a microplate reader in TF-FRET mode under an excitation wavelength of 304 nm. The fluorescence intensity ratio of 665 / 620 was calculated for each well. The percentage inhibition rate of the test compound at each concentration was calculated by comparing the fluorescence intensity ratio with that of the control group (0.1% DMSO). Nonlinear regression analysis was performed using GraphPad Prism 5 software using the test compound concentration as the logarithm of the inhibition rate to obtain the compound's IC value. 50 Values ​​are shown in Table 1 below.

[0318] Table 1 IC values ​​of the inhibitory ability of the compounds of the present invention on the interaction between KRAS G12D and RAF1 protein 50 data

[0319] Example No. <![CDATA[IC 50 (nM)]]> 2 648

[0320] Conclusion: The compounds of the present invention have good inhibitory ability on the interaction between KRAS G12D and RAF1 protein.

[0321] Test Example 4: Determination of the Inhibitory Effect of the Compounds of the Invention on AGS Cell Proliferation

[0322] The following method was used to determine the effect of the compounds of the present invention on AGS cell proliferation. AGS cells (containing the KRAS G12D mutation) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in F12K medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573).

[0323] The experimental method was performed according to the steps in the kit instructions, which are briefly described as follows: the test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample. The final concentration of the compound ranged from 1000nM to 0.015nM. Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 500 cells per well, cultured overnight in a 37°C, 5% CO2 incubator, and then the test compound was added and cultured for 72 hours. After the culture was completed, 50μL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes and then allowed to stand for 10 minutes. The luminescence value of each well of the sample was then read using the Luminescence mode on the microplate reader. The percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.3% DMSO). The nonlinear regression analysis of the compound concentration logarithm-inhibition rate was then performed in GraphPad Prism 5 software to obtain the IC value of the compound for inhibiting cell proliferation. 50 Values ​​are shown in Table 2.

[0324] Table 2 IC values ​​of the compounds of the present invention for inhibition of AGS cell proliferation 50 data

[0325] Example No. <![CDATA[IC 50 (nM)]]> 2 630

[0326] Conclusion: The compound of the present invention has a good proliferation inhibitory effect on AGS cells.

[0327] Unless otherwise defined, the terms used in the present invention have the same meanings as those commonly understood by those skilled in the art.

[0328] The embodiments described in the present invention are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Those skilled in the art may make various other substitutions, changes and improvements within the scope of the present invention. Therefore, the present invention is not limited to the above-mentioned embodiments, but is only limited by the claims.

Claims

1. A compound represented by general formula (III) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in: selected from double bonds; Ring B is selected from naphthyl; Q 1 Selected from N; Q 2 Selected from C; Y is selected from -O-; X 1 、X 2 Each independently selected from N or CR c ; R c is selected from hydrogen, fluorine, bromine or iodine; R 1 Selected from the following groups: for: R 4 Each independently selected from hydrogen atom, C 1-6 Alkyl, halogen or hydroxy; n is selected from 0, 1, 2 or 3.

2. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: are all selected from double bonds; Q 1 Selected from N; Q 2 Selected from C; X 1 、X 2 Selected from CR c ; R c Selected from hydrogen atoms.

3. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: are all selected from double bonds; Q 1 Selected from N; Q 2 Selected from C; X 1 Selected from CR c ; X 2 Selected from N; R c Selected from fluorine.

4. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from:

5. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 Each is independently selected from a hydrogen atom, fluorine, chlorine, bromine, iodine or a hydroxyl group.

6. The compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Selected from the following groups:

7. The compound according to claim 1 or its stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is:

8. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.

9. Use of the compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a KRas G12D inhibitor.

10. Use of the compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, in the preparation of a medicament for treating a disease mediated by KRas G12D mutation, wherein the disease mediated by KRas G12D mutation is selected from cancer, wherein the cancer is selected from cardiac myxoma, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, bile duct cancer, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenal neuroblastoma, myeloid leukemia, acute lymphoblastic leukemia or glioblastoma.

11. The use according to claim 10, wherein the cancer is pancreatic cancer, colorectal cancer or lung cancer.

12. The use according to any one of claims 10 to 11, wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

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