CN116113632A

CN116113632A - Heterocyclic derivative, preparation method and medical application thereof

Info

Publication number: CN116113632A
Application number: CN202280006415.2A
Authority: CN
Inventors: 陈友喜; 龚亮; 向清; 毛文涛; 赵雯雯; 赵伟峰; 程超英; 和燕玲; 叶成; 钱文建; 陈磊
Original assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Current assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Priority date: 2021-03-30
Filing date: 2022-03-29
Publication date: 2023-05-12
Also published as: WO2022206723A1

Abstract

The invention relates to heterocyclic derivatives, a preparation method and medical application thereof. In particular to heterocyclic derivatives shown in a general formula (A-I) or (A-II), a preparation method thereof and application thereof as therapeutic agents, in particular as KRAS G12D inhibitors, wherein the definition of each substituent in the general formula (A-I) or (A-II) is the same as that in the specification,

Description

Heterocyclic derivative, preparation method and medical application thereof

Technical Field

the invention relates to a heterocyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application of the heterocyclic derivative as a therapeutic agent, in particular to an inhibitor of K-Ras GTPase.

Background

RAS represents a closely related group of monomeric globular proteins (21 kDa molecular weight) with 189 amino acids and which are associated with the plasma membrane and bind GDP or GTP. Under normal developmental or physiological conditions, the RAS is activated by receiving growth factors and various other extracellular signals, and is responsible for regulating functions such as cell growth, survival, migration, and differentiation. RAS functions as a molecular switch, the on/off state of the RAS protein is determined by nucleotide binding, the active signaling conformation binds GTP, and the inactive conformation binds GDP. When the RAS contains bound GDP, it is in a dormant or quiescent or off state and is "inactive". When cells are exposed to certain growth promoting stimuli in response, the RAS is induced to convert the bound GDP to GTP. As GTP is bound, the RAS is "on" and is able to interact with and activate other proteins (its "downstream targets"). RAS proteins themselves have a very low inherent ability to hydrolyze GTP back to GDP and thereby turn themselves into an off state. Conversion of the RAS to shut down requires exogenous proteins called Gtpase Activating Proteins (GAPs) that interact with the RAS and greatly promote the conversion of GTP to GDP. Any mutation in the RAS that affects its ability to interact with GAP or convert GTP back to GDP will result in prolonged activation of the protein and thus produce a prolonged signal to the cell that signals it to continue growth and division. These signals may therefore cause cell growth and division, and overactivated RAS signaling may ultimately lead to cancer.

Structurally, RAS proteins contain a G domain responsible for enzymatic activity of the RAS, guanine nucleotide binding and hydrolysis (gtpase reaction), which also includes a C-terminal extension containing a so-called "CAAX box", which can be post-translationally modified and targets the protein to a membrane. The G domain is approximately 21-25kDa in size and contains a phosphate binding loop (P-loop). The P-loop represents the pocket in the protein that binds the nucleotide, 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 so-called switch I regions (residues 30-40) and switch II regions (residues 60-76), both dynamic parts of the protein, often denoted as "spring-loaded" mechanisms due to the ability of the dynamic parts to switch between resting and loaded states. The main interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the gamma-phosphate of GTP, which maintains their active conformation in switch I and switch II, respectively. After hydrolysis of GTP and release of phosphate, both relax to an inactive GDP conformation.

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 three major deadly 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, cholangiocarcinoma, gastric cancer, bladder cancer, diffuse large B-cell lymphoma, rhabdomyosarcoma, cutaneous squamous cell carcinoma, cervical cancer, testicular germ cell carcinoma, etc., whereas KRAS mutations are rarely found (< 2%) in breast, ovarian and brain cancers. 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 increase in the frequency of specific allelic mutations comes mostly from classical smoking-induced classical mutations (G: C to T: A substitutions), resulting in KRAS G12C (GGT to TGT) and G12V (GGT to GTT) mutations.

Large genomics studies indicate that lung cancer KRAS mutations, including G12C, are mutually exclusive from other known driving oncogenic mutations in NSCLC, including EGFR, ALK, ROS, RET, and BRAF, indicating the uniqueness of KRAS mutations in lung cancer. While at the same time KRAS mutations often coincide with certain co-mutations, such as STK11, KEAP1 and TP53, which in cooperation with the mutated RAS transform the cells into highly malignant and invasive tumor cells.

Three RAS oncogenes constitute the most frequently mutated gene family in human cancers. It is disappointing that despite thirty years of research efforts, there is still no clinically effective anti-RAS therapy, and targeting the gene using small molecules is a challenge. Accordingly, there is an urgent need in the art for small molecules for targeting the RAS (e.g., K-RAS, H-RAS, and/or N-RAS) and using the same to treat a variety of diseases, such as cancer.

At present, the clinical development of KRAS G12D inhibitor is in vigorous competition at home and abroad, wherein KRAS G12D inhibitor MRTX-1133 developed by Mirati Therapeutics Inc company already enters a preclinical stage and is used for treating diseases such as large intestine tumor, non-small cell lung cancer, pancreatic cancer and the like. There are a few published KRAS G12D inhibitor patent applications including WO2021041671 by Mirati Therapeutics Inc. Although research and use of KRas G12D inhibitors has advanced somewhat, there is still a tremendous space for improvement and there is still a need to continue to research and develop new KRas G12D inhibitors.

Disclosure of Invention

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

wherein:

selected from single or double bonds as required so that each atom to which it is attached assumes a normal valence state;

ring a is each independently selected from 5-6 membered heteroaryl or 5-10 membered monocyclic heterocyclyl; preferably a 6-to 7-membered monocyclic heterocyclic group; wherein the heteroaryl, monocyclic heterocyclyl contains one or more N or O atoms;

ring B is each independently selected from aryl, heteroaryl, or fused rings;

ring C is each independently selected from a 6-8 membered heterocyclic group containing 2 nitrogen atoms;

Q ¹ selected from N or CR ^a ；Q ¹ Preferably N;

Q ² each independently selected from N, C or CR ^a ；

Y is each independently selected from bond, O or NR ^b ；

X ¹ 、X ² Each independently selected from N, C = O, CR ^c Or CR (CR) ^d R ^e ；

E is each independently selected from hydrogen atoms or

R ^a The same or different are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, or a cyano group; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;

R ^b selected from hydrogen atoms or alkyl groups;

R ^c selected from the group consisting of hydrogen, halogen, cyano, alkyl, or alkoxy; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; r is R ^c Preferably halogen, more preferably fluorine or chlorine;

R ^d and R is ^e The same or different are each independently selected from a hydrogen atom, a halogen, an alkyl group or an alkoxy group; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;

alternatively, R ^d And R is ^e Together with the carbon atom to which it is attached, form a cycloalkyl or heterocyclyl group; preferably cyclopropyl;

R ^f selected from hydrogen atoms or cycloalkyl groups, wherein said cycloalkyl groups are preferably cyclopropyl;

R ¹ each independently selected from hydrogen atom, -L-alkyl, -L-halogen, -L-OR ⁵ 、-L-NR ⁶ R ⁷ 、-L-C(O)OR ⁵ 、-L-C(O)NR ⁶ R ⁷ -L-cycloalkyl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-fused ring or

Wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused ring is optionally further substituted with one or more substituents selected from R ^g Is substituted by a substituent of (2);

R ^g identical 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 、-CH ₂ NHC(O)OR ⁵ 、-CH ₂ NR ⁶ R ⁷ or-S (O) _r R ⁵ Wherein said alkyl, benzyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted with one OR more groups selected from alkyl, halo, 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 、-CH ₂ NHC(O)OR ⁵ 、-CH ₂ NR ⁶ R ⁷ 、-NHS(O) _r R ⁵ or-S (O) _r R ⁵ Is substituted by (2)Substitution;

l are each independently selected from a bond or C ₁ -C ₆ An alkylene group, wherein said alkylene group is optionally further substituted with one or more R ^D Substituted;

R ^D each independently selected from a hydrogen atom, halogen, hydroxy or hydroxymethyl;

alternatively, two R's attached to the same carbon atom ^D Together with the attached carbon atom, form a cycloalkyl group; preferably cyclopropyl;

R ² the same or different are each independently selected from a hydrogen atom, halogen, hydroxy, alkyl or alkoxy, preferably a hydrogen atom or alkyl;

alternatively, any two R ² Together with the atoms to which they are attached, form a cycloalkyl or heterocyclyl group;

R ³ the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy or = O; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; r is R ³ Preferably a hydrogen atom, methyl or = O;

R ⁴ each independently selected from the group consisting of hydrogen, alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, 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 、-CH ₂ NHC(O)OR ⁵ 、-CH ₂ NR ⁶ R ⁷ or-S (O) _r R ⁵ The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted with one OR more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, 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 、-CH ₂ NHC(O)OR ⁵ 、-CH ₂ NR ⁶ R ⁷ or-S (O) _r R ⁵ Is substituted by a substituent of (2);

R ⁵ each independently selected from a hydrogen atom, halogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, 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 、-SO ₂ R ⁸ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

R ⁶ and R is ⁷ Each independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from R ^h Is substituted by a substituent of (2);

R ^h identical 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 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with oneOr a plurality of groups 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 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

alternatively, R ⁶ And R is ⁷ Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) _r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents 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 、-CH ₂ NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

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

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

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

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

r are each independently selected from 0, 1 or 2.

The invention provides a compound shown in a general formula (A-I) or (A-II), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is shown in the general formula (I) or (II), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

Wherein: ring a, ring B, X ¹ 、X ² 、Y、Q ¹ 、Q ² 、R ¹ 、R ² 、R ³ 、R ⁴ The definitions of m, n and k are as described in the general formulae (A-I) or (A-II).

The invention provides a compound shown in a general formula (I) or (II), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is shown in a general formula (III), (IV), (V) or (VI), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

wherein: ring B, X ¹ 、X ² 、Y、Q ¹ 、Q ² 、R ¹ 、R ² 、R ³ 、R ⁴ The definitions of m and n are as described in the general formulae (A-I) or (A-II).

The invention provides a compound shown in a general formula (A-I) or (A-II), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is a compound shown in a general formula (VII), (VIII) or (IX), or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof:

wherein: ring B, X ¹ 、X ² 、Y、Q ¹ 、Q ² 、R ¹ 、R ² 、R ³ 、R ⁴ The definition of m and n is as described in the general formula (A-I) or (A-II).

The present invention provides a compound of the general formula (a-I), (a-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

are each selected from double bonds;

Q ¹ selected from N;

Q ² selected from C;

X ¹ 、X ² each independently selected from N or CR ^c ；

R ^c Selected from hydrogen atoms or halogen, preferably halogen, more preferably fluorine or chlorine.

are each 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 halogen, preferably fluorine or chlorine, more preferably fluorine.

are all selected from single bonds;

X ¹ 、X ² each independently selected from CR ^d R ^e ；

R ^d And R is ^e Selected from hydrogen atoms;

alternatively, R ^d And R is ^e Together with the attached carbon atom, form a 3-5 membered monocyclic cycloalkyl or 3-5 membered monocyclic heterocyclyl; cyclopropyl is preferred.

X ² connected to

Selected from double bonds;

X ¹ and Q ² Between which are located

Selected from single bonds;

X ¹ selected from c=o;

X ² selected from N;

Q ² selected from N.

R ¹ Selected from-L-heterocyclyl; wherein said heterocyclyl is optionally further substituted with one or more substituents selected from alkyl, halogen, alkoxy or =o; wherein said halogen is preferably fluorine;

l is selected from a bond or C ₁ -C ₃ An alkylene group, wherein said alkylene group is optionally further substituted with one or more R ^D Substituted;

alternatively, two R's attached to the same carbon atom ^D Together with the attached carbon atom, form a cycloalkyl group; cyclopropyl is preferred.

l is selected from bond, -CH ₂ -、-CH ₂ CH ₂ -or

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

the present invention provides a compound of the general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ³ The same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy or = O; r is R ³ Preferably a hydrogen atom, methyl or=o.

The present invention provides a compound of the general formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ⁴ The same or different, each independently selected from hydrogen atom, alkyl, halogen, alkoxy, alkynyl, hydroxy, amino, hydroxyalkyl, haloalkyl or haloalkoxy; r is R ⁴ Preferably a hydrogen atom, methyl, fluorine, chlorine, bromine, iodine, hydroxyl, amino, hydroxymethyl or ethynyl.

ring B is selected from phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzothiazolyl, tetrahydronaphthyl,

Ring B is preferably naphthyl or benzothiazolyl.

Selected from the following groups:

the invention provides a compound shown in a general formula (I) or (III) or stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

selected from the following groups:

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

selected from the following groups:

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

selected from the following groups:

typical compounds of the present invention include, but are not limited to:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

Note that: if there is a difference between the drawn structure and the name given to the structure, the drawn structure will be given greater weight.

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

In another aspect, the invention provides a method of inhibiting KRas G12D enzyme, wherein the method comprises: a pharmaceutical composition comprising an effective amount of a compound of formula (a-I), (a-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof, administered to a patient.

The present invention also provides the use of a compound of formula (a-I), (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. as described in the preceding claims), for the manufacture of a medicament for the treatment of 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, stomach cancer, colorectal cancer, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenoblastoma, myelogenous 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.

In another aspect, the present invention provides the use of a compound of formula (a-I), (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. as described in the foregoing claims) for the preparation of a KRas G12D inhibitor.

Another aspect of the 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 (a-I), (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., a pharmaceutical composition as described in the foregoing technical scheme). Wherein the disease mediated by the KRas G12D mutation is selected from cancer, wherein the cancer is selected from cardiac myxoma, lung cancer, stomach cancer, colorectal cancer, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenoneuroblastoma, myelogenous 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.

The invention also provides the use of a compound of general formula (a-I), (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. as described in the preceding claims) for the manufacture of a medicament for the treatment of cancer selected from the group consisting of cardiac myxoma, lung cancer, stomach cancer, colorectal cancer, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenoneuroblastoma, myelogenous 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.

The present invention also provides a method for preventing and/or treating cancer comprising administering to a patient a therapeutically effective amount of a compound of formula (a-I), (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 according to the foregoing technical scheme). Wherein the cancer is selected from the group consisting of cardiac myxoma, lung cancer, stomach cancer, colorectal cancer, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenoneuroblastoma, myelogenous 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.

The pharmaceutical formulations of the present invention may be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocular, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intradermal, intraperitoneal, subcutaneous, subcuticular or by inhalation. Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, 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 in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.

The formulations of the present invention are suitably presented in unit-dose form and may be prepared by any method well known in the pharmaceutical arts. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form can vary depending upon the host 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.

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

When the compounds of the invention are administered to humans and animals in the form of a medicament, the compounds may be provided alone or in the form of a pharmaceutical composition 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.

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 carboxymethyl cellulose, ethyl cellulose, 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) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; (21) Cyclodextrins, e.g., targeting ligands attached to nanoparticles, e.g., accursinTM; and (22) other non-toxic compatible substances used in pharmaceutical formulations, such as polymer-based compositions.

Examples of pharmaceutically acceptable antioxidants include, but are not limited to: (1) Water-soluble antioxidants such as ascorbic acid, cysteamine 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, alpha-tocopherol, and the like; and (3) metal chelators such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like. Solid dosage forms (e.g., capsules, 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 carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerin; (4) Disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) an absorption accelerator, such as a quaternary ammonium compound; (7) Humectants, 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 glycols, sodium lauryl sulfate, and mixtures thereof; and (10) a colorant. 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 inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

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

In addition to the active compounds, ointments, pastes, creams and gels may contain 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.

In addition to the active compounds, the powders and sprays can also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. The spray may contain other conventional propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.

Detailed description of the invention

Unless stated to the contrary, some of the terms used in the specification and claims of the present invention are defined as follows:

"bond" means that the indicated substituent is absent and that the two end portions of the substituent are directly linked to form a bond.

"alkyl" when taken as a group or part of a group is meant to include C ₁ -C ₂₀ Straight chain or branched aliphatic hydrocarbon groups. Preferably C ₁ -C ₁₀ Alkyl, more preferably C ₁ -C ₆ An alkyl group. 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylpropylCyclobutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted.

"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 include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. Alkenyl groups may be optionally substituted or unsubstituted.

"alkynyl" refers to an aliphatic hydrocarbon group containing one carbon-carbon triple bond, which may be straight or branched. Preferably is C ₂ -C ₁₀ More preferably C ₂ -C ₆ Alkynyl, most preferably C ₂ -C ₄ Alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted.

"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocycles. Preferably C ₃ -C ₁₂ Cycloalkyl, more preferably C ₃ -C ₈ Cycloalkyl, most preferably C ₃ -C ₆ Cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred. Cycloalkyl groups may be optionally substituted or unsubstituted.

"spirocycloalkyl" refers to a 5 to 18 membered, two or more cyclic structure, and monocyclic polycyclic groups sharing one carbon atom (called spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro group, a double spiro group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, preferably single spiro group and double spirocycloalkyl group, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.

"fused ring alkyl" refers to an all-carbon polycyclic group having 5 to 18 members, two or more cyclic structures sharing a pair of carbon atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of "fused ring alkyl" include, but are not limited to: bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalinyl, or tetradecahydrophenanthryl.

"bridged cycloalkyl" means an aromatic system having 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups with one another that are not directly attached to a carbon atom, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron, preferably 6 to 12 members, more preferably 7 to 10 members. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1 s,4 s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1 s,5 s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, and (1 r,5 r) -bicyclo [3.3.2] decyl.

"heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, and the like, including monocyclic, fused, bridged and spiro rings. Preferably having a 5 to 7 membered single 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-dioxothiomorpholinyl, piperidinyl, 2-oxopiperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, and piperazinyl. The heterocyclic group may be substituted or unsubstituted.

"spiroheterocyclyl" refers to a 5-to 18-membered, two or more cyclic structure, polycyclic group having single rings sharing one atom with each other, containing 1 or more double bonds in the ring, but no ring having a completely conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) _r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multiple spiro heterocyclic group according to the number of common spiro atoms between rings, and preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of "spiroheterocyclyl" 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 ]]A heptyl group.

"fused heterocyclyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen, or S (O) _r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclyl" 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 (dioxane) or

"bridged heterocyclyl" means a 5 to 14 membered, 5 to 18 membered, polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl and 2-azabicyclo [3.3.2]And (3) a decyl group.

"aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C ₆ -C ₁₀ Aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. Aryl groups may be substituted or unsubstituted.

"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. Examples of "heteroaryl" groups, which are preferably bicyclic heteroaryl groups, 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,

Heteroaryl groups may be substituted or unsubstituted.

"fused ring" means a polycyclic group having two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but at least one of the rings does not have a fully conjugated pi-electron aromatic system, wherein the ring atoms are selected from 0, one or more of the ring atoms are selected from nitrogen, oxygen, or S (O) _r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. The fused ring preferably includes a double-or triple-ring fused ring, wherein the double-ring fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14 membered, more preferably 8 to 10 membered. Examples of "fused rings" include, but are not limited to:

"alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. C (C) ₁ -C ₆ Is preferably selected. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"haloalkyl" refers to a group wherein the alkyl is optionally further substituted with one or more halogens, where alkyl is as defined herein.

"hydroxyalkyl" refers to a group in which the alkyl group is optionally further substituted with one or more hydroxyl groups, where alkyl is as defined herein.

"aminoalkyl" refers to a group in which the alkyl group is optionally further substituted with one or more amino groups, where alkyl is as defined herein.

"hydroxymethyl" refers to a group that is optionally further substituted with one or more hydroxyl groups.

"haloalkoxy" refers to a group in which the alkyl group of (alkyl-O-) is optionally further substituted with one or more halogens, wherein alkoxy is as defined herein.

"hydroxy" refers to an-OH group.

"halogen" refers to fluorine, chlorine, bromine and iodine.

"amino" means-NH ₂ 。

"cyano" refers to-CN.

"nitro" means-NO ₂ 。

"benzyl" means-CH ₂ -phenyl.

"carboxy" means-C (O) OH.

"carboxylate" refers to-C (O) O-alkyl or-C (O) O-cycloalkyl, wherein alkyl, cycloalkyl are as defined above.

"DMSO" refers to dimethyl sulfoxide.

"BOC" refers to t-butoxycarbonyl.

"Ts" refers to p-toluenesulfonyl.

"T3P" refers to propyl phosphoric anhydride.

"DPPA" refers to diphenyl azide phosphate.

"DEA" refers to diethylamine.

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

"MOM" refers to methoxymethyl.

"TBS" means t-butyldimethylsilyl.

"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"substitution" as used herein"or" substituted ", unless otherwise indicated, means that a group may be substituted with one or more groups selected from the group consisting of: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkenyl, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, 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 、-CH ₂ NHC(O)OR ⁵ 、-CH ₂ NR ⁶ R ⁷ or-S (O) _r R ⁵ Is substituted by a substituent of (2);

R ⁵ selected from a hydrogen atom, an alkyl 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 groups selected from a hydroxyl group, a halogen group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =o, -C (O) R ⁸ 、-C(O)OR ⁸ 、-OC(O)R ⁸ 、-NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

R ⁶ and R is ⁷ Each independently selected from a hydrogen atom, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups 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 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

alternatively, R ⁶ And R is ⁷ Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) _r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents 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 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

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

r is 0, 1 or 2.

The compounds of the invention may contain asymmetric or chiral centers and thus 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 (attopiomers) and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

Unless otherwise indicated, the structures described herein also include all stereoisomers (e.g., diastereomers, enantiomers and atropisomers and geometric (conformational) isomeric forms of such structures, e.g., the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.

"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds of formula (A-I), (A-II), (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) may be metal salts, amine salts with suitable acids.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

Synthesis method of compound of the invention

In order to achieve the purpose of the invention, the invention adopts the following technical scheme:

the preparation method of the compound shown in the general formula (I) or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof comprises the following steps:

carrying out Suzuki coupling reaction on the compound shown in the general formula (IA) and the compound shown in the general formula (IB) under the action of a palladium catalyst and an alkaline reagent to obtain a compound shown in the general formula (IC); further deprotecting the compound of formula (IC) to obtain a compound of formula (I);

wherein:

x is a leaving group, preferably chlorine;

PG is a protecting group, preferably t-butoxycarbonyl;

m is selected from-B (OH) ₂ 、-BF ₃ K or

Ring a, ring B, R ¹ ～R ⁴ 、X ¹ 、X ² 、Q ¹ 、Q ² The definitions of Y, k, m and n are as described in the general formula (I).

The preparation method of the compound shown in the general formula (II) or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof comprises the following steps:

Carrying out Suzuki coupling reaction on the compound shown in the general formula (IIA) and the compound shown in the general formula (IB) under the action of a palladium catalyst and an alkaline reagent to obtain a compound shown in the general formula (IIC); further removing the protecting group from the compound of the general formula (IIC) to obtain a compound of the general formula (II);

wherein:

x is a leaving group, preferably chlorine;

PG is a protecting group, preferably t-butoxycarbonyl;

m is selected from-B (OH) ₂ 、-BF ₃ K or

Ring a, ring B, R ¹ ～R ⁴ 、X ¹ 、X ² 、Q ² The definitions of Y, k, m and n are as described in formula (II).

Detailed Description

The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.

Examples

The examples show the preparation of representative compounds represented by formulas (I) and (II) and the relevant structural identification data. It must be understood that the following examples are given by way of illustration and not by way of limitation. ¹ HNMR spectra were determined using a Bruker instrument (400 MHz) and chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. ¹ HNMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.

The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.

In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, all of which are used without further purification and unless otherwise indicated, commercially available manufacturers include, but are not limited to, shanghai Haohong biological medicine technologies, shanghai Shaoshao reagent, shanghai Pico medicine, saen chemical technologies (Shanghai) and Shanghai Ling Kai medicine technologies, and the like.

CD ₃ OD: deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO-d ₆ : deuterated dimethyl sulfoxide.

The examples are not particularly described, and the solution in the reaction is an aqueous solution.

Purifying the compound using an eluent system of column chromatography and thin layer chromatography, wherein the system is selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: dichloromethane and ethyl acetate system, D: dichloromethane and ethanol, wherein the volume ratio of the solvent is different according to the polarity of the compound, and small amount of acidic or alkaline reagent can be added for the conditions such as acetic acid or triethylamine.

Room temperature: 20-30 ℃.

Example 1

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

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

First step

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

(2- ((7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-yl) amino) ethyl) carbamic acid tert-butyl ester

7-bromo-4, 6-dichloro-8-fluoro-3-nitroquinoline 1a (500 mg,1.47mmol, prepared according to published patent WO2019110751A 1) and tert-butyl (2-aminoethyl) carbamate 1b (282.79 mg,1.77 mmol) were added to acetonitrile (8.54 mL), cooled to 0deg.C, N-diisopropylethylamine (570.29 mg,4.41mmol,729.27 μl) was added and allowed to react overnight at room temperature. The reaction solution was extracted with ethyl acetate (100 mL. Times.1), the organic phase was dried with saturated brine (100 mL. Times.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), yield 99.70%, and the product was directly subjected to the next reaction without purification.

LCMS:463.0[M+1] ⁺

Second step

tert-butyl (2- ((3-amino-7-bromo-6-chloro-8-fluoroquinolin-4-yl) amino) ethyl) carbamate (2- ((3-amino-7-bromo-6-chloro-8-fluoroquinolin-4-yl) amino) ethyl) carbamic acid tert-butyl ester

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 it was still hot, the filter cake was washed with methanol (20 mL), the filtrate was extracted with ethyl acetate (100 mL. Times.1), the organic phase was washed with saturated brine (100 mL. Times.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), yield 100.00% and the product was directly subjected to the next reaction without purification.

LCMS:433.0[M+1] ⁺

Third step

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

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

Tert-butyl (2- ((3-amino-7-bromo-6-chloro-8-fluoroquinolin-4-yl) amino) ethyl) carbamate 1d (300 mg, 691.72. Mu. Mol) was added to dichloromethane (5 mL), triethylamine (139.99 mg,1.38 mmol) was added, a solution of 2-chloroacetyl chloride (156.25 mg,1.38 mmol) in dichloromethane (2 mL) was added dropwise at room temperature, the reaction was continued overnight at room temperature, LCMS detected many intermediates without a relevant ring, the reaction solution was extracted with dichloromethane (50 mL. Times.1), the organic phase was washed with saturated brine (100 mL. Times.2), dried over anhydrous sodium sulfate, concentrated, the resulting residue was added to acetic acid (5 mL), heated to 50℃for 2 hours, the reaction solution was cooled to room temperature, the system was made basic with saturated sodium carbonate solution, the ethyl acetate extract (100 mL. Times.1), the organic phase was washed with saturated brine (100 mL. Times.1), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (eluent: A) to give 2-bromo-8-fluoroquinolin-4-yl [ 2- (6-chloro-1-ethyl-1-yl ] carbamate ] (. 7-bromo-8-fluoroquinolin-4-yl) carbamate (38 mg, i.38 mg).

LCMS:492.7[M+1] ⁺

Fourth step

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

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

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. Mu. Mol) is added to dichloromethane (4 mL), and a dioxane solution of hydrogen chloride (4 m,2 mL) is added and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give 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. Mu. Mol), 99.77% yield, which was directly subjected to the next reaction without purification.

LCMS:393.0[M+1] ⁺

Fifth step

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

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

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. Mu. Mol), potassium iodide (6.39 mg, 38.52. Mu. Mol) and potassium carbonate (106.46 mg, 770.30. Mu. Mol) are 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. Times.1), and the organic phase was washed with saturated brine (100 mL. Times.1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1g (136 mg, 382.46. Mu. Mol) of 3-bromo-2-chloro-4-fluoro-8, 9,10, 11-tetrahydropyrazino [1',2':1,2] imidazo [4,5-c ] quinoline in 99.30% yield, which was directly subjected to the next reaction without purification.

LCMS:355.0[M+1] ⁺

Sixth step

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

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

1g (136 mg, 382.46. Mu. Mol) of 3-bromo-2-chloro-4-fluoro-8, 9,10, 11-tetrahydropyrazino [1',2':1,2] imidazo [4,5-c ] quinoline, triethylamine (77.40 mg, 764.92. Mu. Mol) and di-tert-butyl dicarbonate (100.17 mg, 458.95. Mu. Mol) are added to methylene chloride (5 mL) and reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to give 3-bromo-2-chloro-4-fluoro-10, 11-dihydropyrazino [1',2':1,2] imidazo [4,5-c ] quinoline-9 (8H) -carboxylic acid tert-butyl ester (140 mg, 307.21. Mu. Mol) in a yield of 80.33%.

LCMS:456.8[M+1] ⁺

Seventh step

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

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

(2- ((Boc) amino) -5, 7-difluorobenzo [ d ]]Thiazol-4-yl) boronic acid 1i (152.12 mg, 460.82. Mu. Mol, prepared according to published patent US20200115375A 1), 3-bromo-2-chloro-4-fluoro-10, 11-dihydropyrazino [1',2':1,2]]Imidazo [4,5-c]Quinoline-9 (8H) -carboxylic acid tert-butyl ester 1H (140 mg, 307.21. Mu. Mol), sodium carbonate (65.13 mg, 614.43. Mu. Mol) and tetrakis triphenylphosphine palladium (35.50 mg, 30.72. Mu. Mol) were added to a mixed solution of dioxane (4 mL) and water (1 mL), and the mixture was heated to 110℃under argon atmosphere to react overnight. The reaction mixture was cooled, extracted with ethyl acetate (100 mL. Times.1), the organic phase was washed with saturated brine (100 mL. Times.1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I). D; 5 μm,20mL/min; mobile phase a:0.05% TFA+H ₂ O, mobile phase B: CH (CH) ₃ CN) 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. Mu. Mol) in 49.24% yield.

LCMS:660.8[M+1] ⁺

Eighth step

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. Mu. Mol) was added to dichloromethane (5 mL), and a 1, 4-dioxane solution of hydrogen chloride (4M, 3 mL) was added and reacted at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, the system was made basic with saturated sodium carbonate solution, extracted with ethyl acetate (100 mL. Times.1), the organic phase was washed with saturated brine (100 mL. Times.1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 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. Mu. Mol), yield 58.61%.

LCMS:461.0[M+1]

Example 2

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

5-fluoro-4- (2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (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

First step

2-amino-4-bromo-6-fluorobenzamide

2-amino-4-bromo-6-fluoro-benzonitrile 2a (4 g,18.60mmol, commercially available) was added to concentrated sulfuric acid (10 mL), and the mixture was reacted at 65℃for 3 hours. The reaction solution was cooled to room temperature, poured into ice water (100 mL), pH was adjusted to be alkaline with saturated aqueous sodium carbonate, extracted with ethyl acetate (100 mL. Times.1), the organic phase was washed with saturated aqueous saline (100 mL. Times.3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 2-amino-4-bromo-6-fluorobenzamide 2b (4 g,17.16 mmol), the crude product was directly subjected to the next reaction without purification, yield 92.27%.

LCMS:233.0[M+1] ⁺

Second step

7-bromo-5-fluoroquinazoline-2,4-diol

7-bromo-5-fluoroquinazoline-2, 4-diol

2-amino-4-bromo-6-fluorobenzamide 2b (1 g,4.29 mmol) was added to acetonitrile (5 mL), 4-dimethylaminopyridine (1.05 g,8.58 mmol) and triphosgene (636.70 mg,2.15 mmol) was added sequentially, and the reaction was allowed to react at room temperature for 4 hours, with LCMS monitoring the completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give 7-bromo-5-fluoroquinazoline-2, 4-diol 2c (400 mg,1.54 mmol) in 35.99% yield.

LCMS:259.0[M+1] ⁺

Third step

7-bromo-2,4-dichloro-5-fluoroquinazoline

7-bromo-2, 4-dichloro-5-fluoroquinazoline

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, and the reaction was warmed to 80℃for 2 hours and monitored by LCMS to completion. The reaction solution is cooled to room temperature and concentrated under reduced pressure to obtain a crude product 7-bromo-2, 4-dichloro-5-fluoroquinazoline 2d, and the product is directly subjected to the next reaction without purification.

Fourth step

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

4- (7-bromo-2-chloro-5-fluoroquinazolin-4-yl) -3- (((tert-butyldimethylsilyl) oxy) methyl) piperazine-1-carboxylic acid tert-butyl ester

3- (((tert-Butyldimethylsilyloxy) methyl) piperazine-1-carboxylic acid tert-butyl ester 2e (111.70 mg, 337.93. Mu. Mol, prepared according to published patent WO 2003051797) was added to dichloromethane (2 mL), argon was used for protection, cooled to-40 ℃, N-diisopropylethylamine (436.73 mg,3.38 mmol) was added dropwise, the reaction solution was stirred overnight at room temperature, the reaction solution was cooled again to-40 ℃ for the next day, N-diisopropylethylamine (436.73 mg,3.38 mmol) was added dropwise, then a new solution of 7-bromo-2, 4-dichloro-5-fluoroquinazoline 2d (100 mg, 337.93. Mu. Mol) in dichloromethane (2 mL) was added dropwise, the reaction solution was warmed to room temperature for reaction overnight, and S was monitored for completion. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: B system) 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. Mu. Mol), yield 20.06%.

LCMS:589.0[M+1] ⁺

Fifth step

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

4- (7-bromo-5-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3- (((tert-butyldimethylsilyl) oxy) methyl) piperazine-1-carboxylic acid tert-butyl ester

2g (16.19 mg, 101.70. Mu. Mol, prepared according to published patent WO 2020146613) of ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol was added to tetrahydrofuran (5 mL), protected by argon, sodium hydride (4.07 mg, 169.49. Mu. Mol) was added, cooled to 0℃for 30 minutes, then 4- (7-bromo-2-chloro-5-fluoroquinazolin-4-yl) -3- (((tert-butyldimethylsilyl) oxy) methyl) piperazine-1-carboxylic acid tert-butyl ester 2f (40 mg, 67.80. Mu. Mol) was added, and the reaction was allowed to proceed overnight at 70℃under the condition of LCMS monitoring. The reaction solution was cooled to room temperature, quenched with water (5 mL), extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (eluent: B system) to give 4- (7-bromo-5-fluoro-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizin-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3- (((t-butyldimethylsilyl) oxy) methyl) piperazine-1-carboxylic acid tert-butyl ester 2H (30 mg, 42.09. Mu. Mol), yield 62.08%.

LCMS:713.0[M+1] ⁺

Sixth step

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

5-bromo-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8a,9,11, 12-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [5,6,7-de ] quinazolin-10 (8H) -carboxylic acid tert-butyl ester

Tert-butyl 4- (7-bromo-5-fluoro-2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) quinazolin-4-yl) -3- (((tert-butyldimethylsilyl) oxy) methyl) piperazine-1-carboxylate for 2H (55 mg,77.17 μmol) was added to tetrahydrofuran (5 mL), tetrabutylammonium fluoride (40.35 mg,154.33 μmol) was added and reacted overnight at room temperature. The reaction solution was added with water (5 mL), extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: B system) to give the product 5-bromo-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (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 (30 mg, 51.86. Mu. Mol), yield 67.21%.

LCMS:578.0[M+1] ⁺

Seventh step

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

5- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (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

5-bromo-2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -8a,9,11, 12-tetrahydropyrazino [2',1':3,4] [1,4] oxazepino [5,6,7-de ] quinazolin-10 (8H) -carboxylic acid tert-butyl ester 2i (18 mg, 31.12. Mu. Mol) was added to a mixed solvent of 1, 4-dioxane (1 mL) and water (0.2 mL), 2- (8-fluoro-3-methoxymethoxy) naphthalen-1-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane 2j (12.40 mg, 37.34. Mu. Mol), sodium carbonate (9.90 mg, 93.35. Mu. Mol) and tetrakis (triphenylphosphine) palladium (3.60 mg, 3.11. Mu. Mol) were sequentially added, and the mixture was protected at a temperature of 2℃to 80℃for 2 hours. The reaction solution was cooled to room temperature, water (5 mL) was then added thereto, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to give 5- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (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 2k (15 mg, 21.31. Mu. Mol) in a yield of 68.48%.

LCMS:704.0[M+1] ⁺

Eighth step

5- (8-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- (((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (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 2k (15 mg, 21.31. Mu. Mol) was added to acetonitrile (1 mL), stirred, 1, 4-dioxane solution of hydrogen chloride (4M, 0.5 mL) was added and reacted at room temperature for 3 hours, and LCMS monitored for completion. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H) ₂ O, mobile phase B: CH (CH) ₃ CN) to give 5-fluoro-4- (2- (((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (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) was produced in 8.38%.

LCMS:560.0[M+1] ⁺

Biological evaluation

Test example 1 determination of the inhibitory Activity of the Compounds of the invention on p-ERK1/2 in AGS cells

The following methods were used to determine the p-ERK1/2 inhibitory activity of the compounds of the invention on AGS (human gastric adenocarcinoma) cells. The method uses an Advanced phospho-ERK1/2 (Thr 202/tyr 204) kit (cat No. 64 AERPEH) from Cisbio, and the detailed experimental procedure is referred to the kit instructions. AGS cells (containing KRAS G12D mutation) were purchased from the national academy of sciences of life sciences cell resource center.

The experimental procedure is briefly described as follows: AGS cells were cultured in F12K complete medium containing 10% fetal bovine serum, 100U penicillin and 100. Mu.g/mL streptomycin. AGS cells were plated in 96-well plates 40000 per well, with medium being complete medium, at 37℃with 5% CO ₂ The cells were incubated overnight in an incubator. Test compounds were dissolved in DMSO to prepare 10mM stock solutions, followed by dilution with F12K complete medium,100. Mu.L of F12K complete medium containing the test compound at the corresponding concentration was added to each well, the final concentration of the test compound in the reaction system ranged from 1000nM to 0.015nM, the cells were discarded after 3 hours of incubation in a cell incubator, the cells were washed with ice-bath PBS, 50. Mu.L of 1 Xcell phone/total protein lysis buffer (Advanced phone-ERK 1/2 kit component) was added to each well for lysis, and the 96-well plate was placed on ice for half an hour, followed by detection of the lysate with reference to Advanced phone-ERK 1/2 (Thr 202/tyr 204) kit instructions. Finally, the fluorescence intensities of the wells at the excitation wavelength of 304nm were measured on a microplate reader in TF-FRET mode, with emission wavelengths of 620nm and 665nm, and the fluorescence intensity ratio of each well 665/620 was calculated. The percent inhibition of the test compounds at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% dmso) and nonlinear regression analysis was performed by GraphPad Prism 5 software with the test compound concentration log-inhibition to obtain compound IC ₅₀ Values.

The compounds of the invention have a pronounced inhibitory effect on the p-ERK1/2 activity in AGS cells, preferably IC of the compounds ₅₀ <500nM, more preferably IC of compound ₅₀ <200nM。

Test example 2 determination of the inhibition of AsPC-1 cell proliferation by the Compounds of the invention

The following method was used to determine the effect of the compounds of the invention on the proliferation of AsPC-1 (human metastatic pancreatic adenocarcinoma) cells. AsPC-1 cells (containing KRAS G12D mutation) were purchased from Shanghai institute of life sciences cell resource center, academy of sciences of China and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin, 100. Mu.g/mL streptomycin and 1mM Sodium Pyruvate. Cell viability by

Luminescent Cell Viability Assay kit (Promega, cat# G7573).

The experimental method is operated according to the steps of the instruction book of the kit, and is briefly described as follows: test compounds were first dissolved in DMSOPrepared as 10mM stock solution, and then diluted with medium to prepare test samples, the final concentration of the compound ranged from 1000nM to 0.015nM. Cells in the logarithmic growth phase were seeded at a density of 800 cells per well in 96-well cell culture plates at 37℃with 5% CO ₂ The culture was continued overnight in the incubator, followed by the addition of the test compound and continued for 120 hours. After the incubation was completed, a volume of 50. Mu.L of CellTiter-Glo assay solution was added to each well, and after shaking for 5 minutes, the mixture was allowed to stand for 10 minutes, followed by reading the Luminescence values of each well of the sample on a microplate reader using the Luminescence mode. The percent inhibition of compounds at each concentration point was calculated by comparison with the values of the control group (0.3% dmso), followed by nonlinear regression analysis of the compound concentration log-inhibition in GraphPad Prism 5 software to obtain IC compounds that inhibited cell proliferation ₅₀ Values.

The compounds of the invention have a significant inhibitory effect on AsPC-1 cell proliferation, preferably IC of the compounds ₅₀ <500nM, more preferably IC of compound ₅₀ <200nM。

Test example 3 inhibition ability assay of KRAS G12D and RAF1 protein interactions by Compounds of the present invention

The following method was used to determine that the compounds of the invention block KRAS G12D under in vitro conditions: the ability of RAF1 proteins to interact. The method uses KRAS-G12C/SOS1BINDING ASSAY KITS kit (63 ADK000CB21 PEG) from Cisbio, and the detailed experimental operation is referred to the kit instruction.

The experimental procedure is briefly described as follows: working solution concentrations of 5X for Tag1-RAF1 and Tag2-KRAS-G12D proteins were prepared using a current buffer (cat No. 62 DLBDDF). Test compounds were dissolved in DMSO to prepare 10mM stock solutions, which were then diluted using a diluet buffer for use. Firstly, adding 2 mu L of a tested compound (the final concentration of a reaction system is 10000nM-0.1 nM) into a hole, then adding 4 mu L of a Tag1-RAF1 5X working solution and 4 mu L of a Tag2-KRAS-G12D 5X working solution, centrifuging and mixing uniformly, and standing for 15 minutes; then 10 mu L of pre-mixed anti-Tag1-Eu is added ³⁺ And anti-Tag2-XL665, incubated for 4 hours at room temperature; finally using enzyme label instrument to apply TF-FRET mode The fluorescence intensities of the respective wells at excitation wavelengths of 304nm at emission wavelengths of 620nm and 665nm were measured, and the fluorescence intensity ratio of the respective wells 665/620 was calculated. The percent inhibition of the test compounds at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% dmso) and nonlinear regression analysis was performed by GraphPad Prism 5 software with the test compound concentration log-inhibition to obtain compound IC ₅₀ The values are given in Table 1 below.

TABLE 1 IC for the inhibitory potency of the compounds of the invention on KRAS G12D interactions with RAF1 proteins ₅₀ Data

Examples numbering	IC ₅₀ (nM)
2	648

Conclusion: the compound has better inhibition capability on the interaction of KRAS G12D and RAF1 protein.

Test example 4 determination of inhibition of AGS cell proliferation by Compounds of the invention

The following methods were used to determine the effect of the compounds of the invention on AGS cell proliferation. AGS cells (containing KRAS G12D mutation) were purchased from the national academy of sciences of life sciences cell resource center and cultured in F12K medium containing 10% fetal bovine serum, 100U penicillin and 100 μg/mL streptomycin. Cell viability by

Luminescent Cell Viability Assay kit (Promega, cat# G7573).

The experimental method is operated according to the steps of the instruction book of the kit, and is briefly described as follows: test compounds were prepared by first dissolving the test compounds in DMSO to prepare a 10mM stock solution, and then diluting the stock solution with medium to prepare test samples, wherein the final concentration of the compounds ranged from 1000nM to 0.015nM. Cells in the logarithmic growth phase were seeded at a density of 500 cells per well in 96-well cell culture plates at 37℃with 5% CO ₂ The culture was continued overnight in the incubator, followed by the addition of the test compound and continued for 72 hours. After the incubation was completed, a volume of 50. Mu.L of CellTiter-Glo assay solution was added to each well, and after shaking for 5 minutes, the mixture was allowed to stand for 10 minutes, followed by reading the Luminescence values of each well of the sample on a microplate reader using the Luminescence mode. The percent inhibition of compounds at each concentration point was calculated by comparison with the values of the control group (0.3% dmso), followed by nonlinear regression analysis of the compound concentration log-inhibition in GraphPad Prism 5 software to obtain IC compounds that inhibited cell proliferation ₅₀ The values are shown in Table 2.

TABLE 2 IC of the compounds of the invention for inhibition of AGS cell proliferation ₅₀ Data

Examples numbering	IC ₅₀ (nM)
2	630

Conclusion: the compound has better proliferation inhibition effect on AGS cells.

Unless otherwise defined, all terms used herein are intended to have the meanings commonly understood by those skilled in the art.

The described embodiments of the present invention are intended to be illustrative only and not to limit the scope of the invention, and various other alternatives, modifications, and improvements may be made by those skilled in the art within the scope of the invention, and therefore the invention is not limited to the above embodiments but only by the claims.

Claims

A compound of the general formula (a-I) or (a-II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

wherein:

selected from single or double bonds as required so that each atom to which it is attached assumes a normal valence state;

ring a is each independently selected from 5-6 membered heteroaryl or 5-10 membered monocyclic heterocyclyl; preferably a 6-to 7-membered monocyclic heterocyclic group; wherein the heteroaryl, monocyclic heterocyclyl contains one or more N or O atoms;

ring B is each independently selected from aryl, heteroaryl, or fused rings;

ring C is each independently selected from a 6-8 membered heterocyclic group containing 2 nitrogen atoms;

Q ¹ selected from N or CR ^a ；Q ¹ Preferably N;

Q ² each independently selected from N, C or CR ^a ；

Y is each independently selected from bond, O or NR ^b ；

X ¹ 、X ² Each independently selected from N, C = O, CR ^c Or CR (CR) ^d R ^e ；

E is each independently selected from hydrogen atoms or

R ^a The same or different are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, or a cyano group; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;

R ^b Selected from hydrogen atoms or alkyl groups;

R ^c selected from the group consisting of hydrogen, halogen, cyano, alkyl, or alkoxy; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; r is R ^c Preferably halogen, more preferably fluorine or chlorine;

R ^d and R is ^e The same or different are each independently selected from a hydrogen atom, a halogen, an alkyl group or an alkoxy group; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;

alternatively, R ^d And R is ^e Together with the carbon atom to which it is attached, form a cycloalkyl or heterocyclyl group; preferably cyclopropyl;

R ^f selected from hydrogen atoms or cycloalkyl groups, wherein said cycloalkyl groups are preferably cyclopropyl;

R ¹ each independently selected from hydrogen atom, -L-alkyl, -L-halogen, -L-OR ⁵ 、-L-NR ⁶ R ⁷ 、-L-C(O)OR ⁵ 、-L-C(O)NR ⁶ R ⁷ -L-cycloalkyl, -L-heterocyclyl, -L-aryl, -L-heteroaryl, -L-fused ring or
Wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or fused ring is optionally further substituted with one or more substituents selected from R ^g Is substituted by a substituent of (2);

R ^g identical 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 、-CH ₂ NHC(O)OR ⁵ 、-CH ₂ NR ⁶ R ⁷ or-S (O) _r R ⁵ Wherein said alkyl, benzyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted with one OR more groups selected from alkyl, halo, 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 、-CH ₂ NHC(O)OR ⁵ 、-CH ₂ NR ⁶ R ⁷ 、-NHS(O) _r R ⁵ or-S (O) _r R ⁵ Is substituted by a substituent of (2);

l are each independently selected from a bond or C ₁ -C ₆ An alkylene group, wherein said alkylene group is optionally further substituted with one or more R ^D Substituted;

R ^D each independently selected from a hydrogen atom, halogen, hydroxy or hydroxymethyl;

alternatively, two R's attached to the same carbon atom ^D Together with the attached carbon atom, form a cycloalkyl group; preferably cyclopropyl;

R ² the same or different are each independently selected from a hydrogen atom, halogen, hydroxy, alkyl or alkoxy, preferably a hydrogen atom or alkyl;

alternatively, any two R ² Together with the atoms to which they are attached, form a cycloalkyl or heterocyclyl group;

R ³ the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy or = O; wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; r is R ³ Preferably a hydrogen atom, methyl or = O;

R ⁴ Each independently selected from the group consisting of hydrogen, alkyl, halogen, nitro, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, 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 、-CH ₂ NHC(O)OR ⁵ 、-CH ₂ NR ⁶ R ⁷ or-S (O) _r R ⁵ The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl OR heteroaryl is optionally further substituted with one OR more substituents selected from alkyl, halo, nitro, cyano, cycloalkyl, heterocyclyl, 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 、-CH ₂ NHC(O)OR ⁵ 、-CH ₂ NR ⁶ R ⁷ or-S (O) _r R ⁵ Is substituted by a substituent of (2);

R ⁵ each independently selected from a hydrogen atom, halogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, 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 、-SO ₂ R ⁸ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

R ⁶ and R is ⁷ Each independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from R ^h Is substituted by a substituent of (2);

R ^h identical 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 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ The method comprises the steps of carrying out a first treatment on the surface of the Wherein said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl is optionally further substituted with one or more substituents 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 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

alternatively, R ⁶ And R is ⁷ Together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more of N, O or S (O) _r And said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents 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 、-CH ₂ NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Is substituted by a substituent of (2);

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

Each m is independently selected from 0, 1, 2, 3 or 4;

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

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

r are each independently selected from 0, 1 or 2.
The compound according to claim 1, which is a compound represented by the general formula (I) or (II), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

wherein: ring a, ring B, X ¹ 、X ² 、Y、Q ¹ 、Q ² 、R ¹ 、R ² 、R ³ 、R ⁴ The definitions of m, n and k are as defined in claim 1.
A compound according to claim 2, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound of formula (III), (IV), (V), or (VI), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein: ring B, X ¹ 、X ² 、Y、Q ¹ 、Q ² 、R ¹ 、R ² 、R ³ 、R ⁴ The definitions of m and n are as defined in claim 1.
The compound according to claim 1, which is a compound represented by the general formula (VII), (VIII) or (IX), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

wherein: ring B, X ¹ 、X ² 、Y、Q ¹ 、Q ² 、R ¹ 、R ² 、R ³ 、R ⁴ The definitions of m and n are as defined in claim 1.
A compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

Are each selected from double bonds;

Q ¹ selected from N;

Q ² selected from C;

X ¹ 、X ² each independently selected from N or CR ^c ；

R ^c Selected from hydrogen atoms or halogen, preferably halogen, more preferably fluorine or chlorine.
A compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

are each 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 halogen, preferably fluorine or chlorine, more preferably fluorine.
A compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

are all selected from single bonds;

X ¹ 、X ² each independently selected from CR ^d R ^e ；

R ^d And R is ^e Selected from hydrogen atoms;

alternatively, R ^d And R is ^e Together with the attached carbon atom, form a 3-5 membered monocyclic cycloalkyl or 3-5 membered monocyclic heterocyclyl; cyclopropyl is preferred.
A compound according to any one of claims 1 to 4, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

wherein:

X ² connected to
Selected from double bonds;

X ¹ and Q ² Between which are located
Selected from single bonds;

X ¹ selected from c=o;

X ² selected from N;

Q ² selected from N.
A compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

R ¹ Selected from-L-heterocyclyl; wherein said heterocyclyl is optionally further substituted with one or more substituents selected from alkyl, halogen, alkoxy or =o; wherein said halogen is preferably fluorine;

l is selected from a bond or C ₁ -C ₃ An alkylene group, wherein said alkylene group is optionally further substituted with one or more R ^D Substituted;

R ^D each independently selected from a hydrogen atom, halogen, hydroxy or hydroxymethyl;

alternatively, two R's attached to the same carbon atom ^D Together with the attached carbon atom, form a cycloalkyl group; cyclopropyl is preferred.
The compound of claim 9, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: l is selected from bond, -CH ₂ -、-CH ₂ CH ₂ -or
A compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R ¹ Selected from:
a compound according to any one of claims 1 to 11, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: r is R ³ The same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy or = O; r is R ³ Preferably a hydrogen atom, methyl or=o.
A compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: r is R ⁴ The same or different, each independently selected from hydrogen atom, alkyl, halogen, alkoxy, alkynyl, hydroxy, amino, hydroxyalkyl, haloalkyl or haloalkoxy; r is R ⁴ Preferably a hydrogen atom, methyl, fluorine, chlorine, bromine, iodine, hydroxyl, amino, hydroxymethyl or ethynyl.
A compound according to any one of claims 1 to 13, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

ring B is selected from phenyl, naphthaleneA group, a pyridyl group, a quinolyl group, an isoquinolyl group, an indolyl group, an indazolyl group, a benzothiazolyl group, a tetrahydronaphthyl group,

Ring B is preferably naphthyl or benzothiazolyl.
A compound according to any one of claims 1 to 13, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

selected from the following groups:
a compound according to claim 2 or 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: in said general formula (I) or (III)
Selected from the following groups:
a compound according to claim 2 or 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: in said formula (II), (IV), (V) or (VI)
Selected from the following groups:
The compound of claim 4, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: in said general formula (VII), (VIII) or (IX)
Selected from the following groups:
the compound according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:
a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 19, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
Use of a compound according to any one of claims 1 to 19, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the preparation of a KRas G12D inhibitor.
Use of a compound according to any one of claims 1 to 19, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the manufacture of a medicament for the treatment of 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, stomach cancer, colorectal cancer, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenoblastoma, myelogenous leukemia, acute lymphoblastic leukemia or glioblastoma, preferably pancreatic cancer, colorectal cancer, rectal cancer or lung cancer.
Use of a compound according to any one of claims 1 to 19, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the manufacture of a medicament for the treatment of cancer, wherein the cancer is selected from cardiac myxoma, lung cancer, stomach cancer, colorectal cancer, rectal cancer, pancreatic cancer, prostate cancer, bladder cancer, hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, multiple myeloma, uterine cancer, cervical cancer, seminoma, malignant melanoma, cutaneous squamous cell carcinoma, adrenoneuroblastoma, myelogenous leukemia, acute lymphoblastic leukemia or glioblastoma, preferably pancreatic cancer, colorectal cancer, rectal cancer or lung cancer.
The use according to claim 22 or 23, wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.