CN118434748A

CN118434748A - Six-membered and six-membered compound, preparation method, pharmaceutical composition and application

Info

Publication number: CN118434748A
Application number: CN202380015417.2A
Authority: CN
Inventors: 向少云; 刘渝鑫; 吴蕾; 张兵; 王苏月; 杨瑞; 向麦可; 向蜜儿
Original assignee: Hangzhou Duoyu Biotechnology Co ltd
Current assignee: Hangzhou Duoyu Biotechnology Co ltd
Priority date: 2022-04-15
Filing date: 2023-04-14
Publication date: 2024-08-02
Also published as: WO2023198191A1

Abstract

A six-membered and six-membered compound, its preparation method, pharmaceutical composition and application are disclosed. The compound has a good inhibition effect on KRAS G12D, and can be used for treating tumors related to KRAS G12D.

Description

Six-membered and six-membered compound, preparation method, pharmaceutical composition and application

The present application claims priority from chinese patent application 2022104001830, whose filing date is 2022, 4, 15. The present application incorporates the entirety of the above-mentioned chinese patent application.

Technical Field

The invention relates to a six-membered and six-membered compound, a preparation method, a pharmaceutical composition and application.

Background

Ras proteins (KRAS, NRAS and HRAS) are small GTPase signaling proteins consisting of about 190 amino acid residues encoded by the Ras gene, with GTPase activity. Can transmit signals from receptor tyrosine kinases, promote cell proliferation, cell differentiation or cell death. The signal is transferred to the process to play a role of bidirectional switch, the activity of the signal is regulated by the combination of the signal and GTP or GDP, and the signal is in an activated state when the GTP is combined and in an inactivated state when the GDP is combined. Modulation of this switch is often tightly controlled, and mutation of the RAS gene (e.g., cancer) can cause continued activity of the RAS protein, resulting in high activation of downstream signals (cell.2017 Jun 29;170 (1): 17-33).

KRAS mutations account for about 30% of tumor patients, KRAS G12 being the most common mutant residue (89%), mutatable to aspartic acid (G12D, 36%), followed by valine (G12V, 23%) and cysteine (G12C, 14%) (Nature RESEARCH SCIENTIFIC Reports,2019august 13). As shown by the American cancer research institute data, KRAS G12D was present in 4.20% of tumor patients with the highest prevalence of pancreatic, colon, lung, colorectal and rectal adenocarcinomas (https:// www.mycancergenome.org/content/alteration/KRAS-G12D /).

The KRAS protein surface is very smooth, with no pockets to which drugs can be attached. Furthermore, KRAS is a picomolar affinity for GDP and GTP, and substrate analogs are difficult to compete with GTP. Therefore, it has been regarded as a "target site difficult to prepare medicine". With recent 40 years of effort, KRAS G12C small molecule inhibitors developed by the ampoul corporation (AMG 510) were first FDA approved at day 28, 5, 2021 for the treatment of non-squamous, non-small cell lung cancer. Approval of AMG510 is a major breakthrough in the field of drug development of "refractory" KRAS proteins. Despite breakthrough progress in the KRAS (G12C) inhibitor AMG510, the most common and most oncogenic G12 mutant is KRAS (G12D), and clinically no effective drug has been used in KRAS G12D mutated patients, which typically have a poor prognosis. Multivariate analysis also confirmed that KRAS G12D was an independent predictor of poor prognosis (Clin Transl. Gastroentenol. 2016Mar24;7 (3)).

Currently, no KRAS G12D inhibitors have entered clinical trials, and there is still a tremendous medical unmet need for therapeutic intervention in KRAS G12D mutated cancer patients. Our compounds bind to KRAS in the GDP-binding state and selectively block the interaction of KRAS G12D mutations with CRAF effectively without affecting the function of wild-type KRAS protein.

Disclosure of Invention

The invention aims to solve the technical problem that the structure of a compound for inhibiting KRAS G12D is fewer in the prior art, and therefore, the invention provides a six-membered and six-membered compound, a preparation method, a pharmaceutical composition and application. The compounds of the invention have inhibitory effect on KRAS G12D.

The invention provides a six-membered and six-membered compound shown in a formula I or pharmaceutically acceptable salt thereof,

Wherein,Is a double bond or a single bond;

A is N or CR ^A;R^A is cyano or halogen;

b is N or CR ^B;R^B is cyano or halogen;

When (when) When the compound is double bond, E is N or CH;

When (when) When the bond is single bond, E is NH, CR ^E-1R^E-2 or CO; r ^E-1 and R ^E-2 are independently hydrogen or C ₁-C₆ alkyl, or R ^E-1 and R ^E-2 together with the carbon atom to which they are attached form a 3 to 6 membered heterocycloalkyl or C ₃-C₆ cycloalkyl; the heteroatom of the 3-to 6-membered heterocycloalkyl group is N, S or O, and the number of the heteroatom is 1;

G is NH, CR ^G-1R^G-2 or CO; r ^G-1 and R ^G-2 are independently hydrogen, or C ₁-C₆ alkyl, unsubstituted or substituted with one or more halogens, or R ^G-1 and R ^G-2 together with the carbon atom to which they are attached form a 3 to 6 membered heterocycloalkyl or C ₃-C₆ cycloalkyl; the heteroatom of the 3-to 6-membered heterocycloalkyl group is N, S or O, and the number of the heteroatom is 1;

When (when) When the double bond is present, M is N or CH;

When (when) When a single bond, then M is NR ^M-1 or CR ^M-2R^M-3;R^M-1 is hydrogen or C ₁-C₆ alkyl, unsubstituted or substituted with one or more halogens; r ^M-2 and R ^M-3 are independently hydrogen, halogen, or C ₁-C₆ alkyl, unsubstituted or substituted with one or more halogens, or R ^M-2 and R ^M-3 together with the carbon atom to which they are attached form a 3 to 6 membered heterocycloalkyl or C ₃-C₆ cycloalkyl; the heteroatom of the 3-to 6-membered heterocycloalkyl group is N, S or O, and the number of the heteroatom is 1;

R ¹ is 6-to 10-membered heterocycloalkyl, which is unsubstituted or substituted by one or more R ^1-3, C ₁-C₆ alkoxy substituted by one or more R ^1-1, or The heteroatom of the 6-to 10-membered heterocycloalkyl is selected from one or more of N, S and O, and the number of the heteroatom is 1,2 or 3; the 6-to 10-membered heterocycloalkyl is a bridged, spiro or fused ring;

each R ^1-1 is independently one or more Substituted C ₃-C₆ cycloalkyl;

R ^1-2 is C ₁-C₆ alkyl substituted by one or more R ^1-2-1, substituted by one or more Substituted C ₃-C₆ cycloalkyl or 4 to 10 membered heterocycloalkyl, unsubstituted or substituted by one or more C ₁-C₆ alkyl; the heteroatom of the 4-to 10-membered heterocycloalkyl group is N, and the number of the heteroatom is 1;

Each R ^1-2-1 is independently one or more Substituted C ₃-C₆ cycloalkyl or 4 to 10 membered heterocycloalkyl, unsubstituted or substituted by one or more C ₁-C₆ alkyl; the heteroatom of the 4-to 10-membered heterocycloalkyl group is N, and the number of the heteroatom is 1;

Each R ^1-3 is independently cyano, C ₂-C₆ alkynyl, C ₁-C₆ alkyl, hydroxy, halogen or substituted by one or more R ^1-3-1

Each R ^1-3-1 is independently cyano, hydroxy, or halogen;

r ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1, C ₁-C₆ alkyl substituted with one or more R ^2-2, 3-to 6-membered heterocycloalkyl or substituted with one or more R ^2-3 The hetero atoms of the 3-to 6-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3;

each R ^2-1 is independently deuterium, halogen, A5 to 10 membered heterocycloalkyl unsubstituted or substituted by one or more R ^2-1-1, a5 to 6 membered heteroaryl unsubstituted or substituted by one or more R ^2-1-2, or a C ₃-C₆ cycloalkyl unsubstituted or substituted by one or more R ^2-1-3; the heteroatom of the 5-to 10-membered heterocycloalkyl group is selected from one or more of N, S and O, and the number of the heteroatom is1, 2 or 3; the hetero atoms of the 5-to 6-membered heteroaryl are selected from one or more of N, S and O, and the number of the hetero atoms is1, 2 or 3;

Each R ^2-1-1 is independently deuterium, hydroxy, oxo, 6 to 10 membered aryl, halogen, C ₁-C₆ alkyl which is unsubstituted or substituted by one or more R ^2-1-1-1, C ₁-C₆ alkoxy which is unsubstituted or substituted by one or more R ^2-1-1-2, or A5 to 6 membered heteroaryl, unsubstituted or substituted with one or more R ^2-1-1-4; the hetero atoms of the 5-to 6-membered heteroaryl are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3;

each R ^2-1-1-1 is independently deuterium, hydroxy, oxo, halogen, C ₁-C₆ alkyl, C ₁-C₆ alkoxy, 3 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl, unsubstituted or substituted with one or more R ^2-1-1-1-1, The hetero atoms of the 3-to 6-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3; the hetero atoms of the 5-to 6-membered heteroaryl are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3;

each R ^2-1-1-1-1 is independently oxo;

R ^2-1-1-1-2 is a 3 to 6 membered heterocycloalkyl; the hetero atoms of the 3-to 6-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3;

Each R ^2-1-1-2 is independently C ₁-C₆ alkoxy;

R ^2-1-1-3 is C ₆-C₁₀ aryl, unsubstituted or substituted with one or more R ^2-1-1-3-1;

Each R ^2-1-1-3-1 is independently-SO ₂ F;

Each R ^2-1-1-4 is independently C ₁-C₆ alkyl;

Each R ^2-1-2 is independently C ₁-C₆ alkyl or halogen;

Each R ^2-1-3 is independently C ₁-C₆ alkyl, unsubstituted or substituted with one or more R ^2-1-3-1;

Each R ^2-1-3-1 is independently Or a 5 to 10 membered heterocycloalkyl unsubstituted or substituted with one or more R ^2-1-3-1-1; the heteroatom of the 5-to 10-membered heterocycloalkyl group is selected from one or more of N, S and O, and the number of the heteroatom is 1,2 or 3;

Each R ^2-1-3-1-1 is independently halogen;

Each R ^2-2 is independently a 5-to 10-membered heterocycloalkyl unsubstituted or substituted by one or more R ^2-2-1, the heteroatoms of the 5-to 10-membered heterocycloalkyl being selected from one or more of N, S and O, the number of heteroatoms being 1,2 or 3;

each R ^2-2-1 is independently C ₁-C₆ alkoxy;

Each R ^2-3 is independently Or C ₁-C₆ alkyl;

R ^2-4 is 5-to 10-membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^2-4-1, the heteroatom of the 5-to 10-membered heterocycloalkyl is selected from one or more of N, S and O, and the number of the heteroatom is 1,2 or 3;

Each R ^2-4-1 is independently C ₁-C₆ alkyl, unsubstituted or substituted with one or more R ^2-4-1-1;

Each R ^2-4-1-1 is independently C ₁-C₆ alkoxy;

The conditions are as follows: when (when) Is thatR ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1; each R ^2-1 is independently a 5 to 10 membered heterocycloalkyl substituted with one or more R ^2-1-1, the heteroatoms of the 5 to 10 heterocycloalkyl being selected from one or more of N, S and O, the number of heteroatoms being 1,2 or 3; each R ^2-1-1 is independently C ₁-C₆ alkyl or halogen;

R ³ is C ₆-C₁₀ aryl, unsubstituted or substituted with one or more R ^3-1, or 5 to 10 membered heteroaryl, unsubstituted or substituted with one or more R ^3-2; the hetero atoms of the 5-to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3;

Each R ^3-1 and R ^3-2 is independently C ₂-C₆ alkynyl unsubstituted or substituted by one or more R ^3-1-1, C ₁-C₆ alkyl unsubstituted or substituted by one or more R ^3-1-2, C ₃-C₆ cycloalkyl unsubstituted or substituted by one or more R ^3-1-3, C ₁-C₆ alkoxy unsubstituted or substituted by one or more R ^3-1-4, C ₁-C₆ alkylthio unsubstituted or substituted by one or more R ^3-1-5, 5 to 10 membered heteroaryl, hydroxy, halogen, cyano, C ₂-C₆ alkenyl or substituted by one or more R ^3-1-6 The hetero atoms of the 5-to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3; or two adjacent R ^3- ¹ together with the atom to which the C ₆-C₁₀ aryl group is attached form a3 to 6 membered cycloalkyl which is unsubstituted or substituted by one or more R ^3-1-7;

Each R ^3-1-1、R^3-1-2、R^3-1-3、R^3-1-4、R^3-1-5、R^3-1-6 and R ^3-1-7 is independently C ₁-C₆ alkyl, C ₂-C₆ alkynyl, cyano, halogen, deuterium, hydroxy or amino; or two adjacent R ^3-1-7 taken together with the atom to which they 3 to 6 membered cycloalkyl are attached form 3 to 6 membered cycloalkyl which is unsubstituted or substituted by one or more R ^3-1-7-1;

Each R ^3-1-7-1 is independently C ₁-C₆ alkyl;

Each of R ^a and R ^b is independently hydrogen or C ₁-C₆ alkyl, or R ^a and R ^b, and the atoms 3 to 6 membered heterocycloalkyl attached thereto; the hetero atom of the 3-to 6-membered heterocycloalkyl group is selected from one or more of N, S and O, the number of the hetero atoms is 1,2 or 3, and the hetero atom of the 3-to 6-membered heterocycloalkyl group at least comprises one N.

In a certain preferred embodiment, the six-membered and six-membered compound shown in formula I or pharmaceutically acceptable salt thereof; the definition of some groups may be as follows, and the definition of other groups may be as described in any of the above schemes (hereinafter referred to as "certain preferred scheme"): in R ^A, the halogen may be fluorine, chlorine, bromine or iodine, such as fluorine.

In a preferred embodiment, R ^B, the halogen may be fluorine, chlorine, bromine or iodine, such as fluorine.

In a preferred embodiment, when E is CR ^E-1R^E-2, R ^E-1 and R ^E-2 together with the carbon atoms to which they are attached form an epoxybutyl group.

In a preferred embodiment, in E, R ^E-1 and R ^E-2 together with the carbon atom to which they are attached may form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

In a preferred embodiment, in R ^E-1 and R ^E-2, the C ₁-C₆ alkyl group may be independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, and may also be methyl.

In a preferred embodiment, when G is CR ^G-1R^G-2, R ^G-1 and R ^G-2 together with the carbon atoms to which they are attached form an epoxybutyl group.

In a preferred embodiment, when G is CR ^G-1R^G-2, R ^G-1 and R ^G-2 together with the carbon atoms to which they are attached may form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

In a preferred embodiment, in R ^G-1, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, and may also be methyl.

In a preferred embodiment, in R ^G-2, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, and may also be methyl.

In a preferred embodiment, in R ^M-1、R^M-2 and R ^M-3, the C ₁-C₆ alkyl groups may independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl.

In a preferred embodiment, in R ^M-1、R^M-2 and R ^M-3, the halogen may independently be fluorine, chlorine, bromine or iodine, such as fluorine.

In a preferred embodiment, when M is CR ^M-2R^M-3, R ^M-2 and R ^M-3 together with the carbon atoms to which they are attached form an epoxybutyl group.

In a preferred embodiment, when M is CR ^M-2R^M-3, R ^M-2 and R ^M-3 together with the carbon atom to which they are attached may form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, for example cyclopropyl.

In a preferred embodiment, in R ¹, the 6-to 10-membered heterocycloalkyl may be a 6-to 8-membered heterocycloalkyl; the heteroatom of the 6-to 10-membered heterocycloalkyl group is preferably N, S or O, and the number of the heteroatom is preferably 1 or 2; the 6-to 10-membered heterocycloalkyl group is more preferably an 8-membered bridged cycloalkyl group, for example

In a preferred embodiment, in each R ¹, the C ₁-C₆ alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, and may also be methoxy or ethoxy.

In a preferred embodiment, in each R ^1-1, the C ₃-C₆ cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclobutyl or cyclopentyl.

In a preferred embodiment, in R ^1-2, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl.

In a preferred embodiment, in R ^1-2, the C ₃-C₆ cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclobutyl or cyclopentyl.

In a preferred embodiment, in R ^1-2, the 4-to 10-membered heterocycloalkyl may be a 4-to 6-membered heterocycloalkyl; the 4-to 10-membered heterocycloalkyl is preferably a single ring; the 4-to 10-membered heterocycloalkyl group is more preferably an azetidinyl group.

In a preferred embodiment, in each R ^1-2-1, the C ₃-C₆ cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclobutyl or cyclopentyl.

In a preferred embodiment, in each R ^1-2-1, the 4-to 10-membered heterocycloalkyl may be a 4-to 6-membered heterocycloalkyl; the 4-to 10-membered heterocycloalkyl is preferably a single ring; the 4-to 10-membered heterocycloalkyl group is more preferably an azetidinyl group, for example

In a preferred embodiment, in each R ^1-3, the C ₂-C₆ alkynyl group may be a C ₂-C₄ alkynyl group, preferably

In a preferred embodiment, in each R ^1-3, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl or ethyl.

In a preferred embodiment, in each R ^1-3-1, the halogen may be fluorine, chlorine, bromine or iodine, such as fluorine.

In a preferred embodiment, in R ², the C ₁-C₆ alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, and may also be methoxy, ethoxy or n-propoxy.

In a preferred embodiment, in R ², the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl.

In a preferred embodiment, in R ², the heteroatom of the 3-to 6-membered heterocycloalkyl group can be N, S or O; the number of heteroatoms of the 3-to 6-membered heterocycloalkyl group is preferably 1,2 or 3; the 3-to 6-membered heterocycloalkyl is preferably a single ring; the 3-to 6-membered heterocycloalkyl group is more preferably an azetidinyl group, for example

In a preferred embodiment, in each R ^2-1, the halogen may be fluorine, chlorine, bromine or iodine, such as fluorine.

In a preferred embodiment, in each R ^2-1, the heteroatom of the 5 to 10 membered heterocycloalkyl may be N and/or O; the number of heteroatoms of the 5-to 10-membered heterocycloalkyl group is preferably 1 or 2; the 5-to 10-membered heterocycloalkyl group is preferably a 5-to 8-membered heterocycloalkyl group, for example

In a preferred embodiment, in each R ^2-1, the heteroatom of the 5 to 6 membered heteroaryl may be N; the number of heteroatoms of the 5-to 6-membered heteroaryl group is preferably 1,2 or 3; the 5-to 6-membered heteroaryl group is more preferably a pyridyl or imidazolyl group, e.g

In a preferred embodiment, in each R ^2-1, the C ₃-C₆ cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclobutyl or cyclopentyl.

In a preferred embodiment, in each R ^2-1-1, the halogen may be fluorine, chlorine, bromine or iodine, such as fluorine.

In a preferred embodiment, in each R ^2-1-1, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl.

In a preferred embodiment, in each R ^2-1-1, the heteroatom of the 3-to 6-membered heterocycloalkyl may be N, S or O; the number of heteroatoms of the 3-to 6-membered heterocycloalkyl group is preferably 1,2 or 3; the 3-to 6-membered heterocycloalkyl is preferably a single ring; the 3-to 6-membered heterocycloalkyl group is more preferably an azetidinyl group, for example

In a preferred embodiment, in each R ^2-1-1, the heteroatom of the 5 to 6 membered heteroaryl may be N; the number of heteroatoms of the 5-to 6-membered heteroaryl group is preferably 1,2 or 3; the 5-to 6-membered heteroaryl group is more preferably pyrazolyl, e.g

In a preferred embodiment, in R ^2-1-1-1, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl.

In a preferred embodiment, in each R ^2-1-1-1, the C ₁-C₆ alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, and may also be methoxy.

In a preferred embodiment, in each R ^2-1-1-1, the C ₆-C₁₀ aryl group may be aryl or naphthyl, for example aryl.

In a preferred embodiment, in each R ^2-1-1-1, the heteroatom of the 3-to 6-membered heterocycloalkyl may be N and/or O; the number of heteroatoms of the 3-to 6-membered heterocycloalkyl group is 1 or 2; the 3-to 6-membered heterocycloalkyl group is preferably a 5-to 6-membered heterocycloalkyl group, for example

In a preferred embodiment, in each R ^2-1-1-1, the heteroatom of the 5 to 6 membered heteroaryl may be N; the number of heteroatoms of the 5-to 6-membered heteroaryl group is preferably 1,2 or 3; the 5-to 6-membered heteroaryl group is more preferably pyrazolyl, e.g

In a preferred embodiment, in each R ^2-1-1-2, the C ₁-C₆ alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, and may also be methoxy.

In a preferred embodiment, in R ^2-1-1-3, the C ₆-C₁₀ aryl group may be aryl or naphthyl, such as aryl.

In a preferred embodiment, in each R ^2-1-1-4, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl.

In a preferred embodiment, in R ^2-1-1-1-2, the heteroatom of the 3-to 6-membered heterocycloalkyl group may be N and/or O; the number of heteroatoms of the 3-to 6-membered heterocycloalkyl group is 1 or 2; the 3-to 6-membered heterocycloalkyl group is preferably a 5-to 6-membered heterocycloalkyl group, for example

In a preferred embodiment, in each R ^2-1-2, the halogen may be fluorine, chlorine, bromine or iodine, such as fluorine.

In a preferred embodiment, in each R ^2-1-2, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl or isopropyl.

In a preferred embodiment, in each R ^2-1-3, the halogen may be fluorine, chlorine, bromine or iodine, such as fluorine.

In a preferred embodiment, in each R ^2-1-3, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl.

In a preferred embodiment, in each R ^2-1-3-1, the heteroatom of the 5 to 10 membered heterocycloalkyl may be N and/or O; the number of heteroatoms of the 5-to 10-membered heterocycloalkyl group is preferably 1 or 2; the 5-to 10-membered heterocycloalkyl group is preferably a 5-to 6-membered heterocycloalkyl group, for example

In a preferred embodiment, each R ^2-1-3-1-1, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine.

In a preferred embodiment, in each R ^2-2, the heteroatom of the 5 to 10 membered heterocycloalkyl may be N and/or O; the number of heteroatoms of the 5-to 10-membered heterocycloalkyl group is preferably 1 or 2; the 5-to 10-membered heterocycloalkyl group is preferably an 8-membered heterocycloalkyl group, for example

In a preferred embodiment, in each R ^2-2-1, the C ₁-C₆ alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, and may also be methoxy.

In a preferred embodiment, in each R ^2-3, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl or ethyl.

In a preferred embodiment, in each R ^2-4, the heteroatom of the 5 to 10 membered heterocycloalkyl may be N; the number of heteroatoms of the 5-to 10-membered heterocycloalkyl group is preferably 1 or 2; the 5-to 10-membered heterocycloalkyl group is preferably a 5-to 6-membered heterocycloalkyl group, for example

In a preferred embodiment, in each R ^2-4-1, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example n-propyl.

In a preferred embodiment, in each R ^2-4-1-1, the C ₁-C₆ alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, and may also be methoxy.

In a preferred embodiment, in R ³, the C ₆-C₁₀ aryl group may be aryl or naphthyl.

In a preferred embodiment, in R ³, the heteroatom of the 5-to 10-membered heteroaryl group may be N and/or S; the number of heteroatoms of the 5-to 10-membered heteroaryl group is preferably 1 or 2; the 5-to 10-membered heteroaryl group is a five-membered and six-membered heteroaryl group, e.g

In a preferred embodiment, in each of R ^3-1 and R ^3-2, the C ₂-C₆ alkynyl group may be a C ₂-C₄ alkynyl group, preferably For example

In a preferred embodiment, in each of R ^3-1 and R ^3-2, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl, ethyl, n-propyl or isopropyl.

In a preferred embodiment, in each of R ^3-1 and R ^3-2, the C ₃-C₆ cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl.

In a preferred embodiment, in each of R ^3-1 and R ^3-2, the C ₁-C₆ alkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, and may also be methoxy.

In a certain preferred embodiment, in each of R ^3-1 and R ^3-2, the C ₁-C₆ alkylthio group may be a methylthio group, an ethylthio group, a n-propylthio group, an isopropylthio group, a n-butylthio group, an isobutylthiol group, a primary butylthio group, a Zhong Ding group or a tertiary butylthio group, and may also be a methylthio group.

In a preferred embodiment, in each of R ^3-1 and R ^3-2, the heteroatom of the 5 to 10 membered heteroaryl may be N; the number of heteroatoms of the 5-to 10-membered heteroaryl group is preferably 2 or 3; the 5-to 10-membered heteroaryl is a 5-to 6-membered heteroaryl, e.g

In a preferred embodiment, in each of R ^3-1 and R ^3-2, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine, chlorine or bromine.

In a preferred embodiment, each of R ^3-1 and R ^3-2, the C ₂-C₆ alkene may be vinyl, Such as vinyl.

In a preferred embodiment, in each of R ^3-1-1、R^3-1-2、R^3-1-3、R^3-1-4、R^3-1-5、R^3-1-6 and R ^3-1-7, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl.

In a preferred embodiment, each of R ^3-1-1、R^3-1-2、R^3-1-3、R^3-1-4、R^3-1-5、R^3-1-6 and R ^3-1-7, the C ₂-C₆ alkynyl group may beFor example

In a preferred embodiment, in each of R ^3-1-1、R^3-1-2、R^3-1-3、R^3-1-4、R^3-1-5、R^3-1-6 and R ^3-1-7, the halogen may be fluorine, chlorine, bromine or iodine, such as fluorine.

In a preferred embodiment, in each R ^3-1-7-1, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl.

In a preferred embodiment, in each R ^a, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl.

In a preferred embodiment, in each R ^b, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl.

In a preferred embodiment, in each of R ^a and R ^b, the heteroatom of the 3 to 6 membered heterocycloalkyl may be N; the number of heteroatoms of the 3-to 6-membered heterocycloalkyl group is preferably 1 or 2; the 3-to 6-membered heterocycloalkyl is preferably a 5-to 6-membered heterocycloalkyl, for example

In a preferred embodiment, R ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1 or 3 to 6 membered heterocycloalkyl substituted with one or more R ^2-3 orThe hetero atoms of the 3-to 6-membered heterocyclic alkyl are N, and the number of the hetero atoms is 1 or 2.

In a preferred embodiment, at least one R ^2-1 in each R ^2-1 is said 5 to 10 membered heterocycloalkyl or said C ₃-C₆ cycloalkyl.

In a preferred embodiment, each R ^2-1 is independently deuterium,A5 to 8 membered heterocycloalkyl unsubstituted or substituted by one or more R ^2-1-1 or a C ₃-C₆ cycloalkyl unsubstituted or substituted by one or more R ^2-1-3; the hetero atoms of the 5-to 8-membered heterocycloalkyl group are N and/or O, and the number of the hetero atoms is 1 or 2.

In a preferred embodiment, each R ^2-1-1 is independently deuterium, hydroxy, halogen, C ₁-C₆ alkyl, unsubstituted or substituted with one or more R ^2-1-1-1, or C ₁-C₆ alkoxy, unsubstituted or substituted with one or more R ^2-1-1-2.

In a preferred embodiment, each R ^2-1-1-1 is independently halogen, C ₁-C₆ alkoxy or

In a preferred embodiment, each R ^2-1-1-2 is independently C ₁-C₆ alkoxy.

In a preferred embodiment, R ^2-1-1-1-2 is 3 to 6 membered heterocycloalkyl; the hetero atoms of the 3-to 6-membered heterocycloalkyl group are N and/or O, and the number of the hetero atoms is 1 or 2.

In a preferred embodiment, each R ^2-1-3 is independently C ₁-C₆ alkyl, unsubstituted or substituted with one or more R ^2-1-3-1.

In a preferred embodiment, each R ^2-1-3-1 is independentlyOr a 5-to 6-membered heterocycloalkyl unsubstituted or substituted by one or more R ^2-1-3-1-1; the hetero atoms of the 5-to 6-membered heterocycloalkyl group are N, and the number of the hetero atoms is 1.

In a preferred embodiment, each R ^2-1-3-1-1 is independently halogen.

In a preferred embodiment, R ³ is C ₆-C₁₀ aryl, unsubstituted or substituted with one or more R ^3-1, or 5 to 10 membered heteroaryl, unsubstituted or substituted with one or more R ^3-2; the hetero atom of the 5-to 10-membered heteroaryl group is N, and the number of the hetero atoms is 1 or 2.

In a preferred embodiment, each R ^3-1 and R ^3-2 is independently C ₂-C₆ alkynyl, unsubstituted or substituted with one or more R ^3-1-1, C ₁-C₆ alkyl, unsubstituted or substituted with one or more R ^3-1-2, C ₃-C₆ cycloalkyl, unsubstituted or substituted with one or more R ^3-1-3, C ₁-C₆ alkoxy, hydroxy, halogen or cyano, or C ₂-C₆ alkenyl, unsubstituted or substituted with one or more R ^3-1-4.

In a preferred embodiment, each of R ^3-1-1、R^3-1-2、R^3-1-3 and R ^3-1-4 is independently C ₁-C₆ alkyl, halogen, deuterium, or hydroxy.

In a preferred embodiment, A is N.

In a preferred embodiment, B is N.

In a preferred embodiment, E is N, CR ^E-1R^E-2 or CO.

In a preferred embodiment, R ^E-1 and R ^E-2 are independently hydrogen or C ₁-C₆ alkyl; or, R ^E-1 and R ^E-2 together with the carbon atom to which they are attached form a C ₃-C₆ cycloalkyl group.

In a preferred embodiment, G is CR ^G-1R^G-2 or CO; r ^G-1 and R ^G-2 are independently hydrogen, or C ₁-C₆ alkyl, unsubstituted or substituted with one or more halogens, or R ^G-1、R^G-2 together with the carbon atom to which they are attached form a3 to 6 membered heterocycloalkyl or C ₃-C₆ cycloalkyl; the hetero atoms of the 3-to 6-membered heterocycloalkyl group are O, and the number of the hetero atoms is 1.

In a preferred embodiment, M is NH, CH or CH ₂.

In a preferred embodiment, R ¹ is unsubstituted 8 membered heterocycloalkyl, C ₁-C₆ alkoxy substituted with one or more R ^1-1, orThe heteroatom of the 8-membered heterocycloalkyl group is N, and the number of the heteroatom is 1 or 2; the 8-membered heterocycloalkyl is a bridged, spiro or fused ring.

In a preferred embodiment, each R ^1-1 is independently one or moreSubstituted C ₃-C₆ cycloalkyl.

In a preferred embodiment, R ^1-2 is C ₁-C₆ alkyl substituted with one or more R ^1-2-1.

In a preferred embodiment, R ^1-2-1 is one or moreSubstituted C ₃-C₆ cycloalkyl.

In a preferred embodiment, R ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1.

In a preferred embodiment, each R ^2-1 is independently a 5-to 10-membered heterocycloalkyl, unsubstituted or substituted with one or more R ^2-1-1, wherein the 5-to 10-membered heterocycloalkyl has N heteroatoms and 1,2 or 3 heteroatoms.

In a preferred embodiment, each R ^2-1-1 is independently halogen or C ₁-C₆ alkyl, unsubstituted or substituted with one or more halogens.

In a preferred embodiment, whenIs thatWhen each R ^2-1 is independently 5 to 10 membered heterocycloalkyl substituted with one or more R ^2-1-1.

In a preferred embodiment, R ³ is C ₆-C₁₀ aryl, unsubstituted or substituted with one or more R ^3-1, or 5 to 10 membered heteroaryl, unsubstituted or substituted with one or more R ^3-2; the hetero atom of the 5-to 10-membered heteroaryl is selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3.

In a preferred embodiment, each R ^3-1 is independently C ₂-C₆ alkynyl, C ₁-C₆ alkyl, C ₃-C₆ cycloalkyl, hydroxy, halogen orOr two adjacent R ^3-1 together with the atom to which the C ₆-C₁₀ aryl group is attached form a 5 to 6 membered cycloalkyl which is unsubstituted or substituted by one or more R ^3-1-7.

In a preferred embodiment, each R ^3-1-7 is independently C ₁-C₆ alkyl.

In a preferred embodiment, each R ^3-2 is independently C ₁-C₆ alkyl, halogen or amino.

In a preferred embodiment, each of R ^a and R ^b is independently hydrogen or C ₁-C₆ alkyl, or R ^a and R ^b, and the atoms 3 to 6 membered heterocycloalkyl attached thereto; the heteroatom of the 3-to 6-membered heterocycloalkyl group is N, and the number of the heteroatom is 1,2 or 3.

In a preferred embodiment, E is CH ₂.

In a preferred embodiment, G is CO.

In a preferred embodiment, M is CH ₂.

In a preferred embodiment, R ¹ is unsubstituted 8 membered heterocycloalkyl; the heteroatom of the 8-membered heterocycloalkyl group is N, and the number of the heteroatom is 2; the 8-membered heterocycloalkyl is a bridged or spiro ring.

In a preferred embodiment, each R ^2-1 is independently a 5-to 8-membered heterocycloalkyl, unsubstituted or substituted with one or more R ^2-1-1, wherein the 5-to 8-membered heterocycloalkyl has N heteroatoms and 1 heteroatom.

In a preferred embodiment, each R ^2-1-1 is independently halogen;

In a preferred embodiment, R ³ is C ₆-C₁₀ aryl substituted with one or more R ^3-1 or 5 to 10 membered heteroaryl substituted with one or more R ^3-2; the heteroatom of the 5-to 10-membered heteroaryl is N, and the number of the heteroatom is 1,2 or 3.

In a preferred embodiment, each R ^3-1 is independently C ₂-C₆ alkynyl, hydroxy, or halogen;

In a preferred embodiment, each R ^3-2 is independently C ₁-C₆ alkyl.

In a preferred embodiment, the six-membered and six-membered compound shown in formula I or a pharmaceutically acceptable salt thereof as described above,

The six-membered and six-membered compound shown in the formula I is shown in the following scheme 1 or scheme 2;

scheme 1, wherein, Is a single bond;

A is N or CR ^A;R^A is cyano or halogen;

b is N or CR ^B;R^B is cyano or halogen;

E is CR ^E-1R^E-2;R^E-1 and R ^E-2 are independently hydrogen or C ₁-C₆ alkyl;

G is CO;

M is CR ^M-2R^M-3;R^M-1 is hydrogen or C ₁-C₆ alkyl optionally substituted with one or more halogens; r ^M-2 and R ^M-3 are independently hydrogen, halogen, or C ₁-C₆ alkyl, unsubstituted or substituted with one or more halogens;

R ¹、R² and R ³ are as defined above;

Scheme 2: wherein, Is a double bond or a single bond;

A is CR ^A;R^A is cyano;

B is N;

E. G, M, R ¹、R² and R ³ are as defined above.

In a preferred embodiment, the six-membered and six-membered compound represented by formula I as described above or a pharmaceutically acceptable salt thereof,

Scheme 1: wherein, Is a single bond;

A is N or CR ^A;R^A is cyano or halogen;

b is N or CR ^B;R^B is cyano or halogen;

G is CO;

M is CR ^M-2R^M-3;R^M-2 and R ^M-3 are independently hydrogen or C ₁-C₆ alkyl;

R ¹ is unsubstituted 8 membered heterocycloalkyl; the heteroatom of the 8-membered heterocycloalkyl group is N, and the number of the heteroatom is 2; the 8-membered heterocycloalkyl is a bridged or spiro ring;

R ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1;

Each R ^2-1 is independently a 5-to 8-membered heterocycloalkyl that is unsubstituted or substituted with one or more R ^2-1-1, the heteroatom of the 5-to 8-membered heterocycloalkyl being N, the number of heteroatoms being 1;

Each R ^2-1-1 is independently halogen or C ₁-C₆ alkyl;

R ³ is naphthyl substituted with one or more R ^3-1;

Each R ^3-1 is independently C ₂-C₆ alkynyl, hydroxy, or halogen;

Scheme 2: wherein, Is a single bond;

A is CR ^A;R^A is cyano;

B is N;

G is CR ^G-1R^G-2 or CO; r ^G-1 and R ^G-2 are independently hydrogen, or C ₁-C₆ alkyl;

R ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1;

Each R ^2-1-1 is independently halogen or C ₁-C₆ alkyl;

R ³ is naphthyl substituted with one or more R ^3-1;

Each R ^3-1 is independently C ₂-C₆ alkynyl, hydroxy, or halogen.

In a preferred embodiment, the six-membered and six-membered compound shown in formula I can be shown in formula I-A, formula I-B, formula I-C, formula I-D or formula I-E:

in a preferred embodiment, the pharmaceutically acceptable salt may be a salt conventional in the art, such as a formate salt.

In a preferred embodiment of the present invention,Is that

In a preferred embodiment, R ¹ is

In a preferred embodiment, R ² is

In a preferred embodiment, R ³ is

In a certain preferred scheme, the six-membered and six-membered compound shown in the formula I or the pharmaceutically acceptable salt thereof has any structure as follows,

A six-membered and six-membered compound represented by the formula II-A or a pharmaceutically acceptable salt thereof,

Wherein,Is a single bond;

A is N or CR ^A;R^A is cyano;

B is N;

g is O;

R ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1;

Each R ^2-1-1 is independently halogen or C ₁-C₆ alkyl;

R ³ is naphthyl substituted with one or more R ^3-1;

Each R ^3-1 is independently C ₂-C₆ alkynyl, hydroxy, or halogen.

In a preferred embodiment, in each of R ^E-1、R^E-2、R^M-2、R^M-3 and R ^2-1-1, the C ₁-C₆ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, and may be methyl.

In a preferred embodiment, R ¹ is

In a preferred embodiment, in each of R ^2-1-1 and R ^3-1, the halogen may be fluorine, chlorine, bromine or iodine, such as fluorine.

In a preferred embodiment, in R ^2-1, the C ₁-C₆ alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, and may be methoxy.

In a preferred embodiment, in R ^2-1, the 5-to 10-membered heterocycloalkyl is preferably 8-membered heterocycloalkyl; the 5-to 10-membered heterocycloalkyl is preferably bridged, spiro or fused.

In a preferred embodiment, R ^2-1 is said 5-to 10-membered heterocycloalkyl is preferably Preferably is

In a preferred embodiment, R ² is Preferably is

In a preferred embodiment, R ^3-1, the C ₂-C₆ alkynyl is C ₂-C₄ alkynyl, preferably

In a preferred embodiment, R ³ is Preferably is

A six-membered and six-membered compound shown in II-B or pharmaceutically acceptable salt thereof,

Wherein,Is a double bond;

A is N;

B is N;

e is N;

G is CR ^G-1;R^G-1 or halogen;

M is CH;

R ¹ is R ^1-4 is C ₁-C₆ alkyl which is unsubstituted or substituted by one or more R ^1-4-1; each R ^1-4-1 is independently halogen, C ₂-C₄ alkenyl orR ^1-4-1-1 is C ₁-C₆ alkyl;

The definition of R ² and R ³ is as described for the six-membered and six-membered compounds of formula II-A above.

In a preferred embodiment, in each of R ^1-4 and R ^1-4-1-1, the C ₁-C₆ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, and may be methyl.

In a preferred embodiment, R ^1-4-1, said C ₂-C₄ alkenyl group may be

In a preferred embodiment, R ^1-4-1 is C ₂-C₄ alkenyl or

In a preferred embodiment, each of R ^1-4-1 and R ^G-1, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine.

In a preferred embodiment, R ¹ is

A six-membered and six-membered compound or pharmaceutically acceptable salt thereof, which has any one of the following structures,

The invention also provides a preparation method of the six-membered and six-membered compound shown in the formula I, which comprises the following steps: in a solvent, the compound shown in the formula I-1 is subjected to deprotection reaction in the presence of fluorine-containing salt, so that the method is characterized in that:

Wherein A, B, M, E, G, R ² and R ³ are as previously described; r ¹ is R ⁴ is a nitrogen protecting group.

In the deprotection reaction, the nitrogen protecting groups are conventional nitrogen protecting groups for such reactions in the art, preferably Alloc, cbz, boc and Fmoc; such as Alloc.

In the deprotection reaction, the solvent is a conventional solvent for such a reaction in the art, preferably an amide-based solvent, more preferably DMF, for example anhydrous DMF.

In the deprotection reaction, the solvent is used in an amount conventional in the art, preferably the volume molar ratio of the solvent to the compound of formula I-1 is 70-20mL/mmol, for example 54mL/mmol.

In the deprotection reaction, the fluoride salt is a conventional fluoride salt of such a reaction in the art, preferably an alkali metal fluoride salt such as cesium fluoride.

In the deprotection reaction, the amount of the fluorine salt is the amount of the alkali conventional in the art, preferably the molar ratio of the fluorine salt to the compound shown as the formula I-1 is (1-10): 1, for example 5:1.

In the deprotection reaction, the reaction temperature of the deprotection reaction is a reaction temperature conventional in the art, preferably-10℃to 50℃such as room temperature.

The invention also provides a pharmaceutical composition, which comprises a substance Z and pharmaceutical excipients, wherein the substance Z is a six-membered and six-membered compound shown in a formula I or pharmaceutically acceptable salts thereof.

The invention also provides the use of a substance Z or a pharmaceutical composition as described above for the preparation of a medicament for the treatment of a disease associated with KRAS G12D, wherein the substance Z is a compound as described above in formula I or a pharmaceutically acceptable salt thereof, a six-membered and six-membered compound as described above in formula II-A or a pharmaceutically acceptable salt thereof, a six-membered and six-membered compound as described above in formula II-B or a pharmaceutically acceptable salt thereof, or a six-membered and six-membered compound as described above or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for the treatment and/or prophylaxis of a KRAS G12D-related disease comprising administering to a patient an effective amount of a substance Z as described in formula I or a pharmaceutically acceptable salt thereof as described above, a six-membered and six-membered compound as described in formula II-a or a pharmaceutically acceptable salt thereof as described above, a six-membered and six-membered compound as described in formula II-B or a pharmaceutically acceptable salt thereof as described above, or a six-membered and six-membered compound as described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.

In a preferred embodiment, the KRAS G12D-related disease is solid cancer; the solid cancer is preferably pancreatic ductal adenocarcinoma, pancreatic carcinoma, colon carcinoma, malignant colorectal tumor, non-small cell lung cancer, squamous cell lung cancer, gastric cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, glioblastoma, anal squamous cell carcinoma, chordal carcinoma, thyroid undifferentiated carcinoma or uveal melanoma.

Definition of terms

The term "group B which is unsubstituted or substituted by a plurality of groups a" means that one or more hydrogen atoms in group B are independently replaced by group a or B is unsubstituted. When a plurality of A groups are present at the same time, their definitions are independent of each other and do not affect each other unless specifically stated otherwise. For example, "C ₆～C₁₀ aryl substituted with 3 halogens" means that C ₆～C₁₀ aryl will be substituted with 3 halogens, the definition of 3 halogens being independent of each other and independent of each other, including but not limited to: Etc.

The term "plurality" refers to 2 and more than 2, such as 2,3,4, 5.

The term "pharmaceutically acceptable" refers to those compositions which are relatively non-toxic, safe, and suitable for use by a patient.

The term "pharmaceutically acceptable salt" refers to a salt of a compound that is obtained by reaction with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, the base addition salt may be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, bismuth salt, ammonium salt, and the like. When the compound contains a relatively basic functional group, the acid addition salt may be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to: hydrochloride, sulfate, formate, mesylate, and the like. See in particular Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl,Camille G.Wermuth,2011,2nd Revised Edition).

The term "-" in a group means that the group is attached to the remainder of the molecule through that site. For example, CH ₃ -C (=o) -refers to acetyl.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "oxo" refers to = O, an oxygen atom replacing two hydrogens on the same carbon atom, i.e., a carbonyl group replacing a methylene group.

The term "alkyl" refers to a straight or branched, saturated monovalent hydrocarbon radical having the indicated number of carbon atoms (e.g., C ₁～C₆). Alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.

The term "alkoxy" refers to the radical R ^X-O-,R^X as defined by the term "alkyl". Alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

The term "alkenyl" refers to a straight or branched chain, unsaturated, monovalent hydrocarbon radical having the specified number of carbon atoms (e.g., C ₂～C₆) and having one or more (e.g., 1,2, or 3) carbon-carbon sp ² double bonds. Alkenyl groups include, but are not limited to: vinyl group, Etc.

The term "alkynyl" refers to a straight or branched chain, unsaturated, monovalent hydrocarbon radical of the specified number of carbon atoms (e.g., C ₂～C₆) having one or more (e.g., 1,2, or 3) carbon-carbon sp ³ triple bonds. Alkynyl groups include, but are not limited to: ethynyl group, Etc.

As used herein, the term "cycloalkyl" refers to a cyclic, saturated monovalent hydrocarbon group of a specified number of carbon atoms (e.g., C ₃～C₁₀) that is monocyclic or polycyclic (e.g., 2 or 3, bridged, spiro, and cyclic), with more than two carbon atoms shared between the monocyclic rings. Monocyclic rings include, but are not limited to: Etc. Bridged cycloalkyl groups include, but are not limited to: Etc. Spirocycloalkyl groups include, but are not limited to: Etc. And cycloalkyl groups include, but are not limited to: Etc.

The term "aryl", as used herein, refers to a cyclic, unsaturated monovalent hydrocarbon group of a specified number of carbon atoms (e.g., C ₆～C₁₀), which is monocyclic or polycyclic (e.g., 2 or 3), where the monocyclic ring shares two atoms and one bond, and (at least one ring per ring) has aromatic character. The aryl group is attached to the remainder of the molecule through a ring that is aromatic or a ring that is not aromatic. Aryl groups include, but are not limited to: phenyl, naphthyl,Etc.

The term "heterocycloalkyl" refers to a single ring, bridged ring, spiro ring, and ring of a specified heteroatom number (e.g., 1,2, or 3) of a specified heteroatom number (one or more of N, O and S) with a specified number of ring atoms (e.g., 3-10 membered), as not specifically described in the present invention. The (monocyclic) heterocycloalkyl group is attached to the remainder of the molecule via a carbon atom or heteroatom. Monocyclic heterocycloalkyl groups include, but are not limited to: Etc. Spiroheterocycloalkyl groups include, but are not limited to: etc. Bridged heterocycloalkyl groups include, but are not limited to: Etc. And the heterocyclic alkyl group includes

As used herein, the term "heteroaryl" refers to a cyclic, unsaturated monovalent group of a specified number of heteroatoms (e.g., 1,2, or 3) having a specified number of ring atoms (e.g., 5-10 membered), of a specified heteroatom species (one or more of N, O and S), which is monocyclic or polycyclic, with two atoms and one bond in common between the monocyclic rings, and at least one ring having aromaticity. Heteroaryl groups are attached to the remainder of the molecule through a carbon atom or heteroatom; heteroaryl groups are attached to the remainder of the molecule through a ring with a heteroatom or a ring without a heteroatom; heteroaryl groups are attached to the remainder of the molecule through rings that are aromatic or rings that are not aromatic. Heteroaryl groups include, but are not limited to: Etc.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects that: the compound has a good inhibition effect on KRAS G12D, and can be used for treating tumors related to KRAS G12D.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

EXAMPLE 1 Synthesis of the respective intermediates

Synthesis of intermediate M1

(1) Compounds M1-2

To a 50mL single-necked flask under nitrogen atmosphere was added M1-1 (1.0 g,4.5 mmol), pinacol ester (0.28 g,2.2 mmol), potassium acetate (1.32 g,13.5 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.33 g,0.45 mmol) and 20mL 1, 4-dioxane, and reacted at 95℃for 5 hours. The reaction was brought to room temperature, 100mL of water was added, extraction was performed with ethyl acetate (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give M1-2 (0.8 g, yield 66.1%) as a white solid, LCMS M/z=271.1 [ M+H ] ⁺.

(2) Intermediate M1

M1-2 (0.3 g,1.1 mmol), N, N-diisopropylethylamine (0.5 g,3.5 mmol) was added to a 50mL single-necked flask, dissolved in 10mL methylene chloride, and the reaction mixture was cooled to 0℃and bromomethyl ether (0.28 g,2.2 mmol) was added dropwise thereto and reacted at room temperature for 3 hours. 50mL of water was added, extracted with dichloromethane (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give M1 (0.3 g, yield) as a white solid 86.0％),¹H NMR(400MHz,DMSO-d₆)δ8.55(dd,J＝8.2,0.8Hz,1H),7.82(dd,J＝8.4,1.0Hz,1H),7.64(d,J＝2.8Hz,1H),7.57(d,J＝2.6Hz,1H),7.49–7.41(m,2H),5.32(s,2H),3.42(s,3H),1.38(s,12H),LCMS m/z＝315.1[M+H]⁺.

Synthesis of intermediate M2

(1) Compound M2-2

To a solution of M2-1 (1.5 g,7.1 mmol) in methylene chloride (20 mL) at 0deg.C were added allyl chloroformate (1.3 g,10.8 mmol) and triethylamine (2.2 g,21.7 mmol) and reacted for 1 hour. To the reaction was added 20mL of water, 50mL of methylene chloride, and the aqueous phase was separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give M2-2 ((2.0 g, yield 95.5%) as a pale yellow solid, LCMS M/z=241.1 [ m+h ] ⁺.

(2) Intermediate M2

To a solution of M2-2 (2.0 g,6.8 mmol) in 1, 4-dioxane (3 mL) was added 15mL of 4M 1, 4-dioxane solution of hydrochloric acid at 0deg.C, and the reaction was carried out at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give M2 (1.3 g, 98.2% yield) as a yellow oil, LCMS M/z=197.1 [ m+h ] ⁺.

Synthesis of intermediate M3

M3-1 (500 mg,2.8 mmol) was dissolved in 3, 4-dihydro-2H-pyran (1.2 g,14.2 mmol), trifluoroacetic acid (32 mg, 280. Mu. Mol) was added and the mixture was reacted at 90℃for one hour. Concentrated under reduced pressure and the residue was purified by C18 reverse phase column (acetonitrile/water/0.1% formic acid) to give M3 (250 mg, yield 34.3%) as a pale yellow solid, LCMS M/z=283.0 [ m+na ] ⁺.

Example 2 preparation of Compound 1

(1) Compounds 1-2

To an ethyl acetate solution (40 mL) of compound 1-1 (1.2 g,3.9 mmol) under nitrogen was added sodium periodate (2.5 g,11.7 mmol), 40mL of water and ruthenium trichloride (123 mg, 593. Mu. Mol), and the mixture was reacted at room temperature for 3 hours. Water and ethyl acetate were added to dissolve, the organic phase was separated, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 1-2 (964 mg, yield 76.8%) as a white solid, LCMS m/z=218.0 [ m+h ] ⁺.

(2) Compounds 1-3

To a solution of compounds 1-2 (1.37 g,4.3 mmol) in dichloromethane (30 mL) at 0deg.C was added intermediate M2 (949 mg,4.8 mmol) and N, N-diisopropylethylamine (2.8 g,22.0 mmol) was added and reacted at room temperature for 2 hours. The reaction system was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 1-3 (1.9 g, yield 91.3%) as pale yellow solid, LCMS m/z=478.1 [ m+h ] ⁺.

(3) Compounds 1-4

To a solution of ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methanol (944 mg,6.0 mmol) in N, N-dimethylformamide (40 mL) was added sodium hydride (480 mg,12.0 mmol), and the reaction was continued at room temperature for 0.5 hours under nitrogen atmosphere, followed by addition of compound 1-3 (1.42 g,3.0 mmol) and further reaction at room temperature for 3 hours. The system was diluted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by C18 column (acetonitrile/water/0.1% formic acid) to give 1-4 (20 mg, yield 48.4%) as pale yellow solid, LCMS m/z=502.1 [ m+h ] ⁺.

(4) Compounds 1-6

To a solution of compound 1-4 (100 mg, 200. Mu. Mol) in N, N-dimethylformamide (2 mL) was added compound 1-5 (154 mg, 300. Mu. Mol), copper acetate (80 mg, 400. Mu. Mol), cesium carbonate (196 mg, 600. Mu. Mol), 2mL pyridine, and the mixture was reacted under an oxygen atmosphere at 60℃for 2 hours. Insoluble material was removed by filtration and the solution was purified by C18 column (acetonitrile/water/0.1% formic acid) to give 1-6 (33 mg, yield 18.6%) as a dark brown solid, LCMS m/z=885.3 [ m+h ] ⁺.

(5) Compounds 1-7

Compounds 1 to 6 (33 mg, 37. Mu. Mol) were dissolved in 2mL of N, N-dimethylformamide, cesium fluoride (28 mg, 185. Mu. Mol) was added thereto, and the mixture was reacted at room temperature for 2 hours. Insoluble material was removed by filtration, and the filtrate was purified by C18 column (acetonitrile/water/0.1% formic acid) to give 1-7 (25 mg, yield 92.2%) as pale red solid, LCMS m/z=729.2 [ m+h ] ⁺.

(6) Compounds 1-8

Compounds 1-7 (25 mg, 34. Mu. Mol) were dissolved in 3mL of methylene chloride, tetrahydropyrrole (6 mg, 85. Mu. Mol) was added, and tetrakis triphenylphosphine palladium (4 mg, 3. Mu. Mol) was reacted at 0℃for 2 hours. Concentration under reduced pressure gave 1-8 (21 mg, 94.9% yield) as a reddish brown solid, LCMS m/z=645.2 [ m+h ] ⁺.

(7) Compound 1

To a solution of compounds 1-8 (21 mg, 85. Mu. Mol) in 1, 4-dioxane (1 mL) was added 4mL of 4M 1, 4-dioxane solution of hydrochloric acid at 0deg.C, and the reaction was carried out at 0deg.C for 2 hours. Concentrated under reduced pressure, and the residue was purified by preparative HPLC to give yellow solid 1 (7.7 mg, yield 39.4％),¹H NMR(500MHz,DMSO-d₆)δ8.23(1H,s),7.93(1H,dd,J＝9.0Hz,5.5Hz),7.46(1H,t,J＝9.0Hz),7.30(1H,d,J＝2.5Hz),7.23(1H,d,J＝2.5Hz),5.28(1H,d,J＝54Hz),4.38(1H,s),4.01(1H,t,J＝11.0Hz),3.93-3.89(2H,m),3.85(2H,t,J＝6.0Hz),3.80-3.74(3H,m),3.29(2H,d,J＝12.0Hz),3.20(2H,d,J＝12.0Hz),3.11-3.05(4H,m),3.03(1H,s),2.96-2.81(1H,m),2.12-1.99(3H,m),1.86-1.76(7H,m),LCMS m/z＝601.2[M+H]⁺ _.

EXAMPLE 3 Synthesis of Compound 2

Compounds 1-5 were replaced with intermediate M1 using the synthetic procedure of example 2 to example 3: yellow solid ,¹H NMR(500MHz,DMSO-d₆)δ8.25(2H,s),7.76(2H,t,J＝4.2Hz),7.44(1H,t,J＝3.8Hz),7.29(1H,t,J＝3.6Hz),7.18(1H,d,J＝0.8Hz),7.09(1H,s),5.27(1H,d,J＝27Hz),4.10-4.07(1H,m),4.04-4.01(1H,m),3.93-3.76(5H,m),3.68-3.64(1H,m),3.37(1H,d,J＝6.2Hz),3.27-3.19(2H,m),3.10-3.08(2H,m),3.02(1H,s),2.92-2.82(2H,m),2.11-1.99(3H,m),1.86-1.76(7H,m),LCMS m/z＝559.3[M+H]⁺ _.

EXAMPLE 4 Synthesis of Compound 3

Compounds 1-5 were replaced with intermediate M3 using the synthetic procedure of example 2 to example 4: yellow solid ,¹H NMR(400MHz,DMSO-d₆)δ8.43(1H,brs),8.02(1H,d,J＝4.0Hz),7.55(1H,d,J＝4.2Hz),7.42(1H,d,J＝4.4Hz),5.47(1H,d,J＝26.6Hz),4.65-4.55(2H,m),4.39-4.28(2H,m),4.14(2H,s),4.11-4.02(1H,m),3.94-3.67(5H,m),3.61-3.50(2H,m),3.41-3.36(1H,m),3.27-3.22(2H,m),2.57-2.54(1H,m),2.50-2.46(1H,m),2.40(3H,d,J＝1.8Hz),2.40-2.26(3H,m),2.18-2.06(5H,m),2.05-1.98(2H,m),LCMS m/z＝547.3[M+H]⁺ _.

EXAMPLE 5 Synthesis of Compound 17

Compound 17-2

Compound 17-1 (1 g,4.2 mmol), tert-butyl 3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (950 mg,4.2 mmol) was dissolved in 5mL acetonitrile, cesium carbonate (1.16 g,8.4 mmol) was added and reacted at 50℃for 2 hours. Returning to room temperature, insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate) to give 17-2 (350 mg, yield 18.8%) as a yellow solid, LCMS m/z=444.1 [ m+h ] ⁺.

Compound 17-3

Compound 17-2 (350 mg, 787. Mu. Mol) was dissolved in 4mL of ethanol, 1mL of water, and iron powder (220 mg,3.9 mmol), ammonium chloride (63 mg,1.2 mmol) was added thereto and reacted at 80℃for 2 hours. The reaction mixture was brought to room temperature, filtered through celite, washed with ethanol and concentrated under reduced pressure to give 17-3 (310 mg, 95.0% yield) as a pale brown solid, LCMS m/z=414.1 [ m+h ] ⁺.

Compound 17-4

Triethylamine (227 mg,2.2 mmol) was added to a solution of compound 17-3 (310 mg, 748. Mu. Mol) in tetrahydrofuran (3 mL) at 0℃and stirred for 5 minutes, and a solution of oxalyl chloride monomethyl ester (183mg, 3.7 mmol) in 1mL of tetrahydrofuran was added dropwise to the system. The reaction was warmed to room temperature until TLC monitored complete disappearance of starting material. 10mL of saturated sodium bicarbonate solution was added to the system, extracted with dichloromethane (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 17-4 (371 mg, yield 99.1%) as a colorless viscous oil, LCMS m/z=500.1 [ M+H ] ⁺.

Compound 17-5

Compound 17-4 (371 mg, 741. Mu. Mol) was dissolved in 2mL of 1, 2-dichloroethane under nitrogen and reacted at 100℃overnight. To the reaction system was added 5mL of n-hexane, stirred for 5 minutes, and filtered to give 17-5 (267 mg, yield 76.9%) as a white solid, LCMS m/z=468.1 [ m+h ] ⁺.

Compound 17-6

17-5 (200 Mg, 427. Mu. Mol), M1 (161 mg, 513. Mu. Mol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (313 mg, 427. Mu. Mol), cesium carbonate (218 mg, 854. Mu. Mol) were added to a 5mL microwave tube, 2mL 1, 4-dioxane and 0.5mL water were added, and the reaction was carried out at 100℃under nitrogen for 12 hours. 10mL of water was added to the system, extracted with ethyl acetate (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was separated by flash column chromatography on silica gel (dichloromethane/methanol) to give 17-6 (212 mg, yield 86.2%) as a white solid, LCMS m/z=576.2 [ M+H ] ⁺.

Compounds 17-7

Compound 17-6 (50 mg, 87. Mu. Mol) and (2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methanol (28 mg, 174. Mu. Mol) were dissolved in 2mL of acetonitrile, and benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (54 mg, 104. Mu. Mol) and 1, 8-diazabicycloundec-7-ene (13 mg, 87. Mu. Mol, 13. Mu. L) were sequentially added and reacted overnight at room temperature. Concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate) to give 17-7 (42 mg, yield 84.4%) as a white solid, LCMS m/z=717.3 [ m+h ] ⁺.

Compound 17

Compound 17-7 (26 mg, 36. Mu. Mol) was dissolved in 1mL of dichloromethane, 1mL of trifluoroacetic acid was added, and stirring was performed at room temperature until complete disappearance of TCL monitor material. Concentrating under reduced pressure, adding saturated sodium bicarbonate solution to adjust pH to >7, extracting with dichloromethane (10 mL×3), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating the residue by preparative thin layer chromatography to give 17 (11 mg, yield) as white solid 49.2％),¹H NMR(500MHz,MeOD-d₄)δ7.76–7.66(m,3H),7.64–7.58(m,2H),7.43–7.37(m,1H),7.23–7.17(m,1H),7.05(d,J＝2.4Hz,1H),5.47(d,J＝53.1Hz,1H),4.25–4.15(m,3H),4.01(d,J＝5.7Hz,1H),3.68–3.50(m,2H),2.72–2.48(m,4H),2.36–2.25(m,4H),2.22–2.14(m,2H),1.77–1.53(m,7H),LCMS m/z＝287.4[M+2H]²⁺.

EXAMPLE 6 Synthesis of Compound 81

The intermediate M1 was replaced with compounds 1-5 using the synthetic procedure for compound 17 of example 5 to example 6: white solid, LCMS m/z=308.4 [ m+2h ] ²⁺.

EXAMPLE 7 Synthesis of Compound 21

Compound 21-2

To a solution of compound 21-1 (300 mg,1.35 mmol) in 1, 4-dioxane (3 mL) was added N, N-diisopropylethylamine (349 mg,2.70 mmol) and tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (287 mg,1.35 mmol) and reacted at room temperature for 1 hour. To the reaction system was added 20mL of water, extracted with ethyl acetate (30 ml×3), and the organic phases were combined, washed with brine (30 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 21-2 (530 mg, yield 98.6%) as a yellow solid, LCMS m/z=398.1 [ m+h ] ⁺.

Compound 21-3

To a solution of compound 21-2 (530 mg,1.33 mmol) in THF (5 mL) was added 2, 2-trichloroacetyl isocyanate (326 mg,1.73 mmol), and the mixture was reacted at room temperature for 10 minutes. The reaction was concentrated under reduced pressure, and the residue was washed with petroleum ether (20 mL. Times.3) and dried in vacuo to give 21-3 (780 mg, 99.9% yield) as an off-white solid, LCMS m/z=587.1 [ M+H ] ⁺.

Compound 21-4

To a solution of compound 21-3 (780 mg,1.33 mmol) in methanol (10 mL) was added ammonia in methanol (7M, 10 mL) and stirred for 1 hour. The reaction was concentrated under reduced pressure, and the residue was washed with methyl tert-butyl ether (20 mL. Times.3) and dried under vacuum to give 21-4 (530 mg, 97.4% yield) as a yellow solid, LCMS m/z=409.4 [ M+H ] ⁺.

Compounds 21-5

To a solution of compound 21-4 (530 mg,1.30 mmol) and intermediate M1 (814 mg,2.59 mmol) in N, N-dimethylformamide (5 mL) under nitrogen was added copper acetate monohydrate (336 mg,1.69 mmol), cesium carbonate (845 mg,2.59 mmol) and pyridine (5 mL), and the mixture was reacted at 65℃for 16 hours. The reaction was filtered and the filter cake was washed with ethyl acetate (10 mL. Times.3). The filtrate was concentrated under reduced pressure and the residue was purified by C18 column (acetonitrile/water/0.1% formic acid) to give 21-5 (300 mg, yield 38.9%) as a yellow oil, LCMS m/z=595.2 [ m+h ] ⁺.

Compounds 21-6

To a solution of compound 21-5 (150 mg, 252. Mu. Mol) and ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methanol (80 mg, 504. Mu. Mol) in 1, 4-dioxane (2 mL) under nitrogen was added cesium carbonate (164 mg, 504. Mu. Mol), palladium acetate (9 mg, 38. Mu. Mol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (29 mg, 50. Mu. Mol), and the mixture was subjected to microwave reaction at 110℃for 2 hours. Returning to room temperature, filtration, washing of the filter cake with ethyl acetate (10 ml×3), concentration of the filtrate under reduced pressure, purification of the residue by C18 column (acetonitrile/water/0.1% formic acid) gave 21-6 (20 mg, yield 25.7%) as a yellow solid LCMS m/z=718.7 [ m+h ] ⁺.

Compound 21

To a solution of compound 21-6 (19 mg, 26.47. Mu. Mol) in acetonitrile (1 mL) at 0deg.C was added a1, 4-dioxane solution of hydrochloric acid (4M, 132. Mu.L), and the mixture was returned to room temperature and stirred for 1 hour. Concentrated under reduced pressure, the residue was dissolved with methanol (2 mL) and pH was adjusted to 8 with aqueous ammonia. Purification by C18 column (acetonitrile/water/0.1% ammonia) gave 21 (2.3 mg, yield) as a yellow solid 14.0％),¹H NMR(500MHz,Methanol-d₄)δ8.53(s,1H),7.75(d,J＝8.1Hz,1H),7.43–7.39(m,1H),7.27–7.19(m,2H),7.11–7.06(m,1H),5.50–5.45(m,1H),5.37(s,1H),5.34(t,J＝4.7Hz,1H),5.17(s,1H),4.52–4.48(m,2H),4.05(s,2H),3.66–3.59(m,4H),3.40(s,1H),3.27–3.24(m,1H),2.49–2.42(m,2H),2.40–2.33(m,2H),2.20–2.18(m,2H),2.13–2.09(m,2H),2.06–2.02(m,2H),LCMS m/z＝574.3[M+H]⁺.

EXAMPLE 8 Synthesis of Compound 22

Compound 22-2

To a solution of compound 22-1 (2 g,17.37 mmol) in acetonitrile (10 mL) under nitrogen was added ethyl 4-bromobutyrate (6.78 g,34.74 mmol) and N, N-diisopropylethylamine (8.98 g,69.49 mmol) and reacted overnight at 80 ℃. The mixture was recovered to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 22-2 (1.8 g, yield 45.2%) as a yellow oil, LCMS m/z=230.1 [ m+h ] ⁺.

Compound 22-3

To a solution of compound 22-2 (1.8 g,7.85 mmol) in dichloromethane (20 mL) at 0deg.C was added N, N-diisopropylethylamine (2.03 g,15.70mmol,2.73 mL), and the mixture was stirred for 5 minutes, allyl chloroformate (1.42 g,11.78 mmol) was added dropwise and the reaction was resumed at room temperature for 3 hours. Concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 22-3 (2.3 g, 93.5% yield) as a colorless oil, LCMS m/z=314.1 [ m+h ] ⁺.

Compound 22-4

To a solution of compound 22-3 (2.3 g,7.34 mmol) in tetrahydrofuran (23 mL) at 0deg.C was added 10gMolecular sieves and potassium tert-butoxide (4.12 g,36.70 mmol) were reacted at room temperature for 0.5h. The reaction was filtered through celite, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to give 22-4 (2.0 g, 97.1% yield) as a colorless oil, LCMS m/z=282.1 [ m+h ] ⁺.

Compound 22-5

To a solution of compound 22-4 (2.0 g,7.11 mmol) in ethanol (15 mL) was added S-methyl isothiourea sulfate (2.97 g,10.66 mmol) and sodium ethoxide (2.42 g,35.55 mmol), and the mixture was reacted at room temperature for 4h. The reaction system PH was adjusted to ph=7 with 2M hydrochloric acid, extracted with ethyl acetate (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (ethyl acetate) to give 22-5 (1.5 g, yield 68.6%) as a brown solid, LCMS M/z=308.2 [ m+h ] ⁺.

Compound 22-6

To a solution of compound 22-5 (0.8 g,2.60 mmol) in acetonitrile (8 mL) was added 1, 8-diazabicyclo [5.4.0] undec-7-ene (390 mg,2.60 mmol), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (2.71 g,5.21 mmol), TLC monitored for disappearance of starting material, and 3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (829 mg,3.90 mmol) was added and reacted overnight at 50 ℃. Concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 22-6 (1.3 g, 99.6% yield) as a yellow solid with LCMS m/z=502.3 [ m+h ] ⁺.

Compound 22-7

To a solution of compound 22-6 (1.3 g,2.59 mmol) in dichloromethane (13 mL) at 0deg.C was added m-chloroperoxybenzoic acid (1.57 g,9.07 mmol) and the reaction was continued at 0deg.C for 2 hours. Saturated sodium bicarbonate solution was added, extracted with ethyl acetate (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (ethyl acetate) to give 22-7 (1.3 g, 94.0% yield) as a white solid, LCMS m/z=534.2 [ m+h ] ⁺.

Compound 22-8

To a solution of compound 22-7 (1.4 g,2.62 mmol) and ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methanol (501.19 mg,3.15 mmol) in 1, 4-dioxane (14 mL) at 0deg.C was added potassium tert-butoxide (441.57 mg,3.94 mmol) and the reaction was allowed to proceed overnight at room temperature. Saturated ammonium chloride solution was added to quench, extracted with ethyl acetate (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give brown solid 22-8 (1.0 g, yield 62.1%), LCMS m/z=613.4 [ m+h ] ⁺.

Compounds 22-9

To a solution of compound 22-8 (1 g,1.63 mmol) in methylene chloride (10 mL) under nitrogen at 0deg.C was added tetrakis (triphenylphosphine) palladium (89 mg, 163.20. Mu. Mol), tetrahydropyrrole (290 mg,4.08mmol, 338.99. Mu.L) and the reaction was allowed to proceed to room temperature overnight. Concentrated under reduced pressure, and the residue was separated by preparative thin layer chromatography to give 22-9 (250 mg, yield 30.0%) as a brown oil, LCMS m/z=529.4 [ m+h ] ⁺.

Compounds 22-10

In a 5mL microwave reaction tube, compound 22-9 (180 m g, 340.48. Mu. Mol), cesium carbonate (333 mg,1.02 mmol), methanesulfonic acid (2-dicyclohexylphosphine-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2 ' -methylamino-1, 1' -biphenyl-2-yl) palladium (II) (28.95 mg, 34.05. Mu. Mol), 1-bromo-8-fluoronaphthalene (153.26 mg, 680.97. Mu. Mol) and 2mL N, N-dimethylformamide were added under a nitrogen atmosphere, and the reaction was allowed to proceed for 6 hours at 110℃to room temperature, quenched by the addition of saturated ammonium chloride solution, extracted with ethyl acetate (50 mL. Times.3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give yellow solid 22-10 (50 mg, yield 19.2%), S m/z=673.4 [ M+H ] ⁺.

Compound 22

To a solution of 22-10 (10 mg, 14.86. Mu. Mol) of compound (1 mL) in methylene chloride (1 mL) was added dropwise a 1, 4-dioxane solution of hydrochloric acid (4M, 37.16. Mu.L) at 0℃and the reaction was resumed at room temperature for 0.5 hours. 2mL of distilled water was added and stirred for 5 minutes, the organic phase was separated and the aqueous phase was washed with dichloromethane (10 mL. Times.3) and the aqueous phase was lyophilized to give brown solid 22 (6 mg, yield) 66.3％),¹H NMR(500MHz,DMSO-d₆)δ11.66(s,1H),10.08(d,J＝10.0Hz,1H),9.70(d,J＝10.0Hz,1H),7.85(d,J＝8.0Hz,1H),7.76(d,J＝8.0Hz,1H),7.58–7.47(m,1H),7.45–7.39(m,1H),7.39–7.32(m,2H),7.31–7.18(m,1H),5.70–5.41(m,1H),4.42–4.21(m,2H),4.14–4.07(m,2H),3.99–3.91(m,2H),3.77–3.65(m,4H),3.63–3.58(m,2H),3.57–3.53(m,4H),2.87–2.75(m,2H),2.26–2.08(m,4H),2.04–1.96(m,4H),1.94–1.85(m,2H),LCMS m/z＝287.5[M+2H]²⁺.

EXAMPLE 9 Synthesis of Compound 23

Compound 23-2

To a solution of compound 23-1 (5 g,18.4 mmol) in dichloromethane (20 mL) at 0deg.C was added 10mL trifluoroacetic acid and the reaction was returned to room temperature for 1 hour. Concentration under reduced pressure afforded 23-2 (7 g, crude) as a yellow oil, LCMS m/z=172.1 [ m+h ] ⁺.

Compound 23-3

To a solution of compound 23-2 (7 g,18.4 mmol) in dichloromethane (20 mL) at 0deg.C, triethylamine (3.7 g,36.8 mmol) and allyl chloroformate (2.7 g,22.1 mmol) were added sequentially, and the reaction was continued at 0deg.C for 1 hour. Dilution with water, extraction with ethyl acetate (20 ml×3), drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure, and purification of the residue by flash column chromatography on silica gel (petroleum ether/ethyl acetate) afforded 23-3 (3.8 g, 81.0% yield) as a colorless oil, LCMS m/z=256.1 [ m+h ] ⁺.

Compound 23-4

To a solution of compound 23-3 (3.3 g,12.9 mmol) in methanol (5 mL) at 0deg.C was added potassium hydroxide (1.0 g,17.9 mmol), and the mixture was stirred for 5 minutes, followed by addition of 2-cyanothioacetamide (1.5 g,15.4 mmol) and reaction at 60deg.C for 16 hours. The mixture was returned to room temperature, filtered and the filter cake was washed with petroleum ether and dried in vacuo to give 23-4 (3.3 g, 78.3% yield) as a brown solid with LCMS m/z=291.9 [ m+h ] ⁺.

Compound 23-5

To a solution of compound 23-4 (3.0 g,10 mmol) in ethanol (20 mL) at 0deg.C was slowly added methyl iodide (1.5 g,10 mol) dropwise, and after the addition, the temperature was raised to 50deg.C for 16 hours. Concentrated under reduced pressure, the residue was washed with petroleum ether and filtered, and dried under vacuum to give 23-5 as a brown solid (2.7 g, yield 87.2％),¹H NMR(400MHz,CDCl₃)δ12.4(s,1H),5.99–5.90(m,1H),5.32–5.27(m,1H),5.22–5.18(m,1H),4.60–4.57(m,2H),4.54(d,J＝4.4Hz,2H),3.60(s,2H),2.61(s,3H),2.51–2.46(m,2H),LCMS m/z＝306.1[M+H]⁺.

Compound 23-6

To a solution of compound 23-5 (2.4 g,7.8 mmol) in dichloromethane (20 mL) at 0deg.C were added N, N-diisopropylethylamine (2.0 g,15.7 mmol) and trifluoromethanesulfonic anhydride (2.7 g,9.4 mmol), and the reaction was continued at 0deg.C for 1 hour. The reaction was diluted with water, extracted with ethyl acetate (20 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 23-6 (3.8 g, yield 82.2%) as a yellow solid, LCMS m/z=438.0 [ m+h ] ⁺.

Compounds 23-7

To a solution of compound 23-6 (2.8 g,6.4 mmol) in acetonitrile (20 mL) were added N, N-diisopropylethylamine (1.6 g,12.8 mmol) and tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1.6 g, 7.7 mmol), and reacted at 80℃for 1 hour. Returning to room temperature, dilution with water, drying over ethyl acetate (20 ml×3) anhydrous sodium sulfate, filtration and concentration under reduced pressure, the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 23-7 (2.4 g, yield 75.0%) as a yellow solid, LCMS m/z=500.2 [ m+h ] ⁺.

Compounds 23-8

To a solution of compound 23-7 (2.3 g,4.6 mmol) in methylene chloride (20 mL) at 0deg.C was added m-chloroperoxybenzoic acid (0.8 g,4.6 mol) and the reaction was carried out at 0deg.C for 1 hour. The reaction was diluted with water and dried over ethyl acetate (20 ml×3) anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 23-8 (2.1 g, yield 88.3%) as a yellow solid, LCMS m/z=515.9 [ m+h ] ⁺.

Compounds 23-9

To ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methanol (162 mg,1.02 mmol) and under nitrogen atmosphere at 0deg.CPotassium tert-butoxide (151 mg,1.36 mol) was added to a solution of molecular sieve in THF (10 mL), and the reaction was continued for 0.5 hours, then a solution of compound 23-8 (350 mg,0.68 mmol) in THF (5.0 mL) was slowly added dropwise at 0deg.C, and the reaction was continued for 2 hours at 0deg.C. Filtration and concentration under reduced pressure gave 23-9 (270 mg, 65.2% yield) as a yellow solid, LCMS m/z=610.2 [ m+h ] ⁺, which was purified by C18 column (acetonitrile/water/0.1% aqueous ammonia).

Compounds 23-10

To a solution of tetrakis (triphenylphosphine) palladium (220 mg,0.191 mmol) and diethylamine (0.5 mL) in dichloromethane (5.0 mL) was added dropwise a solution of 23-9 (233 mg,0.382 mmol) in dichloromethane (5.0 mL), and the mixture was reacted at room temperature for 2 hours. Concentrated under reduced pressure and the residue was purified by C18 column (acetonitrile/water/0.1% aqueous ammonia) to give 23-10 (133 mg, 66% yield) as a pale yellow solid, LCMS m/z=527.3 [ m+h ] ⁺.

Compounds 23-11

To a solution of the compound 23-10 (40 mg,0.076 mmol) and 1-bromo-3- (methoxymethoxy) naphthalene (33 mg,0.114 mmol) in 1, 4-dioxane (4 mL) was added methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (12.7 mg,0.015 mol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (7 mg,0.015 mmol) and cesium carbonate (74 mg,0.23 mmol) under nitrogen atmosphere, and the mixture was reacted at 75℃for 6 hours. The reaction mixture was brought to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 23-11 (25 mg, yield 46%) as a yellow solid, LCMS m/z=713.3 [ m+h ] ⁺.

Compound 23

To a solution of 23-11 (25 mg,0.035 mmol) in acetonitrile (2 mL) was added 1.0mL of a 4M solution of 1, 4-dioxane hydrochloride at 0℃and the reaction was carried out at 0℃for 1 hour. Concentrated under reduced pressure, and the residue was purified by preparative HPLC to give a white solid (20 mg, yield 73％),¹H NMR(400MHz,DMSO-d₆)δ10.93(s,1H),9.80(s,1H),9.12–8.96(m,2H),7.98(d,J＝8.8Hz,1H),7.69(d,J＝8.8Hz,1H),7.42–7.39(m,1H),7.30–7.26(m,1H),6.89(d,J＝2.0Hz,1H),6.83(d,J＝2.0Hz,1H),5.62(d,J＝14.4Hz,1H),4.59–4.44(m,2H),4.31(brs,2H),4.14–4.13(m,2H),4.00–3.89(m,3H),3.79–3.64(m,3H),3.45–3.24(m,4H),3.05–2.87(m,2H),2.60–2.55(m,1H),2.32–2.20(m,1H),2.20–1.92(m,8H),LCMS m/z＝569.3[M+H]⁺.

EXAMPLE 10 Synthesis of Compound 24

To a solution of compound 1 (25 mg,0.039 mmol) and N, N-diisopropylethylamine (25 mg, 0.195 mmol) in N, N-dimethylformamide (2 mL) was added ethyl 1- (((4-nitrophenoxy) carbonyl) oxy) isobutyrate (12 mg,0.039 mmol) at 0℃for 20 minutes. The reaction system was purified directly by preparative HPLC to give 24 as a yellow solid (7.5 mg, yield 25.4％),¹H NMR(400MHz,DMSO-d₆)δ10.29(s,1H),7.96(dd,J＝8.0,4.0Hz,1H),7.47(t,J＝8.0Hz,1H),7.32(d,J＝4.0Hz,1H),7.27–7.24(m,1H),6.70–6.67(m,1H),5.39(d,J＝8.0Hz,1H),4.78–4.69(m,2H),4.53–4.44(m,3H),3.46–3.68(m,8H),3.25–3.16(m,3H),2.46–2.41(m,1H),2.16–2.08(m,4H),2.00–1.95(m,2H),1.95–1.76(m,1H),1.76–1.68(m,2H),1.45–1.42(m,5H),1.11–1.04(m,6H),LCMS m/z＝759.4[M+H]⁺.

EXAMPLE 11 Synthesis of Compound 25

Compound 25-2

To a solution of 25-1 (3 g,12.82 mmol) in tetrahydrofuran (30 mL) was added dropwise bis (trichloromethyl) carbonate (3.80 g,12.82 mmol) at 0deg.C, and the mixture was allowed to react at 50deg.C for 16 hours. The mixture was recovered to room temperature, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 25-2 (2 g, yield 60.0%) as an off-white solid, LCMS m/z=260.1 [ m+h ] ⁺.

Compound 25-3

To a solution of 25-2 (1.4 g,4.07 mmol) and ethyl 2-cyanoacetate (690.47 mg,6.10 mmol) in N, N-dimethylformamide (14.00 mL) was added N, N-diethylamine (1.65 g,16.28 mmol) under nitrogen atmosphere and the mixture was reacted at 120℃for 16 hours. Returning to room temperature, adding 1M hydrochloric acid solution, adjusting pH to ph=4, filtering, and vacuum drying the filter cake to give 25-3 (1 g, yield 87.0%) of brown solid, LCMS M/z=283.0 [ m+h ] ⁺.

Compound 25-4

To a solution of compound 25-3 (1 g,3.54 mmol) in acetonitrile (3 mL) was added phosphorus oxychloride (18 mL) and reacted at 90℃for 16 hours. The reaction mixture was brought to room temperature, concentrated under reduced pressure, diluted with 60mL of ice water, extracted with dichloromethane (40 mL. Times.3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane) to give 25-4 (1 g, yield 88.5%) as a yellow solid, LCMS m/z=320.9 [ M+H ] ⁺.

Compounds 25-5

To a solution of compound 25-4 (600 mg,1.88 mmol) and tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (597 mg,2.82 mmol) in dichloromethane (6 mL) was added triethylamine (759 mg,7.50 mmol) and the mixture was reacted at room temperature for 1 hour. Concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 25-5 (580 mg, yield 62.4%) as a yellow solid, LCMS m/z=497.1 [ m+h ] ⁺.

Compounds 25-6

To a solution of compound 25-5 (300 mg, 605. Mu. Mol) and ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methanol (193 mg,1.21 mmol) in tetrahydrofuran (3 mL) was added potassium tert-butoxide (203.70 mg,1.82 mmol), and the mixture was reacted at room temperature for 1 hour. The filter cake was filtered, washed with ethyl acetate, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 25-6 (170 mg, 45.4% yield) as a yellow solid, LCMS m/z=618.2 [ m+h ] ⁺.

Compounds 25-7

To a solution of compound 25-6 (170 mg, 275. Mu. Mol), intermediate M1 (112 mg, 357. Mu. Mol), 1.4-dioxane (2 mL) and water (0.7 mL) under nitrogen was added cesium carbonate (269 mg, 825. Mu. Mol) [1, 1-bis (diphenylphosphorus) ferrocene ] palladium dichloride (20 mg, 28. Mu. Mol), and reacted at 110℃for 2 hours. Added to water (20 mL), extracted with ethyl acetate (30 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give a colored oil (80 mg, yield 36.5%), LCMS m/z=726.6 [ m+h ] ⁺.

Compound 25

To a solution of compounds 25-7 (20 mg, 26. Mu. Mol) in acetonitrile (1 mL) was added dropwise a solution of 1, 4-dioxane of hydrochloric acid (4M, 138. Mu.L) at 0℃and reacted at 0℃for 1 hour. The reaction system was charged with 10mL of distilled water, and the aqueous phase was washed with methylene chloride (10 mL. Times.3). The aqueous phase was adjusted to ph=8 with aqueous ammonia, extracted with dichloromethane DCM (10 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give off-white solid 25 (5.2 mg, yield) 30.7％),¹H NMR(500MHz,Methanol-d₄)δ8.11(d,J＝8.6Hz,1H),7.74(d,J＝8.1Hz,1H),7.48–7.44(m,1H),7.41(t,J＝7.5Hz,2H),7.23(d,J＝2.2Hz,1H),7.22–7.17(m,1H),7.09(d,J＝2.3Hz,1H),5.35(d,J＝51.1Hz,1H),4.44–4.27(m,2H),3.94–3.81(m,2H),3.71–3.55(m,4H),3.47–3.36(m,1H),3.28–3.24(m,1H),3.23–3.16(m,1H),3.10–2.98(m,1H),2.37–2.23(m,3H),2.23–2.09(m,2H),2.08–1.88(m,5H),LCMS m/z＝291.9[M+2H]²⁺.

The following compounds were obtained using the synthetic procedure for compound 25 of example 11:

EXAMPLE 46 Compound 60

Compound 60-2

To a solution of compound 60-1 (6.3 g,30.5 mmol) in N, N-dimethylformamide (50 mL) was added cuprous cyanide (4.1 g,45.8 mmol) and the mixture was reacted at 140℃for 3 hours. Returning to room temperature, diluting with 50mL of water, extracting with ethyl acetate (100 mL. Times.3), combining the organic phases, washing with water (50 mL. Times.3), washing with saturated brine, drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure, and purifying the residue by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 60-2 (2.5 g, yield) as a white solid 49％),¹H NMR(400MHz,DMSO-d6)10.43(s,1H),7.96(d,J＝8.0Hz,1H),7.89(d,J＝8.0Hz,1H),7.67(d,J＝2.4Hz,1H),7.58–7.51(m,3H),LCMS m/z＝170.0[M+H]⁺.

Compound 60-3

To a solution of compound 60-2 (2.5 g,14.8 mmol) in toluene (50 mL) at-78℃was added diisobutylaluminum hydride (44.4 mL,44.4mmol,1M in toluene), -the reaction was continued at-78℃for 1 hour. The reaction was quenched with saturated ammonium chloride solution, the organic layer was separated and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 60-3 (2.1 g, yield 83%) as a white solid, LCMS m/z=173.1 [ m+h ] ⁺.

Compound 60-4

To a solution of compound 60-3 (1.8 g,10.4 mmol) in methylene chloride (25 mL) under nitrogen was added N, N-diisopropylethylamine (2.7 g,20.9 mmol) and cooled to 0℃and bromomethane (1.56 g,11.9 mmol) was added. The reaction was continued for 45 minutes at 0 ℃. The reaction was diluted with 25mL of water, extracted with ethyl acetate (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 60-4 (2.0 g, yield 79%) as an off-white solid, LCMS m/z=217.1 [ m+h ] ⁺.

Compound 60-5

To a solution of methyltriphenylphosphonium bromide (4.6 g,12.9 mmol) in tetrahydrofuran (25 mL) was added a solution of n-butyllithium in tetrahydrofuran (5.19 mL,12.9mmol, 2.5M) at-78deg.C, stirred for 30 min, a solution of compound 60-4 (1.4 g,6.48 mmol) in tetrahydrofuran (3.5 mL) was added dropwise, and the reaction was allowed to slowly warm to room temperature for 2 hours. The reaction system was quenched with saturated ammonium chloride solution, diluted with ethyl acetate (50 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 60-5 (800 mg, yield 80%) as a white solid LCMS m/z=215.0 [ m+h ] ⁺.

Compound 60-6

To a solution of compound 60-5 (800 mg,3.74 mmol) in acetonitrile (8 mL) was added 2-thiodihydropyrimidine-4, 6 (1H, 5H) -dione (803 mg,5.60 mmol), water (8 mL) and formaldehyde (37 wt% aqueous solution, 0.6mL,7.48 mmol) and reacted overnight at room temperature. The solid precipitated, was filtered and the filter cake was dried in vacuo to give 60-6 (1.34 g, 97% yield) as a white solid with LCMS m/z=371.2 [ m+h ] ⁺.

Compounds 60-7

To a solution of compound 60-6 (1.34 g,3.62 mmol) in acetonitrile (5 mL) under nitrogen was added potassium carbonate (1.00 g,7.24 mmol), stirred for 10 min, methyl iodide (514 mg,3.62 mmol) was added and the reaction was carried out at room temperature overnight. To the reaction system was added 20mL of water, and extracted with ethyl acetate (30 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 60-7 (1.14 g, yield 82%) as a white solid, LCMS m/z=385.1 [ m+h ] ⁺.

Compounds 60-8

To a solution of 60-7 (250 mg,0.65 mmol) in acetonitrile (3.5 mL) was added tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (207 mg,0.98 mmol), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (510 mg,0.98 mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (145 mg,1.95 mmol) and the mixture was reacted at 70℃for 8 hours. The reaction was directly diluted with 10mL of water, extracted with ethyl acetate (30 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate) to give 60-8 (308 mg, yield 82%) as a white solid, LCMS m/z=579.3 [ m+h ] ⁺.

Compounds 60-9

To a solution of compound 60-8 (308 mg,0.53 mmol) in methylene chloride (3 mL) at 0deg.C was added chloroperoxybenzoic acid (92 mg,0.53 mmol), and the reaction was continued at 0deg.C for 1 hour. The reaction solution was diluted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (dichloromethane/methanol) to give 60-9 (303 mg, yield 96%) as a white solid, LCMS m/z=595.2 [ m+h ] ⁺.

Compounds 60-10

To a solution of ((2R, 7 aS) -2-fluorohexahydro-1H-pyrrolizin-7 a-yl) methanol (122 mg,0.76 mmol) in tetrahydrofuran (8 mL) was added sodium tert-butoxide (147 mg,1.53 mmol) at 0℃and stirred for 10 minutes, compound 60-9 (303 mg,0.51 mmol) was added and the reaction was continued at 0℃for 1 hour. The filter cake was filtered, washed with dichloromethane, the filtrate concentrated under reduced pressure and the residue purified by flash column chromatography on silica gel (dichloromethane/methanol) to give 60-10 (240 mg, 68% yield) as a white solid LCMS m/z=690.3 [ m+h ] ⁺.

Compound 60

To a solution of compound 60-10 (240 mg,0.35 mmol) in acetonitrile (2 mL) was added a solution of 1, 4-dioxane of hydrochloric acid (4M, 4 mL) at 0deg.C, and the reaction was continued for 1 hour at 0deg.C. The reaction solution was concentrated, and the residue was purified by preparative HPLC to give 60 as a white solid (45 mg, yield 20％),¹H NMR(400MHz,DMSO-d₆)δ9.89(s,1H),9.60(brs,2H),7.96(d,J＝8.8Hz,1H),7.65(d,J＝8.0Hz,1H),7.47–7.41(m,1H),7.36–7.30(m,1H),7.22(d,J＝2.0Hz,1H),7.14(d,J＝2.0Hz,1H),6.06(d,J＝6.0Hz,1H),5.53–5.41(m,1H),4.38–4.04(m,5H),3.68–3.56(m,4H),3.40–3.38(m,1H),3.33–3.29(m,1H),3.06–2.96(m,1H),2.46–2.42(m,2H),2.38–2.33(m,2H),2.16–1.84(m,10H),LCMS m/z＝546.0[M+H]⁺.

The following compounds were obtained using the synthetic procedure for compound 60 of example 46:

EXAMPLE 58 Synthesis of Compound 72

Compound 72

A solution of 2, 2-trifluoroethanol (5 mg,0.05 mmol) and triphosgene (5 mg,0.017 mmol) in methylene chloride (1 mL) was cooled to 0℃and stirred for 5 minutes, then a solution of N, N-diisopropylethylamine (6.5 mg,0.05 mmol) in methylene chloride (0.1 mL) was added in portions over 2 minutes and the reaction was continued at 0℃for 1 hour. The resulting reaction solution was slowly added dropwise to a solution of compound 72-1 (30 mg,0.05 mmol) in methylene chloride (3 mL), and the mixture was allowed to react at room temperature for 1 hour. Concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 72 as a white solid (20 mg, yield 54％),¹H NMR(400MHz,DMSO-d₆)δ9.06(s,1H),7.99–7.95(m,1H),7.48–7.44(m,1H),7.39(d,J＝2.4Hz,1H),7.17(d,J＝2.4Hz,1H),5.27(d,J＝14.8Hz,1H),4.83–4.75(m,1H),4.62–4.58(m,1H),4.46–4.43(m,3H),4.12(d,J＝9.2Hz,1H),4.03(d,J＝10.8Hz,1H),3.93(s,1H),3.70–3.62(m,2H),3.12–3.00(m,3H),2.85–2.77(m,1H),2.12–2.00(m,3H),1.89–1.76(m,7H),LCMS m/z＝727.2[M+H]⁺.

EXAMPLE 59 Synthesis of Compound 73

Compound 73

To a solution of compound 72-1 (50 mg,0.0833 mmol) and isopropyl chloroformate (10 mg,0.0833 mmol) in tetrahydrofuran (5.0 mL) was added diisopropylethylamine (0.5 mg, 0.004mol), and the mixture was reacted at room temperature for 2 hours. Concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 73 (28 mg, yield) as a yellow solid 49％),¹H NMR(400MHz,DMSO-d₆)δ10.17(s,1H),9.06(s,1H),7.98(dd,J＝9.1,5.9Hz,1H),7.46(t,J＝9.2Hz,1H),7.39(d,J＝2.0Hz,1H),7.18(d,J＝1.8Hz,1H),5.27(d,J＝12.8Hz,1H),4.90–4.83(m,1H),4.57–4.54(m,1H),4.42–4.35(m,3H),4.12(d,J＝10.3Hz,1H),4.03(d,J＝10.4Hz,1H),3.94(s,1H),3.71–3.59(m,2H),3.09–3.01(m,3H),2.85–2.79(m,1H),2.12–2.00(m,3H),1.85–1.74(m,6H),1.25–1.23(m,7H),LCMS m/z＝687.1[M+H]⁺.

EXAMPLE 60 Synthesis of Compound 74

Compound 74

To a solution of compound 72-1 (50 mg,0.08 mmol) in methanol (5.0 mL) was added diethyl dicarbonate (14 mg,0.08 mmol) and a catalytic amount of diisopropylethylamine (1 mg), and the mixture was reacted at room temperature for 2 hours. Concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 74 as an off-white solid (40 mg, yield 71％),¹H NMR(400MHz,DMSO-d₆)δ10.17(s,1H),9.07(s,1H),8.00–7.95(m,1H),7.49–7.44(m,1H),7.39(d,J＝2.4Hz,1H),7.17(d,J＝2.4Hz,1H),5.30(d,J＝55.6Hz,1H),4.57(d,J＝11.6Hz,1H),4.43–4.37(m,3H),4.19–4.10(m,2H),4.13(q,J＝7.2Hz,2H),3.93(s,1H),3.69–3.62(m,2H),3.31–3.30(m,2H),3.18–2.88(m,4H),2.19–2.04(m,2H),1.86–1.64(m,6H),1.24(t,J＝7.2Hz,3H),LCMS m/z＝673.0[M+H]⁺.

EXAMPLE 61 Synthesis of Compound 75

Synthesis of example 61 Compound 75 Using the procedure for the Synthesis of example 60 Compound 74 substituting diethyl dicarbonate for dimethyl dicarbonate: white solid ,¹H NMR(400MHz,DMSO-d₆)δ10.17(s,1H),9.06(s,1H),8.00-7.95(m,1H),7.49-7.44(m,1H),7.39(d,J＝2.4Hz,1H),7.17(d,J＝2.4Hz,1H),5.30(d,J＝55.6Hz,1H),4.57(d,J＝12.4Hz,1H),4.43-4.38(m,3H),4.16-3.94(m,2H),3.93(s,1H),3.70-3.62(m,5H),3.31-3.30(m,2H),3.13-2.86(m,4H),2.18-2.04(m,2H),1.86-1.74(m,6H),LCMS m/z＝659.0[M+H]⁺.

EXAMPLE 62 Synthesis of Compound 76

Compound 76

To a solution of compound 72-1 (30 mg, 49.95. Mu. Mol) and allylsuccinimidyl carbonate (10.44 mg, 52.44. Mu. Mol) in N, N-dimethylformamide (2 mL) was added N, N-diisopropylethylamine (32.28 mg, 249.74. Mu. Mol) at 0℃and the reaction was continued for 8 hours at 0 ℃. Concentrated under reduced pressure, and the residue was purified by preparative HPLC to give 76 (16.9 mg, yield) as a white solid 47.9％),¹H NMR(400MHz,Methanol-d4)δ8.99(s,1H),7.82(dd,J＝8,4Hz,1H),7.32–7.26(m,2H),7.17(d,J＝4Hz,1H),6.04–5.94(m,1H),5.37–5.31(m,2H),5.24–5.21(m,2H),4.66–4.64(m,3H),4.47(s,2H),4.29–4.19(m,2H),3.75(dd,J＝12,4.0Hz,2H),3.33(d,J＝4Hz,1H),3.26–3.23(m,1H),3.21(s,1H),3.16(s,1H),3.02–2.95(m,1H),2.34–2.08(m,3H),1.98–1.81(m,7H),LCMS m/z＝685.3[M+H]⁺.

The following compounds were obtained using the synthetic procedure for compound 76, example 62:

Effect examples

The alpha LISA method measures the inhibition level of compounds on the interaction of KRAS G12D protein and cRAF

The sources of reagents used in the efficacy test are shown in the following table:

The sources of the instruments used in the efficacy tests are shown in the following table:

the experimental method comprises the following steps:

Composition and final concentration of buffer 1: 25mM N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid pH7.5,10mM magnesium chloride, 0.01% polyethylene glycol octylphenyl ether; composition and final concentration of buffer 2: 25mM N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid pH7.5,10mM magnesium chloride, 0.01% ethylene glycol octylphenyl ether, 1mM dithiothreitol. Compounds were prepared with ECHO555 automated plating apparatus, tested for concentration: the highest concentration detected for the compound was 10 μm, 3-fold dilution, 10 concentrations. The high signal control group had KRAS protein involved in the reaction as 0% inhibition; the low signal group did not have KRAS protein involved in the reaction as 100% inhibition. Adding 5 mu L of KRAS protein solution prepared by buffer solution 1 to each well of a high signal control group and a compound sample well of the test plate; to the low signal control, 5 μl of buffer 1 was added per well. The final concentration of KRAS reaction was 5nM and incubated for 1 hour at room temperature. mu.L of a mixed solution of SOS1 and GTP prepared by buffer 2 was added to each well, and the respective final concentrations of the reaction were 50nM and 125. Mu.M, respectively, and incubated at room temperature for 1 hour. mu.L of a mixture of cRAF and ALPHALISA NICKEL receptor magnetic beads prepared with buffer 2 was added to each well, and the corresponding final reaction concentrations were 50nM and 10. Mu.g/mL, respectively, and incubated at room temperature for 1 hour. mu.L of ALPHASCREEN GSH donor bead solution prepared with buffer 2 was added to each well, and the final concentration of the reaction was 10. Mu.g/mL, and incubated at room temperature for 1 hour. The signal value of the test board is read by an EnVision multifunctional enzyme-labeled instrument, the excitation light wavelength is set to 680nm, and the emission light wavelength is set to 615nm.

According to the signal values of the test plate read by the EnVision multifunctional enzyme label instrument, the average value of a high signal control and a low signal control is calculated respectively, the inhibition rate of a compound sample hole is calculated by the following formula, and concentration response curve fitting is carried out on the inhibition rate of the compound to the experimental signal at different concentrations by using a four-parameter fitting mode (log (inhibitor) vs. response-Variable slope (four parameters)) in GRAPHPAD PRISM software, so as to calculate the IC50 value of the compound.

Inhibition (%) = (high signal control group-sample signal)/(high signal control group-low signal control group) ×100%

The IC50 values of the compounds of the invention are shown in the following table:

from the above table, the compounds of the present invention have a good inhibitory effect on KRAS G12D.

Claims

A six-membered and six-membered compound shown in a formula I or pharmaceutically acceptable salt thereof is characterized in that,

Wherein,Is a double bond or a single bond;

A is N or CR ^A;R^A is cyano or halogen;

b is N or CR ^B;R^B is cyano or halogen;

When (when) When the compound is double bond, E is N or CH;

When (when) When the bond is single bond, E is NH, CR ^E-1R^E-2 or CO; r ^E-1 and R ^E-2 are independently hydrogen or C ₁-C₆ alkyl, or R ^E-1 and R ^E-2 together with the carbon atom to which they are attached form a 3 to 6 membered heterocycloalkyl or C ₃-C₆ cycloalkyl; the heteroatom of the 3-to 6-membered heterocycloalkyl group is N, S or O, and the number of the heteroatom is 1;

G is NH, CR ^G-1R^G-2 or CO; r ^G-1 and R ^G-2 are independently hydrogen, or C ₁-C₆ alkyl, unsubstituted or substituted with one or more halogens, or R ^G-1 and R ^G-2 together with the carbon atom to which they are attached form a 3 to 6 membered heterocycloalkyl or C ₃-C₆ cycloalkyl; the heteroatom of the 3-to 6-membered heterocycloalkyl group is N, S or O, and the number of the heteroatom is 1;

When (when) When the double bond is present, M is N or CH;

When (when) When a single bond, then M is NR ^M-1 or CR ^M-2R^M-3;R^M-1 is hydrogen or C ₁-C₆ alkyl, unsubstituted or substituted with one or more halogens; r ^M-2 and R ^M-3 are independently hydrogen, halogen, or C ₁-C₆ alkyl, unsubstituted or substituted with one or more halogens, or R ^M-2 and R ^M-3 together with the carbon atom to which they are attached form a 3 to 6 membered heterocycloalkyl or C ₃-C₆ cycloalkyl; the heteroatom of the 3-to 6-membered heterocycloalkyl group is N, S or O, and the number of the heteroatom is 1;

R ¹ is 6-to 10-membered heterocycloalkyl, which is unsubstituted or substituted by one or more R ^1-3, C ₁-C₆ alkoxy substituted by one or more R ^1-1, or The heteroatom of the 6-to 10-membered heterocycloalkyl is selected from one or more of N, S and O, and the number of the heteroatom is 1,2 or 3; the 6-to 10-membered heterocycloalkyl is a bridged, spiro or fused ring;

each R ^1-1 is independently one or more Substituted C ₃-C₆ cycloalkyl;

R ^1-2 is C ₁-C₆ alkyl substituted by one or more R ^1-2-1, substituted by one or more Substituted C ₃-C₆ cycloalkyl or 4 to 10 membered heterocycloalkyl, unsubstituted or substituted by one or more C ₁-C₆ alkyl; the heteroatom of the 4-to 10-membered heterocycloalkyl group is N, and the number of the heteroatom is 1;

Each R ^1-2-1 is independently one or more Substituted C ₃-C₆ cycloalkyl or 4 to 10 membered heterocycloalkyl, unsubstituted or substituted by one or more C ₁-C₆ alkyl; the heteroatom of the 4-to 10-membered heterocycloalkyl group is N, and the number of the heteroatom is 1;

Each R ^1-3 is independently cyano, C ₂-C₆ alkynyl, C ₁-C₆ alkyl, hydroxy, halogen or substituted by one or more R ^1-3-1

Each R ^1-3-1 is independently cyano, hydroxy, or halogen;

r ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1, C ₁-C₆ alkyl substituted with one or more R ^2-2, 3-to 6-membered heterocycloalkyl or substituted with one or more R ^2-3 The hetero atoms of the 3-to 6-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3;

each R ^2-1 is independently deuterium, halogen, A5 to 10 membered heterocycloalkyl unsubstituted or substituted by one or more R ^2-1-1, a5 to 6 membered heteroaryl unsubstituted or substituted by one or more R ^2-1-2, or a C ₃-C₆ cycloalkyl unsubstituted or substituted by one or more R ^2-1-3; the heteroatom of the 5-to 10-membered heterocycloalkyl group is selected from one or more of N, S and O, and the number of the heteroatom is1, 2 or 3; the hetero atoms of the 5-to 6-membered heteroaryl are selected from one or more of N, S and O, and the number of the hetero atoms is1, 2 or 3;

Each R ^2-1-1 is independently deuterium, hydroxy, oxo, 6 to 10 membered aryl, halogen, C ₁-C₆ alkyl which is unsubstituted or substituted by one or more R ^2-1-1-1, C ₁-C₆ alkoxy which is unsubstituted or substituted by one or more R ^2-1-1-2, or A5 to 6 membered heteroaryl, unsubstituted or substituted with one or more R ^2-1-1-4; the hetero atoms of the 5-to 6-membered heteroaryl are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3;

each R ^2-1-1-1 is independently deuterium, hydroxy, oxo, halogen, C ₁-C₆ alkyl, C ₁-C₆ alkoxy, 3 to 6 membered heterocycloalkyl, 5 to 6 membered heteroaryl, unsubstituted or substituted with one or more R ^2-1-1-1-1, The hetero atoms of the 3-to 6-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3; the hetero atoms of the 5-to 6-membered heteroaryl are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3;

each R ^2-1-1-1-1 is independently oxo;

R ^2-1-1-1-2 is a 3 to 6 membered heterocycloalkyl; the hetero atoms of the 3-to 6-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3;

Each R ^2-1-1-2 is independently C ₁-C₆ alkoxy;

R ^2-1-1-3 is C ₆-C₁₀ aryl, unsubstituted or substituted with one or more R ^2-1-1-3-1;

Each R ^2-1-1-3-1 is independently-SO ₂ F;

Each R ^2-1-1-4 is independently C ₁-C₆ alkyl;

Each R ^2-1-2 is independently C ₁-C₆ alkyl or halogen;

Each R ^2-1-3 is independently C ₁-C₆ alkyl, unsubstituted or substituted with one or more R ^2-1-3-1;

Each R ^2-1-3-1 is independently Or a 5 to 10 membered heterocycloalkyl unsubstituted or substituted with one or more R ^2-1-3-1-1; the heteroatom of the 5-to 10-membered heterocycloalkyl group is selected from one or more of N, S and O, and the number of the heteroatom is 1,2 or 3;

Each R ^2-1-3-1-1 is independently halogen;

Each R ^2-2 is independently a 5-to 10-membered heterocycloalkyl unsubstituted or substituted by one or more R ^2-2-1, the heteroatoms of the 5-to 10-membered heterocycloalkyl being selected from one or more of N, S and O, the number of heteroatoms being 1,2 or 3;

each R ^2-2-1 is independently C ₁-C₆ alkoxy;

Each R ^2-3 is independently Or C ₁-C₆ alkyl;

R ^2-4 is 5-to 10-membered heterocycloalkyl which is unsubstituted or substituted by one or more R ^2-4-1, the heteroatom of the 5-to 10-membered heterocycloalkyl is selected from one or more of N, S and O, and the number of the heteroatom is 1,2 or 3;

Each R ^2-4-1 is independently C ₁-C₆ alkyl, unsubstituted or substituted with one or more R ^2-4-1-1;

Each R ^2-4-1-1 is independently C ₁-C₆ alkoxy;

The conditions are as follows: when (when) Is thatR ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1; each R ^2-1 is independently a 5-to 10-membered heterocycloalkyl substituted with one or more R ^2-1-1, the heteroatoms of the 5-to 10-membered heterocycloalkyl being selected from one or more of N, S and O, the number of heteroatoms being 1,2 or 3; each R ^2-1-1 is independently C ₁-C₆ alkyl or halogen;

R ³ is C ₆-C₁₀ aryl, unsubstituted or substituted with one or more R ^3-1, or 5 to 10 membered heteroaryl, unsubstituted or substituted with one or more R ^3-2; the hetero atoms of the 5-to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3;

Each R ^3-1 and R ^3-2 is independently C ₂-C₆ alkynyl unsubstituted or substituted by one or more R ^3-1-1, C ₁-C₆ alkyl unsubstituted or substituted by one or more R ^3-1-2, C ₃-C₆ cycloalkyl unsubstituted or substituted by one or more R ^3-1-3, C ₁-C₆ alkoxy unsubstituted or substituted by one or more R ^3-1-4, C ₁-C₆ alkylthio unsubstituted or substituted by one or more R ^3-1-5, 5 to 10 membered heteroaryl, hydroxy, halogen, cyano, C ₂-C₆ alkenyl or substituted by one or more R ^3-1-6 The hetero atoms of the 5-to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3; or two adjacent R ^3- ¹ together with the atom to which the C ₆-C₁₀ aryl group is attached form a3 to 6 membered cycloalkyl which is unsubstituted or substituted by one or more R ^3-1-7;

Each R ^3-1-1、R^3-1-2、R^3-1-3、R^3-1-4、R^3-1-5、R^3-1-6 and R ^3-1-7 is independently C ₁-C₆ alkyl, C ₂-C₆ alkynyl, cyano, halogen, deuterium, hydroxy or amino; or two adjacent R ^3-1-7 taken together with the atom to which they 3 to 6 membered cycloalkyl are attached form 3 to 6 membered cycloalkyl which is unsubstituted or substituted by one or more R ^3-1-7-1;

Each R ^3-1-7-1 is independently C ₁-C₆ alkyl;

Each of R ^a and R ^b is independently hydrogen or C ₁-C₆ alkyl, or R ^a and R ^b, and the atoms 3 to 6 membered heterocycloalkyl attached thereto; the hetero atom of the 3-to 6-membered heterocycloalkyl group is selected from one or more of N, S and O, the number of the hetero atoms is 1,2 or 3, and the hetero atom of the 3-to 6-membered heterocycloalkyl group at least comprises one N.
The six-membered and six-membered compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the six-membered and six-membered compound represented by formula I satisfies one or more of the following conditions:

(1) In R ^A, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine;

(2) In R ^B, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine;

(3) When E is CR ^E-1R^E-2, R ^E-1 and R ^E-2 together with the carbon atom to which they are attached form epoxybutyl;

(4) When E is CR ^E-1R^E-2, R ^E-1 and R ^E-2 together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl;

(5) In R ^E-1 and R ^E-2, the C ₁-C₆ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, and may be methyl;

(6) When G is CR ^G-1R^G-2, R ^G-1 and R ^G-2 together with the carbon atom to which they are attached form an epoxybutyl group;

(7) When G is CR ^G-1R^G-2, R ^G-1 and R ^G-2 together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl;

(8) In R ^G-1, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, and may be methyl;

(9) In R ^G-2, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, and may be methyl;

(10) R ^M-1、R^M-2 and R ^M-3, the C ₁-C₆ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl;

(11) R ^M-1、R^M-2 and R ^M-3, the halogen is independently fluorine, chlorine, bromine or iodine, such as fluorine;

(12) When M is CR ^M-2R^M-3, R ^M-2 and R ^M-3 together with the carbon atoms to which they are attached form epoxybutyl;

(13) When M is CR ^M-2R^M-3, R ^M-2 and R ^M-3 together with the carbon atoms to which they are attached form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl;

(14) In R ¹, the 6-to 10-membered heterocycloalkyl is a 6-to 8-membered heterocycloalkyl; the heteroatom of the 6-to 10-membered heterocycloalkyl group is preferably N, S or O, and the number of the heteroatom is preferably 1 or 2; the 6-to 10-membered heterocycloalkyl group is more preferably an 8-membered bridged cycloalkyl group, for example

(15) In each R ¹, the C ₁-C₆ alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, and can be methoxy or ethoxy;

(16) In each R ^1-1, the C ₃-C₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclobutyl or cyclopentyl;

(17) In R ^1-2, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl;

(18) In R ^1-2, the C ₃-C₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclobutyl or cyclopentyl;

(19) In R ^1-2, the 4-to 10-membered heterocycloalkyl is 4-to 6-membered heterocycloalkyl; the 4-to 10-membered heterocycloalkyl is preferably a single ring; the 4-to 10-membered heterocycloalkyl group is more preferably an azetidinyl group;

(20) In each R ^1-2-1, the C ₃-C₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclobutyl or cyclopentyl;

(21) In each R ^1-2-1, the 4-to 10-membered heterocycloalkyl is a 4-to 6-membered heterocycloalkyl; the 4-to 10-membered heterocycloalkyl is preferably a single ring; the 4-to 10-membered heterocycloalkyl group is more preferably an azetidinyl group, for example

(22) In each R ^1-3, the C ₂-C₆ alkynyl is C ₂-C₄ alkynyl, preferably

(23) In each R ^1-3, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, such as methyl or ethyl;

(24) In each R ^1-3-1, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine;

(25) In R ², the C ₁-C₆ alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, and can be methoxy, ethoxy or n-propoxy;

(26) In R ², the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl, for example methyl;

(27) In R ², the heteroatom of the 3-to 6-membered heterocycloalkyl is N, S or O; the number of heteroatoms of the 3-to 6-membered heterocycloalkyl group is preferably 1,2 or 3; the 3-to 6-membered heterocycloalkyl is preferably a single ring; the 3-to 6-membered heterocycloalkyl group is more preferably an azetidinyl group, for example

(28) In each R ^2-1, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine;

(29) In each R ^2-1, the heteroatom of the 5-to 10-membered heterocycloalkyl is N and/or O; the number of heteroatoms of the 5-to 10-membered heterocycloalkyl group is preferably 1 or 2; the 5-to 10-membered heterocycloalkyl group is preferably a 5-to 8-membered heterocycloalkyl group, for example

(30) In each R ^2-1, the heteroatom of the 5 to 6 membered heteroaryl is N; the number of heteroatoms of the 5-to 6-membered heteroaryl group is preferably 1,2 or 3; the 5-to 6-membered heteroaryl group is more preferably a pyridyl or imidazolyl group, e.g

(31) In each R ^2-1, the C ₃-C₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclobutyl or cyclopentyl;

(32) In each R ^2-1-1, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine;

(33) In each R ^2-1-1, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, for example methyl;

(34) In each R ^2-1-1, the heteroatom of the 3-to 6-membered heterocycloalkyl is N, S or O; the number of heteroatoms of the 3-to 6-membered heterocycloalkyl group is preferably 1,2 or 3; the 3-to 6-membered heterocycloalkyl is preferably a single ring; the 3-to 6-membered heterocycloalkyl group is more preferably an azetidinyl group, for example

(35) In each R ^2-1-1, the heteroatom of the 5 to 6 membered heteroaryl is N; the number of heteroatoms of the 5-to 6-membered heteroaryl group is preferably 1,2 or 3; the 5-to 6-membered heteroaryl group is more preferably pyrazolyl, e.g

(36) In R ^2-1-1-1, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl or tertiary butyl;

(37) In each R ^2-1-1-1, the C ₁-C₆ alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, which can be methoxy;

(38) In each R ^2-1-1-1, the C ₆-C₁₀ aryl is aryl or naphthyl, such as aryl;

(39) In each R ^2-1-1-1, the heteroatom of the 3-to 6-membered heterocycloalkyl may be N and/or O; the number of heteroatoms of the 3-to 6-membered heterocycloalkyl group is 1 or 2; the 3-to 6-membered heterocycloalkyl group is preferably a 5-to 6-membered heterocycloalkyl group, for example

(40) In each R ^2-1-1-1, the heteroatom of the 5 to 6 membered heteroaryl may be N; the number of heteroatoms of the 5-to 6-membered heteroaryl group is preferably 1,2 or 3; the 5-to 6-membered heteroaryl group is more preferably pyrazolyl, e.g

(41) In each R ^2-1-1-2, the C ₁-C₆ alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, which can be methoxy;

(42) In R ^2-1-1-3, the C ₆-C₁₀ aryl is aryl or naphthyl, for example aryl;

(43) In each R ^2-1-1-4, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, such as methyl;

(44) In R ^2-1-1-1-2, the heteroatom of the 3-to 6-membered heterocycloalkyl is N and/or O; the number of heteroatoms of the 3-to 6-membered heterocycloalkyl group is 1 or 2; the 3-to 6-membered heterocycloalkyl group is preferably a 5-to 6-membered heterocycloalkyl group, for example

(45) In each R ^2-1-2, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine;

(46) In each R ^2-1-2, the C ₁-C₆ alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, for example methyl or isopropyl;

(47) In each R ^2-1-3, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine;

(48) In each R ^2-1-3, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, such as methyl;

(49) In each R ^2-1-3-1, the heteroatom of the 5-to 10-membered heterocycloalkyl is N and/or O; the number of heteroatoms of the 5-to 10-membered heterocycloalkyl group is preferably 1 or 2; the 5-to 10-membered heterocycloalkyl group is preferably a 5-to 6-membered heterocycloalkyl group, for example

(50) In each R ^2-1-3-1-1, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine;

(51) In each R ^2-2, the heteroatom of the 5-to 10-membered heterocycloalkyl is N and/or O; the number of heteroatoms of the 5-to 10-membered heterocycloalkyl group is preferably 1 or 2; the 5-to 10-membered heterocycloalkyl group is preferably an 8-membered heterocycloalkyl group, for example

(52) In each R ^2-2-1, the C ₁-C₆ alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, which may be methoxy;

(53) In each R ^2-3, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, such as methyl or ethyl;

(54) In each R ^2-4, the heteroatom of the 5-to 10-membered heterocycloalkyl is N; the number of heteroatoms of the 5-to 10-membered heterocycloalkyl group is preferably 1 or 2; the 5-to 10-membered heterocycloalkyl group is preferably a 5-to 6-membered heterocycloalkyl group, for example

(55) In each R ^2-4-1, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, such as n-propyl;

(56) In each R ^2-4-1-1, the C ₁-C₆ alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, and can also be methoxy;

(57) In R ³, the C ₆-C₁₀ aryl is aryl or naphthyl;

(58) In R ³, the heteroatom of the 5-to 10-membered heteroaryl is N and/or S; the number of heteroatoms of the 5-to 10-membered heteroaryl group is preferably 1 or 2; the 5-to 10-membered heteroaryl group is a five-membered and six-membered heteroaryl group, e.g

(59) In each of R ^3-1 and R ^3-2, the C ₂-C₆ alkynyl is C ₂-C₄ alkynyl, preferably For example

(59) In each of R ^3-1 and R ^3-2, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, for example methyl, ethyl, n-propyl, or isopropyl;

(60) In each of R ^3-1 and R ^3-2, the C ₃-C₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl;

(61) In each of R ^3-1 and R ^3-2, the C ₁-C₆ alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, which may be methoxy;

(62) In each of R ^3-1 and R ^3-2, the C ₁-C₆ alkylthio is methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, primary butylthio, zhong Ding or tertiary butylthio, which can be methylthio;

(63) In each of R ^3-1 and R ^3-2, the heteroatom of the 5 to 10 membered heteroaryl is N; the number of heteroatoms of the 5-to 10-membered heteroaryl group is preferably 2 or 3; the 5-to 10-membered heteroaryl is a 5-to 6-membered heteroaryl, e.g

(64) In each of R ^3-1 and R ^3-2, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine, chlorine or bromine;

(65) In each of R ^3-1 and R ^3-2, the C ₂-C₆ alkene is vinyl, Such as vinyl;

(66) In each of R ^3-1-1、R^3-1-2、R^3-1-3、R^3-1-4、R^3-1-5、R^3-1-6 and R ^3-1-7, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, for example methyl;

(67) In each of R ^3-1-1、R^3-1-2、R^3-1-3、R^3-1-4、R^3-1-5、R^3-1-6 and R ^3-1-7, the C ₂-C₆ alkynyl group may be For example

(68) In each of R ^3-1-1、R^3-1-2、R^3-1-3、R^3-1-4、R^3-1-5、R^3-1-6 and R ^3-1-7, the halogen is fluorine, chlorine, bromine or iodine, for example fluorine;

(69) In each R ^3-1-7-1, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, such as methyl;

(70) In each R ^a, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, such as methyl;

(71) In each R ^b, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, such as methyl;

And (72) each of R ^a and R ^b, the heteroatom of the 3-to 6-membered heterocycloalkyl is N; the number of heteroatoms of the 3-to 6-membered heterocycloalkyl group is preferably 1 or 2; the 3-to 6-membered heterocycloalkyl group is preferably a 5-to 6-membered heterocycloalkyl group, for example
The six-membered and six-membered compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the six-membered and six-membered compound represented by formula I satisfies one or more of the following conditions:

(1) R ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1 or 3 to 6 membered heterocycloalkyl substituted with one or more R ^2-3 or The hetero atoms of the 3-to 6-membered heterocyclic alkyl are N, and the number of the hetero atoms is 1 or 2;

(2) Each R ^2-1 is independently deuterium, A 5 to 8 membered heterocycloalkyl unsubstituted or substituted by one or more R ^2-1-1 or a C ₃-C₆ cycloalkyl unsubstituted or substituted by one or more R ^2-1-3; the hetero atoms of the 5-to 8-membered heterocycloalkyl group are N and/or O, and the number of the hetero atoms is 1 or 2; preferably, in each R ^2-1, at least one R ^2-1 is said 5 to 10 membered heterocycloalkyl or said C ₃-C₆ cycloalkyl;

(3) Each R ^2-1-1 is independently deuterium, hydroxy, halogen, C ₁-C₆ alkyl, unsubstituted or substituted with one or more R ^2-1-1-1, or C ₁-C₆ alkoxy, unsubstituted or substituted with one or more R ^2-1-1-2;

(4) Each R ^2-1-1-1 is independently halogen, C ₁-C₆ alkoxy or

(5) Each R ^2-1-1-2 is independently C ₁-C₆ alkoxy;

(6) R ^2-1-1-1-2 is a3 to 6 membered heterocycloalkyl; the hetero atoms of the 3-to 6-membered heterocycloalkyl group are N and/or O, and the number of the hetero atoms is 1 or 2;

(7) Each R ^2-1-3 is independently C ₁-C₆ alkyl, unsubstituted or substituted with one or more R ^2-1-3-1;

(8) Each R ^2-1-3-1 is independently Or a 5-to 6-membered heterocycloalkyl unsubstituted or substituted by one or more R ^2-1-3-1-1; the hetero atoms of the 5-to 6-membered heterocycloalkyl group are N, and the number of the hetero atoms is 1;

(9) Each R ^2-1-3-1-1 is independently halogen;

(10) R ³ is C ₆-C₁₀ aryl, unsubstituted or substituted with one or more R ^3-1, or 5 to 10 membered heteroaryl, unsubstituted or substituted with one or more R ^3-2; the hetero atom of the 5-to 10-membered heteroaryl is N, and the number of the hetero atoms is 1 or 2;

(11) Each R ^3-1 and R ^3-2 is independently C ₂-C₆ alkynyl, unsubstituted or substituted by one or more R ^3-1-1, C ₁-C₆ alkyl, unsubstituted or substituted by one or more R ^3-1-2, C ₃-C₆ cycloalkyl, unsubstituted or substituted by one or more R ^3-1-3, C ₁-C₆ alkoxy, hydroxy, halogen or cyano, or C ₂-C₆ alkenyl, unsubstituted or substituted by one or more R ^3-1-4;

And (12) each of R ^3-1-1、R^3-1-2、R^3-1-3 and R ^3-1-4 is independently C ₁-C₆ alkyl, halogen, deuterium, or hydroxy.
The six-membered and six-membered compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the six-membered and six-membered compound represented by formula I satisfies one or more of the following conditions:

(1) A is N;

(2) B is N;

(3) E is N, CR ^E-1R^E-2 or CO;

(4) R ^E-1 and R ^E-2 are independently hydrogen or C ₁-C₆ alkyl; or, R ^E-1 and R ^E-2 together with the carbon atom to which they are attached form a C ₃-C₆ cycloalkyl group;

(5) G is CR ^G-1R^G-2 or CO; r ^G-1 and R ^G-2 are independently hydrogen, or C ₁-C₆ alkyl, unsubstituted or substituted with one or more halogens, or R ^G-1、R^G-2 together with the carbon atom to which they are attached form a3 to 6 membered heterocycloalkyl or C ₃-C₆ cycloalkyl; the hetero atoms of the 3-to 6-membered heterocycloalkyl group are O, and the number of the hetero atoms is 1;

(6) M is NH, CH or CH ₂;

(7) R ¹ is unsubstituted 8 membered heterocycloalkyl, C ₁-C₆ alkoxy substituted by one or more R ^1-1, or The heteroatom of the 8-membered heterocycloalkyl group is N, and the number of the heteroatom is 1 or 2; the 8-membered heterocycloalkyl is a bridged, spiro or fused ring;

(8) Each R ^1-1 is independently one or more Substituted C ₃-C₆ cycloalkyl;

(9) R ^1-2 is C ₁-C₆ alkyl substituted with one or more R ^1-2-1;

(10) R ^1-2-1 is one or more Substituted C ₃-C₆ cycloalkyl;

(11) R ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1;

(12) Each R ^2-1 is independently a 5-to 10-membered heterocycloalkyl that is unsubstituted or substituted with one or more R ^2-1-1, the heteroatom of the 5-to 10-membered heterocycloalkyl being N, the number of heteroatoms being 1,2 or 3;

(13) Each R ^2-1-1 is independently halogen or C ₁-C₆ alkyl, unsubstituted or substituted with one or more halogens;

(14) When (when) Is thatWhen each R ^2-1 is independently 5 to 10 membered heterocycloalkyl substituted with one or more R ^2-1-1;

(15) R ³ is C ₆-C₁₀ aryl, unsubstituted or substituted with one or more R ^3-1, or 5 to 10 membered heteroaryl, unsubstituted or substituted with one or more R ^3-2; the hetero atoms of the 5-to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of the hetero atoms is 1,2 or 3;

(16) Each R ^3-1 is independently C ₂-C₆ alkynyl, C ₁-C₆ alkyl, C ₃-C₆ cycloalkyl, hydroxy, halogen or Or two adjacent R ^3-1 together with the atom to which the C ₆-C₁₀ aryl group is attached form a 5 to 6 membered cycloalkyl which is unsubstituted or substituted by one or more R ^3-1-7;

(17) Each R ^3-1-7 is independently C ₁-C₆ alkyl;

(18) Each R ^3-2 is independently C ₁-C₆ alkyl, halogen or amino;

And (19) each of R ^a and R ^b is independently hydrogen or C ₁-C₆ alkyl, or R ^a and R ^b, and the atoms 3 to 6 membered heterocycloalkyl attached thereto; the heteroatom of the 3-to 6-membered heterocycloalkyl group is N, and the number of the heteroatom is 1,2 or 3.
The six-membered and six-membered compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 4, wherein the six-membered and six-membered compound represented by formula I satisfies one or more of the following conditions:

(1) E is CH ₂;

(2) G is CO;

(3) M is CH ₂;

(4) R ¹ is unsubstituted 8 membered heterocycloalkyl; the heteroatom of the 8-membered heterocycloalkyl group is N, and the number of the heteroatom is 2; the 8-membered heterocycloalkyl is a bridged or spiro ring;

(5) R ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1;

(6) Each R ^2-1 is independently a 5-to 8-membered heterocycloalkyl that is unsubstituted or substituted with one or more R ^2-1-1, the heteroatom of the 5-to 8-membered heterocycloalkyl being N, the number of heteroatoms being 1;

(7) Each R ^2-1-1 is independently halogen;

(8) R ³ is C ₆-C₁₀ aryl substituted with one or more R ^3-1 or 5 to 10 membered heteroaryl substituted with one or more R ^3-2; the heteroatom of the 5-to 10-membered heteroaryl is N, and the number of the heteroatom is 1,2 or 3;

(9) Each R ^3-1 is independently C ₂-C₆ alkynyl, hydroxy, or halogen;

and (10) each R ^3-2 is independently C ₁-C₆ alkyl.
The six-membered and six-membered compound according to any one of claims 1 to 5, which is represented by formula I, or a pharmaceutically acceptable salt thereof, wherein the six-membered and six-membered compound is represented by formula I-a, formula I-B, formula I-C, formula I-D or formula I-E:
The six-membered and six-membered compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the six-membered and six-membered compound represented by formula I or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

(1) The pharmaceutically acceptable salt is formate;

(2) Is that

(3) R ¹ is

(4) R ² is

And (5) R ³ is
A six-membered, and six-membered compound according to any one of claims 1 to 7, as shown in formula I, or a pharmaceutically acceptable salt thereof, which satisfies scheme 1 or scheme 2 below;

scheme 1, wherein, Is a single bond;

A is N or CR ^A;R^A is cyano or halogen;

b is N or CR ^B;R^B is cyano or halogen;

E is CR ^E-1R^E-2;R^E-1 and R ^E-2 are independently hydrogen or C ₁-C₆ alkyl;

G is CO;

M is CR ^M-2R^M-3;R^M-1 is hydrogen or C ₁-C₆ alkyl optionally substituted with one or more halogens; r ^M-2 and R ^M-3 are independently hydrogen, halogen, or C ₁-C₆ alkyl, unsubstituted or substituted with one or more halogens;

r ¹、R² and R ³ are as defined in any one of claims 1 to 7;

Scheme 2: wherein, Is a double bond or a single bond;

A is CR ^A;R^A is cyano;

B is N;

E. G, M, R ¹、R² and R ³ are as defined in any one of claims 1 to 7.
The six-membered and six-membered compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 8, which satisfies scheme 1 or scheme 2 as follows;

Scheme 1: wherein, Is a single bond;

A is N or CR ^A;R^A is cyano;

B is N;

E is CR ^E-1R^E-2;R^E-1 and R ^E-2 are independently hydrogen or C ₁-C₆ alkyl;

G is CO;

M is CR ^M-2R^M-3;R^M-2 and R ^M-3 are independently hydrogen or C ₁-C₆ alkyl;

R ¹ is unsubstituted 8 membered heterocycloalkyl; the heteroatom of the 8-membered heterocycloalkyl group is N, and the number of the heteroatom is 2; the 8-membered heterocycloalkyl is a bridged or spiro ring;

R ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1;

Each R ^2-1 is independently a 5-to 8-membered heterocycloalkyl that is unsubstituted or substituted with one or more R ^2-1-1, the heteroatom of the 5-to 8-membered heterocycloalkyl being N, the number of heteroatoms being 1;

Each R ^2-1-1 is independently halogen or C ₁-C₆ alkyl;

R ³ is naphthyl substituted with one or more R ^3-1;

Each R ^3-1 is independently C ₂-C₆ alkynyl, hydroxy, or halogen;

Scheme 2: wherein, Is a single bond;

A is CR ^A;R^A is cyano;

B is N;

E is CR ^E-1R^E-2;R^E-1 and R ^E-2 are independently hydrogen or C ₁-C₆ alkyl;

G is CR ^G-1R^G-2 or CO; r ^G-1 and R ^G-2 are independently hydrogen, or C ₁-C₆ alkyl;

M is CR ^M-2R^M-3;R^M-2 and R ^M-3 are independently hydrogen or C ₁-C₆ alkyl;

R ¹ is unsubstituted 8 membered heterocycloalkyl; the heteroatom of the 8-membered heterocycloalkyl group is N, and the number of the heteroatom is 2; the 8-membered heterocycloalkyl is a bridged or spiro ring;

R ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1;

Each R ^2-1 is independently a 5-to 8-membered heterocycloalkyl that is unsubstituted or substituted with one or more R ^2-1-1, the heteroatom of the 5-to 8-membered heterocycloalkyl being N, the number of heteroatoms being 1;

Each R ^2-1-1 is independently halogen or C ₁-C₆ alkyl;

R ³ is naphthyl substituted with one or more R ^3-1;

Each R ^3-1 is independently C ₂-C₆ alkynyl, hydroxy, or halogen.
The six-membered and six-membered compound shown in the formula I or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the six-membered and six-membered compound shown in the formula I or pharmaceutically acceptable salt thereof has any structure,
A six-membered and six-membered compound shown in a formula II-A or pharmaceutically acceptable salt thereof is characterized in that,

Wherein,Is a single bond;

A is N or CR ^A;R^A is cyano;

B is N;

E is CR ^E-1R^E-2;R^E-1 and R ^E-2 are independently hydrogen or C ₁-C₆ alkyl;

g is O;

M is CR ^M-2R^M-3;R^M-2 and R ^M-3 are independently hydrogen or C ₁-C₆ alkyl;

R ¹ is unsubstituted 8 membered heterocycloalkyl; the heteroatom of the 8-membered heterocycloalkyl group is N, and the number of the heteroatom is 2; the 8-membered heterocycloalkyl is a bridged or spiro ring;

R ² is C ₁-C₆ alkoxy substituted with one or more R ^2-1;

Each R ^2-1 is independently a 5-to 10-membered heterocycloalkyl unsubstituted or substituted by one or more R ^2-1-1, the heteroatom of the 5-to 10-membered heterocycloalkyl being N, the number of heteroatoms being 1;

Each R ^2-1-1 is independently halogen or C ₁-C₆ alkyl;

R ³ is naphthyl substituted with one or more R ^3-1;

Each R ^3-1 is independently C ₂-C₆ alkynyl, hydroxy, or halogen.
The six-membered, six-membered compound of formula II-a, or a pharmaceutically acceptable salt thereof, according to claim 11, wherein the six-membered, six-membered compound of formula II-a satisfies one or more of the following conditions:

(1) In each of R ^E-1、R^E-2、R^M-2、R^M-3 and R ^2-1-1, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, which may be methyl;

(2) In each of R ^2-1-1 and R ^3-1, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine;

(3) R ¹ is

(4) In R ^2-1, the C ₁-C₆ alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, secondary butoxy or tertiary butoxy, and can be methoxy;

(5) In R ^2-1, the 5-to 10-membered heterocycloalkyl is a bridged, spiro or fused ring; preferably is Preferably is

(6) In R ^2-1, the 5-to 10-membered heterocycloalkyl is 8-membered heterocycloalkyl;

(7) R ² is Preferably is

(8) In R ^3-1, the C ₂-C₆ alkynyl is C ₂-C₄ alkynyl, preferably

(9) R ³ is Preferably is
A six-membered and six-membered compound shown in a formula II-B or pharmaceutically acceptable salts thereof, which is characterized in that,

Wherein,Is a double bond;

A is N;

B is N;

e is N;

G is CR ^G-1;R^G-1 or halogen;

M is CH;

R ¹ is R ^1-4 is C ₁-C₆ alkyl which is unsubstituted or substituted by one or more R ^1-4-1; each R ^1-4-1 is independently halogen orR ^1-4-1-1 is C ₁-C₆ alkyl;

r ² and R ³ are as defined in claim 11 or 12.
The six-membered, compound of formula II-B, or a pharmaceutically acceptable salt thereof, according to claim 13, wherein the six-membered, compound of formula II-B satisfies one or more of the following conditions:

(1) In each of R ^1-4 and R ^1-4-1-1, the C ₁-C₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, secondary butyl, or tertiary butyl, which may be methyl;

(2) In R ^1-4-1, the C ₂-C₄ alkenyl group may be

(3) R ^1-4-1 is C ₂-C₄ alkenyl or

(4) In each of R ^1-4-1 and R ^G-1, the halogen may be fluorine, chlorine, bromine or iodine, such as fluorine;

(5) R ¹ is
A six-membered and six-membered compound or a pharmaceutically acceptable salt thereof, wherein the six-membered and six-membered compound or a pharmaceutically acceptable salt thereof has any one of the following structures:
A process for the preparation of a six-membered, parallel-membered compound according to any one of claims 1 to 10, according to formula I, comprising the steps of: in a solvent, the compound shown in the formula I-1 is subjected to deprotection reaction in the presence of fluorine-containing salt, so that the method is characterized in that:

Wherein A, B, M, E, G, R ² and R ³ are as in any one of claims 1-9; r ¹ is R ⁴ is a nitrogen protecting group;

preferably, the deprotection reaction satisfies one or more of the following conditions:

(1) The nitrogen protecting groups are Alloc, cbz, boc and Fmoc; such as Alloc;

(2) The solvent is an amide solvent, preferably DMF, such as anhydrous DMF;

(3) The volume molar ratio of the solvent to the compound shown in the formula I-1 is 70-20mL/mmol, such as 54mL/mmol;

(4) The fluoride salt is an alkali metal fluoride salt, such as cesium fluoride;

(5) The molar ratio of the fluorine salt to the compound shown as the formula I-1 is (1-10): 1, for example 5:1, a step of;

and (6) the deprotection reaction has a reaction temperature of-10℃to 50℃such as room temperature.
A pharmaceutical composition comprising a substance Z which is a six-membered and six-membered compound as shown in formula I or a pharmaceutically acceptable salt thereof, a six-membered and six-membered compound as shown in formula II-a or a pharmaceutically acceptable salt thereof, as shown in any one of claims 11 or 12, a six-membered and six-membered compound as shown in formula II-B or a pharmaceutically acceptable salt thereof, or a six-membered and six-membered compound as shown in any one of claims 13 or 14, or a pharmaceutically acceptable salt thereof, as shown in any one of claims 1 to 10, or a six-membered and six-membered compound as shown in claim 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
Use of a substance Z, or a pharmaceutical composition according to claim 17, for the manufacture of a medicament for the treatment of a KRAS G12D-related disease, wherein the substance Z is a six-membered and six-membered compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, a six-membered and six-membered compound according to any one of claims 11 or 12, or a pharmaceutically acceptable salt thereof, a six-membered and six-membered compound according to any one of claims 13 or 14, or a pharmaceutically acceptable salt thereof, a six-membered and six-membered compound according to any one of claims 15, or a pharmaceutically acceptable salt thereof;

Preferably, the KRAS G12D-related disease is solid cancer; the solid cancer is preferably pancreatic ductal adenocarcinoma, pancreatic carcinoma, colon carcinoma, malignant colorectal tumor, non-small cell lung cancer, squamous cell lung cancer, gastric cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, glioblastoma, anal squamous cell carcinoma, chordal carcinoma, thyroid undifferentiated carcinoma or uveal melanoma.