CN112552294B - Piperazine-containing heterocyclic derivative inhibitors, preparation methods and applications thereof - Google Patents

Abstract

The invention relates to a piperazine heterocyclic derivative inhibitor, a preparation method and application thereof. In particular, the invention relates to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a KRAS inhibitor in treating diseases or symptoms such as leukemia, neuroblastoma, melanoma, breast cancer, lung cancer, colon cancer and the like, wherein each substituent in the general formula (I) is defined as in the specification.

Description

Piperazine-containing heterocyclic derivative inhibitor, preparation method and application thereof

Technical Field

The invention belongs to the field of drug synthesis, and specifically relates to a piperazine-containing heterocyclic derivative inhibitor, a preparation method and an application thereof.

Background Art

Rat sarcoma (RAS) is encoded by the proto-oncogenes HRAS, NRAS and KRAS, and is divided into four proteins: HRAS, NRAS, KRAS4A and KRAS4B. It is a GTP (guanosine triphosphate) binding protein. RAS is located on the inner surface of the cell membrane, with receptor tyrosine kinase (RTK) upstream. After activation, it regulates downstream signaling pathways such as PI3K and RAF, thereby regulating cell growth, survival, migration and differentiation.

RAS has two main states in the body: an inactive state bound to GDP (guanosine diphosphate) and an activated state bound to GTP. Its activity is regulated by two proteins: guanine nucleotide exchange factor (GEF) promotes the release of GDP from the RAS protein, allowing GTP to bind and activate RAS; GTPase activating protein (GAP) activates the GTPase activity of the RAS protein, hydrolyzing the GTP bound to the RAS protein into GDP, inactivating RAS. Under normal circumstances, the RAS protein is in an inactive state. After mutation, the conformation changes, RAS is in a continuously activated state, and the downstream signaling pathway is also continuously activated, leading to the occurrence of various cancers.

As the first confirmed oncogene, RAS is the oncogene with the highest mutation rate, accounting for an average of 25% in human cancers. The most common oncogenic mutation in the RAS family is KRAS (85%), while NRAS (12%) and HRAS (3%) are relatively rare. KRAS mutations are mainly prevalent in a series of cancers such as pancreatic cancer (95%), colorectal cancer (52%) and lung cancer (31%). The most common mutation of KRAS is point mutation, which often occurs in G12, G13 in the p-loop (aa 10-17) and Q61 in the SwitchII region (aa59-76), among which G12 mutation is the most common (83%). In non-small cell lung cancer (NSCLC) and colorectal cancer, KRASG12C is one of the most common mutations.

Although there is a huge clinical need, there is no drug that directly targets KRAS on the market. Currently, patients with KRAS mutations can only be treated with chemotherapy. There are two main factors that make the development of KRAS inhibitors difficult. First, the structure of RAS protein is smooth, and it is difficult for small molecules to bind to the protein surface; second, the affinity of RAS GTPase for GTP is as high as picomolar (pM) level, and the endogenous GTP level is high, and it is difficult for small molecule drugs to block the binding of the two. Recent studies have found that after KRAS 12 glycine (Glycine, Gly) mutates to cysteine (Cysteine, Cys), the conformation changes, forming a new pocket for small molecules to covalently bind, and irreversibly locks KRAS G12C in an inactive state bound to GDP. Therefore, KRAS G12C inhibitors are expected to become the first drugs that directly target KRAS.

Currently, several KRAS G12C inhibitors have entered the clinical research stage, such as AMG 510 developed by Amgen, ARS-3248 developed by Wellspring Biosciences, and MTRX849 developed by Mirati. They are all in Phase I clinical research, but no KRAS G12C inhibitor has been developed and marketed. Among them, AMG 510 has shown good efficacy and good safety in early clinical trials, and it is expected to bring more treatment options to cancer patients with KRAS G12C mutations in the future.

There is currently no specific targeted drug for KRAS G12C, and there is a great clinical need. KRAS G12C inhibitors with higher selectivity, better activity, and better safety have the potential to treat a variety of cancers and have broad market prospects.

Summary of the invention

The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) has the following structure:

in:

X ₁ is selected from CR ₁ or CR ₁ R ₂ ;

X ₂ is selected from N, NR ₃ or CR ₃ ;

X ₃ is selected from C(O), S(O), S(O) ₂ or CLR ₄ ;

X ₄ is selected from O, S, C(O), N, NR ₅ , CR ₅ or CR ₅ R ₆ ;

X ₅ is selected from O, S, C(O), N, NR ₇ , CR ₇ or CR ₇ R ₈ ;

L is selected from the group consisting of bonds, -O(CH ₂ ) _n -, -S(CH ₂ ) _n -, -NR _aa (CH ₂ ) _n -, -(CH ₂ ) _n NR _aa -, -(CH ₂ ) _n O -, -(CH ₂ ) _n -, -(CH ₂ ) _n C(O)-, -(CH ₂ ) _n C(O)O-, -(CH ₂ ) _n NR _aa -, -(CH ₂ ) _n C(O)NR _aa -, -OC(R _aa R _bb ) _n (CH ₂ ) _m -, -(CH ₂ ) _n NR _aa C(O)-, -(CH ₂ ) _n NR _aa C(O )NR _bb -, -(CH ₂ ) _n S(O) _m -, -(CH ₂ ) _n S(O) _m NR _aa -, -(CH ₂ ) _n NR _aa S(O) _m -, -CR _aa = CR _bb (CH ₂ ) _n - or - CR _aa = CR _bb (CH ₂ ) _n NR _aa -;

Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;

R ₁ and R ₂ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

_R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

Alternatively, _R1 and _R3 together with the atoms on which they are located are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

_R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

R ₅ and R ₆ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

R ₇ and R ₈ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

R ^is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

Alternatively, any two adjacent or non-adjacent ^Ras are linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl group may be further substituted;

^R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

Alternatively, any two adjacent or non-adjacent Rb groups are linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

_Raa and _Rbb are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

x is an integer from 0 to 6;

y is an integer from 0 to 6;

m is 0, 1, 2 or 3; and

n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, L is selected from a bond, -O( _{CH2 ) n-} , _{-NRaa ( CH2} ) _n- , -( _CH2 ) _nC (O)-, -(CH2)nC(O)NRaa-, - _{( CH2} )nNRaaC _{( O} )-, - _{( CH2} ) _nS (O) _{m- ,} - _{( CH2} )nS(O) _{mNRaa- , - (} CH2)nNRaaS(O)m- _{, -CRaa} = _CRbb ( _CH2 ) _n- or -OC( _RaaRbb ) _n ( _CH2 ) _m- ;

In a further preferred embodiment of the present invention, L is selected from -O(CH ₂ ) _n -, -(CH ₂ ) _n C(O)- or -CR _aa ＝CR _bb (CH ₂ ) _n -;

R _aa and R _bb are each independently hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C 1-6 alkylthio, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl, and the amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl. C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C _{1-6 alkylthio, C 1-6} haloalkoxy, C 1-6 hydroxyalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

m is 0, 1, 2 or 3; and

n is 0, 1, 2 or 3.

In a preferred embodiment of the present invention, Ring A is selected from C _6-14 aryl or 5-14 membered heteroaryl, preferably C _6-10 aryl or 5-10 membered heteroaryl;

In a further preferred embodiment of the present invention, ring A is selected from phenyl, pyridyl, 5-7 membered nitrogen-containing heteroaryl, benzo 5-7 membered nitrogen-containing heteroaryl or 5-7 membered nitrogen-containing heteroaryl phenyl;

In a further preferred embodiment of the present invention, ring A is selected from the following groups:

In a preferred embodiment of the present invention, _R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, _C1-6 alkyl, _C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 alkylthio, halogenated _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein _{the C1-6 alkyl , C2-6} alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 alkylthio, halogenated _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, C6-14 aryl or 5-14 membered heteroaryl. C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C _1-6 alkylthio, halogenated C _1-6 alkoxy, C 1-6 hydroxyalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

In a further preferred embodiment of the present invention, R ₁ is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-8 cycloalkyl or 3-8 membered heterocyclyl;

In a further preferred embodiment of the present invention, R ₁ is selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, methoxy or ethoxy.

In a preferred embodiment of the present invention, R ₂ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-12 aryl or 5-12 membered heteroaryl;

In a further preferred embodiment of the present invention, R ₂ is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-8 cycloalkyl or 3-8 membered heterocyclyl;

In a further preferred embodiment of the present invention, R ₂ is selected from hydrogen.

In a preferred embodiment of the present invention, _R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, _C1-6 alkyl, _C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 alkylthio, halogenated _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein _{the C1-6 alkyl , C2-6} alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 alkylthio, halogenated _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, C6-14 aryl or 5-14 membered heteroaryl. C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C _1-6 alkylthio, halogenated C _1-6 alkoxy, C 1-6 hydroxyalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

In a further preferred embodiment of the present invention, R ₃ is selected from C _1-6 alkyl, C _6-10 aryl or 5-10 membered heteroaryl, wherein the C _1-6 alkyl, C _6-10 aryl and 5-10 membered heteroaryl are optionally substituted with one or more substituents selected from hydrogen, hydroxyl, halogen, amino and C _1-6 alkyl;

In a further preferred embodiment of the present invention, R ₃ is selected from phenyl and pyridyl, and the phenyl and pyridyl are optionally substituted with one or more substituents selected from hydrogen, hydroxyl, halogen, amino and C _1-6 alkyl;

Alternatively, _R1 and _R3 together with the atoms in which they are located are linked to form a _C3-12 cycloalkyl, a 3-12 membered heterocyclyl, a _C6-14 aryl or a 5-14 membered heteroaryl, wherein the _C3-12 cycloalkyl, the 3-12 membered heterocyclyl, the _C6-14 aryl and the 5-14 membered heteroaryl are optionally substituted by hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, _C1-6 alkyl, C2-6 alkenyl, _C2-6 alkynyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 alkoxy, _C1-6 alkylthio, halogenated C1-6 alkoxy, C1-6 hydroxyalkyl, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-14 aryl or 5-14 membered heteroaryl, wherein the C1-6 alkyl, _{C2-6 alkenyl, C2-6 alkynyl} , C1-6 deuterated alkyl, _C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio, halogenated _C1-6 alkoxy, C1-6 hydroxyalkyl, C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein the _C1-6 alkyl, _C2-6 alkenyl, C The alkyl radical is substituted by one or more substituents selected from _{C 2-6} alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

In a preferred embodiment of the present invention, _R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, _C1-6 alkyl, _C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 alkylthio, halogenated _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein _{the C1-6 alkyl , C2-6} alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 alkylthio, halogenated _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, C6-14 aryl or 5-14 membered heteroaryl. C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C _1-6 alkylthio, halogenated C _1-6 alkoxy, C 1-6 hydroxyalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

In a further preferred embodiment of the present invention, R ₄ is selected from C _3-8 cycloalkyl or 3-8 membered heterocyclic group, wherein the C _3-8 cycloalkyl or 3-8 membered heterocyclic group is optionally substituted with one or more substituents selected from hydrogen, hydroxyl, halogen, amino and C _1-3 alkyl;

In a further preferred embodiment of the present invention, R ₄ is selected from a 3-8 membered nitrogen-containing heterocyclic group substituted by a C _1-3 alkyl group, and the number of the nitrogen atoms is 1-3.

In a preferred embodiment of the present invention, R ₅ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-12 aryl or 5-12 membered heteroaryl;

In a further preferred embodiment of the present invention, R ₅ is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-8 cycloalkyl or 3-8 membered heterocyclyl;

In a further preferred embodiment of the present invention, R ₄ is selected from hydrogen.

In a further preferred embodiment of the present invention, _R6 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, halogenated _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-12 aryl or 5-12 membered heteroaryl;

In a further preferred embodiment of the present invention, R ₆ is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-8 cycloalkyl or 3-8 membered heterocyclyl;

In a further preferred embodiment of the present invention, _R6 is selected from hydrogen.

In a preferred embodiment of the present invention, _R7 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, _C1-6 alkyl, _C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 alkylthio, halogenated _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein _{the C1-6 alkyl , C2-6} alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 alkylthio, halogenated _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, C6-14 aryl or 5-14 membered heteroaryl. C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C 1-6 alkylthio, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C _1-6 alkylthio, halogenated C _1-6 alkoxy, C 1-6 hydroxyalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

In a further preferred embodiment of the present invention, R ₇ is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-8 cycloalkyl or 3-8 membered heterocyclyl;

In a further preferred embodiment of the present invention, _R7 is selected from hydrogen, fluorine, chlorine or methyl.

In a preferred embodiment of the present invention, R ₈ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C _1-6 alkyl, C _{2-6 alkenyl, C 2-6 alkynyl} , C _1-6 deuterated alkyl, C _{1-6 haloalkyl, C 1-6} alkoxy, halogenated C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C _6-12 aryl or 5-12 membered heteroaryl;

In a further preferred embodiment of the present invention, R ₈ is selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-8 cycloalkyl or 3-8 membered heterocyclyl;

In a further preferred embodiment of the present invention, R ₈ is selected from hydrogen.

In a preferred embodiment of the present invention, ^Ra is selected from hydrogen, deuterium, halogen, amino, hydroxyl, _cyano , nitro, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, oxo, thio, C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, halo-substituted _C1-6 alkoxy, _C1-6 hydroxyalkyl or _C1-6 alkyl substituted with cyano;

In a further preferred embodiment of the present invention, ^Ra is selected from hydrogen, _C1-3 alkyl or cyano-substituted _C1-3 alkyl.

In a preferred embodiment of the present invention, ^Rb is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, _C1-6 alkyl, _C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 alkylthio, halogenated _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-14 aryl or 5-14 membered heteroaryl, wherein _{the C1-6 alkyl , C2-6} alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 alkylthio, halogenated _C1-6 alkoxy, _C1-6 hydroxyalkyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, C6-14 aryl or 5-14 membered heteroaryl. _{C 6-14} aryl and 5-14 membered heteroaryl, optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio ,} halogenated C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

In a further preferred embodiment of the present invention, R ^b is selected from hydrogen, halogen, hydroxyl, amino, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-8 cycloalkyl or 3-8 membered heterocyclyl;

In a further preferred embodiment of the present invention, R ^b is selected from hydrogen, fluorine, chlorine, hydroxyl, amino or methyl.

In a further preferred embodiment of the present invention, there is provided a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

In a further preferred embodiment of the present invention, there is provided a compound of formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

in:

X ₅ is selected from N or CR ₇ .

In a further preferred embodiment of the present invention, there is provided a compound of formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

In a further preferred embodiment of the present invention, there is provided a compound of formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

in:

Ring B is selected from 3-14 membered heterocyclic groups or 5-14 membered heteroaryl groups; preferably 3-8 membered heterocyclic groups, more preferably 5-7 membered heterocyclic groups containing 1-3 nitrogen atoms or oxygen atoms, more preferably piperidinyl and morpholinyl;

R ^c is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _1-6 alkyl substituted with cyano, C _{3-12 cycloalkyl} , 3-12 membered heterocyclyl, C _6-12 aryl or 5-12 membered heteroaryl, wherein the amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C 1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _1-6 alkyl substituted with cyano, C _3-12 cycloalkyl, _3-12 membered heterocyclyl, C The _6-12- membered aryl and 5-12-membered heteroaryl are optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, oxo, thio, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _{1-6 alkyl substituted with cyano, C 3-12 cycloalkyl} , 3-12-membered heterocyclyl, C _6-12 aryl and 5-12-membered heteroaryl;

Preferably, it is hydrogen, halogen, amino, hydroxyl, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or 3-8 membered heterocyclyl;

More preferably isopropyl or isobutyl; and

z is an integer from 0 to 6.

In a further preferred embodiment of the present invention, there is provided a compound of formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

in:

X ₄ is selected from O, S, C(O), NR ₅ or CR ₅ R ₆ ; preferably C(O) or CH ₂ .

In the most preferred embodiment of the present invention, the following specific compounds are included:

The present invention also provides a preferred embodiment and relates to a pharmaceutical composition, which comprises a therapeutically effective dose of the compound of the general formula (I) shown and its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present invention further relates to the use of any compound of the general formula (I), its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of KRAS inhibitor drugs; preferably in KRAS G12C mutation drugs.

The present invention also provides a preferred embodiment, and also relates to a method for treating, preventing and/or treating a disease mediated by a KRAS G12C inhibitor using the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition, which comprises administering to a patient a therapeutically effective dose of a compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

In some embodiments, the compounds and compositions of the present invention can be used for the treatment of diseases or conditions such as Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, gastric cancer, lung cancer and colon cancer.

The compounds and compositions of the present invention can be used to treat diseases or conditions such as Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, lung cancer and colon cancer.

In some embodiments, the present invention provides a method of treating a cancer condition comprising administering a compound or composition of the present invention to a patient suffering from a cancer condition.

In some embodiments, the cancer treated by the compounds or compositions of the present invention is Noonan syndrome, Leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, gastric cancer, lung cancer and colon cancer; preferably non-small cell lung cancer, colon cancer, esophageal cancer, head and neck tumors.

Detailed description of the invention

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

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

The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to _-CH2- , "ethylene" refers to -( _CH2 ) _2- , "propylene" refers to -( _CH2 ) _3- , "butylene" refers to -( _CH2 ) _4- , etc. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

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

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

wait;

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

wait.

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

wait.

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

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

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

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

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

wait.

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

wait.

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

wait.

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

wait.

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

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

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

wait.

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

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

wait.

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

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

The term "alkylthio" refers to-S-(alkyl) and-S-(non-substituted cycloalkyl), wherein the definition of alkyl is as described above. The non-limiting examples of alkylthio include: methylthio, ethylthio, propoxy, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. Alkylthio can be optionally substituted or non-substituted, and when substituted, substituent is preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

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

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

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

"Alkenyl" refers to a chain alkenyl group, also known as an alkene group, wherein the alkenyl group can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"Alkynyl" refers to (CH≡C-), wherein the alkynyl can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

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

"Hydroxy" refers to an -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Carbonyl" refers to -C(O)-.

"Carboxy" refers to -C(O)OH.

"i-Pr" refers to -CH(CH ₃ ) ₃ .

"THF" refers to tetrahydrofuran.

"EtOAc" means ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N,N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetylene.

"DMA" refers to N,N-dimethylacetamide.

" _Et2O " refers to diethyl ether.

"DCE" refers to 1,2-dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

"Cbz-Cl" refers to benzyl chloroformate.

"Pd ₂ (dba) ₃ " refers to tris(dibenzylideneacetone)dipalladium.

"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

"HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilylamide.

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triacetoxyborohydride.

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

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

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

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

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

"Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

DETAILED DESCRIPTION

The present invention is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

Example

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard is tetramethylsilane (TMS).

Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer, and HPLC was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C ₁₈ 150×4.6 mm column).

Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

Example 1

Preparation of 4-((S)-4-acryloyl-2-methylpiperazine-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2(1H)-one

Step 1: Preparation of tert-butyl 4-(5-bromo-2-chloro-6-methylpyrimidin-4-yl)piperazine-1-carboxylate

5-Bromo-2,4-dichloro-6-methylpyrimidine (5 g, 20.8 mmol) was dissolved in ACN (50 mL), tert-butylpiperazine-1-carboxylate (5.1 g, 27.4 mmol) and DIPEA (8.1 g, 62.7 mmol) were added, and the mixture was stirred at room temperature for 15 hours. Water was added, and the mixture was extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (Petroether/EtOAc=5:1) to obtain the target product tert-butyl 4-(5-bromo-2-chloro-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (7.9 g, yield: 97%).

MS m/z(ESI): 391.1[M+H] ⁺ , 393.1[M+H+2] ⁺ .

Step 2: Preparation of tert-butyl 4-(5-bromo-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate

Tert-butyl 4-(5-bromo-2-chloro-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (5 g, 12.8 mmol) was dissolved in MeOH (30 mL), and NaOH (1.5 g, 37.5 mmol) was added under ice bath, and the mixture was gradually heated to room temperature and stirred for 5 hours; water and ethyl acetate (50 mL) were added and extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography (Petroether/EtOAc=5:1) to obtain the target product, tert-butyl 4-(5-bromo-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (3.5 g, yield: 71%).

MS m/z(ESI): 387.1[M+H] ⁺ , 389.1[M+H+2] ⁺ .

Step 3: Preparation of tert-butyl 4-(5-formyl-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate

Dissolve tert-butyl 4-(5-bromo-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (3.2 g, 8.3 mmol) in anhydrous THF (100 mL), cool to -78°C under nitrogen protection, add n-BuLi (9.9 mL, 9.9 mmol), and stir for 0.5 hours. Add DMF/THF (1 mL/5 mL), stir at -78°C for 1 hour, and gradually warm to room temperature. Continue stirring for 2 hours. Add water to quench, add water and ethyl acetate (3*50 mL) to extract. Combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product, which is purified by column chromatography (CH ₂ Cl ₂ /MeOH=10:1) to obtain the target product tert-butyl 4-(5-formyl-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (2.0 g, yield: 72%).

MS m/z(ESI):337.1[M+H] ⁺ .

Step 4: Preparation of tert-butyl 4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate

Dissolve tert-butyl 4-(5-formyl-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (1.8 g, 5.4 mmol) in dichloromethane (50 mL), add methylamine hydrochloride (710 mg, 10.6 mmol), NaBH(OAc) ₃ (1.4 g, 6.7 mmol) and glacial acetic acid (30 mg, 0.5 mmol). Stir at room temperature overnight. Add Boc ₂ O (2.3 g, 10.6 mmol) and stir at room temperature for 3 hours. Quench with water, extract with water and ethyl acetate (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography ( _CH2Cl2 / _MeOH =10:1) to give the target product, tert-butyl 4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (1.9 g, yield: 79%).

MS m/z(ESI):452.1[M+H] ⁺ .

Step 5: Preparation of tert-butyl (E)-4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-(2-fluoro-6-methoxyphenylvinyl)-2-methoxypyrimidin-4-yl)piperazine-1-carboxylate

Tert-butyl 4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-methoxy-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (1.8 g, 4.0 mmol) was added to a NaOH aqueous solution (5 M, 100 mL), and 2-fluoro-6-methoxybenzaldehyde (730 mg, 4.8 mmol) and trioctylmethylammonium chloride (220 mg, 0.5 mmol) were added, heated to reflux, and stirred for 5 hours. The mixture was cooled, filtered, and the filter cake was washed with water and purified by column chromatography (CH ₂ Cl ₂ /MeOH=10:1) to give the target product, tert-butyl (E)-4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-(2-fluoro-6-methoxyphenyl)-2-methoxypyrimidin-4-yl)piperazine-1-carboxylate (1.7 g, yield: 73%).

MS m/z(ESI):588.1[M+H] ⁺ .

Step 6: Preparation of 7-(2-fluoro-6-methoxyphenyl)-2-methoxy-6-methyl-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Tert-butyl (E)-4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-(2-fluoro-6-methoxyphenylvinyl)-2-methoxypyrimidin-4-yl)piperazine-1-carboxylate (1.5 g, 2.6 mmol) was dissolved in ethyl acetate (50 mL), 2M HCl in ethyl acetate solution (6 mL) was added, the mixture was stirred at room temperature for 5 hours, and the solvent was removed by concentration; the crude product was dissolved in water (20 mL), K ₂ CO ₃ (720 mg, 5.2 mmol) and KI (430 mg, 2.6 mmol) were added, the mixture was heated to 100° C., stirred for 15 hours, cooled, and water and ethyl acetate (3*30 mL) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography ( _CH2Cl2 / _MeOH =10:1) to obtain the target product 7-(2-fluoro-6-methoxyphenyl)-2-methoxy-6-methyl-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (560 mg, yield: 57%).

MS m/z(ESI):388.1[M+H] ⁺ .

Step 7: Preparation of 1-(4-(7-(2-fluoro-6-methoxyphenyl)-2-methoxy-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

7-(2-fluoro-6-methoxyphenyl)-2-methoxy-6-methyl-4-(piperazine-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (500 mg, 1.3 mmol) was dissolved in dichloromethane (20 mL), DIPEA (820 mg, 3.9 mmol) was added, and acryloyl chloride (140 mg, 1.6 mmol) was added dropwise at room temperature. Stirring was continued for 1 hour after addition. Water was added to quench, and dichloromethane (20 mL) was extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by column chromatography ( _CH2Cl2 / _MeOH =10:1) to give the target product, 1-(4-(7-(2-fluoro-6-methoxyphenyl)-2-methoxy-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (480 mg, yield: 84%).

MS m/z(ESI):442.1[M+H] ⁺ .

Step 7: Preparation of 1-(4-(7-(2-fluoro-6-hydroxyphenyl)-2-hydroxy-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Dissolve 1-(4-(7-(2-fluoro-6-methoxyphenyl)-2-methoxy-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (450 mg, 1.0 mmol) in dichloromethane (50 mL), cool to -40°C, add BBr ₃ (1.3 g, 5.2 mmol) dropwise, gradually warm to room temperature, stir for 2 hours, add saturated NaHCO ₃ aqueous solution, stir for 1 hour, and extract three times with ethyl acetate (10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by column chromatography ( _CH2Cl2 / _MeOH =10:1) to give the target product, 1-(4-(7-(2-fluoro-6-hydroxyphenyl)-2-hydroxy-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (350 mg, yield: 85%).

MS m/z(ESI):414.1[M+H] ⁺ .

Step 8: Preparation of 4-((S)-4-acryloyl-2-methylpiperazine-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2(1H)-one

4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2(1H)-one (100 mg, 0.24 mmol) was dissolved in MeOH (20 mL), 2-isopropyl-4-methyl-3-pyridineboronic acid (90 mg, 0.5 mmol), copper acetate (100 mg, 0.5 mmol), tetramethylethylenediamine (58 mg, 0.5 mmol) were added, heated to 60° C., and stirred for 15 hours. Water and ethyl acetate (10 mL) were added and extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by preparative HPLC to give the target product 4-((S)-4-acryloyl-2-methylpiperazine-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2(1H)-one (12 mg, yield: 9%).

MS m/z(ESI):561.1[M+H] ⁺ .

The preparation of Examples 2 to 6 refers to the route of Example 1.

Example 7

Preparation of 4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-6-methylphenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2(1H)-one

Step 1: Preparation of 4,6-dichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide

Oxalyl chloride (501 mg, 3.95 mmol) was added dropwise to a solution of 4,6-dichloronicotinamide (500 mg, 2.63 mmol) in tetrahydrofuran (30 mL) at room temperature. After the addition, the temperature was raised to 70°C and stirred for 1 hour. The reaction was cooled to room temperature and triethylamine (1063 mg, 10.5 mmol) was added. A solution of 2-isopropyl-4-methylpyridin-3-amine (1184 mg, 7.89 mmol) in tetrahydrofuran (10 mL) was added and stirred for 1 hour. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL×3); the ethyl acetate layer was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated and purified by column chromatography [eluent: water to acetonitrile/water from 0% to 24%] to give a yellow solid 4,6-dichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (380 mg, yield 39%).

MSm/z(ESI): 367.1[M+H] ⁺ , 369.1[M+H+2] ⁺ .

Step 2: Preparation of 7-chloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one

Potassium hexamethyldisilazane (2.5 mL, 2.5 mmol) was added dropwise to a solution of 4,6-dichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (343 mg, 0.937 mmol) in tetrahydrofuran (25 mL) at 0°C, and the mixture was stirred for 2 hours. The reaction was quenched with aqueous ammonium chloride (40 mL), extracted with ethyl acetate (20 mL×3), and the ethyl acetate layer was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated to give 7-chloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one (250 mg, yield 81%) as a light yellow solid.

MS m/z(ESI): 331.1[M+H] ⁺ , 369.1[M+H+2] ⁺ .

Step 3: Preparation of 4,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one

To a solution of 7-chloro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one (240 mg, 0.727 mmol) in acetonitrile (20 mL) was added N,N-diisopropylethylamine (1.4 g, 11 mmol) and phosphorus oxychloride (671 mg, 4.36 mmol) at room temperature, and stirred at 80°C for 1 hour. The mixture was cooled to room temperature and used directly in the next step.

Step 4: Preparation of tert-butyl (S)-4-(7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1,2-dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

Add N,N-diisopropylethylamine (938 mg, 7.27 mmol) to the reaction solution in the previous step, stir for 5 minutes, then add tert-butyl (S)-3-methylpiperazine-1-carboxylate (290 mg, 1.45 mmol), stir for 1 hour, then add tert-butyl (S)-3-methylpiperazine-1-carboxylate (436 mg, 2.18 mmol), stir for 1 hour. The reaction was quenched with aqueous ammonium chloride solution (100 mL), extracted with ethyl acetate (30 mL×3), and the organic phase was washed with aqueous sodium chloride solution (30 mL), and purified by spin-drying column chromatography [eluent: dichloromethane to methanol (containing 1% ammonia water)/dichloromethane from 0% to 5%] to give a yellow solid product, tert-butyl (S)-4-(7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1,2-dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (730 mg, 2-step yield 196%).

MS m/z(ESI): 513.2[M+H] ⁺ , 515.1[M+H+2] ⁺ .

Step 5: Preparation of (S)-7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(2-methylpiperazin-1-yl)pyrido[4,3-d]pyrimidin-2(1H)-one

To a solution of tert-butyl (S)-4-(7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-carbonyl-1,2-dihydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate (586 mg, 1.14 mmol) in dichloromethane (30 mL) was added 2,6-dimethylpyridine (306 mg, 2.85 mmol) and trimethylsilyl trifluoromethanesulfonate (762 mg, 3.43 mmol) at room temperature. If the reaction was not complete, trimethylsilyl trifluoromethanesulfonate (762 mg, 3.43 mmol) was added and stirred for 1 hour. The reaction solution was used directly in the next step.

MS m/z(ESI): 413.2[M+H] ⁺ , 415.1[M+H+2] ⁺ .

Step 6: Preparation of (S)-4-(4-acryloyl-2-methylpiperazine-1-yl)-7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one

Add N,N-diisopropylethylamine (1.2 mL) to the reaction solution of the previous step, cool to 0°C, add acryloyl chloride (261 mg, 2.9 mmol), stir for 1 hour after addition. The reaction solution was quenched with aqueous ammonium chloride (30 mL), extracted with dichloromethane (20 mL×3), and the dichloromethane layer was washed with saturated aqueous sodium bicarbonate (20 mL) and saturated aqueous NaCl (20 mL), respectively, dried over anhydrous sodium sulfate, and purified by column chromatography [eluent: dichloromethane to methanol (containing 1% ammonia water)/dichloromethane from 0% to 5%] to obtain a yellow oily product (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one (400 mg, 2-step yield 75%).

MS m/z(ESI): 467.2[M+H] ⁺ , 469.1[M+H+2] ⁺ .

Step 7: Preparation of (S)-4-(4-acryloyl-2-methylpiperazine-1-yl)-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one

(S)-4-(4-Acryloyl-2-methylpiperazin-1-yl)-7-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one (180 mg, 0.386 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (131 mg, 0.773 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (31 mg, 0.0386 mmol) and cesium carbonate (376 mg, 1.16 mmol) were stirred in dioxane (7 mL) and water (1 mL) in a microwave at 100°C for 1 hour. The reaction solution was spin-dried and purified by column chromatography [eluent: dichloromethane-methanol (containing 1% ammonia water)/dichloromethane from 0% to 5%] to give a yellow solid product (S)-4-(4-acryloyl-2-methylpiperazine-1-yl)-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one (50 mg, yield 23%).

MS m/z(ESI): 557.3[M+H] ⁺ .

Step 8: Preparation of (S)-4-(4-acryloyl-2-methylpiperazine-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one

To a solution of (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one in dichloromethane (10 mL) was added boron tribromide (0.45 mL, 0.45 mmol) dropwise at 0°C. The solution gradually became turbid. After addition of N,N-diisopropylethylamine (0.1 mL), the solution became clear. The reaction was stirred at 0°C for 30 minutes, then heated to room temperature and stirred for 1.5 hours. The reaction solution was poured into an aqueous sodium bicarbonate solution and extracted with dichloromethane (20 mL×3). The dichloromethane phase was washed with a saturated NaCl solution (20 mL). The organic phase was concentrated after drying over anhydrous sodium sulfate and purified by preparative chromatography to obtain a gray solid product (S)-4-(4-acryloyl-2-methylpiperazine-1-yl)-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[4,3-d]pyrimidin-2(1H)-one (1.9 mg, yield 4%).

¹ H NMR (400MHz, Chloroform-d) δ9.32 (br, 1H), 8.64 (s, 1H), 8.26 (d, J=12Hz, 1H), 7.36-7.30 (m, 2H), 6.88-7.07 ( m, 2H), 6.61-6.72 (m, 2H), 6.42 (d, J=16Hz, 1H), 5.83 (d, J=12Hz, 1H), 4.53-4.10 (m, 5H), 3.32-3.00 (m , 3H), 1.26 (d, J=4Hz, 3H).

MS m/z(ESI):543.2[M+H]+.

Embodiment 17

Preparation of 1-(4-(7-(2-fluoro-6-hydroxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

Step 1: Preparation of tert-butyl (S)-4-(5-bromo-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate

Dissolve tert-butyl 4-(5-bromo-2-chloro-6-methylpyrimidin-4-yl)piperazine-1-carboxylate (6 g, 15.3 mmol) in THF (100 mL), add (S)-(1-methylpyrrolidin-2-yl)methanol (2.3 g, 20.0 mmol) and NaHH (800 mg, 20.0 mmol) under ice bath, gradually warm to room temperature and stir for 0.5 hour, heat to 70°C, continue to react for 15 hours; cool to room temperature, add water to quench, add ethyl acetate (50 mL) and extract three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by column chromatography ( _CH2Cl2 / _MeOH =10:1) to obtain the target product, tert-butyl (S)-4-(5-bromo-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (4.3 g, yield: 60%).

MS m/z(ESI): 470.1[M+H] ⁺ , 472.1[M+H+2] ⁺ .

Step 2: Preparation of tert-butyl (S)-4-(5-formyl-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate

Dissolve tert-butyl (S)-4-(5-bromo-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (3.5 g, 7.4 mmol) in anhydrous THF (100 mL), cool to -78 ° C under nitrogen protection, add n-BuLi (8.9 mL, 8.9 mmol), and stir for 0.5 hours. Add DMF/THF (1 mL/5 mL), stir at -78 ° C for 1 hour, and gradually warm to room temperature. Continue stirring for 2 hours. Add water to quench, and add water and ethyl acetate (3*50 mL) to extract. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by column chromatography ( _CH2Cl2 / _MeOH =10:1) to obtain the target product, tert-butyl (S)-4-(5-formyl-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (2.1 g, yield: 68%).

MS m/z(ESI):420.1[M+H] ⁺ .

Step 3: Preparation of tert-butyl (S)-4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate

Tert-butyl (S)-4-(5-formyl-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (2 g, 4.8 mmol) was dissolved in dichloromethane (50 mL), and methylamine hydrochloride (640 mg, 9.6 mmol), NaBH(OAc) ₃ (1.2 g, 5.7 mmol) and glacial acetic acid (30 mg, 0.5 mmol) were added. Stir at room temperature overnight. Add Boc ₂ O (2.1 g, 9.6 mmol) and stir at room temperature for 3 hours. Add water to quench, and extract with water and ethyl acetate (3*50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by column chromatography ( _CH2Cl2 / _MeOH =10:1) to give the target product, tert-butyl (S)-4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (2.1 g, yield: 83%).

MS m/z(ESI):535.1[M+H] ⁺ .

Step 4: Preparation of 7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Tert-butyl (S)-4-(5-(((tert-butoxycarbonyl)(methyl)amino)methyl)-6-methyl-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylate (1.8 g, 3.4 mmol) was added to a NaOH aqueous solution (5 M, 100 mL), and 2-fluoro-6-methoxybenzaldehyde (630 mg, 4.1 mmol) and trioctylmethylammonium chloride (220 mg, 0.5 mmol) were added, heated to reflux and stirred for 5 hours. The reaction mixture was cooled and filtered, and the filter cake was washed with water and purified by column chromatography ( _CH2Cl2 / _MeOH =10:1) to give the target product, 7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.5 g, yield: 66%).

MS m/z(ESI): 671.1[M+H] ⁺ .

Step 5: Preparation of 1-(4-(7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

7-(2-Fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-4-(piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1 g, 1.5 mmol) was dissolved in ethyl acetate (50 mL), 2M HCl in ethyl acetate (6 mL) was added, the mixture was stirred at room temperature for 5 hours, and the solvent was removed by concentration; the crude product was dissolved in water (20 mL), K ₂ CO ₃ (420 mg, 3.0 mmol) and KI (250 mg, 1.5 mmol) were added, the mixture was heated to 100° C., stirred for 15 hours, cooled, and water and ethyl acetate (3*30 mL) were added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by column chromatography ( _CH2Cl2 /MeOH=10:1) to give the target product, 1-(4-(7-(2- _fluoro -6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (320 mg, yield: 45%).

MS m/z(ESI):471.1[M+H] ⁺ .

Step 6: Preparation of 1-(4-(7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (300 mg, 0.64 mmol) was dissolved in dichloromethane (10 mL), DIPEA (400 mg, 1.9 mmol) was added, and acryloyl chloride (69 mg, 0.77 mmol) was added dropwise at room temperature. After addition, stirring was continued for 1 hour. Water was added to quench the mixture, and dichloromethane (10 mL) was used for extraction three times. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by column chromatography ( _CH2Cl2 /MeOH=10:1) to give the target product, 1-(4-(7-(2- _fluoro -6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (310 mg, yield: 93%).

MS m/z(ESI):525.1[M+H] ⁺ .

Step 7: Preparation of 1-(4-(7-(2-fluoro-6-hydroxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(7-(2-fluoro-6-methoxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (100 mg, 0.19 mmol) was dissolved in dichloromethane (20 mL), cooled to -40°C, BBr ₃ (240 mg, 0.96 mmol) was added dropwise, gradually warmed to room temperature, and stirred for 2 hours. Saturated NaHCO ₃ aqueous solution was added and stirred for 1 hour, and extracted three times with ethyl acetate (10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by preparative HPLC to give the target product 1-(4-(7-(2-fluoro-6-hydroxyphenyl)-6-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (23 mg, yield: 24%).

MS m/z(ESI):511.1[M+H] ⁺ .

The preparation of Examples 18 to 23 refers to the route of Example 17.

Biological test evaluation

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

Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on the proliferation activity of H358/Mia PaCa-2 cells

Purpose: The purpose of this test is to measure the inhibitory effect of compounds on the proliferation activity of H358 or MiaPaCa-2 cells.

Experimental instruments: microplate reader (BioTek Synergy H1), pipette (Eppendorf & Rainin) Experimental method: When H358 or Mia PaCa-2 cells are cultured to an appropriate degree of confluence, H358 or Mia PaCa-2 cells are collected, and the cells are adjusted to an appropriate cell concentration using complete culture medium. The cell suspension is plated on a 96-well plate, 90 μL per well, and placed in a 37°C, 5% _CO2 incubator to adhere overnight. Compound solutions of different concentrations are prepared using DMSO and culture medium, and a solvent control is set. The compound solution is added to a 96-well plate, 10 μL per well, and placed in a 37°C, 5% _CO2 incubator for continued culture for 72h to 144h, then the CellTiter-Glo solution is added, shaken to mix evenly, incubated in the dark for 10 minutes, and read using a BioTek Synergy H1 microplate reader.

Verification data processing method:

The inhibition rate was calculated using the luminescent signal value, and the concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC ₅₀ value.

Experimental conclusion:

The above schemes indicate that the compounds of the present invention exhibit biological activities of about 0.01 nM to 1000 nM (IC ₅₀ ) in the H358 or Mia PaCa-2 cell proliferation activity inhibition test.

In some embodiments, the compounds of the present invention have an inhibitory effect on the proliferation activity of H358 or Mia PaCa-2 cells with an IC ₅₀ of less than about 500 nM, preferably less than about 100 nM, further preferably less than about 10 nM, more preferably less than about 1 nM, and most preferably less than 0.1 nM or even less than about 0.01 nM among the compounds listed in the present invention.

Claims (7)

1. A compound represented by general formula (IV), its stereoisomer or its pharmaceutically acceptable salt: in: Ring A is selected from R ₁ is selected from hydrogen, fluorine, chlorine or methyl; R ₃ is selected from pyridyl, and the pyridyl is optionally substituted by one or more substituents among hydrogen, hydroxyl, halogen, amino and C _1-3 alkyl; R ₅ is selected from hydrogen; R ^a is selected from methyl; R ^b is selected from hydrogen, fluorine, chlorine, hydroxyl, amino or methyl; x is an integer from 0 to 6; and y is an integer from 0 to 6. 2. The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, characterized in that it is selected from the following compounds: 3. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1 to 2, its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutical Acceptable carriers, diluents or excipients. 4. The compound according to any one of claims 1 to 2, its stereoisomer or its pharmaceutically acceptable salt, or the application of the pharmaceutical composition according to claim 3 in the preparation of KRAS inhibitor drugs . 5. The application according to claim 4, wherein the KRAS inhibitor drug is a KRAS G12C mutation drug. 6. The compound according to any one of claims 1 to 2, its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 3 for the preparation and treatment of Noonan syndrome, leopard syndrome Application in medicines for skin syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer and colon cancer diseases or conditions. 7. The compound according to any one of claims 1 to 2, its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 3 for the preparation and treatment of non-small cell lung cancer, colon Cancer, esophageal cancer, and head and neck tumor diseases or conditions.