CN113544128A

CN113544128A - KRAS-G12C inhibitors

Info

Publication number: CN113544128A
Application number: CN202080016738.0A
Authority: CN
Inventors: 谢雨礼; 樊后兴
Original assignee: Wigen Biomedicine Technology Shanghai Co Ltd
Current assignee: Wigen Biomedicine Technology Shanghai Co Ltd
Priority date: 2019-06-26
Filing date: 2020-06-22
Publication date: 2021-10-22
Anticipated expiration: 2040-06-22
Also published as: CN110256421A; CN113544128B; WO2020259432A1

Abstract

The invention provides a G12C mutant K-Ras protein irreversible inhibitor, and also discloses the G12C mutant K-Ras protein irreversible inhibitor, a preparation method and application thereof.

Description

KRAS-G12C inhibitors

The present application claims priority from chinese patent application CN2019105708974, filed on 26.6.2019. The present application refers to the above-mentioned chinese patent application in its entirety.

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a novel KRAS-G12C inhibitor, a preparation method thereof and a use method of the compound.

Background

RAS represents a group of closely related monomeric globular proteins (21kDa molecular weight) of 189 amino acids that are associated with the plasma membrane and bind GDP or GTP. Under normal developmental or physiological conditions, RAS is activated upon receipt of growth factors and various other extracellular signals, and is responsible for regulating functions such as cell growth, survival, migration and differentiation. RAS functions as a molecular switch, with the on/off state of the RAS protein determined by nucleotide binding, the active signaling conformation binding GTP, and the inactive conformation binding GDP. When the RAS comprises bound GDP, it is in a dormant or resting or off state and is "inactive," RAS is induced to convert the bound GDP to GTP in response to exposure to certain pro-stimulatory stimuli. With GTP bound, RAS is "on" and is able to interact with and activate other proteins (their "downstream targets"). The RAS protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP and thereby turn itself off. Switching RAS off requires exogenous proteins called Gtpase Activating Proteins (GAPs), which interact with RAS and greatly facilitate conversion of GTP to GDP. Any mutation in the RAS that affects its ability to interact with GAPs or convert GTP back to GDP will result in prolonged activation of the protein and thus produce a prolonged signal to the cell that tells it to continue growing and dividing. These signals can therefore allow cells to grow and divide, and overactivated RAS signal transduction may ultimately lead to cancer.

Among RAS family members, oncogenic mutations are most common in KRAS (85%), whereas NRAS (12%) and HRAS (3%) are less common. KRAS mutations are prevalent in three major cancer types in the united states: pancreatic cancer (95%), colorectal cancer (45%) and lung cancer (25%), while rarely found (< 2%) in breast, ovarian and brain cancers. In non-small cell lung cancer (NSCLC), KRAS G12C is the most common mutation, accounting for nearly half of all KRAS mutations, followed by G12V and G12D. In non-small cell lung cancer, the increase in frequency of specific allelic mutations is mostly due to classical smoking-induced canonical mutations (G: C to T: A substitutions), resulting in KRAS G12C (GGT to TGT) and G12V (GGT to GTT) mutations.

Large genomics studies indicate that lung cancer KRAS mutations, including G12C, are mutually exclusive from other known driver oncogenic mutations in NSCLC, including EGFR, ALK, ROS1, RET, and BRAF, indicating the uniqueness of KRAS mutations in lung cancer. At the same time, KRAS mutations often occur in conjunction with certain co-mutations, such as STK11, KEAP1, and TP53, which cooperate with the mutated RAS to transform cells into highly malignant and aggressive tumor cells.

The three RAS oncogenes constitute the most frequently mutated gene family in human cancers. Disappointingly, despite over thirty years of research efforts, there is still no clinically effective anti-RAS therapy, and the use of small molecules to target this gene is a challenge. Thus, there is an urgent need in the art for small molecules for targeting and utilizing RAS (e.g., K-RAS, H-RAS and/or N-RAS) to treat various diseases, such as cancer.

Disclosure of Invention

The invention aims to provide a compound with a structural general formula shown in formula (1), or optical isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:

in formula (1):

m is 0, 1 or 2;

a is a bivalent 4-12 membered saturated or partially saturated monocyclic, bicyclic, bridged or spirocyclic ring containing 1-2N atoms, optionally substituted with one or more R⁴Substituted when by more than one R⁴When substituted, R⁴May be the same or different;

y is a bond or C1-C6 alkylene;

R ¹is aryl or heteroaryl, which may be substituted with 1to 3 of the following groups: halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl or halogen-substituted C1-C3 alkoxy;

R ²is aminoalkyl, cycloalkyl, alkyl-substituted amido, heterocyclyl, aryl or heteroaryl, said heterocyclyl, aryl or heteroaryl being optionally substituted with one or more R⁵Substituted when by more than one R⁵When substituted, R⁵May be the same or different;

R ³independently selected C1-C3 alkyl or halogenated C1-C3 alkyl;

R ⁴independently selected from H, CN, C1-C3 alkyl, halogen substituted C1-C3 alkyl or cyano substituted C1-C3 alkyl;

R ⁵independently selected from halogen, H, O, CN, OH, alkyl hydroxyl, dialkyl amido, C1-C6 alkyl, C3-C6 cycloalkyl, halogen substituted C1-C3 alkyl or halogen substitutedC1-C3 alkoxy;

e is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of the K-Ras, H-Ras or N-Ras mutant protein.

In another preferred embodiment, wherein in said formula (1), E is a group containing an electrophilic carbon-carbon double bond or carbon-carbon triple bond.

In another preferred embodiment, wherein in the formula (1), E is:

wherein R is_aIs H or F, R_bIs H, -CH₂F、-CHF ₂、

In another preferred embodiment, wherein in said formula (1), a-E are:

wherein n is 1 or 2, R⁴Is H, CN, C1-C3 alkyl, halogen substituted C1-C3 alkyl or cyano substituted C1-C3 alkyl.

In another preferred embodiment, wherein in the formula (1), Y is a bond, -CH₂-, -CH (Me) -or-CH₂CH ₂-。

In another preferred embodiment, wherein in said formula (1), R¹Comprises the following steps:

wherein R is_cAnd R_dIndependently halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl or halogen substituted C1-C3 alkoxy.

In another preferred embodiment, wherein in said formula (1), R²Comprises the following steps:

wherein n is 1 or 2, R_eAnd R_fIndependently H, halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl or halogen substituted C1-C3 alkoxy, R_gIs C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, C1-C3 alkoxyalkyl, halogen substituted C1-C3 alkyl, halogen substituted C3-C6 cycloalkyl or

In another aspect of the present invention, a compound having a general structural formula shown in formula (2), or each optical isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof is provided:

in formula (2):

y is a bond or C1-C6 alkylene;

w is N, C-R⁸Or C-O-R⁶：

Wherein, when W is C-O-R⁶When R is²Is aminoalkyl, cycloalkyl, alkyl-substituted amido, heterocyclyl, aryl or heteroaryl, said heterocyclyl, aryl or heteroaryl being optionally substituted with one or more R⁵Substituted when by more than one R⁵When substituted, R⁵May be the same or different;

wherein, when W is N or C-R⁸When R is²Is aminoalkyl, alkyl-substituted amido or heterocyclyl, said heterocyclyl being optionally substituted with one or more R⁵Substituted when by more than one R⁵When substituted, R⁵May be the same or different;

R ¹is aryl or heteroaryl, which may be substituted with 1to 3 of the following groups: halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy;

R ⁵independently selected from halogen, H, O, CN, OH, alkyl hydroxyl, dialkyl amido, C1-C6 alkyl, C3-C6 cycloalkyl, halogen substituted C1-C3 alkyl or cyano substituted C1-C3 alkyl;

R ⁶is C1-C3 alkyl, halogen substituted C1-C3 alkyl or C3-C6 cycloalkyl;

R ⁷is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy or C2-C4 alkenyl;

R ⁸is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl or halogen substituted C1-C3 alkyl;

In another preferred embodiment, wherein in said formula (2), E is a group containing an electrophilic carbon-carbon double bond or carbon-carbon triple bond.

In another preferred embodiment, wherein in the formula (2), E is:

wherein R is_aIs H or F, R_bIs H, -CH₂F、-CHF ₂、

In another preferred embodiment, wherein in said formula (2), a-E are:

wherein n is 1 or 2, wherein R⁴Is H, CN, C1-C3 alkyl, halogen substituted C1-C3 alkyl or cyano substituted C1-C3 alkyl.

In another preferred embodiment, wherein in the formula (2), Y is a bond, -CH₂-, -CH (Me) -or-CH₂-CH ₂-。

In another preferred embodiment, wherein in said formula (2), R¹Comprises the following steps:

In another preferred embodiment, wherein in said formula (2), W is C-O-R⁶，R ²Comprises the following steps:

wherein n is 1 or 2, R_eAnd R_fIndependently is halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl or halogen substituted C1-C3 alkoxy, R_gIs C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, C1-C3 alkoxyalkyl, halogen substituted C1-C3 alkyl, halogen substituted C3-C6 cycloalkyl or

In another preferred embodiment, wherein in the formula (2), W is N or C-R⁸，R ²Comprises the following steps:

In various embodiments, the compound has one of the structures listed in table 1 below:

table 1 list of representative compounds of the invention:

another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and, as an active ingredient, a compound of the present invention represented by the general formula (1) or (2), or each of the optical isomers thereof, or a pharmaceutically acceptable inorganic or organic salt thereof.

Still another object of the present invention is to provide the use of the above compound, or each optical isomer, pharmaceutically acceptable inorganic or organic salt thereof, for preparing a medicament for treating tumor-related diseases.

It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

Synthesis of Compounds

The following specifically describes the preparation methods of the compounds of the general formulae (1) and (2) of the present invention, but these specific methods do not limit the present invention in any way.

The compounds of formula (1) and formula (2) described above may be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of the compounds may be obtained synthetically or from commercial sources, such as, but not limited to, Aldrich Chemical co. (Milwaukee, Wis.) or Sigma Chemical co. (st. The compounds described herein and other related compounds having various substituents can be synthesized using well-known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4^thEd., (Wiley 1992); carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4^thEd, Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC synthieSIS 3^rdThe method in ed., (Wiley 1999). The general method of compound preparation may be varied by the use of appropriate reagents and conditions for introducing different groups into the formulae provided herein.

In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, and the like, are not limited to the following explanation. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains. In one aspect, the present invention also provides a method for preparing the compounds represented by the general formula (1) and the general formula (2), which is prepared by the following general reaction scheme 1,2, 3 or 4:

general reaction scheme 1

Embodiments of the compounds of formula (1) may be prepared according to general reaction scheme 1 (method A), wherein R¹、R ²、R ⁴A, E and Y are as defined above, X represents I, Br, Cl, OTf, -B (OH)₂And the like. As shown in general reaction scheme 1, intermediate a1 (synthesized with reference to the method described in WO 2017201161) and fragment a produced a2 under basic conditions, the compound of structure a2 produced A3 in the presence of an oxidizing agent, compound A3 produced a4 under basic conditions, a4 under appropriate conditions and R²Reaction of the-Y-X fragment to A5, deprotection of A5 (e.g., Boc) to A6, coupling of A6 and R1-X to A7, deprotection of A7 (e.g., Cbz) to A8, and reaction of A8 with an acid chloride or anhydride compound to A9.

General reaction scheme 2

In one aspect, embodiments of the compounds of formula (2) may be prepared according to general reaction scheme 2 (method B), wherein R¹、R ²、R ⁴、R ⁶、R ⁷A, E and Y are as defined above, X represents I, Br, Cl, OTf, -B (OH)₂And the like. Intermediate B1 (see WO 20161646) as shown in general reaction scheme 275) and fragment a under basic conditions to form B2, compounds of structure B2 under basic conditions to form B3, compounds B3 under basic conditions to form B4, B4 under appropriate conditions and R²Reaction of the fragment of-Y-X to give B5, B5 and R¹Coupling of-X to give B6, continuation of B6 and R⁷Coupling X to give B7, deprotecting B7 (e.g., Cbz) to give B8, reacting B8 with an acid chloride or anhydride compound to give B9.

General reaction scheme 3

On the other hand, embodiments of the compounds of formula (2) may be prepared according to general reaction scheme 3 (method C), wherein R¹、R ²、R ⁴、R ⁷A, E and Y are as defined above, X represents I, Br, Cl, OTf, -B (OH)₂And the like. As shown in general scheme 3, intermediate C1 (synthesized as described in reference to U.S. Pat. No. 3,325,675) is amidated to yield C2, the compound of structure C2 is reacted with an appropriate reagent to yield a substituted isocyanate, which is further reacted to yield C3, compound C3 is reacted under basic conditions to yield pyrimidinedione intermediate C4, C4 is reacted under appropriate conditions with a chlorinating reagent to yield C5, and C5 is reacted under basic conditions to yield C6, C6 and R¹Coupling with-X gives C7, deprotection of C7 (e.g., Boc) gives C8, and reaction of C8 with acid chloride or anhydride compounds gives C9.

General reaction scheme 4

In yet another aspect, embodiments of the compounds of formula (2) may be prepared according to general reaction scheme 4 (method D), wherein R¹、R ²、R ⁴、R ⁷、R ⁸A, E and Y is asAs defined hereinabove. As shown in general scheme 4, intermediate D1 (synthesized as described in WO 2016164675) and fragment A under basic conditions gave D2, the compound of structure D2 gave D3 under basic conditions, D3 under appropriate conditions and R²Reaction of the fragment of-Y-X to yield D4, D4 and R¹Coupling with-X gives D5, deprotection of D5 (e.g., Boc) gives D6, and reaction of D6 with an acid chloride or anhydride compound gives D7.

Further forms of the compounds

"pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, which does not diminish the biological activity or properties of the compound and which is relatively non-toxic, e.g., by being administered to an individual without causing unwanted biological effects or interacting in a deleterious manner with any of the components it contains.

The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain particular aspects, pharmaceutically acceptable salts are obtained by reacting a compound of formula (1) or formula (2) with an acid, such as an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, etc., an organic acid, e.g., formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., and an acidic amino acid, e.g., aspartic acid, glutamic acid, etc.

References to pharmaceutically acceptable salts are understood to include solvent addition forms or crystalline forms, especially solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of the compounds of formula (1) or formula (2) are conveniently prepared or formed according to the methods described herein. For example, the hydrate of the compound of formula (1) or (2) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, using an organic solvent including, but not limited to, dioxane, tetrahydrofuran, ethanol or methanol. In addition, the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to unsolvated forms for purposes of the compounds and methods provided herein.

In other embodiments, the compounds of formula (1) or formula (2) are prepared in different forms, including, but not limited to, amorphous, pulverized, and nano-sized forms. In addition, the compound of formula (1) or formula (2) includes crystalline forms, and may also be polymorphic forms. Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.

In another aspect, the compounds of formula (1) or formula (2) have one or more stereogenic centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and individual diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.

Term(s) for

Unless otherwise defined, terms used in this application, including the specification and claims, are defined as follows. It must be noted that, in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used, if not otherwise stated. In this application, "or" and "means" and/or "are used unless otherwise stated.

"alkyl" means saturatedAliphatic hydrocarbon groups including straight and branched chain groups of 1to 6 carbon atoms. Lower alkyl groups having 1to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH₃，CH ₃CH ₂，CF ₃，CHF ₂，CF ₃CH ₂， ⁱPr， ⁿPr， ⁱBu， ^cPr， ⁿBu or^tBu。

"cycloalkyl" refers to a 3-to 6-membered all-carbon monocyclic aliphatic hydrocarbon group in which one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, cyclohexadiene and the like.

"alkoxy" refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom. Representative of alkoxy groups are alkoxy groups having 1to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, especially alkoxy groups substituted with one or more halogens. Preferred alkoxy groups are selected from OCH₃，OCF ₃，CHF ₂O，CF ₃CH ₂O， ⁱPrO， ⁿPrO， ⁱBuO， ^cPrO， ⁿBuO or^tBuO。

"aryl" refers to a group having at least one aromatic ring structure, i.e., a carbocyclic aryl group having a conjugated pi-electron system, such as a benzene ring and a naphthalene ring.

"heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), the heteroaryl being monocyclic or polycyclic, e.g., a monocyclic heteroaryl ring fused to one or more carbocyclic aromatic groups or other monocyclic heterocyclic groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridyl, and pyrrolopyrimidinyl.

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

The term "bond" or "single bond" refers to a chemical bond between two atoms or between two moieties when the atoms connected by the bond are considered part of a larger structure. In one aspect, when a group described herein is a bond, the absence of a reference group allows for the formation of a bond between the remaining defined groups.

The term "membered ring" includes any cyclic structure. The term "element" is intended to mean the number of backbone atoms constituting a ring. Thus, for example, cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings and cyclopentyl, pyrrolyl, furanyl and thienyl are five-membered rings.

The term "fragment" refers to a specific part or functional group of a molecule. Chemical moieties are generally considered to be chemical entities contained in or attached to a molecule.

Specific pharmaceutical and medical terms

The term "acceptable", as used herein, means that a prescribed component or active ingredient does not unduly adversely affect the health of the general therapeutic target. The terms "treat," "treatment process," or "therapy" as used herein include alleviating, inhibiting, or ameliorating a symptom or condition of a disease; inhibiting the generation of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or condition, such as controlling the development of a disease or condition; alleviating the disease or symptoms; regression of the disease or symptoms; alleviating a complication caused by the disease or symptom, or preventing or treating a symptom caused by the disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, can ameliorate a disease, symptom, or condition, particularly severity, delay onset, slow progression, or reduce duration of a condition. Whether fixed or temporary, sustained or intermittent, may be due to or associated with administration.

"active ingredient" means a compound represented by the general formula (1) or the general formula (2), and a pharmaceutically acceptable inorganic or organic salt of the compound of the general formula (1) or the general formula (2). The compounds of the present invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and individual diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.

The terms "compound", "composition", "medicament" or "drug" are used interchangeably herein and refer to a compound or composition that, when administered to an individual (human or animal), induces a desired pharmaceutical and/or physiological response through local and/or systemic action.

The term "administered" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug (produg), derivative (derivative), or analog (analog) of the active compound, which results in an equivalent amount of the active compound in the individual to whom it is administered.

Although numerical ranges and parameters setting forth the broad scope of the invention are approximate, the values set forth in the specific examples are presented as precisely as possible. Any numerical value, however, inherently contains certain standard deviations found in their respective testing measurements. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within the acceptable standard error of the mean, as considered by those skilled in the art. Except in the experimental examples, or where otherwise expressly indicated, it is to be understood that all ranges, amounts, values and percentages herein used (e.g., to describe amounts of materials, length of time, temperature, operating conditions, quantitative ratios, and the like) are to be modified by the word "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, these numerical parameters are to be understood as meaning the number of significant digits recited and the number resulting from applying ordinary carry notation.

Unless defined otherwise herein, the scientific and technical terms used herein have the same meaning as is commonly understood and used by one of ordinary skill in the art. Furthermore, as used herein, the singular tense of a noun, unless otherwise conflicting with context, encompasses the plural form of that noun; the use of plural nouns also covers the singular form of such nouns.

Therapeutic uses

The invention provides methods of treating conditions, including but not limited to conditions (e.g., cancer) involving G12C K-Ras, G12C H-Ras and/or G12C N-Ras mutations, using the compounds or pharmaceutical compositions of the invention. In some embodiments, there is provided a method for the treatment of cancer, the method comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of structure (1) or (2). In some embodiments, the cancer is mediated by K-Ras, H-Ras and/or G12C N-Ras mutations. In other embodiments, the cancer is lung cancer, pancreatic cancer, colon cancer, MYH-related polyposis, or colorectal cancer.

Route of administration

The compound and the pharmaceutically acceptable salt thereof can be prepared into various preparations, wherein the preparation comprises the compound or the pharmaceutically acceptable salt thereof in a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. Wherein "safe, effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined by the age, condition, course of treatment and the like of a treated subjectThe situation is determined. "pharmaceutically acceptable excipient or carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being blended with the compounds of the present invention and with each other without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifiers

Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like. When the compounds of the present invention are administered, they may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like. In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof. Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary. The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1to 1000mg, preferably 10 to 500 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner. The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.

The various specific aspects, features and advantages of the compounds, methods and pharmaceutical compositions described above are set forth in detail in the following description, which makes the present invention clear. It should be understood herein that the detailed description and examples, while indicating specific embodiments, are given by way of illustration only. After reading the description of the invention, one skilled in the art can make various changes or modifications to the invention, and such equivalents fall within the scope of the invention as defined in the application. In all of the embodiments described herein, the first,¹H-NMR was recorded using a Vian Mercury 400 NMR spectrometer with chemical shifts expressed in delta (ppm); the silica gel used for separation is not illustrated to be 200-300 meshes, and the proportions of the eluents are volume ratios. The invention employs the following abbreviations: ar represents argon; CDCl₃Represents deuterated chloroform; CDI represents 1,1' -carbonyldiimidazole; CD (compact disc)₃OD represents deuterated methanol; CuI represents cuprous iodide; DCM represents dichloromethane; DIPEA stands for diisopropylethylamine; DMF represents dimethylformamide; DMSO represents divaricate knotweed herb; EA represents ethyl acetate; h represents hour; NaOH represents sodium hydroxide; LC-MS stands for liquid-mass spectrometry; m-CPBA represents m-chloroperoxybenzoic acid; MeOH stands for methanol(ii) a min represents min; MS represents mass spectrum; NMR stands for nuclear magnetic resonance; pd (dppf)2Cl2 represents [1,1' -bis (diphenylphosphino) ferrocene]A palladium dichloride dichloromethane complex; PE represents petroleum ether; Ruphos-Pd-G3 represents methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II); TFA represents trifluoroacetic acid; THF represents tetrahydrofuran.

Detailed Description

Example 1 Synthesis of (S) -4- (4-acryloylpiperazin-1-yl) -7- (5-methyl-1H-indazol-4-yl) -1- ((1-methylpyrrolidin-2-yl) methyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-2 (1H) -one (Compound 1)

Compound 1 was prepared according to method a as described below:

4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- (methylthio) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (1-1)

A1(5.2g, 12.11mmol), DIPEA (3.2g, 24.22mmol), benzyl-1-piperazinecarbonate (2.9g, 13.31mmol) and DMF (50mL) were added to a 250mL single-neck flask and the reaction was allowed to warm to 100 ℃ for 1 hour under Ar protection. TLC (PE/EA 10/1) to complete the reaction, cooling the reaction mixture to room temperature, adding water (100mL), extracting with EA (50mL × 2), combining the organic phases, washing with saturated sodium chloride, concentrating the organic phase, and purifying by column chromatography (PE/EA 1/0to 2/1) to give 1-1(6.03g, 99% yield) as a white solid, ESI-MS M/z:500.2[ M + H ], (ESI-MS M/z: 1/0)] ⁺。

4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2- (methylsulfonyl) -5, 8-dihydropyrido [3,4-d ] pyrimidine-7 (6H) -carboxylic acid tert-butyl ester (1-2)

A250 mL single neck flask was charged with 1-1(6.03g, 12.07mmol) and DCM (60mL) under Ar protection, cooled to 0-5 deg.C in an ice bath, charged with m-CPBA (7.29g, 42.24mmol), and reacted in an ice bath for 2 hours. TLC (PE/EA 1/10) and the starting material reacted completely, saturated sodium bicarbonate solution (60mL) was added to the reaction mixture, stirred,liquid separation; the aqueous phase was extracted with DCM (50mL), the organic phases were combined, washed with saturated sodium chloride, the organic phase was concentrated and purified by column chromatography (PE/EA: 1: 0to 1/1) to give 1-2(4.96g, yield 78%) as a white solid, ESI-MS M/z:532.1[ M + H ]/(ESI-M/z): 532.1] ⁺。

4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -2-oxo-2, 5,6, 8-tetrahydropyrido [3,4-d ] pyrimidine-7 (1H) -carboxylic acid tert-butyl ester (1-3)

A 250mL single-neck flask was charged with 1-2(4.694g, 8.83mmol) and 1,4-dioxane (88mL), followed by sodium hydroxide solution (44.1mL, 2N), allowed to react overnight at room temperature, monitored by TLC (PE/EA ═ 1/1), the starting material reacted completely, pH was adjusted to 7 with 2N hydrochloric acid, a solid precipitated, and filtered to give 1-3 as a white solid; extracting the filtrate with EA (30mL), washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, adding EA (5mL) into the crude product, pulping, stirring, filtering to obtain white solid 1-3, mixing to obtain 1-3(3.48g, yield 79%), ESI-MS M/z:470.3[ M + H ]/z] ⁺。

(S) -4- (4- ((benzyloxy) carbonyl) piperazin-1-yl) -1- ((1-methylpyrrolidin-2-yl) methyl) -2-oxo-2, 5,6, 8-tetrahydropyrido [3,4-d ] pyrimidine-7 (1H) -carboxylic acid tert-butyl ester (1-4)

1-3(3.2g,6.74mmol), Cs and water were added to a 100mL closed-loop reactor₂CO ₃(4.4g,13.48mmol), (S) -2- (bromomethyl) -1-methylpyrrolidine (1.8g,10.1mmol), CuI (257mg,1.35mmol) and DMSO (30mL), sealed and warmed to 100 ℃ and the reaction stirred for 20 h. Cooling to room temperature, adding saturated ammonium chloride solution (30mL), quenching, stirring at room temperature for 30min, adding EA (50mL × 2) for extraction, combining organic phases, washing with saturated sodium chloride solution (50mL × 2), concentrating, and purifying residue by column chromatography (DCM/MeOH 30/0 to20/1) to obtain yellow brown solid 1-4(2.1g, yield 55%), ESI-MS M/z 567.3[ M + H ], (ESI-MS M/z)] ⁺。

(S) -4- (1- ((1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydropyrido [3,4-d ] pyrimidin-4 yl) piperazine-1-carboxylic acid benzyl ester (1-5)

A250 mL single neck flask was charged with 1-4(4.66g,8.22mmol), DCM (20mL) and HCl/Dioxane solution (4M,21mL,82mmol), and the mixture was stirred at room temperature for 4 h. After the reaction was monitored by LC-MS for completion, the system was concentrated and DCM was added to the residue(50mL), sodium bicarbonate solution (50mL), stirring at room temperature for 30min, separating the layers, extracting the aqueous phase with DCM (50mL), combining the organic phases, washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, filtering, concentrating to dryness to obtain a yellow-brown oil 1-5(3.96g, 100% yield), ESI-MS M/z:467.3[ M + H ] M/z] ⁺。

Benzyl 4- (7- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2,5,6,7, 8-hexahydropyrido [3,4-d ] pyrimidin-4 yl) piperazine-1-carboxylate (1-6)

A100 mL single-neck flask was charged with 1-5(379mg,0.812mmol), 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (311mg,1.056mmol), sodium tert-butoxide (195mg,2.03mmol), Ruphos-Pd-G3(134mg,0.16mmol) and Dioxane (20mL), and after Ar displacement protection, the flask was heated to reflux and stirred for reaction for 20H. After completion of the reaction monitored by LC-MS, the system was quenched with water, extracted with EA (20 mL. multidot.2), the organic phase was washed with saturated sodium chloride, concentrated to dryness, and pre-TLC preparative purification (DCM/MeOH/NH)₄OH 20/1/0.02) to give 1-6(100mg, 18% yield) as a light brown oil, ESI-MS M/z 481.3[ M + H ]] ⁺。

7- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-2 (1H) -one (1-7)

To a 100mL single-neck flask were added 1-6(100mg,0.147mmol), MeOH (10mL) and 10% Pd/C (20mg, wet% ═ 50%), H₂After three times of replacement, the mixture was stirred at room temperature under normal pressure for 20 hours. After the reaction was completed by LC-MS monitoring, the system was filtered and the filtrate was concentrated to dryness to give 1-7(80mg, yield 100%) yellow solid, ESI-MS M/z:547.2[ M + H ]] ⁺。

4- (4-acryloylpiperazin-1-yl) -7- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-2 (1H) -one (1-8)

A50 mL single-neck flask was charged with 1-7(80mg,0.147mmol), DCM (5mL), DIPEA (38mg,0.294mmol), cooled to 0 ℃ in an ice bath under the protection of Ar, and then a solution of acryloyl chloride (16mg,0.177mmol) in DCM was added dropwise, after that, the system was stirred at 0-5 ℃ for 1 h.LC-MS after reaction completion monitoring, water quenching, liquid separation, aqueous phase extraction with DCM (10mL), organic phase combination with saturated sodium chloride solution (10mL) washing, anhydrous sodium sulfate drying, filtration, concentration to dryness to obtain light yellow solid 1-8(60mg, yield 68%), ESI-MS M/z:601.2[ M + H%] ⁺。

(S) -4- (4-acryloylpiperazin-1-yl) -7- (5-methyl-1H-indazol-4-yl) -1- ((1-methylpyrrolidin-2-yl) methyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidin-2 (1H) -one (1)

A50 mL single vial was charged with 1-8(60mg,0.1mmol), DCM (5mL), TFA (114mg,1mmol), stirred under Ar at room temperature for 2h, LC-MS monitored reaction completion, concentrated to dryness, and residue pre-TLC purified (DCM/MeOH/NH)₄OH 10/1/0.1) gave compound 1 as an off-white solid (25mg, yield 48%).

¹H NMR(400MHz,CDCl ₃)δ:8.03(s,1H),7.17-7.23(m,2H),6.53-6.63(m,1H),6.32(dd,J＝16.9,1.9Hz,1H),5.73(ddd,J＝10.5,3.2,1.9Hz,1H),4.46(d,J＝11.9Hz,1H),4.28(s,2H),3.74(d,J＝17.5Hz,5H),3.48(t,J＝5.4Hz,7H),2.85(s,2H),2.74(s,3H),2.53(s,1H),2.40(d,J＝1.7Hz,3H),2.21(d,J＝24.4Hz,2H),1.86-2.10(m,3H)；ESI-MS m/z:517.3[M+H] ⁺。

EXAMPLE synthesis of 24- (4-Acrylpiperazin-1-yl) -6-cyclopropyl-8-methoxy-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) quinazolin-2 (1H) -one (Compound 53)

Compound 53 was prepared according to method B as described below:

4- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (53-1)

A250 mL single neck flask was charged with B1(5g,15.13mmol), DIPEA (4g,30.3mmol), N-Boc-piperazine (2.96g, 15.89mmol) and DMF (100mL) and heated to 80 ℃ under Ar for 2 h. TLC spot plate (PE/EA: 5/1), complete reaction of raw materials, cooling the reaction solutionAfter cooling to room temperature, water (100mL) was added, extraction was performed with EA (100 mL. times.2), the organic phases were combined, washed with saturated sodium chloride, the organic phase was concentrated, and purification was performed by column chromatography (PE/EA: 1: 0to 2/1) to give 53-1(5.23g, yield 72%) as a white solid, ESI-MS M/z:479.1/481.1[ M + H ],] ⁺。

4- (7-bromo-6-chloro-8-fluoro-2-oxo-1, 2-dihydroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (53-2)

A250 mL single neck flask was charged with 53-1(5.23g,10.89mmol) and THF (100mL), followed by sodium hydroxide solution (2N,10.5mL,21mmol) and allowed to react overnight at room temperature. TLC monitoring (PE/EA: 1/1), starting material was reacted completely, pH adjusted to 7 with 2N HCl, EA (50mL 2) was added and extracted, combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, crude EA (5mL)/PE (20mL) was added and slurried at room temperature and filtered to give 53-2 as a white solid (2.61g, 52% yield), ESI-MS M/z:462.1/463.1[ M + H ],] ⁺。

4- (7-bromo-6-chloro-8-methoxy-2-oxo-1, 2-dihydroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (53-3)

DMF (40mL), sodium methoxide (485mg,8.66mmol) and Ar replacement protection are added into a 250mL three-neck flask, the temperature is reduced to 0-5 ℃, 53-2(2g,4.33mmol) DMF (10mL) solution is added dropwise, and after the dropwise addition, the system is heated to room temperature and stirred for reaction. After the reaction was completed as monitored by LC-MS, the system was quenched with water (50mL), adjusted to neutral pH with 1N HCl, extracted with EA (50 mL. times.2), the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was slurried with EA (5mL)/PE (20mL) at room temperature and filtered to give 53-3(1.68g, 82%) as a white solid, ESI-MS M/z:473.1/475.1[ M + H ], (M + H) ]] ⁺。

(S) -4- (7-bromo-6-chloro-8-methoxy-1- ((1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (53-4)

53-3(840mg,1.773mmol) and Cs are added into a 100mL closed-loop reactor₂CO ₃(1.72g,5.32mmol), (S) -2- (chloromethyl) -1-methylpyrrolidine hydrochloride (600mg,3.55mmol), CuI (67mg,0.355mmol) and DMSO (20mL), sealed and warmed to 100 ℃ and the reaction stirred for 20 h. After the LC-MS monitoring reaction is completed, the system is cooled to room temperature, and saturated chlorination is addedAmmonium solution (20mL) was quenched, stirred at room temperature for 30min, extracted with EA (40mL 2), combined organic phases washed with saturated sodium chloride solution (40mL 2), concentrated, and purified by column chromatography (DCM/MeOH 50/0 to20/1) to give off-white solid 53-4(638mg, 63%) ESI-MS M/z 570.0/572.0[ M + H ] 20/1] ⁺。

4- (6-chloro-8-methoxy-7- (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (53-5)

A100 mL single-neck flask was charged with 53-4(638mg,1.118mmol), 4-bromo-5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (428mg,1.453mmol), sodium tert-butoxide (268mg,2.79mmol), Ruphos-Pd-G3(184mg,0.22mmol) and Dioxane (20mL), and after Ar displacement protection, the reaction was warmed to reflux and stirred for 20H. After completion of the reaction monitored by LC-MS, the system was quenched with water, extracted with EA (20 mL. multidot.2), the organic phase was washed with saturated sodium chloride, concentrated to dryness, and pre-TLC preparative purification (DCM/MeOH/NH)₄OH 20/1/0.02) to give 53-5 as a light brown oil (371mg, 47% yield), ESI-MS M/z 706.2[ M + H ])] ⁺。

4- (6-cyclopropyl-8-methoxy-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinazolin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (53-6)

A100 mL single-neck flask was charged with 53-5(371mg,0.525mmol), cyclopropylboronic acid (68mg,0.788mmol), potassium phosphate anhydrous (278mg,1.313mmol) and Dioxane (10mL), and after Ar displacement protection, Pd (dppf) was added₂Cl ₂(58mg,0.1mmol) and then heated to reflux for 20 h. After the LC-MS monitoring reaction is finished, the mixed solution is concentrated to be dry, the residue is prepared and purified by reverse phase Flash to obtain 53-6(269mg, yield 72%), ESI-MS M/z:712.2[ M + H ]] ⁺。

6-cyclopropyl-8-methoxy-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -4- (piperazin-1-yl) quinazolin-2 (1H) -one (53-7)

A50 mL one-neck flask was charged with 53-6(269mg,0.378mmol), DCM (10mL) and HCl/Dioxane solution (4M,2mL,8mmol), and the mixture was stirred at RT for 20 h. After the reaction was monitored by LC-MSThe system was concentrated to dryness to give 53-7 as a yellow-brown solid (253mg, 100% yield), ESI-MS M/z 527.2[ M + H ]] ⁺。

4- (4-Acryloylpiperazin-1-yl) -6-cyclopropyl-8-methoxy-7- (5-methyl-1H-indazol-4-yl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) quinazolin-2 (1H) -one (53)

A25 mL single-neck bottle is added with 53-7(25mg,0.039mmol), DCM (5mL), DIPEA (25mg,0.196mmol) and Ar protection, then cooled to 0 ℃ in ice bath, and then dropwise added with a DCM solution of acryloyl chloride (2.8mg,0.031mmol), and the system is stirred for 1h at 0-5 ℃. LC-MS monitors the reaction for a small amount of starting material remaining, adds water to quench, separates, extracts the aqueous phase with DCM (10mL), combines the organic phases, concentrates to dryness, and crude pre-TLC (DCM/MeOH/NH)₄OH 20/1/0.02) to give compound 53(8mg, yield 35%).

¹H NMR(400MHz,CDCl ₃)δ:8.05(s,1H),7.15-7.20(m,2H),7.09(s,1H),6.47-6.61(m,1H),6.32(dd,J＝16.9,1.9Hz,1H),5.73(ddd,J＝10.5,3.2,1.9Hz,1H),4.42(s,3H),3.74(m,6H),3.48(t,J＝5.4Hz,4H),2.55(s,3H),2.44(s,3H),2.40(d,J＝1.7Hz,3H),1.86-2.10(m,5H)，0.30-0.51(m,4H)；ESI-MS m/z:582.3[M+H] ⁺。

Example Synthesis of 34- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (Compound 74)

Compound 74 was prepared according to procedure C as described below:

2, 6-dichloro-5-fluoronicotinamide (74-1)

Adding CDI (35.6g,220mmol) into THF (400mL) solution of C1(42g,200mmol) in portions, stirring the mixture for 5min, protecting with Ar, heating to 50 deg.C, reacting for 1h, monitoring by LC-MS, disappearance of raw material, diluting the reaction solution with toluene (100mL), concentrating to half of the initial volume, cooling the obtained mixture to 0 deg.C, and slowly adding hydrogen hydroxideAmmonium (55mL,400 mmol). The reaction was performed at room temperature for 10min, diluted with EA (200mL) and washed with water (100 mL. multidot.3). Anhydrous Na for organic layer₂SO ₄And (5) drying and spin-drying. PE/EA (10/1,200mL) was slurried, filtered, and the remaining mother liquor was concentrated to half the original volume, cooled to 0 deg.C, and the solid precipitated again, filtered. The two solid batches were combined to give the product 74-1 as a pale yellow solid (22.10g, 53% yield) which was used in the next reaction without purification as the initial product, ESI-MS M/z:208.9[ M + H ]] ⁺。

(S) -2, 6-dichloro-5-fluoro-N- (((1-methylpyrrolidin-2-yl) methyl) carbamoyl) nicotinamide (74-2)

Dissolving 74-1(5.2g,25mmol) in THF (50mL), cooling to-78 deg.C under argon protection, slowly adding oxalic acid chlorine (2M solution DCM,13mL,26mmol) through a syringe, after adding, heating the reaction solution to 60 deg.C for reaction for 3.5h, stopping heating, cooling to-78 deg.C, adding TEA (7.6g,75mmol), (S) - (1-methylpyrrolidin-2-yl) methylamine (2.85g,25mmol), after adding, heating to room temperature, stirring for 1h, adding water (120mL) to quench the reaction, EA extracting, combining organic phases, and adding anhydrous Na into the organic phase₂SO ₄Drying and concentrating. Column chromatography (DCM/MeOH 100/1to20/1) afforded 74-2(5.20g, 60% yield) as a pale yellow solid, ESI-MS M/z:349.1[ M + H ]] ⁺。

(S) -7-chloro-6-fluoro-1- ((1-methylpyrrolidin-2-yl) methyl) pyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (74-3)

74-2(3.5g,10mmol) was dissolved in THF (100mL), ice-cooled under argon, KHMDS (1M THF solution, 20mL) was slowly added, stirring was carried out for 10min, the ice-bath was removed, and the reaction was carried out at room temperature for 30 min. The reaction was quenched with saturated ammonium chloride (125mL) and extracted with EA (250 mL). The organic phase was washed with saturated brine, anhydrous Na₂SO ₄Drying and concentrating. Column chromatography (DCM/MeOH 100/1to20/1) afforded 74-3(1.71g, yield) as a pale yellow solid, ESI-MS M/z:313.1[ M + H ]] ⁺。

(S) -4, 7-dichloro-6-fluoro-1- ((1-methylpyrrolidin-2-yl) methyl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (74-4)

74-3(1.56g,5.0mmol) was dissolved in acetonitrile (10mL) and DIPEA (1.9g,15 g) was addedmmol)，POCl ₃(920mg,6.0mmol), and the reaction was stirred at 80 ℃ for 30 min. Monitoring by LC-MS, concentrating after the reaction is finished, directly putting into the next reaction, ESI-MS M/z:331.1[ M + H ]] ⁺。

(S) -4- (7-chloro-6-fluoro-1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (74-5)

74-4 (theoretical amount 5.0mmol) obtained in the above step was dissolved in DMF (15mL), DIPEA (1.9g,15mmol), (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.2g,6.0mmol) was added, the reaction was carried out at room temperature for 30min, LC-MS monitoring was carried out, the reaction was substantially completed, EA was added for dilution, and the mixture was washed with aqueous sodium bicarbonate solution, dried, concentrated, and subjected to column chromatography (DCM/MeOH: 100/1to20/1) to obtain 74-5(2.01g, yield 20%) as a pale yellow solid, ESI-MS M/z:495.2[ M + H/M/z ]: 495.2] ⁺。

(S) -4- (7- (2-hydroxy-6-methylphenyl) -6-fluoro-1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (74-6)

74-5(1.2g,3.0mmol), Pd (dppf) Cl₂(220mg,0.3mmol) and AcOK (2.36g,24mmol) were dissolved in 1,4-dioxane (50mL) and reacted at 90 ℃ under argon protection for 3H, LC-MS monitored for completion of the reaction, concentrated directly, and subjected to column chromatography (DCM/MeOH. RTM. 100/1to20/1) to give 74-6(1.10g, yield 65%) as a pale yellow solid, ESI-MS M/z:567.3[ M + H ], (M + H) ]] ⁺。

4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (74)

74-6(566mg,1.0mmol) was dissolved in TFA (10mL) and reacted at room temperature for 30min, monitored by LC-Ms, and upon completion of the reaction, directly concentrated. The residue was dissolved in DCM, DIPEA (650mg,5.0mmol) was added, acryloyl chloride (100mg,1.1mmol) was added dropwise in an ice bath, after addition, the reaction was carried out at room temperature for 1h, monitored by LC-MS, the reaction was complete, the reaction was diluted with DCM, washed with water, concentrated, and subjected to column chromatography (DCM/MeOH 100/1to20/1) to give 74 as a pale yellow solid (320mg, 61% yield).

¹H NMR(400MHz,CDCl ₃)δ:7.92(s,1H),7.41-7.56(m,3H),6.41-6.55(m,1H),6.31(dd,J＝16.9,1.9Hz,1H),5.73(ddd,J＝10.5,3.2,1.9Hz,1H),3.74(m,5H),3.48(t,J＝5.4Hz,4H),2.45(s,3H),2.40(m,3H),1.86-2.10(m,5H),1.52(d,J＝5.2Hz,2H)；ESI-MS m/z:525.2[M+H] ⁺。

Example synthesis of- ((2S) -1-acryloyl-4- (6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (compound 107):

compound 107 was prepared according to method D as described below:

(S) -4- (7-bromo-2, 6-dichloroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (107-1)

A250 mL single-neck flask was charged with 7-bromo-2, 4, 6-trichloroquinazoline (4.68g, 15.0mmol), DIPEA (3.87g, 30mmol), (S) -tert-butyl 2- (cyanomethyl) piperazine-1-carboxylate (3.55g, 15.75mmol) and DMF (100mL) and heated to 60 ℃ under Ar for 20 h. TLC (PE/EA 10/1) to complete the reaction, cooling the reaction mixture to room temperature, adding water (200mL), extracting with EA (100mL × 2), combining the organic phases, washing with saturated sodium chloride, concentrating the organic phase, and purifying by column chromatography (PE/EA 1/0to 2/1) to give white solid 107-1(5.26g, 70% yield) ESI-MS M/z 500.2/502.2[ M + H ], (M + H) is added to the reaction mixture] ⁺。

(S) -4- (7-bromo-6-chloro-2-oxo-1, 2-dihydroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (107-2)

A 250mL single-neck flask was charged with 107-1(5.26g, 10.5mmol) and 1,4-dioxane (100mL), followed by sodium hydroxide solution (51mL, 2N), allowed to react overnight at room temperature, monitored by TLC (PE/EA ═ 1/1), the starting material reacted completely, pH was adjusted to 7 with 2N hydrochloric acid, a solid precipitated, and filtered to give 107-2 as a white solid; extracting the filtrate with EA (50mL), washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating, adding EA (10mL) into the crude product, and beatingStirring the slurry, filtering to obtain 1-2 as a white solid, combining to obtain 1-2(3.29g, 65% yield), ESI-MS M/z:482.1/484.1[ M + H ]] ⁺。

(S) -4- (7-bromo-6-chloro-1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinazolin-4-yl-tert-butyl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (107-3)

107-2(3.25g,6.74mmol), Cs and water were added to a 100mL closed-loop reactor₂CO ₃(4.4g,13.48mmol), (S) -2- (bromomethyl) -1-methylpyrrolidine (1.8g,10.1mmol), CuI (257mg,1.35mmol) and DMSO (30mL), sealed and warmed to 100 ℃ and the reaction stirred for 20 h. Cooling to room temperature, adding saturated ammonium chloride solution (30mL) to quench, stirring at room temperature for 30min, adding EA (50mL 2) for extraction, combining organic phases, washing with saturated sodium chloride solution (50mL 2), concentrating, and purifying the residue by column chromatography (DCM/MeOH 30/0 to20/1) to obtain yellow-brown solid 107-3(2.58g, yield 66%), ESI-MS M/z 579.1/581.1[ M + H ] 8932] ⁺。

(2S) -4- (6-chloro-7- (2-fluoro-6- ((tetrahydro-2H-pyran-2-yl) oxy) phenyl) -1- (((S) -1- (tert-butylmethylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinazolin-4-yl) -2- (cyanomethyl) piperazine-1-carboxylic acid tert-butyl ester (107-4)

A100 mL single-necked flask was charged with 107-3(565mg,0.974mmol), 2- (2-fluoro-6- ((tetrahydro-2H-pyran-2-yl) oxy) phenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane (376mg, 1.17mmol), potassium acetate (239mg,2, 436mmol), Pd (dppf)₂Cl ₂(81mg,0.1mmol) and Dioxane (20mL), H₂O (5ml) and Ar are replaced and protected, and then the temperature is increased to reflux and stirring for reaction for 6 hours. After completion of the reaction monitored by LC-MS, the system was quenched with water, EA (20 mL. times.2) was extracted, the organic phase was washed with saturated sodium chloride, concentrated to dryness, and column chromatographed (DCM/MeOH. times. 20/1) to give 107-4(508mg, yield 75%) as a light brown oil, ESI-MS M/z:695.1[ M + H ] M/z] ⁺。

2- ((2S) -4- (6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (107-5)

A50 mL single neck flask was charged with 107-4(500mg,0.719mmol), EA (10mL), HCl/Dioxane (3.6)mL,4M,14.4mmol), Ar protection and stirring at room temperature for 2h, and after the reaction is monitored by LC-MS to be complete, the system is concentrated to dryness to obtain light brown solid 107-5(370mg, yield 100%). ESI-MS M/z 511.1[ M + H ]] ⁺

2- ((2S) -1-acryloyl-4- (6-chloro-7- (2-fluoro-6-hydroxyphenyl) -1- (((S) -1-methylpyrrolidin-2-yl) methyl) -2-oxo-1, 2-dihydroquinazolin-4-yl) piperazin-2-yl) acetonitrile (Compound 107)

A25 mL single-neck flask was charged with 107-5(51mg,0.1mmol), DCM (5mL), DIPEA (65mg,0.5mmol), cooled to 0 ℃ in an ice bath under the protection of Ar, and then a solution of acryloyl chloride (10mg,0.11mmol) in DCM was added dropwise, and the system was stirred at 0-5 ℃ for 1 h. After LC-MS monitoring the reaction was complete, water was added for quenching, the layers were separated, the aqueous phase was extracted with DCM (10mL), the combined organic phases were washed with saturated sodium chloride solution (10mL), concentrated to dryness, and the residue was purified by pre-TLC (DCM/MeOH/NH)₄OH 20/1/0.1) gave compound 107 as an off-white solid (24mg, 42.5% yield).

¹H NMR(400MHz,CDCl ₃)δ:9.82(s,1H)，8.33(s,1H),7.93(s,1H),7.37-7.25(m,3H),6.53-6.63(m,1H),6.32(m,1H),5.73(m,1H),3.44(m,7H),3.24(m,2H),2.69(s,3H),2.58(m,3H),2.42(m,2H),1.86-2.10(m,4H)；ESI-MS m/z:565.2[M+H] ⁺。

EXAMPLE 5 detection of Ras-GTP content in H358 cells by Compounds

One million H358 cells are planted in an ultra-low adsorption six-well plate, after one day of growth, a compound to be detected (the concentration is 1 mu M) is added, after the compound acts for 24 hours, after the cells are lysed, GST-Raf1(1-149) (millipore 14-863) is added, after 4-degree incubation overnight, GST beads (millipore, G0924) are added, after 4-degree incubation for 2 hours, then centrifugation is carried out, the beads are taken, after the beads are washed for 3 times by an IP buffer, SDS lysate is added, glue is run, and Ras-GTP content is detected by Ras antibody (CST, 3339) western blot. The percent inhibition of Ras-GTP activity by the compounds was calculated in comparison to the DMSO group and the results are shown in Table 2 below.

TABLE 2 inhibitory Activity of Compounds of the present invention against Ras-GTP in H358 cells

Compound (I)	Inhibition ratio (%)	Compound (I)	Inhibition ratio (%)	Compound (I)	Inhibition ratio (%)
1	+++	2	++	3	++
4	++	5	++	6	++
7	++	8	+	9	++
10	+++	11	+++	12	+++
13	+++	14	+++	15	+++
16	+++	17	+++	18	+++
19	+++	20	++	21	+++
22	+++	23	+++	24	+++

25	+++	26	+++	27	+++
28	+++	29	+++	30	++
31	+++	32	+++	33	+++
34	+++	35	+++	36	++
37	+++	38	+++	39	+++
40	+++	41	+++	42	+++
43	+++	44	+++	45	+++
46	+++	47	+++	48	+++
49	+++	50	+++	51	+++
52	++	53	++	54	+++
55	+++	56	+++	57	+++
58	+++	59	++	60	+++
61	+++	62	+++	63	+++
64	+++	65	+++	66	+++
67	+++	68	+++	69	+++
70	+++	71	+++	72	+++
73	+++	74	+++	75	+++
76	+++	77	+++	78	+++
79	+++	80	++	81	+++
82	+++	83	+++	84	++
85	++	86	+++	87	++
88	++	89	+++	90	+++
91	+++	92	+++	93	+++
94	+++	95	+++	96	+++
97	+++	98	++	99	+++
100	++	101	++	102	+++
103	+++	104	+++	105	+++
106	+++	107	+++	108	+++
109	+++	110	+++	111	+++
112	+++

+ represents an inhibition of at most 50%

+ indicates an inhibition of 50% to 90%

The inhibition ratio is more than 90%

EXAMPLE 6 antiproliferative Activity of Compounds on H358 cells

2500H 358 cells were plated in ultra low adsorption 96-well plates (corning,7007) and after three days of growth, a gradient dilution compound (up to 30uM, 5-fold dilution, five total doses) was added, and after four days of compound addition, Cell Titer Glow (Promega, G9681) was added to evaluate pellet growth and calculate IC₅₀The values, results are given in table 3 below.

TABLE 3 antiproliferative activity of the compounds of the invention on H358 cells

Compound (I)	Inhibition ratio (%)	Compound (I)	Inhibition ratio (%)	Compound (I)	Inhibition ratio (%)
1	+++	2	++	3	++
4	+	5	++	6	++
7	++	8	+	9	++
10	+++	11	+++	12	+++
13	+++	14	+++	15	+++
16	+++	17	+++	18	+++
19	++	20	+++	21	+++
22	+++	23	+++	24	+++
25	+++	26	+++	27	+++
28	+++	29	+++	30	++
31	+++	32	+++	33	+++
34	+++	35	+++	36	+++
37	++	38	+++	39	+++
40	+++	41	+++	42	+++
43	+++	44	+++	45	+++
46	+++	47	+++	48	+++
49	+++	50	+++	51	++
52	++	53	+++	54	+++
55	+++	56	+++	57	+++
58	+++	59	++	60	+++
61	+++	62	+++	63	+++

64	+++	65	+++	66	+++
67	+++	68	+++	69	+++
70	+++	71	+++	72	+++
73	+++	74	+++	75	++
76	+++	77	+++	78	+++
79	+++	80	+++	81	+++
82	+++	83	+++	84	++
85	++	86	+++	87	+++
88	++	89	+++	90	++
91	+	92	++	93	+++
94	+++	95	+++	96	+++
97	+++	98	+++	99	+++
100	+++	101	++	102	+++
103	+++	1104	+++	105	+++
106	+++	107	+++	108	+++
109	+++	110	+++	111	+++
112	+++

+ means greater than 30. mu.M

+ represents an inhibition ratio of 1to 30. mu.M

+ + + + + indicates that the inhibition rate is less than 1 μ M

As can be seen from the data in tables 2 and 3 above, the compounds of the present invention have superior biological activities, including the inhibitory activity of Ras-GTP in H358 cells and the antiproliferative activity of H358 cells.

Although specific embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative and that various changes or modifications may be made without departing from the principles and spirit of the invention. The scope of the invention is therefore defined by the appended claims.

Claims

A compound with a structure shown as a general formula (1) or each optical isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

in formula (1):

m is 0, 1 or 2;

a is a bivalent 4-12 membered saturated or partially saturated monocyclic, bicyclic, bridged or spirocyclic ring containing 1-2N atoms, optionally substituted with one or more R⁴Substituted when by more than one R⁴When substituted, R⁴May be the same or different;

y is a bond or C1-C6 alkylene;

R ¹is aryl or heteroaryl, which may be substituted with 1to 3 of the following groups: halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl or halogen-substituted C1-C3 alkoxy;

R ²is aminoalkyl, cycloalkyl, alkyl-substituted amido, heterocyclyl, aryl or heteroaryl, said heterocyclyl, aryl or heteroaryl being optionally substituted with one or more R⁵Substituted when by more than one R⁵When substituted, R⁵May be the same or different;

R ³independently selected C1-C3 alkyl or halogenated C1-C3 alkyl;

R ⁴independently selected from H, CN, C1-C3 alkyl, halogen substituted C1-C3 alkyl or cyano substituted C1-C3 alkyl;

R ⁵independently selected from halogen, H, O, CN, OH, alkyl hydroxyl, dialkyl amido, C1-C6 alkyl, C3-C6 cycloalkyl, halogen substituted C1-C3 alkyl or halogen substituted C1-C3 alkoxy;

e is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of the K-Ras, H-Ras or N-Ras mutant protein.
The compound according to claim 1, wherein in the formula (1), E is a group having an electrophilic carbon-carbon double bond or carbon-carbon triple bond.
The compound according to claim 2, wherein in the formula (1), E is:
wherein R is_aIs H or F, R_bIs H, -CH₂F、-CHF ₂、
The compound according to claim 1, wherein in the formula (1), a to E are:

wherein n is 1 or 2, R⁴Is H, CN, C1-C3 alkyl, halogen substituted C1-C3 alkyl or cyano substituted C1-C3 alkyl.
The compound according to claim 1, wherein in the formula (1), Y is a bond, -CH₂-, -CH (Me) -or-CH₂CH ₂-。
The compound according to claim 1, wherein in the formula (1), R is¹Comprises the following steps:

wherein R is_cAnd R_dIndependently halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl or halogen substituted C1-C3 alkoxy.
The compound according to claim 1, wherein in the formula (1), R is²Comprises the following steps:

wherein n is 1 or 2, R_eAnd R_fIndependently H, halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl or halogen substituted C1-C3 alkoxy, R_gIs C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, C1-C3 alkoxyalkyl, halogen substituted C1-C3 alkyl, halogen substituted C3-C6 cycloalkyl or
The compound of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:
a compound with a structure shown as a general formula (2) or each optical isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof:

in formula (2):

a is a bivalent 4-12 membered saturated or partially saturated monocyclic, bicyclic, bridged or spirocyclic ring containing 1-2N atoms, optionally substituted with one or more R⁴Substituted when by more than one R⁴When substituted, R⁴May be the same or different;

y is a bond or C1-C6 alkylene;

w is N, C-R⁸Or C-O-R⁶：

Wherein, when W is C-O-R⁶When R is²Is aminoalkyl, cycloalkyl, alkyl-substituted amido, heterocyclyl, aryl or heteroaryl, said heterocyclyl, aryl or heteroaryl being optionally substituted with one or more R⁵Substituted when by more than one R⁵When substituted, R⁵May be the same or different;

wherein, when W is N or C-R⁸When R is²Is aminoalkyl, alkyl-substituted amido or heterocyclyl, said heterocyclyl being optionally substituted with one or more R⁵Substituted when by more than one R⁵When substituted, R⁵May be the same or different;

R ¹is aryl or heteroaryl, which may be substituted with 1to 3 of the following groups: halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy;

R ⁴independently selected from H, CN, C1-C3 alkyl, halogen substituted C1-C3 alkyl or cyano substituted C1-C3 alkyl;

R ⁵independently selected from halogen, H, O, CN, OH, alkyl hydroxyl, dialkyl amido, C1-C6 alkyl, C3-C6 cycloalkyl, halogen substituted C1-C3 alkyl or cyano substituted C1-C3 alkyl;

R ⁶is C1-C3 alkyl, halogen substituted C1-C3 alkyl or C3-C6 cycloalkyl;

R ⁷is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy or C2-C4 alkenyl;

R ⁸is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl or halogen substituted C1-C3 alkyl;

e is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of the K-Ras, H-Ras or N-Ras mutant protein.
The compound according to claim 9, wherein in said formula (2), E is a group containing an electrophilic carbon-carbon double bond or carbon-carbon triple bond.
The compound according to claim 10, wherein in the formula (2), E is:
wherein R is_aIs H or F, R_bIs H, -CH₂F、-CHF ₂、
The compound according to claim 9, wherein in the formula (2), a to E are:

wherein n is 1 or 2, wherein R⁴Is H, CN, C1-C3 alkyl, halogen substituted C1-C3 alkyl or cyano substituted C1-C3 alkyl.
The compound according to claim 9, wherein in the formula (2), Y is a bond, -CH₂-, -CH (Me) -or-CH₂CH ₂-。
The compound according to claim 9, wherein in the formula (2), R is¹Comprises the following steps:

wherein R is_cAnd R_dIndependently isHalogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen-substituted C1-C3 alkyl or halogen-substituted C1-C3 alkoxy.
The compound according to claim 9, wherein in the formula (2), W is C-O-R⁶，R ²Comprises the following steps:

wherein n is 1 or 2, R_eAnd R_fIndependently is halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl or halogen substituted C1-C3 alkoxy, R_gIs C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, C1-C3 alkoxyalkyl, halogen substituted C1-C3 alkyl, halogen substituted C3-C6 cycloalkyl or
The compound according to claim 9, wherein in the formula (2), W is N or C-R⁸，R ²Comprises the following steps:

wherein n is 1 or 2, R_eAnd R_fIndependently is halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl or halogen substituted C1-C3 alkoxy, R_gIs C1-C3 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, C1-C3 alkoxyalkyl, halogen substituted C1-C3 alkyl, halogen substituted C3-C6 cycloalkyl or
The compound of claims 9-16, or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:
a pharmaceutical composition for the treatment, modulation and/or prevention of diseases associated with physiological conditions associated with K-RAS G12C, H-RAS G12C or N-RAS G12C mutant proteins, characterized in that it contains a pharmaceutically acceptable excipient or carrier and, as active ingredient, a compound according to any one of claims 1to 17, or each optical isomer, pharmaceutically acceptable salt, hydrate or solvate thereof.
The pharmaceutical composition of claim 18, wherein the composition is in an oral dosage form.
The pharmaceutical composition of claim 18, wherein the composition is in an injectable dosage form.
Use of a compound according to any one of claims 1to 17, or each optical isomer, each crystalline form, a pharmaceutically acceptable salt, hydrate or solvate thereof, for the treatment of a disorder mediated by a K-RAS G12C, H-RAS G12C or N-RAS G12C mutation in a subject in need thereof.
The method of claim 21 wherein the condition is cancer, and the cancer is hematological cancer and solid tumors.