CN112552294A

CN112552294A - Piperazine heterocyclic derivative inhibitor, preparation method and application thereof

Info

Publication number: CN112552294A
Application number: CN201910856187.8A
Authority: CN
Inventors: 刘世强
Original assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Current assignee: Jiangsu Hansoh Pharmaceutical Group Co Ltd; Shanghai Hansoh Biomedical Co Ltd
Priority date: 2019-09-10
Filing date: 2019-09-10
Publication date: 2021-03-26
Anticipated expiration: 2039-09-10
Also published as: CN112552294B

Abstract

The invention relates to a piperazine heterocyclic derivative inhibitor, a preparation method and application thereof. In particular, the invention relates to compounds of formula (I), a process for their preparation and pharmaceutical compositions containing them, and their use as KRAS inhibitors, inThe application of the compound 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 the specification.

Description

Piperazine heterocyclic derivative inhibitor, preparation method and application thereof

Technical Field

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

Background

Rat sarcoma (RAS), encoded by protooncogenes HRAS, NRAS and KRAS, is divided into 4 proteins HRAS, NRAS, KRAS4A and KRAS4B, a gtp (guanosine triphosphate) -binding protein. The RAS is located on the inner surface of a cell membrane, the upstream is Receptor Tyrosine Kinase (RTK), and after activation, the RAS regulates and controls downstream signal pathways such as PI3K, RAF and the like, thereby regulating and controlling functions such as growth, survival, migration, differentiation and the like of cells.

RAS has two main states in the body: an inactivated state bound to gdp (guanine diphosphate) and an activated state bound to GTP. The activity of the polypeptide is regulated and controlled by two proteins, and a guanosine nucleotideachange factor (GEF) promotes GDP to be released from RAS protein so that GTP is combined to activate RAS; GTPase Activating Protein (GAP) activates GTPase activating protein (GTPase activating protein) of RAS protein, and hydrolyzes GTP bound on RAS protein into GDP, thereby inactivating RAS. Normally, RAS proteins are in an inactive state, conformationally altered after mutation, RAS is in a continuously activated state, and downstream signaling pathways are also continuously activated, leading to the development of a variety of cancers.

RAS is the first identified oncogene with the highest mutation rate, accounting for an average of 25% of human cancers. The most common oncogenic mutations in the RAS family are KRAS (85%), while NRAS (12%) and HRAS (3%) are less common. KRAS mutations are mainly high in a series of cancers such as pancreatic cancer (95%), colorectal cancer (52%) and lung cancer (31%). The most common mutation mode of KRAS is point mutation, which mostly occurs in P-loop (aa 10-17) in G12, G13 and Q61 of SwitchII region (aa59-76), wherein the G12 mutation is the most common (83%). KRAS G12C is one of the most common mutations in non-small cell lung cancer (NSCLC) and colorectal cancer.

Although there is a great clinical need, to date, no drug targeting KRAS directly is on the market, and patients currently treated clinically for KRAS mutations are generally only able to take chemotherapy. The KRAS inhibitor is difficult to develop mainly by two factors, firstly, the RAS protein has a smooth structure, and small molecules are difficult to combine on the surface of the protein; secondly, the affinity of RAS GTP enzyme to GTP is up to the picomolar (pM) level, the endogenous GTP level is high, and the combination of the two is difficult to block by small-molecule drugs. Recent research shows that KRAS 12 Glycine (Glycine, Gly) is mutated into Cysteine (Cys), and then the conformation is changed to form a new pocket for covalent binding of small molecules, and KRAS G12C is irreversibly locked in a non-activated state of being bound with GDP. Therefore, the KRAS G12C inhibitor is expected to become the first drug directly targeting KRAS.

Many KRAS G12C inhibitors are currently in clinical research, such as AMG 510 developed by Amgen, ARS-3248 developed by Wellspring Biosciences, and MTRX849 developed by Mirati, all of which are currently in phase I clinical research, but no KRAS G12C inhibitor is developed on the market. Among them, AMG 510 showed good therapeutic effect and good safety in early clinical, and is expected to bring more treatment options for KRAS G12C mutant cancer patients in the future.

KRAS G12C currently has no specific targeting drug and has a large clinical demand. The KRAS G12C inhibitor with higher selectivity, better activity and better safety has the potential of treating various cancers and has wide market prospect.

Disclosure of Invention

The invention aims to provide a compound shown in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:

wherein:

X₁selected from the group consisting of CR₁Or CR₁R₂；

X₂Selected from N, NR₃Or CR₃；

X₃Selected from C (O), S (O)₂Or C-L-R₄；

X₄Selected from O, S, C (O))、N、NR₅、CR₅Or CR₅R₆；

X₅Selected from O, S, C (O), N, NR₇、CR₇Or CR₇R₈；

L is selected from the group consisting of a bond, -O (CH)₂)_n-、-S(CH₂)_n-、-NR_aa(CH₂)_n-、-(CH₂)_nNR_aa-、-(CH₂)_nO-、-(CH₂)_n-、-(CH₂)_nC(O)-、-(CH₂)_nC(O)O-、-(CH₂)_nNR_aa-、-(CH₂)_nC(O)NR_aa-、-OC(R_aaR_bb)_n(CH₂)_m-、-(CH₂)_nNR_aaC(O)-、-(CH₂)_nNR_aaC(O)NR_bb-、-(CH₂)_nS(O)_m-、-(CH₂)_nS(O)_mNR_aa-、-(CH₂)_nNR_aaS(O)_m-、-CR_aa＝CR_bb(CH₂)_n-or-CR_aa＝CR_bb(CH₂)_nNR_aa-；

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

R₁and R₂Each 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, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being further substituted;

R₃selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, arylthioOr heteroaryl, wherein said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally may be further substituted;

or, R₁And R₃Together with the atoms in which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally may be further substituted;

R₄selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally may be further substituted;

R₅and R₆Each 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, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being further substituted;

R₇and R₈Each 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, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being further substituted;

R^aselected from hydrogen, deuteriumHalogen, amino, hydroxy, mercapto, cyano, nitro, oxo, thioxo, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being further substituted;

or, any two adjacent or non-adjacent R^a(ii) linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally being further substituted;

R^bselected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, oxo, thioxo, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being further substituted;

or, any two adjacent or non-adjacent Rb linkages form a cycloalkyl, heterocyclyl, aryl, or heteroaryl group, which may optionally be further substituted;

R_aaand R_bbEach 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, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being further substituted;

x is an integer of 0-6;

y is an integer of 0 to 6;

m is 0, 1, 2 or 3; and is

n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, L is selected from the group consisting of a bond, -O (CH)₂)_n-、-NR_aa(CH₂)_n-、-(CH₂)_nC(O)-、-(CH₂)_nC(O)NR_aa-、-(CH₂)_nNR_aaC(O)-、-(CH₂)_nS(O)_m-、-(CH₂)_nS(O)_mNR_aa-、-(CH₂)_nNR_aaS(O)_m-、-CR_aa＝CR_bb(CH₂)_n-or-OC (R)_aaR_bb)_n(CH₂)_m-；

In a further preferred embodiment of the invention, L is selected from the group consisting of-O (CH)₂)_n-、-(CH₂)_nC (O) -or-CR_aa＝CR_bb(CH₂)_n-；

R_aaAnd R_bbIndependently of one another hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-to 14-membered heteroaryl, said amino, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical、C_1-6Alkylthio radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl;

m is 0, 1, 2 or 3; and is

n is 0, 1, 2 or 3.

In a preferred embodiment of the invention, ring A is selected from C_6-14Aryl or 5-14 membered heteroaryl, preferably C_6-10Aryl or 5-10 membered heteroaryl;

in a further preferred embodiment of the 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 heteroarylacenyl;

in a further preferred embodiment of the invention, ring a is selected from the following groups:

in a preferred embodiment of the invention, R₁Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl,C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl;

in a further preferred embodiment of the invention, R₁Selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

in a further preferred embodiment of the invention, R₁Selected from hydrogen, fluoro, chloro, methyl, ethyl, propyl, methoxy or ethoxy.

In a preferred embodiment of the invention, R₂Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl or 5-12 membered heteroaryl;

in a further preferred embodiment of the invention, R₂Selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

in a further preferred embodiment of the invention, R₂Selected from hydrogen.

In a preferred embodiment of the invention, R₃Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl;

in a further preferred embodiment of the invention, R₃Is selected from C_1-6Alkyl radical, C_6-10Aryl or 5-to 10-membered heteroaryl, said C_1-6Alkyl radical, C_6-10Aryl and 5-10 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino and C_1-6Substituted by one or more substituents in the alkyl group;

in a further preferred embodiment of the invention, R₃Selected from phenyl and pyridyl, said phenyl and pyridyl being optionally substituted by hydrogen, hydroxy, halogen, amino and C_1-6Substituted by one or more substituents in the alkyl group;

or, R₁And R₃Linked together with the atom in which they are located to form C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl;

in a preferred embodiment of the invention, R₄Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl;

in a further preferred embodiment of the invention, R₄Is selected from C_3-8Cycloalkyl or 3-8 membered heterocyclyl, said C_3-8Cycloalkyl or 3-to 8-membered heterocyclyl, optionally substituted by hydrogen, hydroxyHalogen, amino and C_1-3Substituted by one or more substituents in the alkyl group;

in a further preferred embodiment of the invention, R₄Is selected from C_1-33-8 membered nitrogen-containing heterocyclic group substituted with alkyl group, the number of the nitrogen atom is 1-3.

In a preferred embodiment of the invention, R₅Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl or 5-12 membered heteroaryl;

in a further preferred embodiment of the invention, R₅Selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

in a further preferred embodiment of the invention, R₄Selected from hydrogen.

In a further preferred embodiment of the invention, R₆Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl or 5-12 membered heteroaryl;

in a further preferred embodiment of the invention, R₆Selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

in a further preferred embodiment of the invention, R₆Selected from hydrogen.

In the inventionIn selected embodiments, R₇Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl;

in a further preferred embodiment of the invention, R₇Selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

in a further preferred embodiment of the invention, R₇Selected from hydrogen, fluorine, chlorine or methyl.

In a preferred embodiment of the invention, R₈Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl or 5-12 membered heteroaryl;

in a further preferred embodiment of the invention, R₈Selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

in a further preferred embodiment of the invention, R₈Selected from hydrogen.

In a preferred embodiment of the invention, R^aSelected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, oxo, thioxo, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl or cyano substituted C_1-6An alkyl group;

in a further preferred embodiment of the invention, R^aSelected from hydrogen, C_1-3Alkyl or cyano-substituted C_1-3An alkyl group.

In a preferred embodiment of the invention, R^bSelected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6An alkenyl group,C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-to 12-membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl;

in a further preferred embodiment of the invention, R^bSelected from hydrogen, halogen, hydroxy, amino, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

in a further preferred embodiment of the invention, R^bSelected 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, having the specific structure:

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, having the specific structure:

wherein:

X₅selected from N or CR₇。

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, having the specific structure:

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, having the specific structure:

wherein:

ring B is selected from 3-14 membered heterocyclyl or 5-14 membered heteroaryl; preferably 3-8 membered heterocyclic group, more preferably 5-7 membered heterocyclic group containing 1-3 nitrogen atom or oxygen atom, more preferably piperidyl group and morpholinyl group;

R^cselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl, cyano-substituted C_1-6Alkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl or 5-12 membered heteroaryl, said amino, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl, cyano-substituted C_1-6Alkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl and 5-12 membered heteroaryl optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, oxo, thioxo, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl, cyano-substituted C_1-6Alkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl and 5-12 membered heteroaryl;

preferably hydrogen, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

more preferably isopropyl or isobutyl; and is

z is an integer of 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, having the specific structure:

wherein:

X₄selected from O, S, C (O), NR₅Or CR₅R₆(ii) a Preferably C (O) or CH₂。

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

the invention also provides a preferable scheme and also relates to a pharmaceutical composition which comprises a therapeutically effective dose of the compound shown in the general formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

The invention further relates to any one of the compounds shown in the general formula (I), stereoisomers or pharmaceutically acceptable salts thereof, or an application of the pharmaceutical composition in preparation of KRAS inhibitor drugs; preferably in KRAS G12C mutant drugs.

The invention also provides a preferable scheme, and also relates to a method for treating, preventing and/or treating diseases mediated by the KRAS G12C inhibitor by using the compound shown in the general formula (I) and the stereoisomer or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof, wherein the method comprises the step of administering a therapeutically effective dose of the compound shown in the general formula (I) and the stereoisomer or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof to a patient.

In some embodiments, the compounds and compositions of the present invention are useful for the treatment of diseases or disorders that are characterized by noonan's syndrome, leopard skin 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 invention are useful in methods of treating diseases or disorders in the preparation of a medicament for the treatment of noonan's syndrome, leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, lung cancer and colon cancer thereof.

In some embodiments, the invention provides a method of treating a cancer disorder comprising administering a compound or composition of the invention to a patient having a cancer disorder.

In some embodiments, the cancer treated by a compound or composition of the invention is noonan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, gastric cancer, lung cancer, and colon cancer thereof; preferably non-small cell lung cancer, colon cancer, esophageal cancer, head and neck tumor.

Detailed description of the invention

Unless stated to the contrary, 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 of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH₂-, "ethylene" means- (CH)₂)₂-, "propylene" means- (CH)₂)₃-, "butylene" means- (CH)₂)₄-and the like. 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, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

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

The term "spirocycloalkyl" refers to a5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 3-membered/6-membered, 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered, spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

etc.;

spirocycloalkyl groups also containing a single spirocycloalkyl group with a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:

and the like.

The term "fused cyclic alkyl" refers to a5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:

and the like.

The term "bridged cycloalkyl" refers to a5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:

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

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)_m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms; further preferred is a 3-8 membered heterocyclic group containing 1-3 nitrogen atoms, optionally substituted with 1-2 oxygen atoms, sulfur atoms, oxo groups, including a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing spiro heterocyclic group or a nitrogen-containing fused heterocyclic group.

Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepinyl, 1, 4-diazepanyl, pyranyl, and the like, preferably pyrrolidinyl, morpholinyl, piperidinyl, azepinyl, 1, 4-diazepanyl, and piperazinyl, more preferably pyrrolidinyl, piperidinyl, or morpholinyl. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.

The term "spiroheterocyclyl" refers to a5 to 20 membered polycyclic heterocyclic group wherein one atom (referred to as a spiro atom) is shared between monocyclic rings, wherein one or more ring atoms are selected fromNitrogen, oxygen or S (O)_m(wherein m is an integer of 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 pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:

and the like.

The term "fused heterocyclyl" refers to a5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)_m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

and the like.

The term "bridged heterocyclyl" refers to 5 to 14 membered polycyclic heterocyclic groups, any two rings of which share two atoms not directly attached, which may contain one or more atomsDouble bonds, but no ring having a completely conjugated pi-electron system, in which one or more ring atoms are selected from nitrogen, oxygen or S (O)_m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

and the like.

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

and the like.

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

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused on a heteroaryl, heterocyclic or cycloalkyl ring and comprises 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 comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

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

and the like.

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

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

and the like.

Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.

The term "alkylthio" refers to-S- (alkyl) and-S- (unsubstituted cycloalkyl) groups, wherein alkyl is as defined above. Non-limiting examples of alkylthio groups include: methylthio, ethylthio, propyloxy, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio. Alkylthio groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy 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 the alkoxy group is as defined above.

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

"alkenyl" refers to alkenyl, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"alkynyl" refers to (CH ≡ C-), wherein said alkynyl may be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

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

"hydroxy" refers to an-OH group.

"halogen" means fluorine, chlorine, bromine or iodine.

"amino" means-NH₂。

"cyano" means-CN.

"nitro" means-NO₂。

"carbonyl" means-C (O) -.

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

"i-Pr" means-CH (CH)₃)₃。

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N, N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" refers to acetonitrile.

"DMA" refers to N, N-dimethylacetamide.

“Et₂O "means 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.

“Pd₂(dba)₃"refers to tris (dibenzylideneacetone) dipalladium.

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

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

"KHMDS" refers to potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilyl amide.

"MeLi" refers to methyllithium.

"n-BuLi" refers to n-butyllithium.

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

Different terms 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" and the like all express the same meaning, that is, X can be any one or more of A, B, C.

All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to 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 that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

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

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

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.

Detailed Description

The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.

Examples

The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated methanol (CD)₃OD) and deuterated chloroform (CDCl)₃) Internal standard is Tetramethylsilane (TMS).

LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC determination was carried out using Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18150X 4.6mm chromatographic column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C)₁₈150X 4.6mm column).

The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.

All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.

Example 1

Preparation of 4- ((S) -4-acryloyl-2-methylpiperazin-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

The first step is as follows: preparation of tert-butyl 4- (5-bromo-2-chloro-6-methylpyrimidin-4-yl) piperazine-1-carboxylate

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

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

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

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

The third step: preparation of tert-butyl 4- (5-formyl-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate

Tert-butyl 4- (5-bromo-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (3.2g, 8.3mmol) was dissolved in anhydrous THF (100mL), cooled to-78 ℃ under nitrogen protection, n-BuLi (9.9mL, 9.9mmol) was added and stirred for 0.5 h. DMF/THF (1mL/5mL) was added, stirred at 78 ℃ for 1 hour, and gradually warmed to room temperature. Stirring was continued for 2 hours. Quench with water and extract with water and ethyl acetate (3 × 50 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)₂Cl₂MeOH ═ 10: 1) to give the desired product tert-butyl 4- (5-formyl-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (2.0g, yield: 72%).

MS m/z(ESI)：337.1[M+H]⁺.

The fourth step: preparation of tert-butyl 4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate

Tert-butyl 4- (5-formyl-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (1.8g, 5.4mmol) was dissolved in dichloromethane (50mL), methylamine hydrochloride (710mg, 10.6mmol), NaBH (OAc) was added₃(1.4g, 6.7mmol) and glacial acetic acid (30mg, 0.5 mmol). Stir at room temperature overnight. Addition of Boc₂O (2.3g, 10.6mmol), and stirred at room temperature for 3 hours. Quench with water and extract with water and ethyl acetate (3 × 50 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)₂Cl₂Purification with MeOH ═ 10: 1) afforded the desired product tert-butyl 4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (1.9g, yield: 79%).

MS m/z(ESI)：452.1[M+H]⁺.

The fifth step: preparation of tert-butyl (E) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6- (2-fluoro-6-methoxystyryl) -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 (1.8g, 4.0mmol) was added to an aqueous NaOH solution (5M, 100mL), 2-fluoro-6-methoxybenzaldehyde (730mg, 4.8mmol) and trioctylmethylammonium chloride (220mg, 0.5mmol) were added, and the mixture was heated to reflux and stirred for 5 hours. Cooling, filtering, washing the filter cake with water, and performing column Chromatography (CH)₂Cl₂Purification with MeOH 10: 1) to give the desired product tert-butyl (E) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6- (2-fluoro-6-methoxystyreneYl) -2-methoxypyrimidin-4-yl) piperazine-1-carboxylate (1.7g, yield: 73%).

MS m/z(ESI)：588.1[M+H]⁺.

And a sixth step: 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-methoxystyryl) -2-methoxypyrimidin-4-yl) piperazine-1-carboxylate (1.5g, 2.6mmol) was dissolved in ethyl acetate (50mL), a 2MHCl solution in ethyl acetate (6mL) was added, stirred at room temperature for 5 hours, and the solvent was removed by concentration; the crude product was dissolved in water (20mL) and K was added₂CO₃(720mg, 5.2mmol) and KI (430mg, 2.6mmol), heated to 100 ℃, stirred for 15 hours, cooled, extracted with water and ethyl acetate (3 x 30 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)₂Cl₂(MeOH) ═ 10: 1) to give the desired product 7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-4- (piperazin-1-yl) -5, 6, 7, 8-tetrahydropyrido [4, 3-d]Pyrimidine (560mg, yield: 57%).

MS m/z(ESI)：388.1[M+H]⁺.

The seventh step: 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

Mixing 7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-4- (piperazine-1-yl) -5, 6, 7, 8-tetrahydropyrido [4, 3-d]Pyrimidine (500mg, 1.3mmol) was dissolved in dichloromethane (20mL), DIPEA (820mg, 3.9mmol) was added, acryloyl chloride (140mg, 1.6mmol) was added dropwise at room temperature, and stirring was continued for 1 hour. Quenched with water and extracted with dichloromethane (20mL)Taking three times. Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)₂Cl₂Purification with MeOH ═ 10: 1) to give the desired 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 (480mg, yield: 84%).

MS m/z(ESI)：442.1[M+H]⁺.

The seventh step: 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

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 (450mg, 1.0mmol) was dissolved in dichloromethane (50mL), cooled to-40 deg.C, and BBr was added dropwise₃(1.3g, 5.2mmol), gradually warmed to room temperature, and stirred for 2 hours. Adding saturated NaHCO₃The aqueous solution was stirred for 1 hour, and extracted three times with ethyl acetate (10 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)₂Cl₂Purification with MeOH ═ 10: 1) to give the desired 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 (350mg, yield: 85%).

MS m/z(ESI)：414.1[M+H]⁺.

Eighth step: preparation of 4- ((S) -4-acryloyl-2-methylpiperazin-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 (100mg, 0.24mmol) was dissolved in MeOH (20mL), 2-isopropyl-4-methyl-3-pyridineboronic acid (90mg, 0.5mmol), copper acetate (100mg, 0.5mmol), tetramethylethylenediamine (58mg, 0.5mmol) were added, heated to 60 ℃, and stirred for 15 hours. Water and ethyl acetate (10mL) were added and extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to give a crude product, which was purified by preparative HPLC to give the desired product 4- ((S) -4-acryloyl-2-methylpiperazin-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 (12mg, yield: 9%).

MS m/z(ESI)：561.1[M+H]⁺.

Examples 2-6 were prepared according to the scheme 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

The first step is as follows: preparation of 4, 6-dichloro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) nicotinamide

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

MSm/z(ESI)：367.1[M+H]⁺，369.1[M+H+2]⁺。

The second step is that: preparation of 7-chloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4, 3-d ] pyrimidin-2 (1H) -one

To a solution of 4, 6-dichloro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) nicotinamide (343mg, 0.937mmol) in tetrahydrofuran (25mL) was added dropwise potassium hexamethyldisilazide (2.5mL, 2.5mmol) at 0 deg.C, with stirring for 2 hours. The reaction was quenched with aqueous ammonium chloride (40mL), extracted with ethyl acetate (20 mL. times.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 (250mg, yield 81%) as a pale yellow solid.

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

The third step: 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 (240mg, 0.727mmol) in acetonitrile (20mL) was added N, N-diisopropylethylamine (1.4g, 11mmol) and phosphorus oxychloride (671mg, 4.36mmol) at room temperature, followed by stirring at 80 ℃ for 1 hour. Cooled to room temperature and used directly in the next reaction.

The fourth step: 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

To the reaction mixture in the previous step was added N, N-diisopropylethylamine (938mg, 7.27mmol), and the mixture was stirred for 5 minutes, followed by addition of tert-butyl (S) -3-methylpiperazine-1-carboxylate (290mg, 1.45mmol), and stirring was continued for 1 hour. Tert-butyl (S) -3-methylpiperazine-1-carboxylate (436mg, 2.18mmol) was added thereto, and the mixture was stirred for 1 hour. The reaction was quenched with aqueous ammonium chloride (100mL), extracted with ethyl acetate (30mL × 3), and the organic phase was washed with aqueous sodium chloride (30mL), and subjected to spin-dry column chromatography [ eluent: dichloromethane to methanol (containing 1% ammonia)/dichloromethane from 0% to 5% ] purification afforded 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 (730mg, 196% yield over 2 steps) as a yellow solid product.

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

The fifth step: 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 (586mg, 1.14mmol) in dichloromethane (30mL) was added 2, 6 lutidine (306mg, 2.85mmol), trimethylsilyl trifluoromethanesulfonate (762mg, 3.43mmol) at room temperature. After completion of the reaction, trimethylsilyl trifluoromethanesulfonate (762mg, 3.43mmol) was added and the mixture was 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]⁺。

And a sixth step: preparation of (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

N, N-diisopropylethylamine (1.2mL) was added to the reaction mixture in the previous step, the mixture was cooled to 0 ℃ and acryloyl chloride (261mg, 2.9mmol) was added thereto, and the mixture was stirred for 1 hour. The reaction solution was quenched with an aqueous ammonium chloride solution (30mL), extracted with dichloromethane (20mL × 3), and the dichloromethane layer was washed with a saturated aqueous sodium bicarbonate solution (20mL), a saturated aqueous NaCl solution (20mL), dried over anhydrous sodium sulfate, and subjected to column chromatography [ eluent: dichloromethane-methanol (containing 1% ammonia)/dichloromethane from 0% to 5% ] purification afforded (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 (400mg, 75% over 2 steps) as a yellow oily product.

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

The seventh step: preparation 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

(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 (180mg, 0.386mmol), (2-fluoro-6-methoxyphenyl) boronic acid (131mg, 0.773mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (31mg, 0.0386mmol) and cesium carbonate (376mg, 1.16mmol) in dioxane (7mL) and water (1mL) were stirred with microwave at 100 ℃ for 1 hour. The reaction solution was spin-dried and column chromatographed [ eluent: dichloromethane to methanol (containing 1% ammonia)/dichloromethane from 0% to 5% ] purification afforded (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 (50mg, 23% yield) as a yellow solid.

MS m/z(ESI)：557.3[M+H]⁺。

Eighth step: preparation of (S) -4- (4-acryloyl-2-methylpiperazin-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 (10mL) was added boron tribromide (0.45mL, 0.45mmol) dropwise at 0 ℃ to slowly turn the solution cloudy, N-diisopropylethylamine (0.1mL) was added to clear the solution, the reaction was stirred at 0 ℃ for 30 minutes, then warmed to room temperature and stirred for 1.5 hours. The reaction solution was poured into aqueous sodium hydrogencarbonate solution, extracted with dichloromethane (20mL × 3), the dichloromethane phase was washed with saturated NaCl solution (20mL), dried over anhydrous sodium sulfate and the organic phase was concentrated, and purified by preparative chromatography to give the product (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4, 3-d ] pyrimidin-2 (1H) -one (1.9mg, yield 4%) as a gray solid.

¹H 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]+。

Example 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

The first step is as follows: preparation of tert-butyl (S) -4- (5-bromo-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate

Tert-butyl 4- (5-bromo-2-chloro-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (6g, 15.3mmol) was dissolved in THF (100mL), and (S) - (1-methylpyrrolidin-2-yl) methanol (2.3g, 20.0mmol), NaHH (800mg, 20.0mmol) were added under ice bath, gradually warmed to room temperature, stirred for 0.5 hours, heated to 70 ℃, and the reaction was continued for 15 hours; cooled to room temperature, quenched with water, and extracted three times with ethyl acetate (50 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)₂Cl₂MeOH ═ 10: 1) purification afforded the desired product tert-butyl (S) -4- (5-bromo-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (4.3g, yield: 60%).

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

The second step is that: preparation of tert-butyl (S) -4- (5-formyl-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate

Tert-butyl (S) -4- (5-bromo-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (3.5g, 7.4mmol) was dissolved in anhydrous THF (100mL), cooled to-78 ℃ under nitrogen, n-BuLi (8.9mL, 8.9mmol) was added and stirred for 0.5 h. DMF/THF (1mL/5mL) was added, stirred at 78 ℃ for 1 hour, and gradually warmed to room temperature. Stirring was continued for 2 hours. Quench with water and extract with water and ethyl acetate (3 × 50 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)₂Cl₂Purification with MeOH 10: 1) to obtain the target product tert-butyl (S) -4- (5-formyl-6-methylYl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (2.1g, yield: 68%).

MS m/z(ESI)：420.1[M+H]⁺.

The third step: 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 (2g, 4.8mmol) was dissolved in dichloromethane (50mL), methylamine hydrochloride (640mg, 9.6mmol), NaBH (OAc) was added₃(1.2g, 5.7mmol) and glacial acetic acid (30mg, 0.5 mmol). Stir at room temperature overnight. Addition of Boc₂O (2.1g, 9.6mmol), and stirred at room temperature for 3 hours. Quench with water and extract with water and ethyl acetate (3 × 50 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)₂Cl₂Purification with MeOH ═ 10: 1) afforded the desired 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 (2.1g, yield: 83%).

MS m/z(ESI)：535.1[M+H]⁺.

The fourth step: 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 (1.8g, 3.4mmol) was added to an aqueous NaOH solution (5M, 100mL), 2-fluoro-6-methoxybenzaldehyde (630mg,4.1mmol) and trioctylmethylammonium chloride (220mg, 0.5mmol), heated to reflux and stirred for 5 hours. Cooling, filtering, washing the filter cake with water, and performing column Chromatography (CH)₂Cl₂Purification of the product (10: 1): 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 (1.5g, yield: 66%).

MS m/z(ESI)：671.1[M+H]⁺.

The fifth step: 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

Mixing 7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (piperazine-1-yl) -5, 6, 7, 8-tetrahydropyrido [4, 3-d]Pyrimidine (1g, 1.5mmol) was dissolved in ethyl acetate (50mL), 2M HCl in ethyl acetate (6mL) was added, stirred at room temperature for 5 hours, and concentrated to remove the solvent; the crude product was dissolved in water (20mL) and K was added₂CO₃(420mg, 3.0mmol) and KI (250mg, 1.5mmol), heated to 100 ℃, stirred for 15 hours, cooled, extracted with water and ethyl acetate (3 x 30 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)₂Cl₂Purification with MeOH 10: 1) afforded the desired 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 (320mg, yield: 45%).

MS m/z(ESI)：471.1[M+H]⁺.

And a sixth step: 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 (300mg, 0.64mmol) was dissolved in dichloromethane (10mL), DIPEA (400mg, 1.9mmol) was added, acryloyl chloride (69mg, 0.77mmol) was added dropwise at room temperature, and stirring was continued for 1 hour. Quench with water and extract three times with dichloromethane (10 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)₂Cl₂Purification with MeOH 10: 1) afforded the desired 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 (310mg, yield: 93%).

MS m/z(ESI)：525.1[M+H]⁺.

The seventh step: 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 (100mg, 0.19mmol) was dissolved in dichloromethane (20mL), cooled to-40 deg.C, and BBr was added dropwise₃(240mg, 0.96mmol), gradually warmed to room temperature, and stirred for 2 hours. Adding saturated NaHC0₃The aqueous solution was stirred for 1 hour, and extracted three times with ethyl acetate (10 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to obtain a crude product, and purifying by preparative HPLC to obtain 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 (23mg, yield: 24%).

MS m/z(ESI)：511.1[M+H]⁺.

Examples 18-23 were prepared according to the route of example 17.

Biological test evaluation

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

Test example 1 assay for the inhibitory Effect of the Compound of the present invention on the proliferative Activity of H358/Mia PaCa-2 cells

Purpose of the experiment: the purpose of this test example was to measure the inhibitory effect of compounds on the proliferative activity of H358 or MiaPaCa-2 cells.

An experimental instrument: microplate reader (BioTek Synergy H1), pipette (Eppendorf)&Rainin) experimental method: culturing H358 or Mia PaCa-2 cells to an appropriate confluency, collecting H358 or Mia PaCa-2 cells, adjusting the cells to an appropriate cell concentration using complete medium, plating the cell suspension in a 96-well plate at 90. mu.L/well, placing at 37 ℃ and 5% CO₂Adhering the incubator to the wall overnight, preparing compound solutions with different concentrations by using DMSO and a culture medium, setting a solvent control, adding the compound solutions into a 96-well plate, placing 10 mu L of each well, placing at 37 ℃ and 5% CO₂And (3) continuously culturing for 72-144 h in the incubator, adding CellTiter-Glo solution, shaking and uniformly mixing, incubating for 10 minutes in a dark place, and reading by using a BioTek SynergyH1 enzyme-labeling instrument.

The test data processing method comprises the following steps:

calculating the inhibition rate by using the luminescence signal value, and fitting the concentration and the inhibition rate by using Graphpad Prism software to obtain IC₅₀The value is obtained.

And (4) experimental conclusion:

it was concluded from the above protocol that the compounds of the present invention showed about 0.01nM to 1000nM (IC) in the inhibition assay of H358 or Mia PaCa-2 cell proliferation activity₅₀) The biological activity of (1).

In some embodiments, the inhibition of H358 or Mia PaCa-2 cell proliferative activity by a compound of the invention, IC₅₀Less than about 500nM, optimizationLess than about 100nM of the compound, more preferably less than about 10nM, and even more preferably less than about 1nM, and most preferably less than 0.1nM or even less than about 0.01nM of the compounds listed in the present invention.

Claims

1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:

X₁selected from the group consisting of CR₁Or CR₁R₂；

X₂Selected from N, NR₃Or CR₃；

X₃Selected from C (O), S (O)₂Or C-L-R₄；

X₄Selected from O, S, C (O), N, NR₅、CR₅Or CR₅R₆；

X₅Selected from O, S, C (O), N, NR₇、CR₇Or CR₇R₈；

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

R₁and R₂Each 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, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally being further substituted;

R₃selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally may be further substituted;

or, R₁And R₃Together with the atoms in which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally may be further substituted;

R₄selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally may be further substituted;

R₅and R₆Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitroAlkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally being further substituted;

R₇and R₈Each 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, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally being further substituted;

R^aselected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, oxo, thioxo, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally being further substituted;

R^bselected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyi, heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxy, alkoxy, mercapto, alkoxy, hydroxy, alkoxyAlkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

or, any two adjacent or non-adjacent R^b(ii) linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, said cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally being further substituted;

R_aaand R_bbEach 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, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally being further substituted;

x is an integer of 0-6;

y is an integer of 0 to 6;

m is 0, 1, 2 or 3; and is

n is 0, 1, 2 or 3.

2. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that L is selected from the group consisting of a bond, -O (CH)₂)_n-、-NR_aa(CH₂)_n-、-(CH₂)_nC(O)-、-(CH₂)_nC(O)NR_aa-、-(CH₂)_nNR_aaC(O)-、-(CH₂)_nS(O)_m-、-(CH₂)_nS(O)_mNR_aa-、-(CH₂)_nNR_aaS(O)_m-、-CR_aa＝CR_bb(CH₂)_n-or-OC (R)_aaR_bb)_n(CH₂)_m-；

preferably-O (CH)₂)_n-、-(CH₂)_nC (O) -or-CR_aa＝CR_bb(CH₂)_n-；

R_aaAnd R_bbIndependently of one another hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl, 5-to 14-membered heteroaryl, said amino, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl;

m is 0, 1, 2 or 3; and is

n is 0, 1, 2 or 3.

3. The compound, a stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein ring a is selected from C_6-14Aryl or 5-14 membered heteroaryl, preferably C_6-10Aryl or 5-to 10-membered heteroaryl, more preferably phenyl, pyridyl, 5-to 7-membered nitrogen-containing heteroaryl, benzo 5-to 7-membered nitrogen-containing heteroaryl or 5-to 7-membered nitrogen-containing heteroarylacenyl, further selected from the group consisting of:

4. the compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is₁Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl;

preferably hydrogen, halogen, amino, hydroxy, cyano, nitro, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

more preferably hydrogen, fluorine, chlorine, methyl, ethyl, propyl, methoxy or ethoxy.

5. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is₂Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl or 5-12 membered heteroaryl;

more preferably hydrogen.

6. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is₃Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl;

preferably C_1-6Alkyl radical, C_6-10Aryl or 5-to 10-membered heteroaryl, said C_1-6Alkyl radical, C_6-10Aryl and 5-10 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino and C_1-6Substituted by one or more substituents in the alkyl group;

more preferred are phenyl and pyridyl, optionally substituted by hydrogen, hydroxy, halogen, amino and C_1-6Substituted by one or more substituents in the alkyl group;

or, R₁And R₃Linked together with the atom in which they are located to form C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl.

7. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is₄Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl;

preferably C_3-8Cycloalkyl or 3-8 membered heterocyclyl, said C_3-8Cycloalkyl or 3-8 membered heterocyclyl, optionally substituted by hydrogen, hydroxy, halogen, amino and C_1-3Substituted by one or more substituents in the alkyl group;

more preferably C_1-3Alkyl-substituted 3-to 8-membered heterocyclic groups containing 1 to 3 nitrogen atoms.

8. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is₅Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl or 5-12 membered heteroaryl;

more preferably hydrogen.

9. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is₆Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl or 5-12 membered heteroaryl;

more preferably hydrogen.

10. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is₇Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl;

more preferably hydrogen, fluorine, chlorine or methyl.

11. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is₈Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl or 5-12 membered heteroaryl;

more preferably hydrogen.

12. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is^aSelected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, oxo, thioxo, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl or cyano substituted C_1-6An alkyl group;

preferably hydrogen, C_1-3Alkyl or cyano-substituted C_1-3An alkyl group.

13. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is^bSelected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl, said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl and 5-14 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, mercapto, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio, halo C_1-6Alkoxy radical, C_1-6Hydroxyalkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-14Aryl or 5-14 membered heteroaryl;

preferably hydrogen, halogen, hydroxy, amino, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Hydroxyalkyl radical, C_3-8Cycloalkyl or 3-8 membered heterocyclyl;

more preferably hydrogen, fluorine, chlorine, hydroxyl, amino or methyl.

14. The compound of claim 1, a stereoisomer or pharmaceutically-acceptable salt thereof, wherein formula (I) is further represented by formula (II):

15. the compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein the general formula (I) is further represented by general formula (III):

wherein:

X₅selected from N or CR₇。

16. The compound of claim 15, a stereoisomer, or a pharmaceutically-acceptable salt thereof, wherein formula (I) is further represented by formula (IV):

17. the compound of claim 15, a stereoisomer, or a pharmaceutically-acceptable salt thereof, wherein formula (I) is further represented by formula (V):

wherein:

R^cselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6HalogenatedAlkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl, cyano-substituted C_1-6Alkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl or 5-12 membered heteroaryl, said amino, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl, cyano-substituted C_1-6Alkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl and 5-12 membered heteroaryl optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, oxo, thioxo, C_1-6Deuterated alkyl, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Hydroxyalkyl, cyano-substituted C_1-6Alkyl radical, C_3-12Cycloalkyl, 3-12 membered heterocyclyl, C_6-12Aryl and 5-12 membered heteroaryl;

more preferably isopropyl or isobutyl; and is

z is an integer of 0 to 6.

18. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, further represented by general formula (VI):

wherein:

19. A compound, stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 18, which is selected from the following compounds:

20. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-19, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

21. Use of a compound according to any one of claims 1 to 19, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, in the preparation of a KRAS inhibitor medicament; preferably in KRAS G12C mutant drugs.

22. Use of a compound according to any one of claims 1 to 19, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the manufacture of a medicament for the treatment of diseases or disorders of noonan's syndrome, leopard syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer and colon cancer; non-small cell lung cancer, colon cancer, esophageal cancer and head and neck tumors are preferred.