CN112430234B

CN112430234B - Novel KRAS G12C protein inhibitor and preparation method and application thereof

Info

Publication number: CN112430234B
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: 2023-04-28
Anticipated expiration: 2040-08-24
Also published as: CN112430234A

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 a 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 diseases, anti-inflammatory and anti-autoimmune diseases.

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 novel KRAS G12C protein inhibitor and medical application thereof, in particular to application in preparing medicines for preventing and/or treating diseases mediated at least in part by KRAS G12C protein.

Background

RAS represents a group of monomeric globular proteins of 189 amino acids (21 kDa molecular weight) closely related to each other, which associate with the plasma membrane and bind GDP or GTP. The RAS functions as a molecular switch. When the RAS contains an incorporated GDP, it is in a resting or closed position and is "inactive". When responding to cells exposed to certain growth-promoting stimulus conditions, RAS is induced to exchange its bound GDP for GTP. In the case of bound GTP, the RAS is turned "on" and is able to interact with and activate other proteins (its "downstream targets"). RAS proteins themselves have a very low inherent ability to hydrolyze GTP back to GDP, thereby turning themselves into an off state. Turning off the RAS requires an exogenous protein called Gtpase Activating Protein (GAP), which interacts with the RAS and greatly accelerates the conversion of GTP to GDP. Any mutation that affects the interaction of the RAS with GAP or the conversion of GTP back to GDP by the RAS 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. Since these signals cause cell growth and division, overactive RAS signaling may ultimately lead to cancer.

Research on RAS protein inhibitors has been challenging, mainly because the affinity between RAS and GDP, GTP is strong, picomolar scale can be reached, and intracellular GTP concentration is high, so competitive inhibitors have difficulty in weakening RAS protein binding to GTP; meanwhile, the surface of RAS protein is smoother, and effective small molecule binding sites are lacked. RAS proteins have been considered "non-patentable" targets for many years. The advent of continued new technologies has prompted the advent of new therapeutic approaches to RAS targets. Currently, studies on inhibitors of RAS target signaling pathway have focused mainly on the following aspects: directly acting on RAS proteins, preventing RAS from binding to GTP, acting on upstream and downstream signals, inhibiting interaction between RAS and effector proteins, reducing the positioning of RAS, inhibiting GTPase activity, synthetic lethality and the like.

The most well known members of the RAS subfamily are HRAS, KRAS and NRAS, mainly because of their association with many types of cancer. Mutation of any of the three major isoforms (isospors) (HRAS, NRAS or KRAS) of the RAS gene is the most common event in human tumorigenesis. About 30% of human tumors were found to carry some mutations in the RAS gene. Remarkably, KRAS mutations were detected in 25-30% of tumors. In contrast, the oncogenic mutation rates occurring in NRAS and HRAS family members are much lower (8% and 3%, respectively). In addition, mutations in KRAS are most common in colorectal cancer (45%), lung cancer (35%), and pancreatic cancer (95%). The most common KRAS mutations are at residues G12 and G13 in the P loop and residue Q61. Studies have shown that mutations in the RAS gene are associated with many cancers, and that 99% of the mutations occur in glycine at positions 12 and 13 and glutamate at position 61 (see y. Pylayeva-Gupta, et al, RAS ongenes: weaving a tumorigenic web [ J ], nature reviews cancer,2011, 11:761-774).

The G12C protein is a protein generated after G12C mutation (KRAS G12C for short) of KRAS gene, and specifically, the 12 th site is mutated from glycine (G) to cysteine (C). KRAS G12C is one of the most frequent forms of mutation in the KRAS gene, which has been found in about 13% of carcinogenesis, about 43% of lung cancer genesis, and nearly 100% of MYH-related polyposis (familial colon cancer syndrome). In recent years, a range of inhibitors have been developed against the G12C protein. For example, nature reports an inhibitor with electrophilic groups (e.g., vinylsulfonyl, acryl), and the co-crystal results showed an allosteric binding pocket, which was never found before, that could result in a change of Switch I and Switch II structures in RAS, could attenuate the binding of KRAS (G12C) protein to GTP (see J.M.Ostrem, et al, K-RAS (G12C) inhibitors allosterically control GTP affinity and effector interactions [ J ], nature,2013, 503:548-551). Cell reports a class of compounds that have better inhibition of the G12C protein and also have better results in vivo experiments in mice (see m.r. janes, et al Targeting KRAS Mutant Cancers with a Covalent G C-Specific Inhibitor J, cell,2018,172 (3): 578-589). Some candidate compounds have also entered clinical studies and achieved preliminary clinical efficacy, such as MRTX849 from Mirai, AMG-510 from Amgen, and the like.

Although some candidate compounds enter clinical research stage aiming at KRAS G12C targets, early candidate compounds generally have some problems restricting the drug formation, such as low activity, excessive clinical dosage (AMG-510 dosage: 960 mg/day), excessive metabolism, high liver first pass effect (MRTX 1257) and the like. Thus, there remains a need to develop new compounds with higher activity, better pharmacokinetic properties, or ability to pass the blood brain barrier in order to further enhance therapeutic efficacy, better meet clinical needs, and address the broad range of patients with brain metastases in large numbers (about 40% of patients with non-small cell lung cancer will develop brain metastases progress, but existing clinical candidates including MRTX849 and AMG-510 will exclude these patients), more broadly, in cancer patients.

Disclosure of Invention

Problems to be solved by the invention

The invention aims to provide a series of novel compounds with inhibition 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.

Solution for solving the problem

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 a mixture thereof in any ratio, wherein:

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

l is a single bond, - (CH) ₂ ) _p -、-(CH ₂ ) _p O-、-(CH ₂ O) _p -、-CHR ₇ -、-O-、-NH-、-NR ₇ -、-C(＝O)-、-C(＝S)-、-NH-S(＝O) ₂ -NH-、-NH-S(＝O) ₂ -or-S (=o) _p -；

X ₀ is-CH= -CR ₃ =or-n=;

when X is ₁ And X ₂ X is connected by single bond ₁ And X ₂ Each independently is-CH ₂ -、-C(＝O)-、-CHR ₃ -、-C(R ₃ ) ₂ -、-NH-、-NR ₃ -、-CH ₂ CHR ₃ -、-CH＝CR ₃ -or-CH ₂ CH ₂ -; when X is ₁ And X ₂ When connected by double bonds, X ₁ And X ₂ Each independently is-CH=, -CH ₂ CH＝、-CH ₂ CR ₃ ＝、-C(R ₃ ) ₂ Ch=, -n=, or-CR ₃ ＝；

Each R is ₀ Each independently is hydrogen, deuterium, halogen, hydroxy, amino, alkyl, cyano, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, heterocycloalkyloxy, heterocycloalkylamino, spirocyclic, heterospirocyclic, bridged cyclic, heterobridged cyclic, aryl, arylamino, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; when two R ₀ When both are hydroxyl groups, the two hydroxyl groups form c=o together with the carbon atom to which they are attached after dehydration; when two R ₀ When one of the hydroxyl groups and the other is an amino group, the hydroxyl groups and the amino groups form c=nh together with the carbon atom to which they are attached after dehydration; or two R ₀ Forming a saturated or unsaturated 3-to 6-membered cyclic structure containing 0 to multiple heteroatoms each independently O, N or S together with the carbon atom to which it is attached; and R is ₀ Hydrogen in the structure is optionally substituted with deuterium, alkyl, haloalkyl, or halogen;

each R is ₁ And R is ₃ Each independently is hydrogen, deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic, bridged cyclic, heterobridged cyclic, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or alkoxy; and R is ₁ And R is ₃ Hydrogen in the structure is optionally replaced by 0 to multiple R ₇ Substitution;

each R is ₂ And R is ₆ Each 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 ₂ And/or two R's attached to the same carbon atom ₆ When both are hydroxyl groups, the two hydroxyl groups form c=o together with the carbon atom to which they are attached after dehydration; when two R ₂ And/or two R's attached to the same carbon atom ₆ When one of the hydroxyl groups and the other is an amino group, the hydroxyl groups and the amino groups form c=nh together with the carbon atom to which they are attached after dehydration; and R is ₂ And R is ₆ Hydrogen in the structure is optionally substituted with deuterium, halogen, alkynyl, cyano, amino, hydroxy or alkoxy;

R ₄ 、R ₅ and R is ₇ Each independently is hydrogen, deuterium, halogen, alkyl, haloalkyl, amino, hydroxy, alkylaminoalkyl, cycloalkylaminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic, bridged cyclic, heterobridged cyclic, aryl, arylalkyl, arylalkenyl, arylalkynyl, amido, sulfonamido, sulfamido, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) ₂ ) _q SF ₅ Alkylsulfonyl, alkylphosphoryl, phosphinyl, - (CH) ₂ ) _q NHSO ₂ NH ₂ A heterocycloalkyloxy, alkylamido, alkanoyl, alkylacyloxy, alkoxycarbonyl, alkylaminocarbonyl, aminoacyl, alkylsulfinylamino or cyano group; and R is ₄ 、R ₅ And R is ₇ Hydrogen in the structure is optionally substituted with 1 to more substituents each independently deuterium, halogen, alkoxy, hydroxy, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfinylamino or cyano;

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

In a second aspect, the present invention provides a method for preparing the above compound having the structure of formula I, comprising the steps of:

1) Reacting the compound I-1 with a 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 of formula I;

wherein: y is chloro, bromo, iodo, methanesulfonyloxy or p-toluenesulfonyloxy; z is hydroxy, bromo or chloro; PG represents a protecting group; A. l, X ₀ 、X ₁ 、X ₂ 、R ₀ 、R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ M 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 ') deprotecting 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 ') deprotecting 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 chloro, bromo, iodo, methanesulfonyloxy or p-toluenesulfonyloxy; z is hydroxy, bromo or chloro; PG and PG' represent protecting groups; A. l, X ₀ 、X ₁ 、X ₂ 、R ₀ 、R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ M 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 above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or a mixture thereof in any ratio.

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

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

In a sixth aspect, the present application provides the use of a compound having the structure of formula I above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or a mixture thereof in any ratio, or a pharmaceutical composition as 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 preventing and/or treating a disease mediated at least in part by KRAS G12C protein, comprising the steps of: a therapeutically effective amount of a compound having the structure of formula I above or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or mixtures thereof in any ratio, or a pharmaceutical composition, as described above, is administered to a patient in need thereof.

In an eighth aspect, the present invention provides a pharmaceutical combination comprising a compound having the structure of formula I above, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or a mixture of any ratio thereof, or a pharmaceutical composition 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: a therapeutically effective amount of a compound having the structure of formula I above or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug, or a mixture of any ratio thereof, or a pharmaceutical composition or combination of the foregoing, is administered to a patient in need thereof.

ADVANTAGEOUS EFFECTS OF INVENTION

The invention provides a compound with a novel structure, which can be used as a high-efficiency KRAS G12C protein inhibitor and has various pharmacological activities such as anti-tumor, anti-proliferative diseases, anti-inflammatory, anti-autoimmune diseases 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.

By "pharmaceutically acceptable salt" is meant a salt of a compound having the structure of formula I that is substantially non-toxic to an organism. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed from the compounds of the present invention by reaction with pharmaceutically acceptable inorganic/organic acids or inorganic/organic bases, 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 association of a compound of the invention, or a pharmaceutically acceptable salt thereof, with 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 association of a compound of the invention or a pharmaceutically acceptable salt thereof with water by non-covalent intermolecular forces. Common hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.

The term "isomer" refers to compounds having the same number and type of atoms and thus the same molecular weight, but different spatial arrangements or configurations of atoms.

The term "stereoisomer" refers to an isomer produced by the atoms in a molecule in a different spatial arrangement, and includes both "configurational isomer" and "conformational isomer". The term "configurational isomer" refers to isomers of atoms in a molecule that result from different spatial arrangements, and includes both "cis-trans isomers" and "optical isomers". The term "cis-trans isomer" refers to an isomer in which atoms (or groups) located on both sides of a double bond or ring system are located on the same side of the double bond or ring system as the result of the different positions relative to a reference plane, and in which atoms (or groups) are located on the opposite side of the double bond or ring system as the result of the trans-isomer, wherein "double bond" generally refers 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 at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby enabling rotation of plane polarized light. The present invention also includes stereoisomers and mixtures thereof, due to the presence of asymmetric centers and other chemical structures in the compounds of the present invention which may lead to stereoisomers. Since the compounds of the present invention and salts thereof include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, mixtures of enantiomers and diastereomers. Typically, these compounds can be prepared in the form of a racemic mixture. However, if desired, such compounds can 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 below, individual stereoisomers of the compounds are prepared synthetically from optically active starting materials containing the desired chiral centers 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 enantiomers on chiral chromatographic columns. Starting compounds having specific stereochemistry are either commercially available or prepared according to the methods described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that have non-overlapping mirror images of each other. The term "diastereoisomer" 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 portions of individual enantiomers. All stereoisomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.

The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can be converted to each other by a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerisation, imine-enamine isomerisation, amide-imine alcohol isomerisation, 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 substituting a specific atom in a structure with its isotopic atom. Unless otherwise indicated, the compounds of the invention include various isotopes of H, C, N, O, F, P, S, cl, e.g ² H(D)、 ³ H(T)、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ¹⁸ F、 ³¹ P、 ³² P、 ³⁵ S、 ³⁶ S and ³⁷ Cl。

the term "prodrug" refers to a derivative compound that is capable of providing a compound of the invention directly or indirectly after administration to a patient. Particularly preferred derivative compounds or prodrugs are compounds that, when administered to a patient, may increase the bioavailability of the compounds of the invention (e.g., are more readily absorbed into the blood) or promote delivery of the parent compound to the site of action (e.g., the lymphatic system). All prodrug forms of the compounds of the invention are within the scope of the invention unless otherwise indicated, and the various prodrug forms are well known in the art.

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

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur. The description includes the occurrence and non-occurrence of the event or condition. For example, ethyl "optionally" substituted with halogen means that ethyl can be unsubstituted (CH ₂ CH ₃ ) Monosubstituted (e.g. CH ₂ CH ₂ F) Polysubstituted (e.g. CHFCH ₂ F、CH ₂ CHF ₂ Etc.) or fully substituted (CF) ₂ CF ₃ ) The method comprises the steps of carrying out a first treatment on the surface of the "optionally" substituted with 1 to 3R's for a 5-to 10-membered aryl or heteroaryl group means that the 5-to 10-membered aryl or heteroaryl group may be unsubstituted or substituted with 1 to 3R's. It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substituents or substitution patterns are introduced which are sterically impossible and/or can not be synthesized.

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

The term "phosphinyl" refers to a monovalent group that is formed by the loss of hydroxyl groups from hypophosphorous acidAnd is linked to the parent nucleus (-P (=O) H) by a single bond to the phosphorus atom ₂ ). The phosphinyl group can be attached in unsubstituted form to the structural parent nucleus of the compounds of formula I according to the invention, or can be substituted by other substituents. Common substituted phosphinyl groups include, but are not limited to, dialkylphosphinyl (-P (=o) (Alk) ₂ Such as dimethylphosphinyl), diarylphosphinoyl (-P (=O) (Ar) ₂ Such as diphenylphosphinyl), alkylaryl phosphinyl (-P (=O) (Alk) (Ar), such as methylphenylphosphinyl), dialkoxyphosphinyl (-P (=O) (OAlk) ₂ Such as dimethoxy phosphinyl), and the like.

The term "phosphoryl" refers to a monovalent group which is formed by the loss of a hydroxyl group from phosphoric acid and which is linked to the parent nucleus (-P (=o) (OH) by a single bond to the phosphorus atom ₂ )。

The term "alkyl" refers to a monovalent straight or branched chain alkane group consisting of carbon and hydrogen atoms, free of unsaturation, and attached to the parent nucleus by a single bond, preferably C ₁ -C ₆ Alkyl, more preferably C ₁ -C ₄ An alkyl group; common alkyl groups include, but are not limited to, methyl (-CH) ₃ ) Ethyl (-CH) ₂ CH ₃ ) N-propyl (-CH) ₂ CH ₂ CH ₃ ) Isopropyl (-CH (CH) ₃ ) ₂ ) N-butyl (-CH) ₂ CH ₂ CH ₂ CH ₃ ) Sec-butyl (-CH (CH) ₃ )CH ₂ CH ₃ ) Isobutyl (-CH) ₂ CH(CH ₃ ) ₂ ) Tert-butyl (-C (CH) ₃ ) ₃ ) N-pentyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) Neopentyl (-CH) ₂ C(CH ₃ ) ₃ ) Etc.

The term "alkenyl" refers to a monovalent linear or branched olefinic group consisting of only carbon and hydrogen atoms, containing at least one double bond, and linked to the parent nucleus by one single bond, preferably C ₂ -C ₆ Alkenyl groups; 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 -CH ₃ ) 1-penten-1-yl (-ch=ch-CH) ₂ -CH ₂ -CH ₃ ) 1, 3-butadiene-1-yl (-ch=ch) ₂ ) 1, 4-pentadien-1-yl (-ch=ch-CH) ₂ -CH＝CH ₂ ) Etc.

The term "alkynyl" refers to a monovalent, linear or branched alkyne group consisting of only carbon and hydrogen atoms, containing at least one triple bond, and linked to the parent nucleus by one single bond, preferably C ₂ -C ₆ Alkynyl; 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-pentadiyn-1-yl- >

Etc.

The term "alkoxy" refers to a monovalent, linear or branched 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 C ₁ -C ₄ An alkoxy group; common alkoxy groups include, but are not limited to, methoxy (-OCH) ₃ ) Ethoxy (-OCH) ₂ CH ₃ ) N-propoxy (-OCH) ₂ CH ₂ CH ₃ ) Isopropoxy (-OCH (CH) ₃ ) ₂ ) N-butoxy (-OCH) ₂ CH ₂ CH ₂ CH ₃ ) Sec-butoxy (-OCH (CH) ₃ )CH ₂ CH ₃ ) Isobutoxy (-OCH) ₂ CH(CH ₃ ) ₂ ) T-butoxy (-OC (CH) ₃ ) ₃ ) N-pentyloxy (-OCH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) Neopentyloxy (-OCH) ₂ C(CH ₃ ) ₃ ) Etc.

The term "alkanoyl" refers to a monovalent, linear or branched radical consisting of carbon, hydrogen and oxygen atoms only, free of unsaturation other than the carbonyl group in its own structure, and linked to the parent nucleus by a single bond to the carbonyl group, preferably C ₁ -C ₄ An alkyl acyl group; common alkanoyl groups include, but are not limited to, formyl (-C (=o) H), acetyl (-C (=o) CH) ₃ ) N-propionyl (-C (=O) CH ₂ CH ₃ ) N-butyryl (-C (=O) CH ₂ CH ₂ CH ₃ ) Isobutyryl (-C (=O) CH (CH) ₃ ) ₂ ) N-pentanoyl (-C (=O) CH ₂ CH ₂ CH ₂ CH ₃ ) Pivaloyl (-C (=O) C (CH) ₃ ) ₃ ) Etc.

The term "alkylamido" refers to a monovalent, linear or branched radical composed solely of carbon, hydrogen, oxygen and nitrogen atoms, free of unsaturation other than the carbonyl groups in its own structure, and linked to the parent nucleus by a single bond to the nitrogen atom, preferably C ₁ -C ₄ An alkylamido group; common alkylamido groups include, but are not limited to, formylamino (-NHC (=O) H), acetamido (-NHC (=O) CH ₃ ) N-propionylamino (-NHC (=O) CH ₂ CH ₃ ) N-butyrylamino (-NHC (=O) CH ₂ CH ₂ CH ₃ ) Isobutyrylamino (-NHC (=o) CH (CH) ₃ ) ₂ ) N-pentanoylamino (-NHC (=o) CH ₂ CH ₂ CH ₂ CH ₃ ) Pivaloylamino (-NHC (=O) C (CH) ₃ ) ₃ ) Etc.

The term "alkanoyloxy" means a monovalent, linear or branched radical consisting of only carbon, hydrogen and oxygen atoms, free of unsaturation other than the carbonyl group in its own structure, and linked to the parent nucleus by a single bond to the oxygen atom, preferably C ₁ -C ₄ Alkyl acyloxy; common alkanoyloxy groups include, but are not limited to, formyloxy (-OC (=o) H), acetoxy (-OC (=o) CH ₃ ) N-propionyloxy (-OC (=O) CH ₂ CH ₃ ) N-butyryloxy (-OC (=O) CH ₂ CH ₂ CH ₃ ) Isobutyryloxy (-OC (=O) CH (CH) ₃ ) ₂ ) N-pentanoyloxy (-OC (=o) CH ₂ CH ₂ CH ₂ CH ₃ ) Pivaloyloxy (-OC (=O) C (CH) ₃ ) ₃ ) Etc.

The term "alkoxycarbonyl" refers to a monovalent, linear or branched radical consisting of carbon, hydrogen and oxygen atoms only, free of unsaturation other than the carbonyl group in its own structure, and linked to the parent nucleus by a single bond to the carbonyl group, preferably C ₁ -C ₄ An alkoxycarbonyl group; common alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl (-C (=o) OCH) ₃ ) Ethoxycarbonyl (-C (=O) OCH) ₂ CH ₃ ) N-propoxycarbonyl (-C (=O) OCH) ₂ CH ₂ CH ₃ ) Isopropoxycarbonyl (-C (=O) OCH (CH) ₃ ) ₂ ) N-butoxycarbonyl (-C (=O) OCH ₂ CH ₂ CH ₂ CH ₃ ) Boc (-C (=O) OC (CH) ₃ ) ₃ ) Etc.

The term "cycloalkyl" refers to a monovalent, monocyclic, non-aromatic ring system consisting of only carbon and hydrogen atoms, containing no unsaturation, and being attached to the parent nucleus by one 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 consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, free of unsaturation, and linked 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 having two single rings sharing one carbon atom, consisting of only carbon and hydrogen atoms, free of unsaturation, and linked to the parent nucleus by one single bond; the number of the spiro atoms can be classified into a single spiro compound, a double spiro compound, a triple spiro compound, and the like; common spirocyclic groups include, but are not limited to, spiro [2.4] heptane-1-yl, spiro [3.5] nonan-2-yl, spiro [4.5] decane-2-yl, dispiro [5.2.5.2] hexadecan-3-yl, and the like.

The term "heterospirocyclic group" refers to a monovalent, non-aromatic ring system having two monocyclic rings sharing one carbon atom, consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, free of unsaturation, and linked to the parent nucleus by one 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 ring radical" refers to a monovalent, non-aromatic ring system in which any two single rings share two carbon atoms that are not directly connected, are composed of only carbon and hydrogen atoms, do not contain 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, and the like; common bridged ring groups include, but are not limited 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 ring radical" refers to a monovalent, non-aromatic ring system of any two single rings sharing two carbon atoms that are not directly connected, consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus, free of unsaturation, and linked to the parent nucleus by a single bond; common heterobridged ring groups include, but are not limited to, 1, 4-diazabicyclo [2.2.2] octane-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 attached to the parent nucleus by a single bond; common aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like.

The term "arylalkyl" refers to a monovalent, linear or branched, alkane radical consisting of only carbon and hydrogen atoms containing at least one aromatic groupA group, and is linked to the parent nucleus by a single bond, preferably C ₆ -C ₁₀ aryl-C ₁ -C ₆ Alkyl, more preferably C ₆ -C ₁₀ aryl-C ₁ -C ₄ An alkyl group; common arylalkyl groups include, but are not limited to, benzyl, beta-phenylethyl, alpha-phenylethyl, naphthylmethyl, and the like.

The term "arylalkenyl" refers to a monovalent linear or branched alkene group consisting of only carbon and hydrogen atoms, containing at least one double bond and at least one aryl group, and linked to the parent nucleus by one single bond, preferably C ₆ -C ₁₀ aryl-C ₂ -C ₆ Alkenyl groups; 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) ₂ Ph), 2-phenyl-1-propen-1-yl (-ch=cph-CH) ₃ ) 4-phenyl-1, 3-butadiene-1-yl (-ch=ch-ch=chph), 4-diphenyl-1, 3-butadiene-1-yl (-ch=ch-ch=cph) ₂ ) Etc.

The term "arylalkynyl" refers to a monovalent, linear or branched alkyne group consisting of only carbon and hydrogen atoms, containing at least one triple bond and at least one aryl group, and linked to the parent nucleus by one single bond, preferably C ₆ -C ₁₀ aryl-C ₂ -C ₆ Alkynyl; common arylalkynyls include, but are not limited to, phenylethynyl (-C.ident.CPh), 3-phenyl-1-propyn-1-yl (-C.ident.C-CH) ₂ Ph), 3-diphenyl-1-propyn-1-yl (-c≡c-CHPh) ₂ ) 4-phenyl-1, 3-diacetyn-1-yl (-C.ident.C-C.ident.CPh), and the like.

The term "heteroaryl" refers to a monovalent, monocyclic or polycyclic (including fused forms) aromatic ring system consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, and linked to the parent nucleus by a single bond; common heteroaryl groups include, but are not limited to, benzopyrrolyl, 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, linear or branched, alkanyl radical composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing at least one heteroaryl group, and linked to the parent nucleus by a single bond, preferably a 5-10 membered heteroaryl-C ₁ -C ₆ Alkyl, more preferably 5-10 membered heteroaryl-C ₁ -C ₄ An 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 linear or branched alkene radical composed 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 linked to the parent nucleus by a single bond, preferably a 5-10 membered heteroaryl-C ₂ -C ₆ Alkenyl groups; common heteroarylalkenyl groups 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-butadiene-1-yl, and the like.

The term "heteroarylalkynyl" refers to a monovalent, linear or branched 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 linked to the parent nucleus by one single bond, preferably a 5-10 membered heteroaryl-C ₂ -C ₆ Alkynyl; common heteroarylalkynyl groups 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-lambda ⁶ "sulfanyl" (also known as "sulfur pentafluoride") refers to a monovalent group consisting of only sulfur and fluorine atoms and linked to the parent nucleus (-SF) by a single bond ₅ )。

Reference in the specification to "an embodiment," "one embodiment," "some embodiments," "certain embodiments," or "portions of embodiments" means that a particular reference element, structure, or feature 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 in the specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

The terms "include" and variations thereof such as "comprises" and "comprising" are to be interpreted in an open-ended sense, i.e. "including but not limited to".

It should be understood that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reaction comprising a "catalyst" may comprise one catalyst, or two or more catalysts.

[ Compounds of the general formula ]

The present invention provides a compound of formula I:

X ₀ is-CH= -CR ₃ =or-n=;

Each R is ₁ And R is ₃ Each independently is hydrogen, deuterium, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkylA group, spirocyclic group, heterospirocyclic group, bridged ring group, heterobridged ring group, aryl group, arylalkyl group, arylalkenyl group, arylalkynyl group, heteroaryl group, heteroarylalkyl group, heteroarylalkenyl group, heteroarylalkynyl group, or alkoxy group; and R is ₁ And R is ₃ Hydrogen in the structure is optionally replaced by 0 to multiple R ₇ Substitution;

each R is ₂ And R is ₆ Each 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 ₂ And/or two R's attached to the same carbon atom ₆ When both are hydroxyl groups, the two hydroxyl groups form c=o together with the carbon atom to which they are attached after dehydration; when two R ₂ And/or two R's attached to the same carbon atom ₆ When one of the hydroxyl groups and the other is an amino group, the hydroxyl groups and the amino groups form c=nh together with the carbon atom to which they are attached after dehydration; and R is ₂ And R is ₆ Hydrogen in the structure is optionally substituted with deuterium, halogen, alkynyl, cyano, amino, hydroxy or alkoxy;

R ₄ 、R ₅ And R is ₇ Each independently is hydrogen, deuterium, halogen, alkyl, haloalkyl, amino, hydroxy, alkylaminoalkyl, cycloalkylaminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic, bridged cyclic, heterobridged cyclic, aryl, arylalkyl, arylalkenyl, arylalkynyl, amido, sulfonamido, sulfamido, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) ₂ ) _q SF ₅ Alkylsulfonyl, alkylphosphoryl, phosphinyl, - (CH) ₂ ) _q NHSO ₂ NH ₂ A heterocycloalkyloxy, alkylamido, alkanoyl, alkylacyloxy, alkoxycarbonyl, alkylaminocarbonyl, aminoacyl, alkylsulfinylamino or cyano group; and R is ₄ 、R ₅ And R is ₇ The hydrogens in the structure are optionally substituted with 1 to more substituents each independently deuteriumHalogen, alkoxy, hydroxy, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfinylamino 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:

X ₀ is-CH= -CR ₃ =or-n=;

Each R is ₀ Each independently is hydrogen, deuterium, halogen, hydroxy, amino, alkyl, cyano, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, heterocycloalkyloxy, heterocycloalkylamino, spirocyclic, heterospirocyclic, bridged cyclic, heterobridged cyclic, aryl, arylamino, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; when two R ₀ When both are hydroxyl groups, the two hydroxyl groups are dehydratedAnd then together with the carbon atom to which it is attached form c=o; when two R ₀ When one of the hydroxyl groups and the other is an amino group, the hydroxyl groups and the amino groups form c=nh together with the carbon atom to which they are attached after dehydration; or two R ₀ Forming a saturated or unsaturated 3-to 6-membered cyclic structure containing 0 to multiple heteroatoms each independently O, N or S together with the carbon atom to which it is attached; and R is ₀ Hydrogen in the structure is optionally substituted with deuterium, alkyl, haloalkyl, or halogen;

R ₄ 、R ₅ and R is ₇ Each independently is hydrogen, deuterium, halogen, alkyl, haloalkyl, amino, hydroxy, alkylaminoalkyl, cycloalkylaminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic,Bridged ring radicals, heterobridged ring radicals, aryl radicals, arylalkyl radicals, arylalkenyl radicals, arylalkynyl radicals, acylamino radicals, sulfonylamino radicals, sulfamoylamino radicals, heteroalkyl radicals, heteroaryl radicals, heteroarylalkyl radicals, heteroarylalkenyl radicals, heteroarylalkynyl radicals, alkoxy radicals, - (CH) ₂ ) _q SF ₅ Alkylsulfonyl, alkylphosphoryl, phosphinyl, - (CH) ₂ ) _q NHSO ₂ NH ₂ A heterocycloalkyloxy, alkylamido, alkanoyl, alkylacyloxy, alkoxycarbonyl, alkylaminocarbonyl, aminoacyl, alkylsulfinylamino or cyano group; and R is ₄ 、R ₅ And R is ₇ Hydrogen in the structure is optionally substituted with 1 to more substituents each independently deuterium, halogen, alkoxy, hydroxy, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfinylamino 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 IB:

Wherein:

X ₀ is-CH= -CR ₃ =or-n=;

X ₁ and X ₂ Each independently is-CH ₂ -、-C(＝O)-、-CHR ₃ -、-C(R ₃ ) ₂ -, -NH-, -CH=CH-or-CH ₂ CH ₂ -；

Each R is ₀ Each independently is hydrogen, deuterium, halogen, hydroxy, amino, alkyl, cyano, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxyA group, alkylamino, heterocycloalkyloxy, heterocycloalkylamino, spirocyclic, heterospirocyclic, bridged, heterobridged, aryl, arylamino, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; when two R ₀ When both are hydroxyl groups, the two hydroxyl groups form c=o together with the carbon atom to which they are attached after dehydration; when two R ₀ When one of the hydroxyl groups and the other is an amino group, the hydroxyl groups and the amino groups form c=nh together with the carbon atom to which they are attached after dehydration; or two R ₀ Forming a saturated or unsaturated 3-to 6-membered cyclic structure containing 0 to multiple heteroatoms each independently O, N or S together with the carbon atom to which it is attached; and R is ₀ Hydrogen in the structure is optionally substituted with deuterium, alkyl, haloalkyl, or halogen;

each R is ₂ And R is ₆ Each 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 ₂ And/or two R's attached to the same carbon atom ₆ When both are hydroxyl groups, the two hydroxyl groups form c=o together with the carbon atom to which they are attached after dehydration; when two R ₂ And/or two R's attached to the same carbon atom ₆ When one of the hydroxyl groups and the other is an amino group, the hydroxyl groups and the amino groups form c=nh together with the carbon atom to which they are attached after dehydration; and R is ₂ And R is ₆ Hydrogen in the structure is optionally substituted with deuterium, halogen, alkynyl, cyano, Amino, hydroxy or alkoxy substitution;

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:

X ₀ is-CH= -CR ₃ =or-n=;

X ₁ and X ₂ Each independently is-CH=, -CH ₂ CH＝、-CH ₂ CR ₃ ＝、-C(R ₃ ) ₂ Ch=, -n=, or-CR ₃ ＝；

Each R is ₀ Each independently is hydrogen, deuterium, halogen, hydroxy, amino, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, alkylamino, or heterocycloalkyloxy; when two R ₀ When both are hydroxyl groups, the two hydroxyl groups form c=o together with the carbon atom to which they are attached after dehydration; when two R ₀ When one of the hydroxyl groups and the other is an amino group, the hydroxyl groups and the amino groups form c=nh together with the carbon atom to which they are attached after dehydration; and R is ₀ Hydrogen in the structure is optionally substituted with deuterium, alkyl, haloalkyl, or halogen;

each R is ₁ And R is ₃ Each independently is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic, bridged cyclic, heterobridged cyclic, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or alkoxy; and R is ₁ And R is ₃ Hydrogen in the structure is optionally replaced by 0 to multiple R ₇ Substitution;

R ₄ 、R ₅ and R is ₇ Each independently is hydrogen, deuterium,Halogen, alkyl, haloalkyl, amino, hydroxy, alkylaminoalkyl, cycloalkylaminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic, bridged cyclic, heterobridged cyclic, aryl, arylalkyl, arylalkenyl, arylalkynyl, amido, sulfonamido, sulfamido, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) ₂ ) _q SF ₅ Alkylsulfonyl, alkylphosphoryl, phosphinyl, - (CH) ₂ ) _q NHSO ₂ NH ₂ A heterocycloalkyloxy, alkylamido, alkanoyl, alkylacyloxy, alkoxycarbonyl, alkylaminocarbonyl, aminoacyl, alkylsulfinylamino or cyano group; and R is ₄ 、R ₅ And R is ₇ Hydrogen in the structure is optionally substituted with 1 to more substituents each independently deuterium, halogen, alkoxy, hydroxy, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfinylamino 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 ID:

wherein:

X ₀ is-CH= -CR ₃ =or-n=;

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:

X ₀ is-CH= -CR ₃ =or-n=;

R ₁ Is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic, bridged cyclic, heterobridged cyclic, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or alkoxy; and R is ₁ Hydrogen in the structure is optionally replaced by 0 to multiple R ₇ Substitution;

each R is ₃ Each independently is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic, bridged cyclic, heterobridged cyclic, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; and R is ₃ Hydrogen in the structure is optionally replaced by 0 to multiple R ₇ Substitution;

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:

X ₀ is-CH= -CR ₃ =or-n=;

X ₁ and X ₂ Each independently is-CH ₂ -、-C(＝O)-、-CHR ₃ -, -NH-, -CH=CH-or-CH ₂ CH ₂ -；

each R is ₆ Each 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 are attached to the same carbon atom ₆ When both are hydroxyl groups, the two hydroxyl groups form c=o together with the carbon atom to which they are attached after dehydration; when two R's are attached to the same carbon atom ₆ When one of the hydroxyl groups and the other is an amino group, the hydroxyl groups and the amino groups form c=nh together with the carbon atom to which they are attached after dehydration; and R is ₆ Hydrogen in the structure is optionally substituted with deuterium, halogen, alkynyl, cyano, amino, hydroxy or alkoxy;

R ₄ 、R ₅ and R is ₇ Each independently ofIn the alternative, the amino group is hydrogen, deuterium, halogen, alkyl, haloalkyl, amino, hydroxyl, alkylaminoalkyl, cycloalkylaminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic, bridged cyclic, aryl, arylalkyl, arylalkenyl, arylalkynyl, amido, sulfonamido, sulfamido, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) ₂ ) _q SF ₅ Alkylsulfonyl, alkylphosphoryl, phosphinyl, - (CH) ₂ ) _q NHSO ₂ NH ₂ A heterocycloalkyloxy, alkylamido, alkanoyl, alkylacyloxy, alkoxycarbonyl, alkylaminocarbonyl, aminoacyl, alkylsulfinylamino or cyano group; and R is ₄ 、R ₅ And R is ₇ Hydrogen in the structure is optionally substituted with 1 to more substituents each independently deuterium, halogen, alkoxy, hydroxy, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfinylamino 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 IG:

wherein:

X ₀ is-CH= -CR ₃ =or-n=;

X ₁ and X ₂ Each independently is-ch=, -n=, or-CR ₃ ＝；

R ₁ Is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic groupA heterospirocyclic group, bridged ring group, heterobridged ring group, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or alkoxy group; and R is ₁ Hydrogen in the structure is optionally replaced by 0 to multiple R ₇ Substitution;

R ₄ 、R ₅ and R is ₇ Each independently is hydrogen, deuterium, halogen, alkyl, haloalkyl, amino, hydroxy, alkylaminoalkyl, cycloalkylaminoalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, spirocyclic, heterospirocyclic, bridged cyclic, heterobridged cyclic, aryl, arylalkyl, arylalkenyl, arylalkynyl, amido, sulfonamido, sulfamido, heteroalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, - (CH) ₂ ) _q SF ₅ Alkylsulfonyl, alkylphosphoryl, phosphinyl, - (CH) ₂ ) _q NHSO ₂ NH ₂ Heterocyclic alkyloxy, alkylamido, alkanoyl, alkylacyloxy, alkoxycarbonylA group, an alkylaminocarbonyl group, an aminoacyl group, an alkylsulfinylamino group or a cyano group; and R is ₄ 、R ₅ And R is ₇ Hydrogen in the structure is optionally substituted with 1 to more substituents each independently deuterium, halogen, alkoxy, hydroxy, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfinylamino 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 IH:

wherein:

l is a single bond, - (CH) ₂ ) _p -、-(CH ₂ ) _p O-、-(CH ₂ O) _p -、-CHR ₇ -、-O-、-NH-、-NR ₇ -、-NH-S(＝O) ₂ -or-S (=o) _p -；

X ₀ is-CH= -CR ₃ =or-n=;

when X is ₁ And X ₂ X is connected by single bond ₁ And X ₂ Each independently is-CH ₂ -、-C(＝O)-、-CHR ₃ -、-C(R ₃ ) ₂ -、-CH ₂ CHR ₃ -、-CH＝CR ₃ -or-CH ₂ CH ₂ -; when X is ₁ And X ₂ When connected by double bonds, X ₁ And X ₂ Each independently is-ch=or-CR ₃ ＝；

Each R is ₁ And R is ₃ Each independently is hydrogen, deuterium, halogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or alkoxy; and R is ₁ And R is ₃ Hydrogen in the structure is optionally replaced by 0 to multiple R ₇ Substitution;

each R is ₂ And R is ₆ Each independently is hydrogen, deuterium, halogen, alkyl, cycloalkyl, cyano, cyanoalkyl, alkylamino, amino,Alkoxy, hydroxy, haloalkyl or haloalkoxy; when two R ₂ And/or two R's attached to the same carbon atom ₆ When both are hydroxyl groups, the two hydroxyl groups form c=o together with the carbon atom to which they are attached after dehydration; when two R ₂ And/or two R's attached to the same carbon atom ₆ When one of the hydroxyl groups and the other is an amino group, the hydroxyl groups and the amino groups form c=nh together with the carbon atom to which they are attached after dehydration; and R is ₂ And R is ₆ Hydrogen in the structure is optionally substituted with deuterium, halogen, alkynyl, cyano, amino, hydroxy or alkoxy;

R ₄ 、R ₅ and R is ₇ Each independently is hydrogen, deuterium, halogen, alkyl, haloalkyl, amino, hydroxy, alkylaminoalkyl, cycloalkylaminoalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, - (CH) ₂ ) _q SF ₅ Alkylsulfonyl, alkylphosphoryl, - (CH) ₂ ) _q NHSO ₂ NH ₂ An alkylamido, alkanoyl, alkylacyloxy, alkoxycarbonyl, alkylaminocarbonyl or cyano group; and R is ₄ 、R ₅ And R is ₇ Hydrogen in the structure is optionally substituted with 1 to more substituents each independently deuterium, halogen, alkoxy, hydroxy, amino, alkanoyl, alkanoyloxy, alkoxycarbonyl, alkylsulfinylamino or cyano;

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

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

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[ preparation method ]

The invention provides a preparation method of the compound shown in the formula I, which comprises the following steps:

1) Reacting the compound I-1 with a 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 chloro, bromo, iodo, methanesulfonyloxy or p-toluenesulfonyloxy; z is hydroxy, bromo or chloro; PG represents a protecting group; A. l, X ₀ 、X ₁ 、X ₂ 、R ₀ 、R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ M and n are as defined for the compounds of formula I.

In some embodiments of the invention, steps 1) and 2) of the above preparation process are performed by substitution reactions under alkaline conditions. Reagents used to provide basic conditions include, but are not limited to, triethylamine (TEA), sodium hydrogen (NaH), potassium t-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, tetramethyl ethylenediamine, hexamethyldisilylaminopotassium, hexamethyldisilylaminosodium, 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-Hartmay reactions (Buchwald-Hartwig reactions), suzuki reactions (Suzuki reactions), heck reactions (Heck reactions), still reactions (Stille reactions), bacterial head Coupling reactions (Sogonoshira Coupling), xiong Tian Coupling reactions (Kumada Coupling) reactions, root-bank Coupling reactions (Negishi Coupling), juniper mountain Coupling reactions (Hiyama Coupling), and the like.

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

in some embodiments of the invention, step 4) of the above preparation process is performed by a substitution reaction under alkaline conditions. Reagents used to provide basic conditions include, but are not limited to, triethylamine, sodium hydrogen, potassium t-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, hexamethyldisilazane sodium amide, and the like.

In some embodiments of the invention, step 4) of the above preparation process 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-hydroxysulfosuccinimide sodium salt, catter condensing agent (BOP), benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (PyBOP), tripyrrolidinylphosphonium bromide hexafluorophosphate (PyBrOP), 1-hydroxy-7-azobenzotriazole (HOAT), 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (Cl-HOBt), O- (7-azobenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU), 6-chlorobenzotriazol-1, 3-tetramethyluronium Hexafluorophosphate (HCTU), O- (1, 2-dihydro-2-oxo-pyridinyl) -1, 3-tetramethyluronium tetrafluoroborate (TPTU) and the like.

Or comprises the following steps:

2 ') deprotecting the compound I-2' to obtain a compound I-3';

4 ') deprotecting the compound I-4' to obtain a compound I-5';

wherein: y is chloro, bromo, iodo, methanesulfonyloxy or p-toluenesulfonyloxy; z is hydroxy, bromo or chloro; PG and PG' represent protecting groups; A. l, X ₀ 、X ₁ 、X ₂ 、R ₀ 、R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ M and n are as defined for the compounds of formula I.

In some embodiments of the invention, steps 1 ') and 3') of the above preparation method are performed by substitution reaction under alkaline conditions. Reagents used to provide basic conditions include, but are not limited to, triethylamine, sodium hydrogen, potassium t-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, hexamethyldisilazane sodium amide, and the like.

In some embodiments of the invention, steps 1 ') and 3') of the above preparation method are performed by a coupling reaction. Coupling reactions include, but are not limited to, buchwald-Hartmay reactions (Buchwald-Hartwig reactions), suzuki reactions (Suzuki reactions), heck reactions (Heck reactions), still reactions (Stille reactions), bacterial head Coupling reactions (Sogonoshira Coupling), xiong Tian Coupling reactions (Kumada Coupling) reactions, root-bank Coupling reactions (Negishi Coupling), juniper mountain Coupling reactions (Hiyama Coupling), 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 method is performed by substitution reaction under alkaline conditions. Reagents used to provide basic conditions include, but are not limited to, triethylamine, sodium hydrogen, potassium t-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, hexamethyldisilazane sodium amide, and the like.

In some embodiments of the invention, step 5') of the above preparation method is performed by a condensation reaction. Condensing agents employed include, but are not limited to, N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, N- (3-dimethylaminopropyl) -N '-ethylcarbodiimide hydrochloride, 4, 5-dicyanoimidazole, N, N' -carbonyldiimidazole, N-hydroxysuccinimide sodium salt, carbot condensing agent, benzotriazol-1-yl-oxy-tripyrrolidinylphosphine, tripyrrolidinylphosphonium hexafluorophosphate, 1-hydroxy-7-azobenzotriazole, 1-hydroxybenzotriazole, 6-chloro-1-hydroxybenzotriazole, O- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, 6-benzotriazol-1, 3-dimethylurea hexafluoroborate, 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 a 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 pharmaceutical excipients that are 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 adjusting agents, solvents, co-solvents, surfactants, and the like.

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

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

[ medical use ]

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

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

The term "disease mediated at least in part by KRAS G12C protein" refers to a disease in which the pathogenesis includes at least a portion of the factors associated with KRAS G12C protein, 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 preventing and/or treating a disease mediated at least in part by KRAS G12C protein comprising the steps of: a therapeutically effective amount of a compound of formula I above or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture of any ratio thereof, or a pharmaceutical composition, is administered to a patient in need thereof.

The term "therapeutically effective amount" refers to a dose of a pharmaceutically active ingredient capable of eliciting 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 present invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (e.g., a pharmaceutical composition of the present invention) to a patient or a cell, tissue, organ, biological fluid, etc. thereof, such that the pharmaceutically active ingredient or pharmaceutical composition is in contact with the patient or a cell, tissue, organ, biological fluid, etc. 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 of a physician or other caregiver that the patient needs or will benefit from the prevention and/or treatment process based on various factors of the physician or other caregiver in their expertise.

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

[ Combined drug administration ]

The present invention provides a pharmaceutical combination comprising a compound of formula I above or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, isotopic label, prodrug or a mixture of any ratio thereof, or a pharmaceutical composition 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, an ability to inappropriately invade surrounding tissues, and/or an ability to establish new growth in ectopic sites. Common cancers include, but are not limited to, brain cancer, liver cancer, gall bladder cancer, bronchus cancer, lung cancer, bladder cancer, ovarian cancer, cervical cancer, testicular cancer, lip cancer, tongue cancer, hypopharynx cancer, larynx cancer, esophagus cancer, stomach cancer, bowel cancer (e.g., colon cancer, rectal cancer), thyroid cancer, salivary gland cancer, pancreatic cancer, breast cancer, prostate cancer, blood cancer (or leukemia), lymph cancer (or lymphoma), bone cancer, and skin cancer.

The term "cancer therapeutic" refers to a pharmaceutical composition or pharmaceutical formulation capable of effectively controlling and/or combating cancer, including but not limited to cytotoxic drugs, anti-angiogenic drugs, DNA repair agents, epigenetic interference agents, immune modulators, and the like. Common cancer therapeutic agents include, but are not limited to, anti-purine agents (e.g., pravastatin, etc.), anti-pyrimidine 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., camptothecins), intercalating DNA interfering nucleic acid synthetic agents (e.g., epirubicin), anti-feed drugs (e.g., asparaginase), interfering tubulin forming agents (e.g., paclitaxel), interfering ribosomal function agents (e.g., cephalotaxine), cytokines (e.g., IL-1), thymosin, tumor cell proliferative viruses (e.g., adenovirus ONYX-015), DNA repair agents such as PARP inhibitors (e.g., olaparib, talazoparib, niraparib, etc.), anti-angiogenic agents such as inhibitors (e.g., roxudustat/FG-4592, 2-methoxyestradiol/2-me2, FG-2216, etc.), or VEGF signaling pathway inhibitors (e.g., bixaduride, monoclonal anti-tumor, CTLA, anti-tumor agents (e.g., PDs), anti-tumor agents (e.g., PDs, etc.).

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

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are for illustration of the invention only and are not intended to limit the scope of the invention. If the experimental methods in the following examples do not specify specific conditions, the conditions are generally either conventional or suggested by the manufacturer. The percentages and parts appearing in the following examples are by weight unless otherwise indicated.

Example 1: synthesis of 2- ((S) -1-propenoyl-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: DMF was added to a round bottom flask containing intermediates 1-1 and 1-2 (1.1 eq.). Stirring the solution, adding N, N-diisopropylethylamine, stirring the mixture for reaction until TLC detection reaction is complete. Saturated aqueous NaCl solution and ethyl acetate are added for extraction, the organic phase is concentrated, and silica gel column chromatography is carried out for separation, thus obtaining an intermediate 1-3.LC-MS 594.35[ M+1 ] ] ⁺ 。

S2: intermediate 1-3 (5 mmol) was dissolved in methanol, wet Pd/C was added, nitrogen was substituted 3 times, the reaction was stirred at room temperature with a hydrogenation balloon, and TLC detection was complete. 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 a yield of 90%, LC-MS:504.30[ M+1 ]] ⁺ 。

S3: intermediate 1-4, intermediate 1-5 (1 eq.) and Pd ₂ (dba) ₃ (1%, w/w%), ruPhos (1%, w/w%) and Cs ₂ CO ₃ (1 eq.) was dissolved in toluene, purged with nitrogen and heated to 110 ℃. TLC detection reaction is complete, cooling to room temperature, concentrating organic phase, separating by silica gel column chromatography to obtain intermediate 1-6 (mobile phase: dichloromethane)Methanol=3:1). LC-MS 644.36[ M+1 ]] ⁺ 。

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

S5: intermediate 1-7 was dissolved in dry THF, cooled to 0 ℃, acryloyl chloride (1.1 eq.) was slowly added dropwise, and after 1 hour of reaction TLC detection reaction was complete. The reaction was quenched with water, concentrated, and chromatographed on a column 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-propenoyl-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 give the objective compound 2.LC-MS 564.34[ M+1 ]] ⁺ 。

Example 3: synthesis of 2- ((S) -1-propenoyl-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 of example 1 was followed to give the objective compound 3.LC-MS 566.32[ M+1 ]] ⁺ 。

Example 4: synthesis of 2- ((S) -1-propenoyl-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 give the target compound 4.LC-MS 566.32[ M+1 ]] ⁺ 。

Example 5: synthesis of 2- ((S) -1-propenoyl-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 were seen in S2-S5 of example 3, to finally give the objective compound 5.LC-MS 580.33[ M+1 ]] ⁺ 。

Example 6: synthesis of 2- ((S) -1-propenoyl-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 give the target compound 6.LC-MS 580.33[ M+1 ]] ⁺ 。

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

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

Example 8: synthesis of 2- ((S) -1-propenoyl-4- (7- (8-methylnaphthalen-1-yl) -2- (2- ((S) -tetrahydrofurane-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 give the target compound 8.LC-MS 567.30[ M+1 ] ] ⁺ 。

Example 9: synthesis of 2- ((S) -1-propenoyl-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 give the objective compound 9.LC-MS 580.33[ M+1 ]] ⁺ 。

Example 10: synthesis of 2- ((S) -1-propenoyl-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).

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

Example 11: synthesis of 2- ((S) -1-propenoyl-4- (7- (8-methylnaphthalen-1-yl) -2- (((R) -tetrahydrofurane-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 (R) -3-hydroxy-tetrahydrofuran starting material was used to finally give the objective compound 11.LC-MS 553[ M+H ]] ⁺ ； ¹ H NMR(400MHz,CDCl ₃ )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-propenoyl-4- (7- (8-methylnaphthalen-1-yl) -2- (((S) -tetrahydrofurane-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 (900 mg,10.03 mmol) in DMF (30 mL) was added 60% NaH (700 mg,17.5 mmol) under stirring, and the reaction mixture was stirred for 30 min. Then 2- (chloromethyl) -4-hydroxy-5, 8-dihydropyridine [3,4-d ] is added thereto]And pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (1 g,3.34 mmol). After stirring the reaction mixture at room temperature for 1 hour, the reaction mixture was diluted with about 100ml of water, pH 7 or so was adjusted with citric acid, and extracted with DCM (100 ml×2). The organic layers were combined and then saturated brine, anhydrous Na ₂ SO ₄ After drying and concentration under reduced pressure, silica gel column chromatography (eluent: ethyl acetate: petroleum ether from 0 to 30%) gave intermediate 3 (600 mg,97% yield). LC-MS 352[ M+H ]] ⁺ 。

Synthesis of intermediate 4: 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 (630 mg,2.34 mmol) was suspended in DCM (30 mL) under nitrogen, to which DIPEA (910 mg,7.02 mmol) and trifluoromethanesulfonic anhydride (1.2 g,4.67 mmol) were added sequentially under stirring at 0deg.C. The reaction was stirred for about 1 hour, and the reaction mixture was concentrated to give intermediate 4 as a brown oil, which was used in the next reaction without purification. L (L)C-MS:484[M+H] ⁺ 。

Synthesis of intermediate 5: tert-butyl (S) -2- (((tetrahydrofuran-3-yl) oxy) methyl) -4- (((trifluoromethyl) sulfonic acid) oxy) -5, 8-dihydropyridine [3,4-d ] under the protection of nitrogen ]Pyrimidine-7 (6H) -carboxylic acid tert-butyl ester 4 (250 mg,0.52 mmol), (S) -2- (cyanomethyl) piperidine-1-carboxylic acid benzyl ester (174 mg,0.67 mmol), DIPEA (135 mg,1.04 mmol) in CH ₃ CN (20 mL) was mixed well, heated to 90℃and reacted for 2 hours with stirring. After the reaction, the mixture was concentrated in vacuo and the residue was chromatographed on silica gel (eluent: meOH: CH) ₂ Cl ₂ From 0-5%) to give intermediate 5 (400 mg crude) as a yellow solid. 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 an ice bath]To a solution of pyrimidine-7 (6H) -carboxylic acid tert-butyl ester intermediate 5 (400 mg crude) in dichloromethane (10 mL) was added TFA (10 mL). The reaction was stirred at 0deg.C for 1 hour. The reaction mixture was poured into saturated NaHCO ₃ In solution. Dichloromethane extraction for several times, combining organic layers and then anhydrous Na ₂ SO ₄ Drying and concentration under reduced pressure gave intermediate 6 (400 mg crude) as a brown solid. LC-MS 493[ M+H ]] ⁺ 。

Synthesis of intermediate 7: under the protection of nitrogen, the (S) -2- (cyanomethyl) -4- (2- ((((S) -tetrahydrofuran-3-yl) oxy) methyl) -5,6,7, 8-tetrahydropyrido [3, 4-d)]Benzyl pyrimidin-4-yl) piperazine-1-carboxylate 6 (400 mg,0.82 mmol) and 1-bromo-8-methylnaphthalene (290 mg,1.30 mmo) were dissolved in toluene (40 mL) and Cs was added ₂ CO ₃ (794 mg,2.43 mmol), ruphos (100 mg,0.21 mmol) and Pd ₂ dba ₃ (100 mg,0.11 mmol). The reaction mixture was warmed to reflux under nitrogen and stirred overnight. Filtering, concentrating the filtrate, and subjecting the concentrated filtrate to silica gel column chromatography (eluent: meOH: CH) ₂ Cl ₂ Intermediate 7 (300 mg,58% yield) was obtained from 0-10%). LC-MS 633[ M+H ]] ⁺ 。

Synthesis of intermediate 8: to (S) -2- (cyanomethyl) -4- (7- (8-methylnaphthalen-1-yl) -2- ((((S) -tetrahydrofurane-3-yl) oxy) methyl) -5,6,7, 8-tetrahydropyrido [3, 4-d) under nitrogen protection]To a solution of benzyl pyrimidin-4-yl-piperazine-1-carboxylate 7 (200 mg,0.32 mmol) in methanol (10 mL) was addedAfter displacement with 10% Pd/C (20 mg), the reaction was stirred at room temperature under hydrogen balloon pressure for about 2 hours, filtered and the filtrate was concentrated to give intermediate 8 (150 mg,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) -tetrahydrofurane-3-yl) oxy) methyl) -5,6,7, 8-tetrahydropyrido [3, 4-d) under ice bath]To a solution of pyrimidin-4-yl) piperazin-2-yl) acetonitrile intermediate 8 (150 mg,0.31 mmol) and DIPEA (104 mg,0.8 mmol) in dichloromethane (20 mL) was added a solution of acryloyl chloride (40 mg,0.44 mmol) in dichloromethane (1 mL). The reaction was stirred at 0deg.C for 1 hour, then quenched by addition of saturated sodium carbonate solution and extracted with dichloromethane (100 mL. Times.2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a liquid phase which was prepared to give 2- ((S) -1-propenoyl-4- (7- (8-methylnaphthalen-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) (47 mg,27% yield). LC-MS 553[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )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-propenoyl-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, starting from (S) -1-methylpyrrolidin-2-yl methanol, the title compound 13 (49 mg,22% yield) was finally obtained. LC-MS 580[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )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-propenoyl-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, starting from (S) -1-methylpyrrolidin-2-yl methanol, the title compound 14 was finally obtained. LC-MS 580[ M+H ]] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )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-propenoyl-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, starting from (R) -1-methylpyrrolidin-3-ol, the target compound 15 was finally obtained (22% yield). LC-MS 566[ M+H ] ] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )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, starting from (R) -1-methylpyrrolidin-3-ol, the desired compound 16 was finally obtained (13% yield). LC-MS: [ M+H ]] ⁺ 566； ¹ H 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 give the objective compound 17.LC-MS 614.28[ M+1 ]] ⁺ 。

Example 18: synthesis of Compound 18.

Referring to example 17, the substitution of 17-1 with its enantiomer eventually gave the target 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 give 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 give 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. Intermediate 21-1 (5 mmol) was dissolved in dry DCM, cooled to 0deg.C, and a solution of intermediate 21-2 in DCM was slowly added dropwise and after 1 hour the reaction was complete by TLC. The reaction was quenched with water, concentrated, and chromatographed on a silica gel column to give the target 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 give 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 give 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 give the target 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 give 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 give the target 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 give the target 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 give the target 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 give the title 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 give the target 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 give the title 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 give the target 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 give the title 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 give the target 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 give the title 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 give the target compound 35.LC-MS 556.31[ M+1 ]] ⁺ 。

Example 37: synthesis of Compound 37.

S1: DMF was added to a round bottom flask containing intermediates 37-1 and 37-2 (1.1 eq.). Stirring the solution, adding N, N-diisopropylethylamine, stirring the mixture for reaction until TLC detection reaction is complete. Saturated aqueous NaCl solution was added, extracted 3 times with ethyl acetate, the organic phase concentrated and chromatographed on a silica gel column to give intermediate 37-3 (mobile phase: dichloromethane/methanol=3:1). LC-MS 571.33[ M+1 ]] ⁺ 。

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

S3: intermediate 37-4, intermediate 37-5 (1 eq.) and Pd ₂ (dba) ₃ (1%, w/w%), ruPhos (1%, w/w%) and Cs ₂ CO ₃ (1 eq.) was dissolved in toluene, purged with nitrogen and heated to 110 ℃. TLC detection reaction is complete, cooling to room temperature, concentrating organic phase, separating by silica gel column chromatography to obtain intermediate 3 7-6 (mobile phase: dichloromethane/methanol=3:1). LC-MS 611.34[ M+1 ]] ⁺ 。

S4: intermediate 37-6 was dissolved in methanol, wet Pd/C (5%, w/w%) was added, nitrogen was substituted 3 times, the reaction was stirred at room temperature and was complete by TLC. 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 desired intermediate 37-7 was obtained in 90% yield. LC-MS 477.30[ M+1 ]] ⁺ 。

S5: intermediate 37-7 is dissolved in dry THF, cooled to 0 ℃, and then acryloyl chloride is slowly added dropwise, and after 1 hour of reaction, TLC detection reaction is complete. The reaction was quenched with water, concentrated, and chromatographed on a column 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, the intermediate 37-1 was replaced with its enantiomer, 37-2 was replaced with benzyl (3 s,5 r) -3, 5-dimethylpiperazine-1-carboxylate, and the title compound 38 was finally obtained. 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 give 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 give the target compound 39.LC-MS 602.30[ M+1 ]] ⁺ 。

Example 41: synthesis of Compound 41.

Referring to example 3, intermediate 3-1The substitution was 41-1 to finally give 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 give the target compound 42.LC-MS 580.30[ M+1 ]] ⁺ 。

Example 43: synthesis of Compound 43.

Referring to example 37, substitution of 37-2 with benzyl (2 r,5 s) -2, 5-dimethylpiperazine-1-carboxylate resulted in the final title compound 43.LC-MS 545.M+1] ⁺ 。

Example 44: synthesis of Compound 44.

Referring to example 37, 37-1 was replaced with its enantiomer, 37-2 was replaced with benzyl (2 s,5 r) -2, 5-dimethylpiperazine-1-carboxylate, and the target compound 44 was finally obtained. LC-MS 545.M+1] ⁺ 。

Example 45: synthesis of Compound 45.

S1: intermediate 45-1, intermediate 45-2 (1 eq.) and Pd ₂ (dba) ₃ (1%, w/w%), ruPhos (1%, w/w%) and Cs ₂ CO ₃ (1 eq.) was dissolved in toluene, purged with nitrogen and heated to 110 ℃. TLC detection was complete, cooled to room temperature, the organic phase concentrated and chromatographed on silica gel to give intermediate 45-3 (mobile phase: dichloromethane/methanol=5:1). LC-MS 602.34[ M+1 ] ] ⁺ 。

The subsequent procedure is as described in example 3, finally giving 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, the intermediate 3-1 was replaced with 46-1 and 3-2 was replaced with 46-2, and the objective compound 46 was finally obtained. 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 give the title 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, 47-5 was replaced with 1-bromo-4-fluoro-2- (trifluoromethyl) benzene, and the title compound 48 was finally obtained. LC-MS 616.20[ M+1 ]] ⁺ 。

Example 49: synthesis of Compound 49.

Referring to example 37, the substitution of 37-2 for 49-2 and 37-5 for 8-bromo-2-naphthol resulted in the final product of the title compound 49.LC-MS 568.30[ M+1 ]] ⁺ 。

Example 50: synthesis of Compound 50.

Referring to example 49, substitution of 49-1 with its enantiomer, substitution of 49-5 with 5-bromoquinoline, resulted in the final title 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, the enantiomer of 51-1 was replaced to obtain the final target 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, ultimately yielding 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 give the target 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 give the target 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 give the target 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 afford the title 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 give the target 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 give 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 give the target 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 give 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 give the target 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 give the target 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 give the target 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 give 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 give the target 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 give the title 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 give the target compound 68.LC-MS 570.27[ M+1 ]] ⁺ 。

Example 69: synthesis of Compound 69.

Referring to example 3, intermediate 3-5 was replaced with 1-bromo-3-fluoro-2- (trifluoromethyl) benzene to finally 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 give the target 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 finally afford 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 its enantiomer to finally give the target compound 72.LC-MS 570.32[ M+1 ] ] ⁺ 。

Example 73: synthesis of Compound 73.

Referring to example 3, the intermediate 3-5 was replaced with 1-bromo-8-chlorophenol and the 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 give the target 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 give 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 enantiomerThe structure finally gives the target 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 give the target 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 give the title 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 give the target 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 yield 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 give the target 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 give the title 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 give the target 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 give the target compound 84.LC-MS 454.29[ M+1 ]] ⁺ 。

Example 85: synthesis of Compound 85.

With reference to example 3, the corresponding intermediate is modified to obtainTo 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 give the target 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 give the target 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 give the 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 give 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 give the title 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 give 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 give the target compound 92.LC-MS 592.33[ M+1 ]] ⁺ 。

Example 93: synthesis of Compound 93.

Referring to example 92, the intermediate 92-5 was replaced with 5-bromo-1, 2,3, 4-tetrahydrophenanthrene to finally give the target compound93。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 give the target 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 afford the title 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 give the target 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 give the 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 give the target 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 give the title compound 99.LC-MS 588.26[ M+1 ]] ⁺ 。

Example 100: synthesis of Compound 100.

Referring to example 3, intermediate 3-5 was replaced with 1-bromo-8-chloronaphthalene to finally give the target 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 replaced1-bromo-8-chloronaphthalene, and finally the target compound 101 is obtained. 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 finally afford 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 finally 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 yield the title 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 intermediate 3-5 was replaced with 1-bromo-2, 3-dimethylbenzene to finally afford the target compound 105.LC-MS 530.32[ M+1 ]] ⁺ 。

Example 106: synthesis of Compound 106.

Referring to example 3, the substitution of intermediate 3-1 with 106-1,3-5 with 4-bromo-2-naphthol ultimately affords the title 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 give the target 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, most preferablyThe target compound 108 is finally obtained. 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 give the target 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 afford the title 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 give the target compound 111.LC-MS 612.28[ M+1 ]] ⁺ 。

Example 112: synthesis of Compound 112.

Referring to example 56, the intermediate 56-5 was replaced with 1-bromo-8-chloronaphthalene to finally give the 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 give the target 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- (tridentate methyl) naphthalene, ultimately yielding the target 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- (tridentate methyl) naphthalene to finally give the title compound 115.LC-MS 569.34[ M+1 ]] ⁺ 。

Example 116: synthesis of Compound 116.

Referring to example 3, intermediate 3-1Replacement by its enantiomeric form, replacement of 3-5 by 1-bromo-2- (1-methylcyclopropyl) benzene, ultimately gives the title 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 give the title 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 give the target 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 give the target compound 119.LC-MS 567.31[ M+1 ]] ⁺ 。

Example 120: synthesis of compound 120.

Referring to example 3, the substitution of acryloyl chloride with 2-fluoroacryloyl chloride resulted in the final product of 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 the acryloyl chloride was replaced with 2-fluoroacryloyl chloride to finally give the title compound 121.LC-MS 584.31[ M+1 ]] ⁺ 。

Example 122: synthesis of Compound 122.

Referring to example 3, the substitution of acryloyl chloride with (E) -4, 4-trifluoro-2-butenoyl chloride eventually yielded the target 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-trifluoro-2-butenoyl chloride to finally give the target compound 123.LC-MS 634.30[ M+1 ]] ⁺ 。

Example 124: synthesis of Compound 124.

Referring to example 3, the substitution of acryloyl chloride with 2- (trifluoromethyl) acryloyl chloride eventually led to 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 the acryloyl chloride was replaced with 2- (trifluoromethyl) acryloyl chloride to finally give the title 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 the acryloyl chloride was replaced with 2-fluoroacryloyl chloride to finally give the title 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 give the target 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 the acryloyl chloride was replaced with (E) -4, 4-trifluoro-2-butenoyl chloride, to finally give the title 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-trifluoro-2-butenoyl chloride, to finally give the title compound 129.LC-MS 654.25[ M+1 ] ] ⁺ 。

Example 130: synthesis of compound 130.

Referring to example 3, the intermediate 3-5 was replaced with 1-bromo-8-chloronaphthalene and the acryloyl chloride was replaced with 2- (trifluoromethyl) acryloyl chloride, to finally give 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 the acryloyl chloride was replaced with 2- (trifluoromethyl) acryloyl chloride, to finally give the objective 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 the acryloyl chloride was replaced with 2-fluoroacryloyl chloride to finally give the target compound 132.LC-MS 586.29[ M+1 ]] ⁺ 。

Example 133: synthesis of Compound 133.

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 2-fluoroacryloyl chloride, to finally give the title compound 133.LC-MS 586.29[ M+1 ]] ⁺ 。

Example 134: synthesis of Compound 134.

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

Example 137: synthesis of Compound 137.

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 2- (trifluoromethyl) acryloyl chloride to finally give the title compound 137.LC-MS 636.28[ M+1] ⁺ 。

Example 138: synthesis of Compound 138.

Referring to example 3, the substitution of acryloyl chloride with 2-fluoroacryloyl chloride resulted in the final product 138.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 the acryloyl chloride was replaced with 2-fluoroacryloyl chloride to finally 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 the acryloyl chloride was replaced with 2-fluoroacryloyl chloride, to finally obtain the target compound 140.LC-MS 604.25[ M+1 ]] ⁺ 。

Example 141: synthesis of Compound 141.

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 141.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 the acryloyl chloride was replaced with 2-methacryloyl chloride to finally give the title compound 142.LC-MS 582.31[ M+1 ]] ⁺ 。

Example 143: synthesis of Compound 143.

Referring to example 3, 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 give the target compound 143.LC-MS 604.25[ M+1 ]] ⁺ 。

Example 144: synthesis of Compound 144.

Referring to example 3, the substitution of acryloyl chloride with (E) -4-fluoro-2-butenoyl chloride eventually yielded the target 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 give the target 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 the acryloyl chloride was replaced with (E) -4-fluoro-2-butenoyl chloride, to finally give the target compound 146.LC-MS 618.27[ M+1 ]] ⁺ 。

Example 147: synthesis of Compound 147.

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-fluoro-2-butenoyl chloride, to finally give the title 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 the acryloyl chloride was replaced with (E) -4-fluoro-2-butenoyl chloride to finally give the title compound 148.LC-MS 600.30[ M+1 ]] ⁺ 。

Example 149: synthesis of Compound 149.

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-fluoro-2-butenoyl chloride, to finally give the title compound 149.LC-MS 600.30[ M+1 ]] ⁺ 。

Example 150: synthesis of Compound 150.

Referring to example 3, the substitution of acryloyl chloride with (E) -4- (cyclopropylamino) -2-butenoyl chloride eventually gave the title 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 the acryloyl chloride was replaced with (E) -4- (cyclopropylamino) -2-butenoyl chloride, to finally give the title compound 151.LC-MS 635.37[ M+1 ]] ⁺ 。

Example 152: synthesis of Compound 152.

Referring to example 3, the substitution of acryloyl chloride with (E) -4- (cyclopropylamino) -2-butenoyl chloride, and the substitution of intermediate 3-5 with 1-bromo-8-chloronaphthalene, resulted in 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, and intermediate 3-5 was replaced with 1-bromo-8-chloronaphthalene, to finally give the target compound 153.LC-MS 655.32[ M+1 ]] ⁺ 。

Example 154: synthesis of Compound 154.

Referring to example 3, the substitution of acryloyl chloride with (E) -4- (cyclopropylamino) -2-butenoyl chloride, and the substitution of intermediate 3-5 with 4-bromo-2-naphthol, resulted in the title 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, acryloyl chloride was replaced with (E) -4- (cyclopropylamino) -2-butenoyl chloride, and intermediate 3-5 was replaced with 4-bromo-2-naphthol, to finally give the objective 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, ERK protein phosphorylation assays were selected for evaluation.

H358 cells expressing KRAS G12C protein (ATCC, CRL-5807) were inoculated at 6000 cells/well in polylysine coated 384 well cell culture plates (Corning, BD 356663) in medium composition RPMI 1640 (Gibco, A10491-01), 10% FBS (Gibco, 10099141C) and 1% pen/Strep (Gibco, 15140-122) at 5% CO ₂ Culturing in a cell incubator for 16 hours; adding the gradient diluted compound into a cell culture medium by using Echo550, wherein the final concentration of DMSO is 0.5%, and culturing for 3 hours; then 40. Mu.L/well of 8% paraformaldehyde (Solarbio, P1112) was added and incubated at room temperature for 20min; after one PBS wash, 40. Mu.L/well cold 100% methanol was added, chamberPenetrating at temperature for 10min; after one washing with PBS, 20. Mu.L/well of blocking solution (LI-COR, 927-40000) was added and blocked at room temperature for 1h; then, the rabbit anti-phospho-p 44/42MAPK (T202/Y204) antibody (CST, 4370S) was diluted 1:1000 with blocking solution, the mouse anti-GAPDH (D4℃ 6R) antibody (CST, 97166S) was diluted 1:2000, added to the cells at 20. Mu.L/well, and blocked overnight at 4 ℃; PBST was washed 3 times, incubated 2min each, after which sheep anti-rabbit 800CW antibody (LI-COR, 926-32211) and sheep anti-mouse 680RD antibody (LI-COR, 926-68070) were diluted 1:1000 with blocking solution, added to cells at 20. Mu.L/well and incubated for 45min at room temperature; PBST was washed 3 times, each incubated for 2min, and finally the cell culture plates were back-off centrifuged at 1000rpm,1min before fluorescent signal values were read with Odyssey CLx.

The data were expressed by XLFIT 5.0 as a 4-parameter formula Y=bottom+ (Top-Bottom)/(1+10 ((LogIC) ₅₀ -X) ×hillslope)) fit calculation IC ₅₀ The values and results are shown in Table 1. "A" is IC ₅₀ <1. Mu.M; "B" is IC ₅₀ ≥1μM；

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

As can be seen from the above table data, most of the compounds of the present invention are effective in inhibiting KRAS G12C protein-mediated downstream H358 cell signaling (p-ERK) phosphorylation and are useful as KRAS G12C protein inhibitors.

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

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 cells H358.

1) Reagent, consumable 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 rinsed once with DPBS.

c) At Room Temperature (RT) or 37℃with 2mL TrypLE ^TM Express enzyme performs trptinize on cells until cells 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 fresh medium and passed through Countess ^TM II cells were counted.

f) The cell seeds were returned to the T75 flask for further culture or placed in assay plates for 3D cell proliferation assays.

3) 3D cell proliferation assay Experimental procedure:

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

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

c) Recording signals using Envision

4) Data analysis:

a) Test robustness check was performed using 0.5% dmso and medium blank data:

h = mean (DMSO); l=mean (medium);

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

CV% (DMSO) =100 x (SD DMSO/mean DMSO);

CV% (medium) =100 x (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) Fitting cpd IC50 according to the nonlinear regression equation:

y=peak valley+ (peak top-peak valley)/(1+10;

x: logarithm of compound concentration;

Y: percent inhibition (% inh);

peak top value and peak valley value: the unit of the platform period is the same as Y;

log ic50: the same logarithmic units as X;

HillSlope: gradient coefficient or Hill gradient;

4) The results are summarized in table 2.

TABLE 2 inhibition of proliferation of H358 tumor cells by test compounds

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Claims

1. A compound having the structure of formula IE:

or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof in any ratio, wherein:

l is-O-;

X ₀ is-n=;

X ₁ and X ₂ Each independently is-ch=;

R ₁ is pyrrolidin-2-yl; and R is ₁ Hydrogen in the structure is optionally replaced by 0 to multiple R ₇ Substitution; each R is ₇ Each independently is C ₁ -C ₄ An alkyl group;

R ₃ phenyl, naphthyl or pyridyl; and R is ₃ Hydrogen in the structure is optionally replaced by 0 to multiple R ₇ Substitution; each R is ₇ Each independently is halogen, C ₁ -C ₄ Alkyl, halogenated C ₁ -C ₄ Alkyl or amino;

n is 2; two R ₂ Are hydroxyl groups, and after dehydration, the two hydroxyl groups together with the carbon atom to which they are attached form c=o;

m is 1; r is R ₆ Is cyano C ₁ -C ₄ An alkyl group;

R ₄ and R is ₅ Each independently is hydrogen.

2. The compound having the structure of formula IE according to claim 1, which is a compound selected from the following structures:

3. a pharmaceutical composition comprising a compound having the structure of formula IE according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or mixture thereof in any proportion.

4. Use of a compound having the structure of formula IE according to claim 1 or 2 or a pharmaceutically acceptable salt, stereoisomer or mixture thereof in any proportion or a pharmaceutical composition according to claim 3 for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by KRAS G12C protein.