CN112430234A

CN112430234A - Novel KRAS G12C protein inhibitor and preparation method and application thereof

Info

Publication number: CN112430234A
Application number: CN202010857163.7A
Authority: CN
Inventors: 张龙; 宋国伟; 杨智亮
Original assignee: Innovent Biologics Suzhou Co Ltd
Current assignee: Innovent Biologics Suzhou Co Ltd
Priority date: 2019-08-26
Filing date: 2020-08-24
Publication date: 2021-03-02
Anticipated expiration: 2040-08-24
Also published as: CN112430234B

Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to a novel KRAS G12C protein inhibitor, and a preparation method and application thereof. Specifically, the invention provides a compound with a structure shown in formula I, which can be used as a high-efficiency KRAS G12C protein inhibitor and has various pharmacological activities such as anti-tumor, anti-proliferative disease, anti-inflammatory and anti-autoimmune disease.

Description

Novel KRAS G12C protein inhibitor and preparation method and application thereof

Technical Field

The invention belongs to the field of medicinal chemistry, and relates to a novel KRAS G12C protein inhibitor, a preparation method thereof, a pharmaceutical composition containing the same, and a medical application of the KRAS G12C protein inhibitor, in particular to an application of the KRAS G12C protein inhibitor in preparation of medicines for preventing and/or treating diseases mediated by at least part of KRAS G12C protein.

Background

RAS represents a group of monomeric globular proteins of 189 amino acids (21kDa molecular weight) that are closely related to each other, are associated with the plasma membrane and bind GDP or GTP. RAS functions as a molecular switch. When the RAS contains a bound GDP, it is in the resting or closed position and is "inactive". In response to exposure to certain growth-promoting stimulus conditions, RAS is induced to exchange its bound GDP for GTP. In the case of bound GTP, RAS is turned "on" and is able to interact with other proteins (their "downstream targets") and be activated. The RAS protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP, thereby turning itself off. Turning RAS off requires an exogenous protein called Gtpase Activator Protein (GAP) that interacts with RAS and greatly accelerates the conversion of GTP to GDP. Any mutation that affects the RAS interaction with the GAP or affects the RAS conversion of GTP back to GDP will result in long-term activation of the protein and thus long-term signals conducted to the cell that command the cell to continue to grow and divide. As these signals cause cell growth and division, hyperactive RAS signaling may ultimately lead to cancer.

The reason why the research on RAS protein inhibitors has been challenging is mainly that the affinity between RAS and GDP, GTP is strong, picomolar level can be achieved, and intracellular GTP concentration is high, so that competitive inhibitors have difficulty in weakening the binding of RAS protein and GTP; meanwhile, the surface of RAS protein is smooth and lacks effective small molecule binding sites. RAS proteins have been considered as "non-druggable" targets for many years. The advent of continued new technologies has prompted the emergence of new therapeutic approaches to RAS targets. Currently, the research on RAS target signaling pathway inhibitors is mainly focused on the following aspects: direct action on RAS proteins, prevention of binding of RAS to GTP, action on upstream and downstream signals, inhibition of RAS interaction with effector proteins, reduction of RAS localization, inhibition of gtpase activity, and synthesis death.

The most well-known members of the RAS subfamily are HRAS, KRAS and NRAS, primarily because of their association with many types of cancer. Mutation of any of the three major isoforms of the RAS gene (isoform) (HRAS, NRAS or KRAS) is the most common event in human tumorigenesis. It was found that approximately 30% of human tumors carry some mutations in the RAS gene. Strikingly, KRAS mutations were detected in 25-30% of tumors. In contrast, the rate of oncogenic mutations that occur in NRAS and HRAS family members is much lower (8% and 3%, respectively). In addition, mutations in KRAS are most common in colorectal (45%), lung (35%) and pancreatic (95%) cancers. The most common KRAS mutations are located at residues G12 and G13 and at residue Q61 in the P loop. Mutations in the RAS gene have been shown to be associated with many cancers, and 99% of mutations occur in glycine at positions 12 and 13 as well as in glutamate at position 61 (see Y. Pvlayeva-Gupta, et al., RAS oncogenes: weaved a genomic web [ J ], Nature reviews cancer,2011,11: 761-774).

The G12C protein is a protein generated after the KRAS gene is subjected to G12C mutation (KRAS G12C for short), and specifically, glycine (G) is mutated into cysteine (C) at the 12 th position. KRAS G12C is the most frequently occurring form of mutation in the KRAS gene, which has been found in about 13% of carcinogenesis, about 43% of lung cancer, and almost 100% of MYH-related polyposis (familial colon cancer syndrome). In recent years, a series of inhibitors have been developed against the G12C protein. For example, Nature reports an inhibitor with electrophilic groups (e.g., vinylsulfonyl, acryloyl), and the eutectic results show an allosteric binding pocket never found before, which can lead to a change in the structure of Switch I and Switch II in RAS, which can attenuate the binding of KRAS (G12C) protein to GTP (see J.M. Ostrem., et al., K-RAS (G12C) inhibitors of allergic control GTP affinity and effector interactions [ J ], Nature,2013,503: 548-. Cell reports a class of compounds that have better inhibitory effects on G12C protein and also gave better results in vivo experiments in mice (see M.R. Janes, et al, Targeting KRAS Mutant cancer with a common G12C-Specific Inhibitor [ J ], Cell,2018,172(3): 578-. Some candidate compounds have also been studied clinically and have achieved primary clinical efficacy, such as MRTX849 from Mirati, AMG-510 from Amgen, and the like.

Although some candidate compounds have entered clinical research stage aiming at KRAS G12C target, the early candidate compounds have problems of low activity, large clinical dosage (AMG-510 dosage: 960 mg/day), rapid metabolism, high first pass effect of liver (MRTX1257) and the like which restrict the drug property. Therefore, there is still a need to develop new compounds with higher activity, better pharmacokinetic properties or capable of passing the blood brain barrier, in order to further improve the efficacy, better meet the clinical needs, cope with the large number of patients with brain metastases (about 40% of patients with non-small cell lung cancer will develop brain metastases, but the existing clinical candidates including MRTX849 and AMG-510 exclude these patients), and more broadly benefit cancer patients.

Disclosure of Invention

Problems to be solved by the invention

The invention aims to provide a series of novel compounds with inhibiting effect on KRAS G12C protein, a preparation method of the series of compounds, a pharmaceutical composition containing the series of compounds and medical application of the series of compounds.

Means for solving the problems

In a first aspect, the present invention provides a compound having the structure of formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion thereof, wherein:

a is an aromatic, heteroaromatic, alicyclic, heteroalicyclic, spirocyclic, heterospirocyclic, bridged or heterobridged ring containing from 1 to more heteroatoms each independently N, O, S or P;

l is a single bond, - (CH)₂)_p-、-(CH₂)_pO-、-(CH₂O)_p-、-CHR₇-、-O-、-NH-、-NR₇-、-C(＝O)-、-C(＝S)-、-NH-S(＝O)₂-NH-、-NH-S(＝O)₂-or-S (═ O)_p-；

X₀is-CH ═ CR₃or-N ═ or;

when X is present₁And X₂When connected by a single bond, X₁And X₂Each independently is-CH₂-、-C(＝O)-、-CHR₃-、-C(R₃)₂-、-NH-、-NR₃-、-CH₂CHR₃-、-CH＝CR₃-or-CH₂CH₂-; when X is present₁And X₂When connected by a double bond, X₁And X₂Each independently is-CH ═ CH₂CH＝、-CH₂CR₃＝、-C(R₃)₂CH, -N or-CR₃＝；

Each R₀Each independently is hydrogen, deuterium, halogen, hydroxy, amino, alkyl, cyano, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, heterocycloalkyloxy, heterocycloalkylamino, spiro, heterospiro, bridged, heterobridged, aryl, arylamino, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; when two R are₀When both are hydroxyl groups, the two hydroxyl groups, after dehydration, together with the carbon atom to which they are attached, form CO; when two R are₀When one is hydroxy and the other is amino, the hydroxy and amino groups are dehydrated to form C ═ NH together with the carbon atom to which they are attached; or two R₀Together with the carbon atoms to which they are attached form a saturated or unsaturated 3 to 6 membered cyclic structure containing 0 to more heteroatoms each independently O, N or S; and R is₀Hydrogen in the structure is optionally substituted with deuterium, alkyl, haloalkyl or halogen;

each R₁And R₃Each independently is hydrogen, deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or alkoxy; and R is₁And R₃Hydrogen in the structure is optionally substituted with 0 to more than one R₇Substitution;

each R₂And R₆Each independently is hydrogen, deuterium, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, cyano, cyanoalkyl, alkoxyalkyl, alkylaminoalkyl, acyl, substituted acyl, sulfonyl, alkylamino, amino, alkoxy, hydroxy, haloalkyl or haloalkoxy; when two R are₂And/or two R's bound to the same carbon atom₆When both are hydroxyl, the two hydroxyl groups, after dehydration, together with the carbon atoms to which they are attached, form C ═ O; when two R are₂And/or two R's bound to the same carbon atom₆When one is hydroxy and the other is amino, the hydroxy and amino groups are dehydrated to form C ═ NH together with the carbon atom to which they are attached; and R is₂And R₆Hydrogen in the structure is optionally substituted with deuterium, halogen, alkynyl, cyano, amino, hydroxy or alkoxy;

R₄、R₅and R₇Each independently is hydrogen, deuterium, halogen, alkyl, haloalkyl, amino, hydroxy, alkylaminoalkyl, cycloalkylaminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkylArylalkenyl, arylalkynyl, amido, sulfonamido, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_qSF₅Alkylsulfonyl, alkylphosphoryl, hypophosphoryl, - (CH)₂)_qNHSO₂NH₂Heterocycloalkyloxy, alkylamido, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylaminocarbonyl, aminoacyl, alkylsulfonamido or cyano; and R is₄、R₅And R₇The hydrogens in the structure are optionally substituted with 1 to more substituents each independently being deuterium, halogen, alkoxy, hydroxy, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, or cyano;

n, m, p and q are each independently 0, 1 or 2.

In a second aspect, the present invention provides a process for the preparation of a compound having the structure of formula I as described above, comprising the steps of:

1) reacting the compound I-1 with the compound I-a to obtain a compound I-2;

2) reacting the compound I-2 with the compound I-b to obtain a compound I-3;

3) carrying out deprotection reaction on the compound I-3 to obtain a compound I-4;

4) reacting the compound I-4 with a compound I-c to obtain a compound shown in the formula I;

wherein: y is chlorine, bromine, iodine, methylsulfonyloxy or p-toluenesulfonyloxy; z is hydroxyl, bromine or chlorine; PG represents a protecting group; A. l, X₀、X₁、X₂、R₀、R₁、R₂、R₃、R₄、R₅、R₆M and n are as defined above for compounds having the structure of formula I;

or comprises the following steps:

1 ') reacting the compound I-1' with the compound I-a 'to obtain a compound I-2';

2 ') carrying out deprotection reaction on the compound I-2 ' to obtain a compound I-3 ';

3 ') reacting the compound I-3' with the compound I-b 'to obtain a compound I-4';

4 ') carrying out deprotection reaction on the compound I-4 ' to obtain a compound I-5 ';

5 ') reacting compound I-5 ' with compound I-c ' to obtain a compound of formula I;

wherein: y is chlorine, bromine or iodineMethanesulfonyloxy or p-toluenesulfonyloxy; z is hydroxyl, bromine or chlorine; PG and PG' represent protecting groups; A. l, X₀、X₁、X₂、R₀、R₁、R₂、R₃、R₄、R₅、R₆M and n are as defined above for compounds having the structure of formula I.

In a third aspect, the present invention provides a pharmaceutical composition comprising a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or mixture thereof, in any proportion.

In a fourth aspect, the present invention provides a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or a mixture thereof in any ratio, or a pharmaceutical composition thereof, as described above, for use as an inhibitor of KRAS G12C protein.

In a fifth aspect, the present invention provides a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or a mixture thereof in any ratio, or a pharmaceutical composition thereof, for use as an inhibitor of KRAS G12C protein.

In a sixth aspect, the present application provides a use of the compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or a mixture thereof in any ratio, or the pharmaceutical composition described above, in the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by KRAS G12C protein.

In a seventh aspect, the present invention provides a method for the prevention and/or treatment of a disease mediated at least in part by the KRAS G12C protein, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition as described above.

In an eighth aspect, the present invention provides a pharmaceutical combination comprising a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or a mixture thereof in any proportion, or a pharmaceutical composition as described above, and at least one additional cancer therapeutic agent.

In a ninth aspect, the present invention provides a method for preventing and/or treating cancer, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound having the structure of formula I, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition or combination thereof as described above.

ADVANTAGEOUS EFFECTS OF INVENTION

The invention provides a compound with a novel structure shown in a formula I, which can be used as a high-efficiency KRAS G12C protein inhibitor and has various pharmacological activities such as tumor resistance, proliferative disease resistance, inflammation resistance, autoimmune disease resistance and the like.

Detailed Description

Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[ definition of terms ]

Unless otherwise indicated, the following terms have the following meanings.

"pharmaceutically acceptable salt" refers to salts of compounds having the structure of formula I that are substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting a compound of the invention with a pharmaceutically acceptable inorganic/organic acid or inorganic/organic base, such salts also being referred to as acid addition salts or base addition salts. Common inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like, common organic acids include, but are not limited to, trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, oxalic acid, formic acid, acetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, common inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, and the like, and common organic bases include, but are not limited to, diethylamine, triethylamine, ethambutol, and the like.

The term "solvate" refers to a substance formed by the binding of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to at least one solvent molecule by non-covalent intermolecular forces. The term "solvate" includes "hydrate". Common solvates include, but are not limited to, hydrates, ethanolates, acetonates, and the like.

The term "hydrate" refers to a substance formed by the non-covalent intermolecular binding of a compound of the present invention or a pharmaceutically acceptable salt thereof with water. Common hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.

The term "isomers" refers to compounds having the same number and type of atoms and thus the same molecular weight, but differing in the spatial arrangement or configuration of the atoms.

The term "stereoisomer" refers to isomers resulting from the different arrangement of atoms in a molecule, and includes both "configurational isomers" and "conformational isomers". The term "configurational isomers" refers to isomers resulting from different spatial arrangements of atoms in a molecule, and includes both "cis-trans isomers" and "optical isomers". The term "cis-trans isomer" refers to isomers in which the atoms (or groups) on both sides of a double bond or ring system are in different positions relative to a reference plane, in the cis isomer the atoms (or groups) are on the same side of the double bond or ring system, and in the trans isomer the atoms (or groups) are on the opposite side of the double bond or ring system, wherein "double bond" refers generally to a carbon-carbon double bond and also includes a carbon-nitrogen double bond and a nitrogen-nitrogen double bond. The term "optical isomer" refers to a stable isomer having a perpendicular asymmetric plane due to having at least one chiral factor (including a chiral center, a chiral axis, a chiral plane, etc.) so that plane polarized light can be rotated. Because of the presence of asymmetric centers and other chemical structures in the compounds of the present invention that may lead to stereoisomers, the present invention also includes such stereoisomers and mixtures thereof. Since the compounds of the present invention and their salts comprise asymmetric carbon atoms, they can exist in the form of single stereoisomers, racemates, mixtures of enantiomers and diastereomers. Generally, these compounds can be prepared in the form of a racemic mixture. However, if desired, such compounds may be prepared or isolated to give pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in single stereoisomers (purity. gtoreq.98%,. gtoreq.95%,. gtoreq.93%,. gtoreq.90%,. gtoreq.88%,. gtoreq.85% or. gtoreq.80%). As described hereinafter, individual stereoisomers of compounds are prepared synthetically from optically active starting materials containing the desired chiral center, or by preparation of mixtures of enantiomeric products followed by separation or resolution, e.g., conversion to mixtures of diastereomers followed by separation or recrystallization, chromatography, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. The starting compounds of a particular stereochemistry are either commercially available or may be prepared according to the methods described hereinafter and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that have non-superimposable mirror images of each other. The term "diastereomer" or "diastereomer" refers to optical isomers that do not form mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of the two R and S enantiomers). The term "non-racemic mixture" refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.

The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "isotopic label" refers to a compound formed by replacing a particular atom in a structure with its isotopic atom. Unless otherwise indicated, compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as²H(D)、³H(T)、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶S and³⁷Cl。

the term "prodrug" refers to a derivatized compound that, upon application to a patient, is capable of providing, directly or indirectly, a compound of the invention. Particularly preferred derivative compounds or prodrugs are those which, when administered to a patient, increase the bioavailability of the compounds of the invention (e.g., are more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are well known in the art.

The term "independently of each other" means that at least two groups (or ring systems) present in the structure in the same or similar range of values may have the same or different meaning in a particular case. For example, X and Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, and when X is hydrogen, Y is either hydrogen or halogen, hydroxy, cyano, alkyl or aryl; similarly, when Y is hydrogen, X may be hydrogen, or may be halogen, hydroxy, cyano, alkyl or aryl.

The term "optional" or "optionally" means that the description which follows is followedAn event or circumstance may or may not occur. The description includes instances where the event or circumstance occurs and instances where it does not. For example, ethyl is "optionally" substituted with halo, meaning that ethyl may be unsubstituted (CH)₂CH₃) Monosubstituted (e.g. CH)₂CH₂F) Polysubstituted (e.g. CHFCH)₂F、CH₂CHF₂Etc.) or fully substituted (CF)₂CF₃) (ii) a A5-10 membered aryl or heteroaryl group "optionally" substituted with 1 to 3R means that the 5-10 membered aryl or heteroaryl group can be unsubstituted or substituted with 1 to 3R. It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substituents or substitution patterns which are sterically impossible and/or cannot be synthesized.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) located in group VII of the periodic Table of the elements, preferably fluorine, chlorine and bromine, more preferably fluorine and chlorine.

The term "hypophosphoryl" refers to a monovalent group formed by hypophosphorous acid upon loss of the hydroxyl group and attached to the parent (-P (═ O) H) by a single bond to the phosphorus atom₂). The phosphoryl group can be attached in unsubstituted form to the structural parent nucleus of the compounds of the formula I according to the invention, or the hydrogen atom can be replaced by other substituents. Common substituted phosphoryl groups include, but are not limited to, dialkylphosphoryl (-P (═ O) (Alk)₂E.g. dimethylphosphoryl), diarylphosphoryl (- ═ O) (Ar)₂E.g. diphenylphosphinyl), alkylarylphosphinylphosphinyl (-P (═ O) (Alk) (Ar), e.g. methylphenylphosphinyl), dialkoxyphosphinyl (-P (═ O) (OAlk)₂Such as dimethoxyphosphoryl) and the like.

The term "phosphoryl" refers to a monovalent group formed by the loss of a hydroxyl group from a phosphoric acid and attached to the parent (-P (═ O) (OH) by a single bond to the phosphorus atom₂)。

The term "alkyl" refers to a monovalent straight or branched chain alkane group consisting of carbon and hydrogen atoms, containing no unsaturation, and attached to the parent by a single bondNucleus, preferably C₁-C₆Alkyl, more preferably C₁-C₄An alkyl group; common alkyl groups include, but are not limited to, methyl (-CH)₃) Ethyl (-CH)₂CH₃) N-propyl (-CH)₂CH₂CH₃) Isopropyl (-CH (CH)₃)₂) N-butyl (-CH)₂CH₂CH₂CH₃) Sec-butyl (-CH (CH)₃)CH₂CH₃) Isobutyl (-CH)₂CH(CH₃)₂) T-butyl (-C (CH))₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) Neopentyl (-CH)₂C(CH₃)₃) And the like.

The term "alkenyl" refers to a monovalent straight or branched chain alkene group consisting of only carbon and hydrogen atoms, containing at least one double bond, and connected to the parent nucleus by a single bond, preferably C₂-C₆An alkenyl group; common alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) 1-propen-1-yl (-CH ═ CH-CH)₃) 1-buten-1-yl (-CH ═ CH-CH)₂-CH₃) 1-penten-1-yl (-CH ═ CH-CH)₂-CH₂-CH₃)1, 3-butadien-1-yl (-CH ═ CH)₂)1, 4-pentadien-1-yl (-CH ═ CH-CH)₂-CH＝CH₂) And the like.

The term "alkynyl" refers to a monovalent straight or branched chain alkyne group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, and connected to the parent nucleus by a single bond, preferably C₂-C₆An alkynyl group; common alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propyn-1-yl (i.e., propynyl) (-C.ident.C-CH)₃) 1-butyn-1-yl (i.e. butynyl)

Pentyn-1-yl

1, 3-diacetylene-1-yl (-C.ident.C-C.ident.CH), 1, 4-pentadiyne-1-yl

And the like.

The term "alkoxy" refers to a monovalent straight or branched chain radical consisting solely of carbon, hydrogen and oxygen atoms, which may contain unsaturation, and which is attached to the parent nucleus by a single bond to the oxygen atom, preferably C₁-C₄An alkoxy group; common alkoxy groups include, but are not limited to, methoxy (-OCH)₃) Ethoxy (-OCH)₂CH₃) N-propoxy group (-OCH)₂CH₂CH₃) I-propoxy (-OCH (CH)₃)₂) N-butoxy (-OCH)₂CH₂CH₂CH₃) Sec-butoxy (-OCH (CH)₃)CH₂CH₃) Isobutoxy (-OCH)₂CH(CH₃)₂) T-butoxy (-OC (CH))₃)₃) N-pentyloxy (-OCH)₂CH₂CH₂CH₂CH₃) Neopentyloxy (-OCH)₂C(CH₃)₃) And the like.

The term "alkanoyl" refers to a monovalent straight or branched chain radical consisting only of carbon, hydrogen and oxygen atoms, containing no unsaturation other than the carbonyl group in its structure, and attached to the parent nucleus by a single bond to the carbonyl group, preferably C₁-C₄An alkyl acyl group; common alkanoyl groups include, but are not limited to, formyl (-C (═ O) H), acetyl (-C (═ O) CH₃) N-propionyl (-C (═ O) CH₂CH₃) N-butyryl (-C (═ O) CH₂CH₂CH₃) Isobutyryl group (-C (═ O) CH (CH)₃)₂) N-pentanoyl (-C (═ O) CH₂CH₂CH₂CH₃) Pivaloyl (-C (═ O) C (CH)₃)₃) And the like.

The term "alkylamido" refers to a monovalent straight or branched chain radical consisting of only carbon, hydrogen, oxygen and nitrogen atoms, containing no unsaturation other than the carbonyl group in its structure, and attached to the parent nucleus by a single bond to the nitrogen atom, preferably C₁-C₄An alkylamido group; common alkylamido groups include, but are not limited to, formylamino (-NHC (═ O) H), acetamido (-NHC (═ O) CH₃) N-propionylamino (-NHC (═ O) CH₂CH₃) N-butylamido (-NHC (═ O) CH₂CH₂CH₃) Isobutyramido (-NHC (═ O) CH (CH)₃)₂) N-pentanoylamino (-NHC (═ O) CH₂CH₂CH₂CH₃) Pivaloylamino (-NHC (═ O) C (CH)₃)₃) And the like.

The term "alkanoyloxy" refers to a monovalent straight or branched chain radical consisting of only carbon, hydrogen and oxygen atoms, containing no unsaturation other than the carbonyl group in its structure, and attached to the parent nucleus by a single bond to the oxygen atom, preferably C₁-C₄An alkyl acyloxy group; common alkanoyloxy groups include, but are not limited to, formyloxy (-OC (═ O) H), acetyloxy (-OC (═ O) CH₃) N-propionyloxy (-OC (═ O) CH₂CH₃) N-butyryloxy (-OC (═ O) CH₂CH₂CH₃) Isobutyroyloxy (-OC (═ O) CH (CH)₃)₂) N-valeryloxy (-OC (═ O) CH₂CH₂CH₂CH₃) Pivaloyloxy (-OC (═ O) C (CH)₃)₃) And the like.

The term "alkoxycarbonyl" refers to a monovalent straight or branched chain radical consisting only of carbon, hydrogen and oxygen atoms, containing no unsaturation other than the carbonyl group in its structure, and attached to the parent nucleus by a single bond to the carbonyl group, preferably C₁-C₄An alkoxycarbonyl group; common alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl (-C (═ O) OCH₃) Ethoxycarbonyl (-C (═ O) OCH₂CH₃) N-propoxycarbonyl (-O) OCH₂CH₂CH₃) Iso-propoxycarbonyl (-C (═ O) OCH (CH)₃)₂) N-butoxycarbonyl (-C (═ O) OCH₂CH₂CH₂CH₃) T-butyloxycarbonyl (-C (═ O) OC (CH)₃)₃) And the like.

The term "cycloalkyl" refers to a monovalent monocyclic, non-aromatic ring system consisting only of carbon and hydrogen atoms, containing no unsaturation, and connected to the parent nucleus by a single bond; common cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "heterocycloalkyl" refers to a monovalent monocyclic non-aromatic ring system composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing no unsaturation, and connected to the parent nucleus by a single bond; common heterocycloalkyl groups include, but are not limited to, oxiranyl, oxetan-3-yl, azetidin-3-yl, tetrahydrofuran-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, tetrahydro-2H-pyran-4-yl, piperidin-2-yl, piperidin-4-yl, and the like.

The term "spirocyclic group" refers to a monovalent non-aromatic ring system in which two single rings share a carbon atom, which consists only of carbon and hydrogen atoms, contains no unsaturation, and is connected to the parent nucleus by a single bond; according to the number of spiro atoms, they can be classified into mono-spiro compounds, di-spiro compounds, tri-spiro compounds, etc.; common spirocyclic groups include, but are not limited to, spiro [2.4] heptan-1-yl, spiro [3.5] nonan-2-yl, spiro [4.5] decan-2-yl, dispiro [5.2.5.2] hexadecan-3-yl, and the like.

The term "heterospirocyclic" refers to a monovalent non-aromatic ring system of two monocyclic rings sharing a single carbon atom, consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing no unsaturation, and being linked to the parent nucleus by a single bond; common heterospirocyclic groups include, but are not limited to, 6-oxaspiro [3.3] heptan-2-yl, 7-methyl-7-azaspiro [3.5] nonan-2-yl, 7-methyl-2, 7-diazaspiro [3.5] nonan-2-yl, 9-methyl-9-phosphaspiro [5.5] undecan-3-yl, and the like.

The term "bridged cyclic group" refers to a monovalent non-aromatic ring system in which any two monocyclic rings share two carbon atoms that are not directly connected, are composed of only carbon and hydrogen atoms, contain no unsaturation, and are connected to the parent nucleus by a single bond; according to the number of constituent rings, they can be classified into bicyclic compounds, tricyclic compounds, tetracyclic compounds, etc.; common bridging groups include (but are not limited to)Not restricted to) decahydronaphthalen-1-yl, bicyclo [3.2.1]Octane-1-yl, tricyclo [2.2.1.0^2.6]Heptane-1-yl, 1-adamantyl, and the like.

The term "heterobridged cyclic group" refers to a monovalent non-aromatic ring system in which any two monocyclic rings share two carbon atoms not directly connected, are composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, contain no unsaturation, and are connected to the parent nucleus by a single bond; common heterobridged cyclic groups include, but are not limited to, 1, 4-diazabicyclo [2.2.2] octan-2-yl, 2, 8-diazabicyclo [4.3.0] nonan-8-yl, and the like.

The term "aryl" refers to a monovalent monocyclic or polycyclic (including fused forms) aromatic ring system consisting of only carbon and hydrogen atoms and being linked to the parent nucleus by a single bond; common aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like.

The term "arylalkyl" refers to a monovalent straight or branched chain alkyl radical consisting solely of carbon and hydrogen atoms, containing at least one aryl group, and connected to the parent nucleus by a single bond, preferably C₆-C₁₀aryl-C₁-C₆Alkyl, more preferably C₆-C₁₀aryl-C₁-C₄An alkyl group; common arylalkyl groups include, but are not limited to, benzyl, β -phenylethyl, α -phenylethyl, naphthylmethyl, and the like.

The term "arylalkenyl" refers to a monovalent straight or branched chain alkene group consisting of only carbon and hydrogen atoms, containing at least one double bond and at least one aryl group, and being connected to the parent nucleus by a single bond, preferably C₆-C₁₀aryl-C₂-C₆An alkenyl group; common arylalkenyl groups include, but are not limited to, 1-styryl (-CPh ═ CH)₂) 2-styryl (-CH ═ CHPh), 3-phenyl-1-propen-1-yl (-CH ═ CH-CH)₂Ph), 2-phenyl-1-propen-1-yl (-CH ═ CPh-CH)₃) 4-phenyl-1, 3-butadien-1-yl (-CH ═ CHPh), 4-diphenyl-1, 3-butadien-1-yl (-CH ═ CH-CH ═ CPh)₂) And the like.

The term "arylalkynyl" refers to a monovalent radicalA straight-chain or branched alkyne radical of (a), consisting exclusively of carbon atoms and hydrogen atoms, containing at least one triple bond and at least one aryl group and being connected to the parent nucleus by a single bond, preferably C₆-C₁₀aryl-C₂-C₆An alkynyl group; common arylalkynyl groups include, but are not limited to, phenylethynyl (-C ≡ CPh), 3-phenyl-1-propyn-1-yl (-C ≡ C-CH)₂Ph), 3-diphenyl-1-propyn-1-yl (-C.ident.C-CHPh)₂) And 4-phenyl-1, 3-diacetylene-1-yl (-C.ident.C-C.ident.CPh).

The term "heteroaryl" refers to a monovalent monocyclic or polycyclic (including fused forms) aromatic ring system composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, and connected to the parent nucleus by a single bond; common heteroaryl groups include, but are not limited to, benzopyrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, acridinyl, carbazolyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, indazolyl, indolizinyl, indolyl, quinolinyl, isoquinolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, purinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridyl, triazolyl, tetrazolyl, and the like.

The term "heteroarylalkyl" refers to a monovalent straight or branched chain alkane group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing at least one heteroaryl group, and connected to the parent nucleus by a single bond, preferably a 5-to 10-membered heteroaryl-C₁-C₆Alkyl, more preferably 5-10 membered heteroaryl-C₁-C₄An alkyl group; common heteroarylalkyl groups include, but are not limited to, pyrrol-2-ylmethyl, furan-2-ylmethyl, thiophen-2-ylmethyl, 1H-pyrazol-3-ylmethyl, quinolin-4-ylmethyl, and the like.

The term "heteroarylalkenyl" refers to a monovalent straight or branched chain alkene group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing at least one double bond and at least one heteroaryl group, and connected to the parent nucleus by a single bond, preferably a 5-to 10-membered heteroaryl-C₂-C₆An alkenyl group; common and commonHeteroarylalkenyl groups of (a) include, but are not limited to, 2- (pyrrol-2-yl) vinyl, 2- (furan-2-yl) vinyl, 2- (thiophen-2-yl) vinyl, 4- (1H-pyrazol-3-yl) -1, 3-butan-1-yl, and the like.

The term "heteroarylalkynyl" refers to a monovalent straight or branched chain alkyne group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing at least one triple bond and at least one heteroaryl group, and connected to the parent nucleus by a single bond, preferably a 5-to 10-membered heteroaryl-C₂-C₆An alkynyl group; common heteroarylalkynyls include, but are not limited to, (pyrrol-2-yl) ethynyl, (furan-2-yl) ethynyl, (thiophen-2-yl) ethynyl, (1H-pyrazol-3-yl) ethynyl, (1H-pyrazol-4-yl) ethynyl, (1-methyl-1H-pyrazol-4-yl) ethynyl, and the like.

The term "pentafluoro- λ⁶-thioalkyl "(also known as" sulfur pentafluoride ") means a monovalent group consisting of only a sulfur atom and a fluorine atom, and is bonded to the parent nucleus (-SF) by a single bond₅)。

Reference in the specification to "an embodiment," "one embodiment," "some embodiments," "certain embodiments," or "some embodiments" means that a particular reference element, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in some embodiments" or "in another embodiment" or "in certain embodiments" or "in some embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

The terms "comprise/include/have" and its english variants such as "comprise/include/have" and "including/connecting/having" should be interpreted in an open-ended sense, i.e., "including but not limited to".

It should be understood that, unless expressly specified otherwise, references to the singular forms "a", "an" and "the" in this specification and claims also include the plural reference. Thus, for example, a reaction comprising "a catalyst" may comprise one catalyst, or two or more catalysts.

[ Compound of the general formula ]

The present invention provides a compound of formula I:

X₀is-CH ═ CR₃or-N ═ or;

Each R₀Each independently is hydrogen, deuterium, halogen, hydroxy, amino, alkyl, cyano, haloalkyl, heteroalkyl,Alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, heterocycloalkyloxy, heterocycloalkylamino, spiro, heterospiro, bridged, heterobridged, aryl, arylamino, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; when two R are₀When both are hydroxyl, the two hydroxyl groups, after dehydration, together with the carbon atoms to which they are attached, form C ═ O; when two R are₀When one is hydroxy and the other is amino, the hydroxy and amino groups are dehydrated to form C ═ NH together with the carbon atom to which they are attached; or two R₀Together with the carbon atoms to which they are attached form a saturated or unsaturated 3 to 6 membered cyclic structure containing 0 to more heteroatoms each independently O, N or S; and R is₀Hydrogen in the structure is optionally substituted with deuterium, alkyl, haloalkyl or halogen;

each R₂And R₆Each independently is hydrogen, deuterium, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, cyano, cyanoalkyl, alkoxyalkyl, alkylaminoalkyl, acyl, substituted acyl, sulfonyl, amino, alkoxy, alkylamino, hydroxy, haloalkyl or haloalkoxy; when two R are₂And/or two R's bound to the same carbon atom₆When both are hydroxyl, the two hydroxyl groups, after dehydration, together with the carbon atoms to which they are attached, form C ═ O; when two R are₂And/or two R's bound to the same carbon atom₆When one is hydroxy and the other is amino, the hydroxy and amino groups are dehydrated to form C ═ NH together with the carbon atom to which they are attached; and R is₂And R₆In the structure ofOptionally substituted with deuterium, halogen, alkynyl, cyano, amino, hydroxy or alkoxy;

R₄、R₅and R₇Each independently hydrogen, deuterium, halogen, alkyl, haloalkyl, amino, hydroxy, alkylaminoalkyl, cycloalkylaminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spiro, hetero-spiro, bridged, hetero-bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, amido, sulfonamido, sulfamoylamino, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_qSF₅Alkylsulfonyl, alkylphosphoryl, hypophosphoryl, - (CH)₂)_qNHSO₂NH₂Heterocycloalkyloxy, alkylamido, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylaminocarbonyl, aminoacyl, alkylsulfonamido or cyano; and R is₄、R₅And R₇The hydrogens in the structure are optionally substituted with 1 to more substituents each independently being deuterium, halogen, alkoxy, hydroxy, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, or cyano;

n, m, p and q are each independently 0, 1 or 2.

In some embodiments of the invention, the compound of formula I above is a compound of formula IA:

wherein:

X₀is-CH ═ CR₃or-N ═ or;

Each R₀Each independently is hydrogen, deuterium, halogen, hydroxy, amino, alkyl, cyano, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, heterocycloalkyloxy, heterocycloalkylamino, spiro, heterospiro, bridged, heterobridged, aryl, arylamino, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; when two R are₀When both are hydroxyl, the two hydroxyl groups, after dehydration, together with the carbon atoms to which they are attached, form C ═ O; when two R are₀When one is hydroxy and the other is amino, the hydroxy and amino groups are dehydrated to form C ═ NH together with the carbon atom to which they are attached; or two R₀Together with the carbon atoms to which they are attached form a saturated or unsaturated 3 to 6 membered cyclic structure containing 0 to more heteroatoms each independently O, N or S; and R is₀Hydrogen in the structure is optionally substituted with deuterium, alkyl, haloalkyl or halogen;

each R₂And R₆Each independently is hydrogen, deuterium, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, cyano, cyanoalkyl, alkoxyalkyl, alkylaminoalkyl, acyl, substituted acyl, sulfonyl, amino, alkoxy, alkylamino, hydroxy, haloalkyl or haloalkoxy; when two R are₂And/or two R's bound to the same carbon atom₆When both are hydroxyl, the two hydroxyl groups, after dehydration, together with the carbon atoms to which they are attached, form C ═ O; when two R are₂And/or two R's bound to the same carbon atom₆When one is hydroxy and the other is amino, the hydroxy and amino groups are dehydrated to form C ═ NH together with the carbon atom to which they are attached; and R is₂And R₆Hydrogen in the structure is optionally substituted with deuterium, halogen, alkynyl, cyano, amino, hydroxy or alkoxy;

n, m, p and q are each independently 0, 1 or 2.

In some embodiments of the invention, the compound of formula I above is a compound of formula IB:

wherein:

X₀is-CH ═ CR₃or-N ═ or;

X₁and X₂Each independently is-CH₂-、-C(＝O)-、-CHR₃-、-C(R₃)₂-, -NH-, -CH-or-CH₂CH₂-；

each R₁And R₃Each independently is hydrogen, deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spiro, heterospiro, bridged, cyclic, or heterocyclic,Heterocyclyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl or alkoxy; and R is₁And R₃Hydrogen in the structure is optionally substituted with 0 to more than one R₇Substitution;

R₄、R₅and R₇Each independently hydrogen, deuterium, halogen, alkyl, haloalkyl, amino, hydroxy, alkylaminoalkyl, cycloalkylaminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spiro, hetero-spiro, bridged, hetero-bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, amido, sulfonamido, sulfamoylamino, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_qSF₅Alkylsulfonyl, alkylphosphoryl, hypophosphoryl, - (CH)₂)_qNHSO₂NH₂Heterocycloalkyloxy, alkylamido, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylaminocarbonyl, aminoacyl, alkylsulfonamido or cyano; and R is₄、R₅And R₇The hydrogens in the structure are optionally substituted with 1 to more substituents each independently being deuterium, halogen, alkoxy, hydroxy, amino, alkylAcyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido or cyano;

n, m, p and q are each independently 0, 1 or 2.

In some embodiments of the invention, the compound of formula I above is a compound of formula IC:

wherein:

X₀is-CH ═ CR₃or-N ═ or;

X₁and X₂Each independently is-CH ═ CH₂CH＝、-CH₂CR₃＝、-C(R₃)₂CH, -N or-CR₃＝；

Each R₀Each independently is hydrogen, deuterium, halogen, hydroxy, amino, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, or heterocycloalkyloxy; when two R are₀When both are hydroxyl, the two hydroxyl groups, after dehydration, together with the carbon atoms to which they are attached, form C ═ O; when two R are₀When one is hydroxy and the other is amino, the hydroxy and amino groups are dehydrated to form C ═ NH together with the carbon atom to which they are attached; and R is₀Hydrogen in the structure is optionally substituted with deuterium, alkyl, haloalkyl or halogen;

each R₁And R₃Each independently is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or alkoxy;and R is₁And R₃Hydrogen in the structure is optionally substituted with 0 to more than one R₇Substitution;

n, m, p and q are each independently 0, 1 or 2.

In some embodiments of the invention, the compound of formula I above is a compound of formula ID:

wherein:

X₀is-CH ═ CR₃or-N ═ or;

Each R₁And R₃Each independently is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or alkoxy; and R is₁And R₃Hydrogen in the structure is optionally substituted with 0 to more than one R₇Substitution;

each R₂And R₆Each independently is hydrogen, deuterium, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, cyano, cyanoalkyl, alkoxyalkyl, alkylaminoalkyl, acyl, substituted acyl, sulfonyl, amino, alkoxy, alkylamino, hydroxy, haloalkyl or haloalkoxy; when two R are₂And/or two R's bound to the same carbon atom₆When both are hydroxyl, the two hydroxyl groups, after dehydration, together with the carbon atoms to which they are attached, form C ═ O; when two R are₂And/or two R's bound to the same carbon atom₆When one of them is a hydroxyl group and the other is an amino group, the hydroxyl group and the amino groupAfter dehydration together with the carbon atom to which it is attached form C ═ NH; and R is₂And R₆Hydrogen in the structure is optionally substituted with deuterium, halogen, alkynyl, cyano, amino, hydroxy or alkoxy;

n, m, p and q are each independently 0, 1 or 2.

In some embodiments of the invention, the compound of formula I above is a compound of formula IE:

wherein:

X₀is-CH ═,-CR₃or-N ═ or;

R₁Is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic, bridged cyclic, heterobridged cyclic, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or alkoxy; and R is₁Hydrogen in the structure is optionally substituted with 0 to more than one R₇Substitution;

each R₃Each independently is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic, bridged cyclic, heterobridged cyclic, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; and R is₃Hydrogen in the structure is optionally substituted with 0 to more than one R₇Substitution;

R₄、R₅and R₇Each independently is hydrogen, deuterium, halogen, alkyl, haloalkyl, amino, hydroxy, alkylaminoalkyl, cycloalkylaminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spiro, heterospiro, bridgeCyclyl, heterocyclyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, amido, sulfonamido, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_qSF₅Alkylsulfonyl, alkylphosphoryl, hypophosphoryl, - (CH)₂)_qNHSO₂NH₂Heterocycloalkyloxy, alkylamido, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylaminocarbonyl, aminoacyl, alkylsulfonamido or cyano; and R is₄、R₅And R₇The hydrogens in the structure are optionally substituted with 1 to more substituents each independently being deuterium, halogen, alkoxy, hydroxy, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, or cyano;

n, m, p and q are each independently 0, 1 or 2.

In some embodiments of the invention, the compound of formula I above is a compound of formula IF:

wherein:

X₀is-CH ═ CR₃or-N ═ or;

X₁and X₂Each independently is-CH₂-、-C(＝O)-、-CHR₃-, -NH-, -CH-or-CH₂CH₂-；

Each R₁And R₃Each independently is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic, bridged cyclic, heterobridged cyclic, aryl, arylalkyl, arylalkenyl(iii) arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl or alkoxy; and R is₁And R₃Hydrogen in the structure is optionally substituted with 0 to more than one R₇Substitution;

each R₆Each independently is hydrogen, deuterium, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, cyano, cyanoalkyl, alkoxyalkyl, alkylaminoalkyl, acyl, substituted acyl, sulfonyl, amino, alkoxy, alkylamino, hydroxy, haloalkyl or haloalkoxy; when two R's of the same carbon atom are bound₆When both are hydroxyl, the two hydroxyl groups, after dehydration, together with the carbon atoms to which they are attached, form C ═ O; when two R's of the same carbon atom are bound₆When one is hydroxy and the other is amino, the hydroxy and amino groups are dehydrated to form C ═ NH together with the carbon atom to which they are attached; and R is₆Hydrogen in the structure is optionally substituted with deuterium, halogen, alkynyl, cyano, amino, hydroxy or alkoxy;

n, m, p and q are each independently 0, 1 or 2.

In some embodiments of the invention, the compound of formula I above is a compound of formula IG:

wherein:

X₀is-CH ═ CR₃or-N ═ or;

X₁and X₂Each independently is-CH, -N or-CR₃＝；

each R₆Each independently is hydrogen, deuterium, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, cyano, cyanoalkyl, alkoxyalkyl, alkylaminoalkyl, acyl, substituted acyl, sulfonyl, amino, alkoxy, alkylamino, hydroxy, haloalkyl or haloalkoxy; when two R's of the same carbon atom are bound₆When both are hydroxyl, the two hydroxyl groups, after dehydration, together with the carbon atoms to which they are attached, form C ═ O; when in useTwo R's bound to the same carbon atom₆When one is hydroxy and the other is amino, the hydroxy and amino groups are dehydrated to form C ═ NH together with the carbon atom to which they are attached; and R is₆Hydrogen in the structure is optionally substituted with deuterium, halogen, alkynyl, cyano, amino, hydroxy or alkoxy;

n, m, p and q are each independently 0, 1 or 2.

In some embodiments of the invention, the compound of formula I above is a compound of formula IH:

wherein:

l is a single bond, - (CH)₂)_p-、-(CH₂)_pO-、-(CH₂O)_p-、-CHR₇-、-O-、-NH-、-NR₇-、-NH-S(＝O)₂-or-S (═ O)_p-；

X₀is-CH ═ CR₃or-N ═ or;

when X is present₁And X₂When connected by a single bond, X₁And X₂Each independently is-CH₂-、-C(＝O)-、-CHR₃-、-C(R₃)₂-、-CH₂CHR₃-、-CH＝CR₃-or-CH₂CH₂-; when X is present₁And X₂When connected by a double bond, X₁And X₂Each independently is-CH or-CR₃＝；

Each R₁And R₃Each independently is hydrogen, deuterium, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or alkoxy; and R is₁And R₃Hydrogen in the structure is optionally substituted with 0 to more than one R₇Substitution;

each R₂And R₆Each independently is hydrogen, deuterium, halogen, alkyl, cycloalkyl, cyano, cyanoalkyl, alkylamino, amino, alkoxy, hydroxy, haloalkyl or haloalkoxy; when two R are₂And/or two R's bound to the same carbon atom₆When both are hydroxyl, the two hydroxyl groups, after dehydration, together with the carbon atoms to which they are attached, form C ═ O; when two R are₂And/or two R's bound to the same carbon atom₆When one is hydroxy and the other is amino, the hydroxy and amino groups are dehydrated to form C ═ NH together with the carbon atom to which they are attached; and R is₂And R₆Hydrogen in the structure is optionally substituted with deuterium, halogen, alkynyl, cyano, amino, hydroxy or alkoxy;

R₄、R₅and R₇Each independently hydrogen, deuterium, halogen, alkyl, haloalkyl, amino, hydroxy, alkylaminoalkyl, cycloalkylaminoalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, - (CH)₂)_qSF₅Alkyl sulfonyl, alkyl phosphoryl, - (CH)₂)_qNHSO₂NH₂Alkyl acylamino, alkyl acyl, alkylAcyloxy, alkoxycarbonyl, alkylaminocarbonyl, or cyano; and R is₄、R₅And R₇The hydrogens in the structure are optionally substituted with 1 to more substituents each independently being deuterium, halogen, alkoxy, hydroxy, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, or cyano;

n, m, p and q are each independently 0, 1 or 2.

In addition, the invention also provides the compound of the formula I, wherein the specific structure and name are shown in the following table:

[ production method ]

The present invention provides a process for the preparation of a compound of formula I as described above, comprising the steps of:

1) reacting the compound I-1 with the compound I-a to obtain a compound I-2;

2) reacting the compound I-2 with the compound I-b to obtain a compound I-3;

wherein: y is chlorine, bromine, iodine, methylsulfonyloxy or p-toluenesulfonyloxy; z is hydroxyl, bromine or chlorine; PG represents a protecting group; A. l, X₀、X₁、X₂、R₀、R₁、R₂、R₃、R₄、R₅、R₆M and n are as defined for compounds of formula I.

In some embodiments of the invention, steps 1) and 2) of the above preparation process are carried out by substitution reaction under basic conditions. Reagents used to provide basic conditions include, but are not limited to, Triethylamine (TEA), sodium hydrogen (NaH), potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, N-Diisopropylethylamine (DIPEA), pyridine, Triethylenediamine (TEDA), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 4-Dimethylaminopyridine (DMAP), N-methylmorpholine, tetramethylethylenediamine, potassium hexamethyldisilazide, sodium hexamethyldisilazide, and the like.

In some embodiments of the invention, steps 1) and 2) of the above preparation process are carried out by a coupling reaction. Coupling reactions include, but are not limited to, Buchwald-Hartwig Reaction, Suzuki Reaction, Heck Reaction, Steille Reaction, germ head Coupling Reaction, bear field Coupling Reaction, root-shore Coupling Reaction, Juniperus Coupling Reaction, and the like.

In some embodiments of the present invention, the protecting groups and removing conditions in step 3) of the above preparation method include (but are not limited to) the combinations shown in the following table:

in some embodiments of the invention, step 4) of the above preparation method is carried out by substitution reaction under basic conditions. Reagents used to provide basic conditions include, but are not limited to, triethylamine, sodium hydrogen, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, N-diisopropylethylamine, pyridine, triethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 4-dimethylaminopyridine, N-methylmorpholine, tetramethylethylenediamine, potassium hexamethyldisilazide, sodium hexamethyldisilazide, and the like.

In some embodiments of the invention, step 4) of the above preparation method is performed by a condensation reaction. Condensing agents employed include, but are not limited to, N '-Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC), N- (3-dimethylaminopropyl) -N '-ethylcarbodiimide hydrochloride (EDC. HCl), 4, 5-Dicyanoimidazole (DCI), N' -Carbonyldiimidazole (CDI), N-hydroxysuccinimide (HOSu), N-hydroxythiosuccinimide sodium salt, Cartesian condensing agent (BOP), benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate (PyBOP), tripyrrolidinylphosphonium bromide hexafluorophosphate (PyBrOP), 1-hydroxy-7-azobenzotriazol (HOAT), 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), O- (7-azabenzotriazole) -N, N ' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N ' -tetramethyluronium Hexafluorophosphate (HBTU), O-benzotriazol-N, N ' -tetramethyluronium tetrafluoroborate (TBTU), 6-chlorobenzotriazole-1, 1,3, 3-tetramethyluronium Hexafluorophosphate (HCTU), O- (1, 2-dihydro-2-oxo-pyridinyl) -1,1,3, 3-tetramethyluronium tetrafluoroborate (TPTU), and the like.

Or comprises the following steps:

wherein: y is chlorine, bromine, iodine, methylsulfonyloxy or p-toluenesulfonyloxy; z is hydroxyl, bromine or chlorine; PG and PG' represent protecting groups; A. l, X₀、X₁、X₂、R₀、R₁、R₂、R₃、R₄、R₅、R₆M and n are as defined for compounds of formula I.

In some embodiments of the invention, steps 1 ') and 3') of the above preparation process are carried out by substitution reaction under basic conditions. Reagents used to provide basic conditions include, but are not limited to, triethylamine, sodium hydrogen, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, N-diisopropylethylamine, pyridine, triethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 4-dimethylaminopyridine, N-methylmorpholine, tetramethylethylenediamine, potassium hexamethyldisilazide, sodium hexamethyldisilazide, and the like.

In some embodiments of the invention, steps 1 ') and 3') of the above preparation process are carried out by a coupling reaction. Coupling reactions include, but are not limited to, Buchwald-Hartwig Reaction, Suzuki Reaction, Heck Reaction, Steille Reaction, germ head Coupling Reaction, bear field Coupling Reaction, root-shore Coupling Reaction, Juniperus Coupling Reaction, and the like.

In some embodiments of the present invention, the protecting groups and removal conditions in steps 2 ') and 4') of the above preparation method include (but are not limited to) the combinations shown in the following table:

in some embodiments of the invention, step 5') of the above preparation process is carried out by substitution reaction under basic conditions. Reagents used to provide basic conditions include, but are not limited to, triethylamine, sodium hydrogen, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, N-diisopropylethylamine, pyridine, triethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 4-dimethylaminopyridine, N-methylmorpholine, tetramethylethylenediamine, potassium hexamethyldisilazide, sodium hexamethyldisilazide, and the like.

In some embodiments of the invention, step 5') of the above preparation process is carried out by a condensation reaction. The condensing agents used include, but are not limited to, N '-dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N '-ethylcarbodiimide hydrochloride, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, N-hydroxysuccinimide, N-hydroxythiosuccinimide sodium salt, Carter condensing agent, benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate, tripyrrolidinylphosphonium bromide hexafluorophosphate, 1-hydroxy-7-azobenzotriazol, 1-hydroxybenzotriazole, 6-chloro-1-hydroxybenzotriazole, O- (7-azabenzotriazole) -N, n ', N' -tetramethylurea hexafluorophosphate, benzotriazole-N, N '-tetramethylurea hexafluorophosphate, O-benzotriazole-N, N' -tetramethylurea tetrafluoroborate, 6-chlorobenzotriazole-1, 1,3, 3-tetramethylurea hexafluorophosphate, O- (1, 2-dihydro-2-oxo-pyridinyl) -1,1,3, 3-tetramethylurea tetrafluoroborate, and the like.

When the compound of the formula I has a specific configuration, the invention also provides a corresponding preparation method so as to obtain the compound with the specific configuration. These compounds having a specific configuration and the process for their preparation are likewise part of the present invention.

[ pharmaceutical composition ]

The term "pharmaceutical composition" refers to a composition that can be used as a medicament, comprising a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient that is compatible with the pharmaceutically active ingredient and not deleterious to the subject, including, but not limited to, diluents (or fillers), binders, disintegrants, lubricants, wetting agents, thickening agents, glidants, flavoring agents, preservatives, antioxidants, pH adjusters, solvents, co-solvents, surfactants, and the like.

The present invention provides a pharmaceutical composition comprising a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion.

In some preferred embodiments of the present invention, the above pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[ medical use ]

The compound of the formula I, pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, isotopic labels, prodrugs or mixtures thereof in any proportion, or the pharmaceutical composition can inhibit KRAS G12C protein, further inhibit phosphorylation of downstream signals (p-ERK), and therefore can be used as KRAS G12C protein inhibitors. Accordingly, the present invention provides the use of a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition as described above, as an inhibitor of KRAS G12C protein.

In addition, the application also provides the application of the compound of the formula I or the pharmaceutically acceptable salt, the solvate, the hydrate, the stereoisomer, the tautomer, the isotopic marker, the prodrug or the mixture of the prodrug in any proportion, or the pharmaceutical composition in the preparation of medicines for preventing and/or treating diseases at least partially mediated by the KRAS G12C protein.

The term "a disease mediated at least in part by KRAS G12C protein" refers to a disease that involves at least a portion of the involvement of KRAS G12C protein in the pathogenesis, including, but not limited to, cancer (e.g., cervical cancer), proliferative diseases, inflammation, ocular diseases (e.g., cataracts), autoimmune diseases (e.g., rheumatoid arthritis), and the like.

[ method of treatment ]

The present invention provides a method for the prevention and/or treatment of a disease mediated at least in part by the KRAS G12C protein comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition as described above.

The term "therapeutically effective amount" refers to a dose of a pharmaceutically active ingredient that is capable of inducing a biological or medical response in a cell, tissue, organ or organism (e.g., a patient).

The term "administering" refers to the process of applying a pharmaceutically active ingredient (such as a compound of the invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (e.g., a pharmaceutical composition of the invention) to a patient or a cell, tissue, organ, biological fluid, etc. site thereof, such that the pharmaceutically active ingredient or pharmaceutical composition contacts the patient or the cell, tissue, organ, biological fluid, etc. site thereof. Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, intraperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like.

The term "in need thereof refers to a judgment by a physician or other caregiver that a patient needs or will benefit from a prophylactic and/or therapeutic procedure, the judgment being made based on various factors of the physician or other caregiver in their area of expertise.

The term "patient" (or subject) refers to a human or non-human animal (e.g., a mammal).

[ combination drug ]

The present invention provides a pharmaceutical combination comprising a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition as described above, and at least one additional cancer therapeutic agent.

The term "cancer" refers to a cellular disorder characterized by uncontrolled or deregulated cell proliferation, reduced cell differentiation, inappropriate ability to invade surrounding tissues, and/or the ability to establish new growth at an ectopic site. Common cancers include, but are not limited to, brain, liver, gall bladder, bronchial, lung, bladder, ovarian, cervical, testicular, lip, tongue, hypopharynx, larynx, esophageal, stomach, intestinal (e.g., colon, rectum), thyroid, salivary gland, pancreatic, breast, prostate, blood (or leukemia), lymph (or lymphoma), bone, and skin cancers.

The term "cancer therapeutic agent" refers to a pharmaceutical composition or pharmaceutical formulation effective in controlling and/or combating cancer, including, but not limited to, cytotoxic drugs, anti-angiogenic drugs, DNA repair agents, epigenetic disruptors, immunomodulators and the like. Common cancer therapeutic agents include, but are not limited to, anti-puring agents (e.g., pentostatin, etc.), anti-pyrimidinizing agents (e.g., fluorouracil), antifolates (e.g., methotrexate), DNA polymerase inhibitors (e.g., cytarabine), alkylating agents (e.g., cyclophosphamide), platinum complexes (e.g., cisplatin), DNA damaging antibiotics (e.g., mitomycin), topoisomerase inhibitors (e.g., camptothecin), intercalating DNA interfering nucleic acid synthesizers (e.g., epirubicin), anti-feed drugs (e.g., asparaginase), interfering tubulin forming drugs (e.g., paclitaxel), interfering ribosome function drugs (e.g., cephalotaxine), cytokines (e.g., IL-1), thymosin peptides, tumor cell proliferation viruses (e.g., adenovirus ONYX-015), DNA repair agents such as PARP inhibitors (e.g., Olaparib, Talazoparib, Niraparib, etc.), Anti-angiogenic drugs such as HIF-1 inhibitors (e.g., Roxadustat/FG-4592, 2-methoxyestradiol/2-MeOE 2, FG-2216, etc.) or VEGF signaling pathway inhibitors (e.g., bevacizumab, sunitinib, sorafenib, etc.), epigenetic disruptors (e.g., HADC inhibitors), histone demethylation inhibitors, immune checkpoint inhibitors (e.g., PD-1/PD-L1 monoclonal antibody, CTLA-4 monoclonal antibody, etc.), IDO inhibitors, etc.

In addition, the present invention provides a method for preventing and/or treating cancer, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of a compound of formula I as described above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion, or a pharmaceutical composition as described above or a pharmaceutical combination as described above.

The invention will be further illustrated with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. If the experimental procedures in the following examples do not specify particular conditions, conventional conditions or conditions recommended by the manufacturer are generally followed. Unless otherwise indicated, percentages and parts appearing in the following examples are by weight.

Example 1: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- (2- ((S) -1-methylpyrrolidin-2-yl) ethyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 1).

S1: in the presence of intermediates 1-1 and 1-2 (1)1eq.) into a round bottom flask was added DMF. Stirring to dissolve, adding N, N-diisopropylethylamine, and stirring to react until the TLC detection reaction is complete. Adding saturated NaCl water solution, extracting with ethyl acetate, concentrating the organic phase, and separating with silica gel column chromatography to obtain intermediate 1-3. LC-MS 594.35[ M +1 ]]⁺。

S2: dissolving the intermediate 1-3(5mmol) in methanol, adding wet Pd/C, replacing with nitrogen for 3 times, adding hydrogen balloon, stirring at room temperature for reaction, and detecting by TLC to obtain the final product. The Pd/C was removed by filtration through celite, the celite was washed twice with ethyl acetate, and the reaction mixture was concentrated in vacuo. Without any purification, the target intermediate 1-4 was obtained in 90% yield, LC-MS:504.30[ M +1 ]]⁺。

S3: intermediate 1-4, intermediate 1-5(1eq.), Pd₂(dba)₃(1%, w/w%), RuPhos (1%, w/w%) and Cs₂CO₃(1eq.) in toluene, purged with nitrogen and heated to 110 ℃. The reaction was completed by TLC, cooled to room temperature, the organic phase was concentrated and separated by silica gel column chromatography to give intermediate 1-6 (mobile phase: dichloromethane/methanol ═ 3: 1). LC-MS 644.36[ M +1 ]]⁺。

S4: the intermediates 1-6 and 1-chloroethyl chloroformate (2eq.) were dissolved in 1, 2-dichloroethane, heated to 80 ℃ and stirred until the reaction was complete as detected by TLC. Cooled to room temperature, saturated aqueous NaCl solution was added, extracted 3 times with ethyl acetate, the organic phase was concentrated, and separated by silica gel column chromatography (mobile phase: dichloromethane/methanol ═ 3:1) to give intermediates 1 to 7. LC-MS 510.33[ M +1 ]]⁺。

S5: and dissolving the intermediate 1-7 in dry THF, cooling to 0 ℃, slowly adding acryloyl chloride (1.1eq.) dropwise, reacting for 1 hour, and detecting complete reaction by TLC. The reaction was quenched with water, concentrated, and separated by gel column chromatography to give the target compound 1 (mobile phase: dichloromethane/methanol ═ 3: 1). LC-MS 564.34[ M +1 ]]⁺。

Example 2: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- (2- ((R) -1-methylpyrrolidin-2-yl) ethyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 2).

Referring to example 1, intermediate 1-1 was replaced with its enantiomer to finally obtain the objective compound 2. LC-MS 564.34[ M +1 ]]⁺。

Example 3: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- (((R) -1-methylpyrrolidin-2-yloxy) methyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 3).

The procedure was carried out in accordance with the procedures described in example 1 to give the titled compound 3. LC-MS 566.32[ M +1 ]]⁺。

Example 4: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- (((S) -1-methylpyrrolidin-2-yloxy) methyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 4).

Referring to example 3, intermediate 3-1 was replaced with its enantiomer to finally obtain the objective compound 4. LC-MS 566.32[ M +1 ]]⁺。

Example 5: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- (2- ((R) -1-methylpyrrolidin-2-yloxy) ethyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 5).

Referring to example 3, intermediate 3-1 was replaced with 5-1 and the remaining steps are depicted as S2-S5 in example 3, to finally obtain the target compound 5. LC-MS 580.33[ M +1 ]]⁺。

Example 6: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- (2- ((S) -1-methylpyrrolidin-2-yloxy) ethyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 6).

Referring to example 5, intermediate 5-1 was replaced with its enantiomer to finally obtain the objective compound 6. LC-MS 580.33[ M +1 ]]⁺。

Example 7: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- (2- ((R) -tetrahydrofuran-3-yloxy) ethyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 7).

Referring to example 3, intermediate 3-1 was replaced with 7-1 to finally obtain the objective compound 7. LC-MS 567.30[ M +1 ]]⁺。

Example 8: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- (2- ((S) -tetrahydrofuran-3-yloxy) ethyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 8).

Referring to example 7, intermediate 7-3 was replaced with its enantiomer to finally obtain the objective compound 8. LC-MS 567.30[ M +1 ]]⁺。

Example 9: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- (2- ((R) -1-methylpyrrolidin-3-yloxy) ethyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 9).

Referring to example 3, intermediate 3-1 was replaced with 9-1 to finally obtain the objective compound 9. LC-MS 580.33[ M +1 ]]⁺。

Example 10: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- (2- ((S) -1-methylpyrrolidin-3-yloxy) ethyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 10).

Referring to example 9, intermediate 9-1 was replaced with its enantiomer to finally obtain the objective compound 10. LC-MS 580.33[ M +1 ]]⁺。

Example 11: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- (((R) -tetrahydrofuran-3-yloxy) methyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 11).

Referring to example 12, the target compound 11 was finally obtained using (R) -3-hydroxy-tetrahydrofuran as a starting material. LC-MS:553[ M + H]⁺；¹H NMR(400MHz,CDCl₃)δ7.73-7.60(m,2H),7.45-7.30(m,3H),7.25-7.18(m,2H),6.69-6.51(m,2H),6.40(d,J＝16.6Hz,1H),5.83(d,J＝10.2Hz,1H),5.14-5.00(m,1H),4.60-4.50(m,2H),4.40-4.27(m,2H),4.13(d,J＝13.7Hz,1H),3.96-3.82(m,5H),3.53-3.48(m,1H),3.28-3.05(m,3H),2.88-2.61(m,3H),2.19-1.94(m,2H),1.28-0.89(m,7H)。

Example 12: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- (((S) -tetrahydrofuran-3-yloxy) methyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 12).

Synthesis of intermediate 3: to a solution of 3-hydroxy-tetrahydrofuran (900mg,10.03mmol) in DMF (30mL) with stirring60% NaH (700mg,17.5mmol) was added, and the reaction mixture solution was stirred for 30 minutes. Then adding 2- (chloromethyl) -4-hydroxy-5, 8-dihydropyridine [3,4-d ] to the mixture]And pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (1g,3.34 mmol). After stirring the reaction mixture at room temperature for an additional 1 hour, the reaction mixture was diluted with about 100mL of water, adjusted to pH 7 with citric acid and extracted with DCM (100mL × 2). The organic layers were combined and then saturated with brine, anhydrous Na₂SO₄Drying, concentration under reduced pressure and chromatography on silica gel (eluent: ethyl acetate: petroleum ether from 0-30%) gave intermediate 3(600mg, 97% yield). LC-MS 352[ M + H ]]⁺。

Synthesis of intermediate 4: the intermediate 3(S) -4-hydroxy-2- (((tetrahydrofuran-3-yl) oxy) methyl) -5, 8-dihydropyridine [3,4-d]Pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (820mg,2.34mmol) was suspended in DCM (30mL) under nitrogen protection and to this was added DIPEA (910mg,7.02mmol) and trifluoromethanesulfonic anhydride (1.2g,4.67mmol) sequentially with stirring at 0 ℃. The reaction was stirred for about 1 hour and the reaction was concentrated to give intermediate 4 as a brown oil which was used in the next reaction without purification. LC-MS 484[ M + H ]]⁺。

Synthesis of intermediate 5: under the protection of nitrogen, tert-butyl (S) -2- (((tetrahydrofuran-3-yl) oxy) methyl) -4- (((trifluoromethyl) sulfonic acid) oxy) -5, 8-dihydropyridine [3,4-d]Pyrimidine-7 (6H) -carboxylic acid tert-butyl ester 4(250mg,0.52mmol), (S) -2- (cyanomethyl) piperidine-1-carboxylic acid benzyl ester (174mg,0.67mmol), DIPEA (135mg,1.04mmol) in CH₃CN (20mL) and heated to 90 ℃ to stir for 2 hours. After the reaction is complete, it is concentrated in vacuo and the residue is chromatographed on silica gel (eluent: MeOH: CH)₂Cl₂From 0-5%) gave intermediate 5 as a yellow solid (400mg crude). LC-MS 593[ M + H ]]⁺。

Synthesis of intermediate 6: to 4- ((S) -4- ((benzyloxy) carbonyl) -3- (cyanomethyl) piperazin-1-yl) -2- (((((S) -tetrahydrofuran-3-yl) oxy) methyl) -5, 8-dihydropyridine [3,4-d ] under ice bath]To a solution of pyrimidine-7 (6H) -carboxylic acid tert-butyl ester intermediate 5(400mg crude) in dichloromethane (10mL) was added TFA (10 mL). The reaction was stirred at 0 ℃ for 1 hour. The reaction mixture was poured into saturated NaHCO₃In solution. Extracting with dichloromethane for several times, combining organic layers, and collecting anhydrous Na₂SO₄Drying and concentration under reduced pressure gave intermediate 6 as a brown solid (400mg crude). LC-MS 493[ M + H ]]⁺。

Synthesis of intermediate 7: under the protection of nitrogen, (S) -2- (cyanomethyl) -4- (2- ((((S) -tetrahydrofuran-3-yl) oxy) methyl) -5,6,7, 8-tetrahydropyrido [3,4-d]Pyrimidin-4-yl) piperazine-1-carboxylic acid benzyl ester 6(400mg,0.82mmol) and 1-bromo-8-methylnaphthalene (290mg,1.30 mmol) in toluene (40mL) was added Cs₂CO₃(794mg,2.43mmol), Ruphos (100mg,0.21mmol) and Pd₂dba₃(100mg,0.11 mmol). The reaction mixture was warmed to reflux under nitrogen and stirred overnight. Filtering, concentrating the filtrate, and performing silica gel column chromatography (eluent: MeOH: CH)₂Cl₂From 0-10%) gave intermediate 7(300mg, 58% yield). LC-MS 633[ M + H ]]⁺。

Synthesis of intermediate 8: to (S) -2- (cyanomethyl) -4- (7- (8-methylnaphthalen-1-yl) -2- ((((S) -tetrahydrofuran-3-yl) oxy) methyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] under nitrogen]After 10% Pd/C (20mg) was added to a methanol solution (10mL) of benzyl pyrimidin-4-yl) piperazine-1-carboxylate 7(200mg,0.32mmol), the mixture was replaced with hydrogen, and the mixture was stirred under pressure with a hydrogen balloon at room temperature for about 2 hours, filtered, and the filtrate was concentrated to give intermediate 8(150mg, 99% yield) as a yellow solid. LC-MS 499[ M + H ]]⁺。

Synthesis of compound 12: to 2- ((S) -4- (7- (8-methylnaphthalen-1-yl) -2- (((((S) -tetrahydrofuran-3-yl) oxy) methyl) -5,6,7, 8-tetrahydropyrido [3, 4-d) was added under ice-bath]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile intermediate 8(150mg,0.31mmol) and DIPEA (104mg,0.8mmol) in dichloromethane (20mL) was added to a solution of acryloyl chloride (40mg,0.44mmol) in dichloromethane (1 mL). The reaction was stirred at 0 ℃ for 1 hour, then quenched by addition of saturated sodium carbonate solution and extracted with dichloromethane (100 mL. times.2). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating under reduced pressure to prepare a liquid phase to obtain 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalene-1-yl) -2- ((((S) -tetrahydrofuran-3-yl) oxy) methyl) -5,6,7, 8-tetrahydropyrido [3,4-d]Pyrimidin-4-yl) piperazin-2-yl) acetonitrile (compound 12) (47mg, 27% yield). LC-MS:553[ M + H]⁺；¹H NMR(400MHz,DMSO-d₆)δ8.32(d,J＝9.1Hz,1H),7.97-7.86(m,2H),7.60-7.47(m,3H),6.90-6.78(m,1H),6.16(d,J＝16.5Hz,1H),5.75(d,J＝16.5Hz,1H),4.94-4.73(m,1H),4.37-4.27(m,3H),4.28-4.25(m,1H),4.09(q,J＝13.0Hz,2H),3.91-3.88(m,1H),3.74-3.59(m,7H),3.09-2.95(m,2H),2.79-2.62(m,4H),2.08-1.80(m,4H),1.14-0.81(m,7H)。

Example 13: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- ((((S) -1-methylpyrrolidin-2-yl) methoxy) methyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 13).

Referring to example 12, (S) -1-methylpyrrol-2-ylmethanol was used as a starting material to finally obtain the objective compound 13(49mg, 22% yield). LC-MS 580[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d₆)δ7.78(d,J＝8.0Hz,1H),7.72-7.70(m,1H),7.50-7.44(m,1H),7.38-7.33(m,2H),7.27(d,J＝6.7Hz,1H),6.97-6.77(m,1H),6.21(d,J＝16.5Hz,1H),5.80(d,J＝16.8Hz,1H),4.99-4.79(m,1H),4.54-4.37(m,2H),4.09-3.96(m,3H),3.85-3.75(m,1H),3.65-3.59(m,2H),3.21-2.97(m,5H),2.92-2.80(m,5H),2.74-2.62(m,2H),2.45(s,3H),2.37-2.36(m,1H),1.99-1.88(m,1H),1.72-1.49(m,3H)。

Example 14: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- ((((R) -1-methylpyrrolidin-2-yl) methoxy) methyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 14).

Referring to example 13, (S) -1-methylpyrrol-2-ylmethanol was used as a starting material to finally obtain the objective compound 14. LC-MS 580[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d₆)δ7.77(d,J＝8.0Hz,1H),7.72-7.70(m,1H),7.50-7.44(m,1H),7.38-7.33(m,2H),7.29(d,J＝6.7Hz,1H),6.96-6.76(m,1H),6.21(d,J＝16.5Hz,1H),5.80(d,J＝16.8Hz,1H),4.99-4.80(m,1H),4.47-4.38(m,2H),4.10-3.98(m,3H),3.83-3.75(m,1H),3.58-3.53(m,2H),3.19-3.07(m,5H),2.93-2.80(m,5H),2.69-2.60(m,2H),2.45(s,3H),2.16-2.06(m,1H),1.88-1.77(m,1H),1.67-1.49(m,3H)。

Example 15: synthesis of 2- ((S) -1-acryloyl-4- (7- (8-methylnaphthalen-1-yl) -2- (((R) -1-methylpyrrolidin-3-yloxy) methyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-4-yl) piperazin-2-yl) acetonitrile (Compound 15).

Referring to example 12, (R) -1-methylpyrrole-3-ol was used as a starting material to finally obtain the objective compound 15 (22% yield). LC-MS 566[ M + H ]]⁺；¹H NMR(400MHz,DMSO-d₆)δ7.76(d,J＝8.1Hz,1H),7.71(dd,J＝7.7,4.5Hz,1H),7.49-7.43(m,1H),7.42-7.22(m,3H),6.96-6.77(brs,1H),6.19(d,J＝16.9Hz,1H),5.79(d,J＝11.9Hz,1H),4.97-4.87(brs,1H),4.52-4.49(m,2H),4.21-3.88(m,4H),3.79-3.73(m,2H),3.54-3.45(m,2H),3.19-3.00(m,5H),2.76-2.73(m,1H),2.22-2.19(m,1H),2.07-1.73(m,3H)。

Example 16: synthesis of Compound 16.

Referring to example 12, (R) -1-methylpyrrole-3-ol was used as a starting material to finally obtain the objective compound 16 (13% yield). LC-MS: [ M + H]⁺566；¹H NMR(400MHz,DMSO)δ8.37(s,1H),7.77-7.69(m,2H),7.49-7.44(m,1H),7.39-7.33(m,2H),7.28-7.26(m,1H),6.96-6.80(brs,1H),6.19(d,J＝16.7Hz,1H),5.78(d,J＝12.7Hz,1H),4.99-4.88(m,1H),4.46-4.39(m,1H),4.36-4.35(m,2H),4.20-4.16(m,1H),4.14-3.88(m,4H),3.83-3.73(m,1H),3.00(s,4H),2.87(s,3H),2.67-2.61(m,2H),2.35-2.30(m,1H),2.09-1.94(m,2H),1.77-1.62(m,1H)。

Example 17: synthesis of Compound 17.

Referring to example 3, intermediate 3-1 was replaced with 17-1 to finally obtain the objective compound 17. LC-MS 614.28[ M +1 ]]⁺。

Example 18: synthesis of Compound 18.

Referring to example 17, 17-1 was replaced with its enantiomer to finally obtain the objective compound 18. LC-MS 614.28[ M +1 ]]⁺。

Example 19: synthesis of Compound 19.

Referring to example 3, intermediate 3-1 was replaced with 19-1 and intermediate 3-5 was replaced with 1-bromo-2-methylbenzene to finally obtain the objective compound 19. LC-MS 530.28[ M +1 ]]⁺。

Example 20: synthesis of Compound 20.

Referring to example 3, intermediate 3-1 was replaced with 20-1 to finally obtain the objective compound 20. LC-MS 629.29[ M +1 ]]⁺。

Example 21: synthesis of Compound 21.

Referring to example 3, intermediate 21-1 was obtained. Dissolving the intermediate 21-1(5mmol) in dry DCM, cooling to 0 ℃, slowly adding the DCM solution of the intermediate 21-2 dropwise, reacting for 1 hour, and detecting the reaction completion by TLC. The reaction was quenched with water, concentrated, and separated by silica gel column chromatography to obtain the objective compound 21 (mobile phase: dichloromethane/methanol 3: 1). LC-MS 635.37[ M +1 ]]⁺。

Example 22: synthesis of Compound 22.

Referring to example 3 and example 21, intermediate 3-1 was replaced with its enantiomer to finally obtain the objective compound 22. LC-MS 635.37[ M +1 ]]⁺。

Example 23: synthesis of Compound 23.

Referring to example 3, intermediate 3-1 was replaced with 23-1 to finally obtain the objective compound 23. LC-MS 580.30[ M +1 ]]⁺。

Example 24: synthesis of compound 24.

Referring to example 23, intermediate 23-1 was replaced with its enantiomer to finally obtain the objective compound 24. LC-MS 580.30[ M +1 ]]⁺。

Example 25: synthesis of Compound 25.

Referring to example 3, intermediate 3-1 was replaced with 25-1 to finally obtain the objective compound 25. LC-MS 578.28[ M +1 ]]⁺。

Example 26: synthesis of compound 26.

Referring to example 25, intermediate 25-1 was replaced with its enantiomer to finally obtain the objective compound 26. LC-MS 578.28[ M +1 ]]⁺。

Example 27: synthesis of Compound 27.

Referring to example 3, intermediate 3-1 was replaced with 27-1 and intermediate 3-5 was replaced with 2-bromo-4-chloro-3-fluoroaniline, to finally obtain the objective compound 27. LC-MS 581.21[ M +1 ]]⁺。

Example 28: synthesis of Compound 28.

Referring to example 27, intermediate 27-1 was replaced with its enantiomer to finally obtain the objective compound 28. LC-MS 581.21[ M +1 ]]⁺。

Example 29: synthesis of Compound 29.

Referring to example 27, intermediate 27-5 was replaced with 29-5 (3-bromo-2-isopropyl-4-methylpyridine) to finally obtain the objective compound 29. LC-MS 571.31[ M +1 ]]⁺。

Example 30: synthesis of Compound 30.

Referring to example 29, intermediate 29-1 was replaced with its enantiomer to finally obtain the objective compound 30. LC-MS 571.31[ M +1 ]]⁺。

Example 31: synthesis of Compound 31.

Referring to example 3, intermediate 3-5 was replaced with 31-5 (1-bromo-2- (1-methylcyclopropyl) benzene) to finally obtain the objective compound 31. LC-MS 556.33[ M +1 ]]⁺。

Example 32: synthesis of Compound 32.

Referring to example 31, intermediate 31-1 was replaced with its enantiomer to finally obtain the objective compound 32. LC-MS 556.33[ M +1 ]]⁺。

Example 33: synthesis of Compound 33.

Referring to example 3, intermediate 3-5 was replaced with 33-5 (7-bromo-1-methyl-1H-indole) to finally obtain the objective compound 33. LC-MS 555.31[ M +1 ]]⁺。

Example 34: synthesis of compound 34.

Referring to example 33, intermediate 33-1 was replaced with its enantiomer to finally obtain the objective compound 34. LC-MS 555.31[ M +1 ]]⁺。

Example 35: synthesis of Compound 35.

Referring to example 3, intermediate 3-5 was replaced with 35-5 (7-bromo-1-methyl-1H-indazole) to finally obtain the objective compound 35. LC-MS 556.31[ M +1 ]]⁺。

Example 36: synthesis of Compound 36.

Referring to example 35, intermediate 35-1 was replaced with its enantiomer to finally obtain the objective compound 35. LC-MS 556.31[ M +1 ]]⁺。

Example 37: synthesis of Compound 37.

S1: DMF was added to the round bottom flask containing intermediates 37-1 and 37-2(1.1 eq.). Stirring deviceAnd (4) stirring to be clear, adding N, N-diisopropylethylamine, and reacting under stirring until the reaction is completely detected by TLC. Saturated aqueous NaCl solution was added, extracted 3 times with ethyl acetate, the organic phase was concentrated and separated by silica gel column chromatography to give intermediate 37-3 (mobile phase: dichloromethane/methanol ═ 3: 1). LC-MS 571.33[ M +1 ]]⁺。

S2: the intermediate 37-3 and 1-chloroethyl chloroformate (2eq.) were dissolved in 1, 2-dichloroethane, heated to 80 ℃ and stirred until the reaction was complete as detected by TLC. Cooled to room temperature, saturated aqueous NaCl solution was added, extracted 3 times with ethyl acetate, the organic phase was concentrated, and separated by silica gel column chromatography to give intermediate 37-4 (mobile phase: dichloromethane/methanol ═ 3: 1). LC-MS 481.28[ M +1 ]]⁺。

S3: intermediate 37-4, intermediate 37-5(1eq.), Pd₂(dba)₃(1%, w/w%), RuPhos (1%, w/w%) and Cs₂CO₃(1eq.) in toluene, purged with nitrogen and heated to 110 ℃. The reaction was completed by TLC, cooled to room temperature, the organic phase was concentrated and separated by silica gel column chromatography to give intermediate 37-6 (mobile phase: dichloromethane/methanol ═ 3: 1). LC-MS 611.34[ M +1 ]]⁺。

S4: dissolving the intermediate 37-6 in methanol, adding wet Pd/C (5%, w/w%), replacing with nitrogen for 3 times, adding hydrogen into a balloon, stirring at room temperature for reaction, and detecting by TLC to complete the reaction. The Pd/C was removed by filtration through celite, the celite was washed twice with ethyl acetate, and the reaction mixture was concentrated in vacuo. Without any purification, the target intermediate 37-7 was obtained in 90% yield. LC-MS 477.30[ M +1 ]]⁺。

S5: and dissolving the intermediate 37-7 in dry THF, cooling to 0 ℃, slowly dropwise adding acryloyl chloride, reacting for 1 hour, and detecting complete reaction by TLC. The reaction was quenched with water, concentrated, and separated by gel column chromatography to give the target compound 37 (mobile phase: dichloromethane/methanol ═ 3: 1). LC-MS 531.31[ M +1 ]]⁺。

Example 38: synthesis of compound 38.

Referring to example 37, intermediate 37-1 was replaced with its enantiomer and 37-2 was replaced with benzyl (3S,5R) -3, 5-dimethylpiperazine-1-carboxylate to finally obtain the objective compound 38. LC-MS 545.31[ M +1 ]]⁺。

Example 39: synthesis of Compound 39.

Referring to example 3, intermediate 3-1 was substituted for 39-1 to finally obtain the objective compound 39. LC-MS 602.30[ M +1 ]]⁺。

Example 40: synthesis of Compound 40.

Referring to example 39, 39-1 was replaced with its enantiomer to finally obtain the objective compound 39. LC-MS 602.30[ M +1 ]]⁺。

Example 41: synthesis of Compound 41.

Referring to example 3, intermediate 3-1 was replaced with 41-1 to finally obtain the objective compound 41. LC-MS 580.30[ M +1 ]]⁺。

Example 42: synthesis of Compound 42.

Referring to example 41, intermediate 41-1 was replaced with its enantiomer to finally obtain the objective compound 42. LC-MS 580.30[ M +1 ]]⁺。

Example 43: synthesis of Compound 43.

Referring to example 37, substitution of 37-2 with benzyl (2R,5S) -2, 5-dimethylpiperazine-1-carboxylate finally gave the title compound 43. LC-MS 545.33[ M +1 ]]⁺。

Example 44: synthesis of compound 44.

Referring to example 37, substitution of 37-1 for its enantiomer and 37-2 for benzyl (2S,5R) -2, 5-dimethylpiperazine-1-carboxylate finally gave the title compound 44. LC-MS 545.33[ M +1 ]]⁺。

Example 45: synthesis of Compound 45.

S1: intermediate 45-1, intermediate 45-2(1eq.), Pd₂(dba)₃(1%, w/w%), RuPhos (1%, w/w%) and Cs₂CO₃(1eq.) in toluene, purged with nitrogen and heated to 110 ℃. The reaction was completed by TLC, cooled to room temperature, the organic phase was concentrated and separated by silica gel column chromatography to give intermediate 45-3 (mobile phase: dichloromethane/methanol ═ 5: 1). LC-MS 602.34[ M +1 ]]⁺。

Subsequent steps refer to example 3 to finally obtain the target compound 45 (mobile phase: dichloromethane/methanol-3: 1). LC-MS 572.33[ M +1 ]]⁺。

Example 46: synthesis of compound 46.

Referring to example 3, intermediate 3-1 was replaced with 46-1, and 3-2 was replaced with 46-2 to finally obtain the objective compound 46. LC-MS 544.33[ M +1 ]]⁺。

Example 47: synthesis of Compound 47.

Referring to example 25, intermediate 25-5 was replaced with 1-bromo-3-chloro-2- (trifluoromethyl) benzene to finally obtain the objective compound 47. LC-MS 616.20[ M +1 ]]⁺。

Example 48: synthesis of Compound 48.

Referring to example 47, intermediate 47-1 was replaced with its enantiomer and 47-5 was replaced with 1-bromo-4-fluoro-2- (trifluoromethyl) benzene to finally obtain the objective compound 48. LC-MS 616.20[ M +1 ]]⁺。

Example 49: synthesis of Compound 49.

Referring to example 37, substitution of 37-2 with 49-2 and substitution of 37-5 with 8-bromo-2-naphthol finally gave the objective compound 49. LC-MS 568.30[ M +1 ]]⁺。

Example 50: synthesis of Compound 50.

Referring to example 49, 49-1 was replaced with its enantiomer and 49-5 was replaced with 5-bromoquinoline to finally obtain the objective compound 50. LC-MS 553.30[ M +1 ]]⁺。

Example 51: synthesis of Compound 51.

Referring to example 47, 47-5 was replaced with 1-bromo-2- (trifluoromethyl) benzene to finally obtain the objective compound 51. LC-MS 582.24[ M +1 ]]⁺。

Example 52: synthesis of Compound 52.

Referring to example 51, 51-1 was replaced with its enantiomer to finally obtain the objective compound 52. LC-MS 582.24[ M +1 ]]⁺。

Example 53: synthesis of Compound 53.

Referring to example 3, intermediate 3-5 was replaced with 4-bromo-1H-indazole to give the title compound 53. LC-MS 542.29[ M +1 ]]⁺。

Example 54: synthesis of Compound 54.

Referring to example 53, intermediate 53-1 was replaced with its enantiomer to finally obtain the objective compound 54. LC-MS 542.29[ M +1 ]]⁺。

Example 55: synthesis of Compound 55.

Referring to example 3, intermediate 3-1 was replaced with 55-1 to finally obtain the objective compound 55. LC-MS 569.34[ M +1 ]]⁺。

Example 56: synthesis of Compound 56.

Referring to example 55, intermediate 55-1 was replaced with its enantiomer to finally obtain the objective compound 56. LC-MS 569.34[ M +1 ]]⁺。

Example 57: synthesis of Compound 57.

Referring to example 3, intermediate 3-5 was replaced with 4-bromo-2-naphthol to finally obtain the objective compound 57. LC-MS 568.30[ M +1 ]]⁺。

Example 58: synthesis of Compound 57.

Referring to example 57, intermediate 57-1 was replaced with its enantiomer to finally obtain the objective compound 57. LC-MS 568.30[ M +1 ]]⁺。

Example 59: synthesis of Compound 59.

Referring to example 3, intermediate 3-1 was replaced with 59-1 to finally obtain the objective compound 59. LC-MS 592.33[ M +1 ]]⁺。

Example 60: synthesis of Compound 60.

Referring to example 59, intermediate 59-1 was replaced with its enantiomer to finally obtain the objective compound 60. LC-MS 592.33[ M +1 ]]⁺。

Example 61: synthesis of Compound 61.

Referring to example 3, intermediate 3-1 was replaced with 61-1 to finally obtain the objective compound 61. LC-MS 634.30[ M +1 ]]⁺。

Example 62: synthesis of compound 62.

Referring to example 61, intermediate 61-1 was replaced with its enantiomer to finally obtain the objective compound 62. LC-MS 634.30[ M +1 ]]⁺。

Example 63: synthesis of Compound 63.

Referring to example 3, intermediate 3-5 was replaced with 1-bromo-8-chloronaphthol to finally obtain the objective compound 63. LC-MS 586.26[ M +1 ]]⁺。

Example 64: synthesis of Compound 64.

Referring to example 63, intermediate 63-1 was replaced with its enantiomer to finally obtain the objective compound 64. LC-MS 586.26[ M +1 ]]⁺。

Example 65: synthesis of Compound 65.

Referring to example 3, the intermediate 3-5 was replaced with 1-bromonaphthol to finally obtain the objective compound 65. LC-MS 552.30[ M +1 ]]⁺。

Example 66: synthesis of Compound 65.

Referring to example 65, intermediate 65-1 was replaced with its enantiomer to finally obtain the objective compound 66. LC-MS 552.30[ M +1 ]]⁺。

Example 67: synthesis of Compound 67.

Referring to example 3, intermediate 3-5 was replaced with 1-bromo-2- (trifluoromethyl) benzene to finally obtain the objective compound 67. LC-MS 570.27[ M +1 ]]⁺。

Example 68: synthesis of compound 68.

Referring to example 67, intermediate 67-1 was replaced with its enantiomer to finally obtain the objective compound 68. LC-MS 570.27[ M +1 ]]⁺。

Example 69: synthesis of Compound 69.

Referring to example 3, intermediates 3-5 were replaced with 1-bromo-3-fluoro-2- (trifluoromethyl) benzene to give the title compound 69. LC-MS 588.26[ M +1 ]]⁺。

Example 70: synthesis of Compound 70.

Referring to example 69, intermediate 69-1 was replaced with its enantiomer to finally obtain the objective compound 70. LC-MS 588.26[ M +1 ]]⁺。

Example 71: synthesis of Compound 71.

Referring to example 3, intermediate 3-5 was replaced with 4-bromo-5, 6-dimethyl-1H-indazole to give the title compound 71. LC-MS 570.32[ M +1 ]]⁺。

Example 72: synthesis of compound 72.

Referring to example 71, intermediate 71-1 was replaced with itEnantiomer, finally obtaining the target compound 72. LC-MS 570.32[ M +1 ]]⁺。

Example 73: synthesis of Compound 73.

Referring to example 3, intermediate 3-5 was replaced with 1-bromo-8-chlorophenol and acryloyl chloride was replaced with 2-fluoroacryloyl chloride to finally obtain the objective compound 73. LC-MS 604.25[ M +1 ]]⁺。

Example 74: synthesis of Compound 74.

Referring to example 73, intermediate 73-1 was replaced with its enantiomer to finally obtain the objective compound 74. LC-MS 604.25[ M +1 ]]⁺。

Example 75: synthesis of compound 75.

Referring to example 3, the corresponding intermediate was modified to finally obtain the target compound 75. LC-MS 602.30[ M +1 ]]⁺。

Example 76: synthesis of Compound 76.

Referring to example 75, intermediate 75-1 was replaced with its enantiomer to finally obtain the objective compound 76. LC-MS 602.30[ M +1 ]]⁺。

Example 77: synthesis of Compound 77.

Referring to example 3, the corresponding intermediate was modified to finally obtain the objective compound 77. LC-MS 541.32[ M +1 ]]⁺。

Example 78: synthesis of compound 78.

Referring to example 77, intermediate 77-1 was replaced with its enantiomer to finally obtain the objective compound 78. LC-MS 541.32[ M +1 ]]⁺。

Example 79: synthesis of Compound 79.

Referring to example 3, the corresponding intermediate was modified to finally obtain the objective compound 79. LC-MS 442.25[ M +1 ]]⁺。

Example 80: synthesis of Compound 80.

Referring to example 3, the corresponding intermediate was modified to finally obtain the target compound 80. LC-MS 513.34[ M +1 ]]⁺。

Example 81: synthesis of Compound 81.

Referring to example 3, the corresponding intermediate was modified to finally obtain the objective compound 81. LC-MS 594.35[ M +1 ]]⁺。

Example 82: synthesis of Compound 82.

Referring to example 81, intermediate 81-1 was replaced with its enantiomer to finally obtain the objective compound 82. LC-MS 594.35[ M +1 ]]⁺。

Example 83: synthesis of Compound 83.

Referring to example 3, the corresponding intermediate was modified to finally obtain the objective compound 83. LC-MS 454.29[ M +1 ]]⁺。

Example 84: synthesis of compound 84.

Referring to example 83, intermediate 83-1 was replaced with its enantiomer to finally obtain the objective compound 84. LC-MS 454.29[ M +1 ]]⁺。

Example 85: synthesis of Compound 85.

Referring to example 3, the corresponding intermediate was modified to finally obtain the target compound 85. LC-MS 548.36[ M +1 ]]⁺。

Example 86: synthesis of Compound 86.

Referring to example 85, intermediate 85-1 was replaced with its enantiomer to finally obtain the objective compound 86. LC-MS 548.36[ M +1 ]]⁺。

Example 87: synthesis of Compound 87.

Referring to example 3, the corresponding intermediate was modified to finally obtain the objective compound 87. LC-MS 584.33[ M +1 ]]⁺。

Example 88: synthesis of compound 88.

Referring to example 87, intermediate 87-1 was replaced with its enantiomer to finally obtain target compound 88. LC-MS 584.33[ M +1 ]]⁺。

Example 89: synthesis of Compound 89.

Referring to example 3, the corresponding intermediate was modified to finally obtain the target compound 89. LC-MS 556.30[ M +1 ]]⁺。

Example 90: synthesis of Compound 90.

Referring to example 89, intermediate 89-1 was replaced with its enantiomer to finally obtain the objective compound 90. LC-MS 556.30[ M +1 ]]⁺。

Example 91: synthesis of Compound 91.

Referring to example 3, the corresponding intermediate was modified to finally obtain the target compound 91. LC-MS 559.34[ M +1 ]]⁺。

Example 92: synthesis of Compound 92.

Referring to example 3, intermediate 3-5 was replaced with 92-5 to finally obtain the objective compound 92. LC-MS 592.33[ M +1 ]]⁺。

Example 93: synthesis of compound 93.

Referring to example 92, intermediate 92-5 was replaced with 5-bromo-1, 2,3, 4-tetrahydrophenanthrene to finally obtain target compound 93. LC-MS 606.35[ M +1 ]]⁺。

Example 94: synthesis of Compound 94.

Referring to example 3, intermediate 3-1 was replaced with its enantiomer and 3-5 was replaced with 4-bromo-2-naphthol to finally obtain the objective compound 94. LC-MS 568.30[ M +1 ]]⁺。

Example 95: synthesis of Compound 95.

Referring to example 3, intermediate 3-5 was replaced with 4-bromo-2-naphthol to finally obtain the objective compound 94. LC-MS 568.30[ M +1 ]]⁺。

Example 96: synthesis of Compound 96.

Referring to example 3, intermediate 3-5 was replaced with 1, 2-dibromo-4-fluorobenzene to finally obtain the objective compound 96. LC-MS 598.19[ M +1 ]]⁺。

Example 97: synthesis of Compound 97.

Referring to example 3, intermediate 3-1 was replaced with its enantiomeric form, and intermediate 3-5 was replaced with 1, 2-dibromo-4-fluorobenzene, to finally obtain target compound 97. LC-MS 598.19[ M +1 ]]⁺。

Example 98: synthesis of Compound 98.

Referring to example 3, intermediate 3-1 was replaced with its enantiomeric form and intermediate 3-5 was replaced with 1-bromo-4-fluoro-2-trifluoromethylbenzene to finally obtain the objective compound 98. LC-MS 588.26[ M +1 ]]⁺。

Example 99: synthesis of Compound 99.

Referring to example 3, intermediate 3-5 was replaced with 1-bromo-4-fluoro-2-trifluoromethylbenzene to finally obtain the objective compound 99. LC-MS 588.26[ M +1 ]]⁺。

Example 100: synthesis of compound 100.

Referring to example 3, intermediates 3-5 were replaced with 1-bromo-8-chloronaphthalene to finally obtain the objective compound 100. LC-MS 586.26[ M +1 ]]⁺。

Example 101: synthesis of compound 101.

Referring to example 3, intermediate 3-1 was replaced with its enantiomeric form and intermediate 3-5 was replaced with 1-bromo-8-chloronaphthalene to finally obtain the objective compound 101. LC-MS 586.26[ M +1 ]]⁺。

Example 102: synthesis of compound 102.

Referring to example 3, intermediate 3-5 was replaced with 4-bromo-5, 6-dimethyl-1H-indazole to give the title compound 102. LC-MS 570.32[ M +1 ]]⁺。

Example 103: synthesis of compound 103.

Referring to example 3, intermediate 3-1 was replaced with its enantiomeric form and intermediate 3-5 was replaced with 4-bromo-5, 6-dimethyl-1H-indazole, to give the title compound 103. LC-MS 570.32[ M +1 ]]⁺。

Example 104: synthesis of compound 104.

Referring to example 3, intermediate 3-5 was replaced with 1-bromo-2, 3-dimethylbenzene to finally obtain the objective compound 104. LC-MS 530.32[ M +1 ]]⁺。

Example 105: synthesis of compound 105.

Referring to example 3, intermediate 3-1 was replaced with its enantiomeric form,and replacing the intermediate 3-5 with 1-bromo-2, 3-dimethylbenzene to finally obtain the target compound 105. LC-MS 530.32[ M +1 ]]⁺。

Example 106: synthesis of compound 106.

Referring to example 3, intermediate 3-1 was replaced with 106-1, and 3-5 was replaced with 4-bromo-2-naphthol, to finally obtain the objective compound 106. LC-MS 594.31[ M +1 ]]⁺。

Example 107: synthesis of compound 107.

Referring to example 106, intermediate 106-1 was replaced with its enantiomer to finally obtain the objective compound 107. LC-MS 594.31[ M +1 ]]⁺。

Example 108: synthesis of compound 108.

Referring to example 106, intermediate 106-5 was replaced with 1-bromo-8-methylnaphthalene to finally obtain the objective compound 108. LC-MS 592.33[ M +1 ]]⁺。

Example 109: synthesis of compound 109.

Referring to example 106, intermediate 106-1 was replaced with its enantiomer and intermediate 106-5 was replaced with 1-bromo-8-methylnaphthalene to finally obtain the objective compound 109. LC-MS 592.33[ M +1 ]]⁺。

Example 110: synthesis of compound 110.

Referring to example 106, intermediate 106-5 was replaced with 1-bromo-8-chloronaphthalene to finally obtain the objective compound 110. LC-MS 612.28[ M +1 ]]⁺。

Example 111: synthesis of compound 111.

Referring to example 106, intermediate 106-1 was replaced with its enantiomer and intermediate 106-5 was replaced with 1-bromo-8-chloronaphthalene to finally obtain the objective compound 111. LC-MS 612.28[ M +1 ]]⁺。

Example 112: synthesis of compound 112.

Referring to example 56, intermediate 56-5 was replaced with 1-bromo-8-chloronaphthalene to giveA target compound 112. LC-MS 589.28[ M +1 ]]⁺。

Example 113: synthesis of Compound 113.

Referring to example 55, intermediate 55-5 was replaced with 1-bromo-8-chloronaphthalene to finally obtain the objective compound 111. LC-MS 589.28[ M +1 ]]⁺。

Example 114: synthesis of compound 114.

Referring to example 3, intermediate 3-1 was replaced with its enantiomeric form and compound 3-5 was replaced with 1-bromo-8- (trideuteromethyl) naphthalene to finally obtain the objective compound 114. LC-MS 569.34[ M +1 ]]⁺。

Example 115: synthesis of compound 115.

Referring to example 3, intermediate 3-5 was replaced with 1-bromo-8- (trideuteromethyl) naphthalene to finally obtain the objective compound 115. LC-MS 569.34[ M +1 ]]⁺。

Example 116: synthesis of compound 116.

Referring to example 3, intermediate 3-1 was replaced with its enantiomeric form and 3-5 was replaced with 1-bromo-2- (1-methylcyclopropyl) benzene to finally obtain the objective compound 116. LC-MS 556.33[ M +1 ]]⁺。

Example 117: synthesis of Compound 117.

Referring to example 3, intermediate 3-5 was replaced with 1-bromo-2- (1-methylcyclopropyl) benzene to finally obtain the objective compound 117. LC-MS 556.33[ M +1 ]]⁺。

Example 118: synthesis of compound 118.

Referring to example 3, intermediate 3-5 was replaced with 4-bromo-5-methylisoquinoline to finally obtain the objective compound 118. LC-MS 567.31[ M +1 ]]⁺。

Example 119: synthesis of compound 119.

Referring to example 3, intermediate 3-1 was replaced with its enantiomer and 3-5 was replaced with 4-bromo-5-methylisoquinoline to finally obtain the objective compound 119. LC-MS 567.31[ M +1 ]]⁺。

Example 120: synthesis of compound 120.

Referring to example 3, acryloyl chlorideReplacing the compound with 2-fluoro acryloyl chloride to finally obtain the target compound 120. LC-MS 584.31[ M +1 ]]⁺。

Example 121: synthesis of compound 121.

Referring to example 3, intermediate 3-1 was replaced with its enantiomer and acryloyl chloride was replaced with 2-fluoroacryloyl chloride to give the target compound 121. LC-MS 584.31[ M +1 ]]⁺。

Example 122: synthesis of compound 122.

Referring to example 3, acryloyl chloride was replaced with (E) -4,4, 4-trifluoro-2-butenoyl chloride to finally obtain the objective compound 122. LC-MS 634.30[ M +1 ]]⁺。

Example 123: synthesis of Compound 123.

Referring to example 3, intermediate 3-1 was replaced with its enantiomer and acryloyl chloride was replaced with (E) -4,4, 4-trifluoro-2-butenoyl chloride to finally obtain the objective compound 123. LC-MS 634.30[ M +1 ]]⁺。

Example 124: synthesis of compound 124.

Referring to example 3, acryloyl chloride was replaced with 2- (trifluoromethyl) acryloyl chloride to finally obtain the target compound 124. LC-MS 634.30[ M +1 ]]⁺。

Example 125: synthesis of compound 125.

Referring to example 3, intermediate 3-1 was replaced with its enantiomer and acryloyl chloride was replaced with 2- (trifluoromethyl) acryloyl chloride to finally obtain the target compound 125. LC-MS 634.30[ M +1 ]]⁺。

Example 126: synthesis of compound 126.

Referring to example 3, the intermediate 3-5 was replaced with 1-bromo-8-chloronaphthalene and acryloyl chloride was replaced with 2-fluoroacryloyl chloride to finally obtain the objective compound 126. LC-MS 604.25[ M +1 ]]⁺。

Example 127: synthesis of compound 127.

Referring to example 3, the intermediate 3-1 was replaced with its enantiomer, 3-5 was replaced with 1-bromo-8-chloronaphthalene, and acryloyl chloride was replaced with 2-fluoroacryloyl chloride, to finally obtain the objective compound 127. LC-MS 604.25[ M +1 ]]⁺。

Example 128: synthesis of compound 128.

Referring to example 3, the intermediate 3-5 was replaced with 1-bromo-8-chloronaphthalene and acryloyl chloride was replaced with (E) -4,4, 4-trifluoro-2-butenoyl chloride to finally obtain the objective compound 128. LC-MS 654.25[ M +1 ]]⁺。

Example 129: synthesis of compound 129.

Referring to example 3, intermediate 3-1 was replaced with its enantiomer, 3-5 was replaced with 1-bromo-8-chloronaphthalene, and acryloyl chloride was replaced with (E) -4,4, 4-trifluoro-2-butenoyl chloride to finally obtain the objective compound 129. LC-MS 654.25[ M +1 ]]⁺。

Example 130: synthesis of compound 130.

Referring to example 3, intermediates 3 to 5 were replaced with 1-bromo-8-chloronaphthalene and acryloyl chloride was replaced with 2- (trifluoromethyl) acryloyl chloride to finally obtain the target compound 130. LC-MS 654.25[ M +1 ]]⁺。

Example 131: synthesis of compound 131.

Referring to example 3, the intermediate 3-1 was replaced with its enantiomer, 3-5 was replaced with 1-bromo-8-chloronaphthalene, and acryloyl chloride was replaced with 2- (trifluoromethyl) acryloyl chloride, to finally obtain the target compound 131. LC-MS 654.25[ M +1 ]]⁺。

Example 132: synthesis of compound 132.

Referring to example 3, the intermediate 3-5 was replaced with 4-bromo-2-naphthol, and acryloyl chloride was replaced with 2-fluoroacryloyl chloride, to finally obtain the objective compound 132. LC-MS 586.29[ M +1 ]]⁺。

Example 133: synthesis of compound 133.

Referring to example 3, the intermediate 3-1 was replaced with its enantiomer, 3-5 was replaced with 4-bromo-2-naphthol, and acryloyl chloride was replaced with 2-fluoroacryloyl chloride, to finally obtain the objective compound 133. LC-MS 586.29[ M +1 ]]⁺。

Example 134: synthesis of compound 134.

Referring to example 3, intermediates 3-5 were replaced with 4-bromo-2-naphthol and acryloyl chloride was replaced with (E) -4,4, 4-trifluoro-2-butenoyl chlorideAnd finally obtaining the target compound 134. LC-MS 636.28[ M +1 ]]⁺。

Example 135: synthesis of compound 135.

Referring to example 3, intermediate 3-1 was replaced with its enantiomer, 3-5 was replaced with 4-bromo-2-naphthol, and acryloyl chloride was replaced with (E) -4,4, 4-trifluoro-2-butenoyl chloride, to finally obtain the objective compound 135. LC-MS 636.28[ M +1 ]]⁺。

Example 136: synthesis of compound 136.

Referring to example 3, the intermediate 3-5 was replaced with 4-bromo-2-naphthol, and acryloyl chloride was replaced with 2- (trifluoromethyl) acryloyl chloride, to finally obtain the objective compound 136. LC-MS 636.28[ M +1 ]]⁺。

Example 137: synthesis of Compound 137.

Referring to example 3, the intermediate 3-1 was replaced with its enantiomer, 3-5 with 4-bromo-2-naphthol, and acryloyl chloride with 2- (trifluoromethyl) acryloyl chloride, to finally obtain the objective compound 137. LC-MS 636.28[ M +1 ]]⁺。

Example 138: synthesis of compound 138.

Referring to example 3, the target compound 138 was finally obtained by replacing acryloyl chloride with 2-fluoroacryloyl chloride. LC-MS 584.31[ M +1 ]]⁺。

Example 139: synthesis of compound 139.

Referring to example 3, intermediate 3-1 was replaced with its enantiomer and acryloyl chloride was replaced with 2-fluoroacryloyl chloride to give the title compound 139. LC-MS 584.31[ M +1 ]]⁺。

Example 140: synthesis of compound 140.

Referring to example 3, the intermediate 3-5 was replaced with 1-bromo-8-chloronaphthalene and acryloyl chloride was replaced with 2-fluoroacryloyl chloride to finally obtain the objective compound 140. LC-MS 604.25[ M +1 ]]⁺。

Example 141: synthesis of Compound 141.

Referring to example 3, intermediate 3-1 was replaced with its enantiomer, 3-5 was replaced with 1-bromo-8-chloronaphthalene, acryloyl chloride was replaced with 2-fluoroacryloyl chloride, and the mostThe target compound 141 is finally obtained. LC-MS 604.25[ M +1 ]]⁺。

Example 142: synthesis of compound 142.

Referring to example 3, the intermediate 3-5 was replaced with 4-bromo-2-naphthol, and acryloyl chloride was replaced with 2-methacryloyl chloride, to finally obtain the objective compound 142. LC-MS 582.31[ M +1 ]]⁺。

Example 143: synthesis of compound 143.

Referring to example 3, the intermediate 3-1 was replaced with its enantiomer, 3-5 was replaced with 1-bromo-3-chloronaphthalene, and acryloyl chloride was replaced with 2-fluoroacryloyl chloride, to finally obtain the target compound 143. LC-MS 604.25[ M +1 ]]⁺。

Example 144: synthesis of compound 144.

Referring to example 3, acryloyl chloride was replaced with (E) -4-fluoro-2-butenoyl chloride to finally obtain the objective compound 145. LC-MS 598.32[ M +1 ]]⁺。

Example 145: synthesis of Compound 145.

Referring to example 3, intermediate 3-1 was replaced with its enantiomer and acryloyl chloride was replaced with (E) -4-fluoro-2-butenoyl chloride to finally obtain the objective compound 145. LC-MS 598.32[ M +1 ]]⁺。

Example 146: synthesis of compound 146.

Referring to example 3, the intermediate 3-5 was replaced with 1-bromo-8-chloronaphthalene and acryloyl chloride was replaced with (E) -4-fluoro-2-butenoyl chloride to finally obtain the objective compound 146. LC-MS 618.27[ M +1 ]]⁺。

Example 147: synthesis of compound 147.

Referring to example 3, the intermediate 3-1 was replaced with its enantiomer, 3-5 was replaced with 1-bromo-8-chloronaphthalene, and acryloyl chloride was replaced with (E) -4-fluoro-2-butenoyl chloride, to finally obtain the objective compound 147. LC-MS 618.27[ M +1 ]]⁺。

Example 148: synthesis of compound 148.

Referring to example 3, the intermediate 3-5 was replaced with 4-bromo-2-naphthol, and acryloyl chloride was replaced with (E) -4-fluoro-2-butenoyl chloride, to finally obtain the objective compound 148. LC-MS 600.30[M+1]⁺。

Example 149: synthesis of Compound 149.

Referring to example 3, the intermediate 3-1 was replaced with its enantiomer, 3-5 with 4-bromo-2-naphthol, and acryloyl chloride with (E) -4-fluoro-2-butenoyl chloride, to finally obtain the objective compound 149. LC-MS 600.30[ M +1 ]]⁺。

Example 150: synthesis of compound 150.

Referring to example 3, acryloyl chloride was replaced with (E) -4- (cyclopropylamino) -2-butenoyl chloride to finally obtain the objective compound 150. LC-MS 635.37[ M +1 ]]⁺。

Example 151: synthesis of compound 151.

Referring to example 3, intermediate 3-1 was replaced with its enantiomer and acryloyl chloride was replaced with (E) -4- (cyclopropylamino) -2-butenoyl chloride to finally obtain the objective compound 151. LC-MS 635.37[ M +1 ]]⁺。

Example 152: synthesis of compound 152.

Referring to example 3, acryloyl chloride was replaced with (E) -4- (cyclopropylamino) -2-butenoyl chloride and intermediate 3-5 was replaced with 1-bromo-8-chloronaphthalene to give the title compound 152. LC-MS 655.32[ M +1 ]]⁺。

Example 153: synthesis of compound 153.

Referring to example 3, intermediate 3-1 was replaced with its enantiomer, acryloyl chloride was replaced with (E) -4- (cyclopropylamino) -2-butenoyl chloride, intermediate 3-5 was replaced with 1-bromo-8-chloronaphthalene, and the title compound 153 was finally obtained. LC-MS 655.32[ M +1 ]]⁺。

Example 154: synthesis of compound 154.

Referring to example 3, acryloyl chloride was replaced with (E) -4- (cyclopropylamino) -2-butenoyl chloride and intermediate 3-5 was replaced with 4-bromo-2-naphthol, to finally obtain the objective compound 154. LC-MS 637.35[ M +1 ]]⁺。

Example 155: synthesis of Compound 155.

Referring to example 3, intermediate 3-1 was replaced with its enantiomer and acryloyl chloride was replaced with (E) -4- (cyclopropyl)Amino) -2-butenoyl chloride, and the intermediate 3-5 is replaced with 4-bromo-2-naphthol to finally obtain the target compound 155. LC-MS 637.35[ M +1 ]]⁺。

Experimental example 1: ERK protein phosphorylation assay.

To examine the inhibitory activity of the compounds of the present invention on KRAS G12C protein at the cellular level, the ERK protein phosphorylation assay was selected for evaluation.

H358 cells (ATCC, CRL-5807) expressing KRAS G12C protein were seeded at a concentration of 6000 cells/well in polylysine-coated 384-well cell culture plates (Corning, BD356663) composed of RPMI 1640(Gibco, A10491-01), 10% FBS (Gibco, 10099141C) and 1% Pen/Strep (Gibco, 15140-₂Culturing for 16h in a cell culture box; adding the compound diluted in the gradient into a cell culture medium by using Echo550, wherein the final concentration of DMSO is 0.5%, and continuously culturing for 3 hours; then 40. mu.L/well of 8% paraformaldehyde (Solambio, P1112) was added and incubated at room temperature for 20 min; washing with PBS once, adding 40 μ L/cold 100% methanol, and percolating at room temperature for 10 min; after PBS is washed once, 20 mu L/hole of sealing liquid (LI-COR, 927-; then, rabbit anti-phospho-p 44/42MAPK (T202/Y204) antibody (CST, 4370S) was diluted 1:1000 with blocking solution, mouse anti-GAPDH (D4℃ 6R) antibody (CST, 97166S) was diluted 1:2000, added to the cells at 20. mu.L/well, and blocked at 4 ℃ overnight; PBST washing 3 times, each time of 2min incubation, after that using the blocking solution according to 1:1000 dilution of goat anti-rabbit 800CW antibody (LI-COR, 926 and 32211) and goat anti-mouse 680RD antibody (LI-COR, 926 and 68070), according to 20 u L/hole added to the cells, at room temperature for 45min incubation; PBST washing 3 times, each time incubated for 2min, the cell culture plate was inverted and centrifuged, 1000rpm, 1min later, and the fluorescence signal value was read with Odyssey CLx.

Data are represented by XLFit 5.0 according to the 4-parameter formula Y ═ Bottom + (Top-Bottom)/(1+10^ ((Logicc)₅₀-X) HillSlope)) fit calculation IC₅₀The results are shown in Table 1. "A" is IC₅₀<1 mu M; "B" is IC₅₀≥1μM；

TABLE 1 inhibition of KRAS Gl2C protein-mediated downstream signaling (p-ERK) phosphorylation Activity results

As can be seen from the data in the table, most of the compounds of the invention can effectively inhibit KRAS G12C protein-mediated phosphorylation of H358 cell downstream signal (p-ERK), and can be used as KRAS G12C protein inhibitors.

Experimental example 2: tumor cell in-vitro 3D culture cell proliferation inhibition test.

To investigate the antitumor activity of the compounds of the present invention, we tested the proliferation inhibitory activity of representative compounds of the present invention on KRAS G12C mutant tumor cell H358.

1) Reagent, consumables and equipment information:

2) cell culture:

a) on day 1, seed cells were placed in T75 flasks.

b) On day 3, the medium was removed and washed once with DPBS.

c) At Room Temperature (RT) or 37 ℃ with 2mL TrypLE^TMExpress enzyme Trpsinize cells until they detach.

d) 5mL of fresh medium was added, the cells were suspended, and then centrifuged at 1000rpm for 5 minutes at room temperature.

e) The supernatant was discarded and the cells were resuspended in 5mL of fresh medium and passed through Countess^TMII, counting the cells.

f) The cells were seeded back into T75 flasks for further culture or placed into assay plates for 3D cell proliferation assays.

3)3D cell proliferation assay protocol:

a) day 1. 200nl of diluted compound (test compound starting at 1uM concentration, 3-fold gradient dilution) was added to each well using Echo. The cells were plated at a density of 600 cells/well in 384-well plates at 40. mu.l medium per well and a final DMSO concentration of 0.5%.

b) Day 4. To each well was added 3D CTG reagent, shaken at room temperature for 1 h.

c) Recording signals using Envision

4) And (3) data analysis:

a) test robustness check was performed using 0.5% DMSO and media blank control data:

h ═ mean (DMSO); l ═ mean (medium);

SD(H)＝STDEV(DMSO)；SD(L)＝STDEV(Medium)；

CV% (DMSO) ═ 100 (SD DMSO/mean DMSO);

CV% (medium) ═ 100 × (SD medium/mean medium);

S/B-mean DMSO/mean medium;

z' ═ 1-3 (SD DMSO + SD medium)/(mean DMSO-mean medium);

cell viability inhibition,% (mean _ H-sample)/(mean _ H-mean _ L) x 100;

b) cpd IC50 was fitted according to a nonlinear regression equation:

y ═ peak-to-valley value + (peak-to-valley value)/(1 +10^ ((LogIC50-X) × HillSlope));

x: the logarithm of compound concentration;

y: percent inhibition (% inh);

peak top and peak bottom: the plateau period unit is the same as Y;

logIC 50: the same logarithmic unit as X;

HillSlope: gradient coefficient or Hill gradient;

4) the results are summarized in table 2.

TABLE 2 inhibition of H358 tumor cell proliferation by test compounds

Claims

1. A compound having the structure of formula I:

X₀is-CH ═ CR₃or-N ═ or;

n, m, p and q are each independently 0, 1 or 2.

2. The compound of claim 1 having the structure of formula I, which is a compound having the structure of formula IA:

wherein:

X₀is-CH ═ CH-CR₃or-N ═ or;

n, m, p and q are each independently 0, 1 or 2.

3. The compound having the structure of formula I according to claim 1 or 2, which is a compound having the structure of formula IB:

wherein:

X₀is-CH ═ CR₃or-N ═ or;

n, m, p and q are each independently 0, 1 or 2.

4. A compound having the structure of formula I according to claim 1 or 2, which is a compound having the structure of formula IC:

wherein:

X₀is-CH ═ CR₃or-N ═ or;

each R₁And R₃Each independently is alkyl, heteroAlkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spiro, heterospiro, bridged, heterobridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl or alkoxy; and R is₁And R₃Hydrogen in the structure is optionally substituted with 0 to more than one R₇Substitution;

R₄、R₅and R₇Each independently hydrogen, deuterium, halogen, alkyl, haloalkyl, amino, hydroxy, alkylaminoalkyl, cycloalkylaminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spiro, hetero-spiro, bridged, hetero-bridged, aryl, arylalkyl, arylalkenyl, arylalkynyl, amido, sulfonamido, sulfamoylamino, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH)₂)_qSF₅Alkylsulfonyl, alkylphosphoryl, hypophosphoryl, - (CH)₂)_qNHSO₂NH₂Heterocycloalkyloxy, alkylamido, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylaminocarbonyl, aminoacyl, alkylsulfonamido or cyano; and R is₄、R₅And R₇Hydrogen in the structure is optionally substituted by 1 to more substituentsEach of said substituents is independently deuterium, halogen, alkoxy, hydroxy, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido or cyano;

n, m, p and q are each independently 0, 1 or 2.

5. A compound having the structure of formula I according to any one of claims 1,2 and 3, which is a compound having the structure of formula ID:

wherein:

X₀is-CH ═ CR₃or-N ═ or;

X₁and X₂Each independently is-CH₂-、-CHR₃-、-C(＝O)-、-C(R₃)₂-, -NH-, -CH-or-CH₂CH₂-；

each R₂And R₆Each independently is hydrogen, deuterium, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, cyano, cyanoalkyl, alkoxyalkyl, alkylaminoalkyl, acyl, substituted acyl, sulfonyl, amino, alkoxy, alkylamino, hydroxy, haloalkyl or halogenAn alkoxy group; when two R are₂And/or two R's bound to the same carbon atom₆When both are hydroxyl, the two hydroxyl groups, after dehydration, together with the carbon atoms to which they are attached, form C ═ O; when two R are₂And/or two R's bound to the same carbon atom₆When one is hydroxy and the other is amino, the hydroxy and amino groups are dehydrated to form C ═ NH together with the carbon atom to which they are attached; and R is₂And R₆Hydrogen in the structure is optionally substituted with deuterium, halogen, alkynyl, cyano, amino, hydroxy or alkoxy;

n, m, p and q are each independently 0, 1 or 2.

6. A compound having the structure of formula I according to any one of claims 1,2 and 4, which is a compound having the structure of formula IE:

wherein:

X₀is-CH ═ CR₃or-N ═ or;

each R₂And R₆Each independently is hydrogen, deuterium, halogen, alkyl, cycloalkyl, alkenyl, alkynyl, cyano, cyanoalkyl, alkoxyalkyl, alkylaminoalkyl, acyl, substituted acyl, sulfonyl, amino, alkoxy, alkylamino, hydroxy, haloalkyl or haloalkoxy; when two R are₂And/or two R's bound to the same carbon atom₆When both are hydroxyl, the two hydroxyl groups, after dehydration, together with the carbon atoms to which they are attached, form C ═ O; when two R are₂And/or two R's bound to the same carbon atom₆One is hydroxy and the other is amino, said hydroxy and amino groups being dehydrated together with the carbon atom one attached theretoForm C ═ NH; and R is₂And R₆Hydrogen in the structure is optionally substituted with deuterium, halogen, alkynyl, cyano, amino, hydroxy or alkoxy;

n, m, p and q are each independently 0, 1 or 2.

7. The compound having the structure of formula I according to claim 1 or 2, which is a compound having the structure of formula IH:

wherein:

X₀is-CH ═ CR₃or-N ═ or;

R₄、R₅and R₇Each independently hydrogen, deuterium, halogen, alkyl, haloalkyl, amino, hydroxy, alkylaminoalkyl, cycloalkylaminoalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, - (CH)₂)_qSF₅Alkyl sulfonyl, alkyl phosphoryl, - (CH)₂)_qNHSO₂NH₂An alkylamido, an alkanoyl, an alkanoyloxy, an alkoxycarbonyl, an alkylaminocarbonyl or a cyano group; and R is₄、R₅And R₇The hydrogens in the structure are optionally substituted with 1 to more substituents each independently being deuterium, halogen, alkoxy, hydroxy, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfonamido, or cyano;

n, m, p and q are each independently 0, 1 or 2.

8. The compound having the structure of formula I according to any one of claims 1 to 7, which is a compound selected from the following structures:

9. a pharmaceutical composition comprising a compound having the structure of formula I according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or mixture thereof in any proportion.

10. Use of a compound having the structure of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture thereof in any proportion, or a pharmaceutical composition according to claim 9, for the preparation of a medicament for the prevention and/or treatment of a disease mediated at least in part by the KRAS G12C protein.