CN110256421A

CN110256421A - KRAS-G12C inhibitor

Info

Publication number: CN110256421A
Application number: CN201910570897.4A
Authority: CN
Inventors: 樊后兴; 谢雨礼
Original assignee: Wigen Biomedicine Technology Shanghai Co Ltd
Current assignee: Wigen Biomedicine Technology Shanghai Co Ltd
Priority date: 2019-06-26
Filing date: 2019-06-26
Publication date: 2019-09-20
Also published as: CN113544128A; WO2020259432A1; CN113544128B

Abstract

The present invention provides G12C mutant K-Ras albumen irreversible inhibitors, and the invention also discloses above-mentioned G12C mutant K-Ras albumen irreversible inhibitors and its preparation method and application.

Description

KRAS-G12C inhibitor

Technical field

The invention belongs to field of medicinal chemistry, more specifically, are related to a kind of novel KRAS-G12C inhibitor, and its The application method of preparation method and such compound.

Background technique

RAS represents one group of monomer globular protein being closely related (21kDa molecular weight), have 189 amino acid and It is connected with plasma membrane and combines GDP or GTP.Under normal development or physiological condition, RAS receives growth factor and various other thin Extracellular signal and be activated, be responsible for adjust cell growth, survival, migration and differentiation etc. functions.RAS plays molecular switch, RAS The open/close state of albumen is combined by nucleotide and is determined, activation signal conducts conformation combination GTP, nonactive conformation combination GDP. When RAS includes the GDP combined, it is in suspend mode or static or closed state, and be " inactive ", in response to exposure It is stimulated in certain growth-promotings, the induction combining GDP of RAS is converted to GTP.As GTP is combined, RAS is " unlatching ", and It can be with other protein-interactings and the other albumen (its " downstream targets ") of activation.RAS albumen itself has extremely low by GTP Hydrolysis returns to GDP and thus itself will become the capability of closed state.RAS is converted to close off and needs referred to as GTP enzyme The extrinsic protein of activator protein (GAPs) interacts with RAS and can greatly promote conversion of the GTP to GDP.It is any The mutation of the ability for influencing its GDP that interacts with GAP or be converted back to GTP in RAS, it will lead to the albumen Extended activation, and the extended signal for arriving cell is therefore generated, which informs its continued growth and division.Therefore these Signal can make cell grow and divide, and the RAS signal transduction of overactivity may eventually lead to cancer.

In RAS family member, Cancer-causing mutation is most commonly in KRAS (85%), and NRAS (12%) and HRAS (3%) are then It is more rare.KRAS mutation is generally existing in the big fatal cancer types in the U.S. three: cancer of pancreas (95%), colorectal cancer (45%) and lung cancer (25%), seldom (< 2%) is found in breast cancer, oophoroma and the cancer of the brain.In non-small cell lung cancer (NSCLC) in, KRAS G12C is the most common mutation, the nearly half of Zhan Suoyou KRAS mutation, followed by G12V and G12D. In non-small cell lung cancer, the increase of specific allelic mutation frequency is mutated mostly from classical by the typical of smoking induction (G:C to T:A displacement), so as to cause KRAS G12C (GGT to TGT) and G12V (GGT to GTT) mutation.

Large-scale genomics is studies have shown that lung cancer KRAS mutation, including driving other known in G12C, with NSCLC cause Cancer mutation is mutually exclusive, including EGFR, ALK, ROS1, RET and BRAF, shows uniqueness of the KRAS mutation in lung cancer.And it is same When, KRAS mutation is often cooperated with certain total common generations of mutation, such as STK11, KEAP1 and TP53, they and the RAS being mutated It is the tumour cell of high malignancy and invasion by cell transformation.

Three kinds of RAS oncogenes, which constitute, is mutated most frequent gene family in human cancer.It is disappointed to be, although through More than 30 years research efforts are crossed, clinically still without effective anti-RAS therapy, targeting the gene using small molecule is that item is chosen War.Therefore, there is an urgent need in the art to small molecule and the utilizations for targeting RAS (for example, K-RAS, H-RAS and/or N-RAS) It treats a variety of diseases, such as cancer.

Summary of the invention

The present invention is intended to provide a structural general formula such as formula (1) compound represented or its each optical isomer, each crystalline substance Type, pharmaceutically acceptable salt, hydrate or solvate:

In formula (1):

M is 0,1 or 2；

A is monocycle, bicyclic, bridged ring or the spiral shell of 4-12 member saturation or fractional saturation that a divalent contains 1-2 N atom Ring, the monocycle, bicyclic, bridged ring or loop coil can be optionally by one or more R⁴It is replaced, when by multiple R⁴When substitution, R⁴It can be with It is identical or different；

Y is chemical bond or C1-C6 alkylidene；

R¹For aryl or heteroaryl, the aryl or heteroaryl can be replaced 1-3 following radicals: halogen, hydroxyl, ammonia Base, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen replace C1-C3 alkyl or halogen to replace C1- C3 alkoxy；

R²For aminoalkyl, naphthenic base, alkyl substituted amide base, heterocycle, aryl or heteroaryl, the heterocycle, virtue Base or heteroaryl can be optionally by one or more R⁵It is replaced, when by multiple R⁵When substitution, R⁵It can be identical or different；

R³Independent choice C1-C3 alkyl or halogenated C1-C3 alkyl；

R⁴It is independently selected from H, CN, C1-C3 alkyl, halogen replaces C1-C3 alkyl or cyano replaces C1-C3 alkyl；

R⁵Be independently selected from halogen, H, O, CN, OH, alkyl hydroxy, dialkyl amino, C1-C6 alkyl, C3-C6 naphthenic base, Halogen replaces C1-C3 alkyl or halogen to replace C1-C3 alkoxy；

E is can to form covalent bond with the cysteine residues of 12 of K-Ras, H-Ras or N-Ras mutant protein Electrophilic moiety.

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

In another preferred example, wherein in the formula (1), E are as follows:Wherein, R_aFor H Or F, R_bFor H ,-CH₂F、-CHF₂、

In another preferred example, wherein in the formula (1), A-E are as follows: Wherein, n is 1 or 2, R⁴For H, CN, C1-C3 alkyl, halogen replace C1-C3 alkyl or cyano to replace C1-C3 alkyl.

In another preferred example, wherein in the formula (1), Y is chemical bond ,-CH₂,-CH (Me)-or-CH₂CH₂-。

In another preferred example, wherein in the formula (1), R¹Are as follows: Wherein R_cAnd R_dIt independently is halogen, hydroxyl Base, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen replace C1-C3 alkyl or halogen to take For C1-C3 alkoxy.

In another preferred example, wherein in the formula (1), R²Are as follows: Wherein n is 1 or 2, R_eAnd R_fIndependently be H, halogen, hydroxyl, Amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen replace C1-C3 alkyl or halogen to replace C1-C3 alkoxy, R_gIt is taken for C1-C3 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkyl-alkyl, C1-C3 alkoxyalkyl, halogen For C1-C3 alkyl, halogen replace C3-C6 naphthenic base or

Another aspect of the present invention a, it is desirable to provide structural general formula such as formula (2) compound represented or its each optics are different Structure body, each crystal form, pharmaceutically acceptable salt, hydrate or solvate:

In formula (2):

Y is chemical bond or C1-C6 alkylidene；

W is N, C-R⁸Or C-O-R⁶Or:

Wherein, when W is C-O-R⁶When, R²For aminoalkyl, naphthenic base, alkyl substituted amide base, heterocycle, aryl or miscellaneous Aryl, the heterocycle, aryl or heteroaryl can be optionally by one or more R⁵It is replaced, when by multiple R⁵When substitution, R⁵It can be with It is identical or different；

Wherein, when W is N or C-R⁸When, R²For aminoalkyl, alkyl substituted amide base or heterocycle, the heterocycle can appoint Choosing is by one or more R⁵It is replaced, when by multiple R⁵When substitution, R⁵It can be identical or different；

R¹For aryl or heteroaryl, the aryl or heteroaryl can be replaced 1-3 following radicals: halogen, hydroxyl, ammonia Base, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen replace C1-C3 alkyl, halogen to replace C1- C3 alkoxy；

R⁵It is independently selected from halogen, H, O, CN, OH, alkyl hydroxy, dialkyl amino, C1-C6 alkyl, C3-C6 naphthenic base, halogen Element replaces C1-C3 alkyl or cyano to replace C1-C3 alkyl；

R⁶Replace C1-C3 alkyl or C3-C6 naphthenic base for C1-C3 alkyl, halogen；

R⁷Replace C1-C3 alkyl, halogen for H, halogen, C1-C3 alkyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen Replace C1-C3 alkoxy or C2-C4 alkenyl；

R⁸Replace C1-C3 alkyl for H, halogen, C1-C3 alkyl, C3-C6 naphthenic base or halogen；

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

In another preferred example, wherein in the formula (2), E are as follows:Wherein, R_aFor H Or F, R_bFor H ,-CH₂F、-CHF₂、

In another preferred example, wherein in the formula (2), A-E are as follows: Wherein, n is 1 or 2, wherein R⁴C1-C3 alkyl or cyano is replaced to replace C1-C3 alkyl for H, CN, C1-C3 alkyl, halogen.

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

In another preferred example, wherein in the formula (2), R¹Are as follows: Wherein R_cAnd R_dIt independently is halogen, hydroxyl Base, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen replace C1-C3 alkyl or halogen to take For C1-C3 alkoxy.

In another preferred example, wherein in the formula (2), W C-O-R⁶, R²Are as follows: Wherein n is 1 or 2, R_eAnd R_fIt independently is halogen, hydroxyl, amino, C1-C3 alkane Base, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen replace C1-C3 alkyl or halogen to replace C1-C3 alcoxyl Base, R_gReplace C1-C3 alkane for C1-C3 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkyl-alkyl, C1-C3 alkoxyalkyl, halogen Base, halogen replace C3-C6 naphthenic base or

In another preferred example, wherein in the formula (2), W is N or C-R⁸, R²Are as follows: Wherein n is 1 or 2, R_eAnd R_fIt independently is halogen, hydroxyl, amino, C1-C3 alkane Base, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen replace C1-C3 alkyl or halogen to replace C1-C3 alkoxy, R_gFor C1-C3 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkyl-alkyl, C1-C3 alkoxyalkyl, halogen replace C1-C3 alkyl, Halogen replace C3-C6 naphthenic base or

In various different embodiments, compound has one in institute's array structure in the following table 1:

Table 1: representative compound list of the present invention:

Another object of the present invention is to provide a kind of pharmaceutical composition, it contain pharmacologically acceptable excipient or Compound or its each optical isomer in carrier, and general formula of the present invention (1) or general formula (2), it is pharmaceutically acceptable inorganic or Organic salt is as active constituent.

Another object of the present invention provides above compound or its each optical isomer of the invention, pharmaceutically may be used The inorganic or organic salt received is used to prepare the application in the relevant disease for the treatment of tumour.

It should be understood that foregoing general description of the invention and it is described in detail below be all exemplary and illustrative, it is intended to Further explanation to the claimed invention is provided.

The synthesis of compound

The preparation method of formula of the present invention (1) and general formula (2) structural compounds is described specifically below, but these have Body method does not form any restrictions to the present invention.

The synthetic technology or well known technology and text of general formula (1) described above and the usable standard of general formula (2) compound The method of middle combination synthesizes.In addition, solvent, temperature and other reaction conditions can change as mentioned herein.For compound The starting material of synthesis can obtain by synthesizing or from commercial source, e.g., but be not limited to Aldrich Chemical Co. (Milwaukee, Wis.) or Sigma Chemical Co. (St.Louis, Mo.).Compound as described herein has with other Different substituents have related compounds that well known technology and raw material can be used to synthesize, including are found in M argon gas ch, ADVANCED ORGANIC CHEMISTRY 4^thEd., (Wiley 1992)；C argon gas ey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4^thEd., Vols.A and B (Plenum 2000,2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^rdEd., the method in (Wiley 1999).The conventional method of compound preparation can be by making Not isoplastic condition is introduced with reagent appropriate and provided herein in molecular formula to change.

On the one hand, compound as described herein is according to method well known in technique.However the condition of method, such as react Following explanation is not limited to the time required to object, solvent, alkali, the amount of compound used therefor, reaction temperature, reaction etc..Chemical combination of the present invention Various synthetic methods describing in the present specification or known in the art can also optionally be combined and easily be made by object , such combination can readily be carried out by those skilled in the art in the invention.On the one hand, the present invention also provides one kind The preparation method of compound shown in the formula (1) and general formula (2), uses following General reactions process 1,2,3 or 4 Preparation:

General reactions process 1

The embodiment of general formula (1) compound can be prepared according to General reactions process 1 (method A), wherein R¹、 R²、R⁴、A、 E and Y are as hereinbefore defined, and X indicates I, Br, Cl, OTf ,-B (OH)₂Equal groups.As shown in General reactions process 1, intermediate A1 (synthesis of the method referring to described in WO2017201161) and segment A produce A2 under alkaline condition, and structure A2 compound exists Generate A3 in the presence of oxidant, compound A-13 generates A4 under alkaline condition, and A4 is under proper condition and R²The segment of-Y-X is anti- It should generate A5, A5 deprotection base (such as Boc) obtains A6, A6 and R1-X and is coupled to obtain A7, A7 deprotection base (such as Cbz A8, A8 and acyl chlorides) are obtained or anhydride compound reaction generates A9.

General reactions process 2

On the one hand, the embodiment of general formula (2) compound can be prepared according to General reactions process 2 (method B), wherein R¹、 R²、R⁴、R⁶、R⁷, A, E and Y it is as hereinbefore defined, X indicate I, Br, Cl, OTf ,-B (OH)₂Equal groups.Such as General reactions process Shown in 2, intermediate B 1 (synthesis of the method referring to described in WO2016164675) and segment A generate B2 under alkaline condition, knot Structure B2 compound generates B3 under alkaline condition, and compound B3 generates B4 under alkaline condition, and B4 is under proper condition and R²-Y- The segment reaction of X generates B5, B5 and R1-X and is coupled to obtain B6, and B6 continues and R⁷X is coupled to obtain B7, B7 deprotection base (such as Cbz B8, B8 and acyl chlorides) are obtained or anhydride compound reaction generates B9.

General reactions process 3

On the other hand, the embodiment of general formula (2) compound can be prepared according to General reactions process 3 (method C), wherein R¹、R²、R⁴、R⁷, A, E and Y it is as hereinbefore defined, X indicate I, Br, Cl, OTf ,-B (OH)₂Equal groups.Such as General reactions process 3 Shown, intermediate C1 (synthesis of the method referring to described in US2016164675) carries out amidation process and generates C2, and structure C 2 is changed It closes object and reagent appropriate reaction generates and replaces isocyanates, further reaction generates C3, and compound C3 is under alkaline condition Reaction generates hybar X intermediate C4, C4 and reacts generation C5, C5 with chlorination reagent under proper condition in alkaline condition reaction Generate C6, C6 and R¹- X is coupled to obtain C7, and C7 deprotection base (such as Boc) obtains C8, C8 and acyl chlorides or anhydride compound is anti- C9 should be generated.

General reactions process 4

In another aspect, the embodiment of general formula (2) compound can be prepared according to General reactions process 4 (method D), wherein R¹、R²、R⁴、R⁷、R⁸, A, E and Y it is as hereinbefore defined.As shown in General reactions process 4, intermediate D1 (reference Method described in WO2016164675 synthesis) and segment A generate D2 under alkaline condition, structure D2 compound is in alkaline item Generate D3 under part, D3 is under proper condition and R²The segment reaction of-Y-X generates D4, D4 and R1-X and is coupled to obtain D5, and D5 removing is protected Shield base (such as Boc) obtains D6, D6 and acyl chlorides or anhydride compound reaction generates D7.

The further form of compound

" pharmaceutically acceptable " herein refers to a kind of substance, such as carrier or dilution, will not make compound bioactivity or Property disappears, and relative nontoxic e.g. gives individual something, will not cause undesired biotic influence or in harmful manner It interacts with any component that it contains.

Term " pharmaceutically acceptable salt " refers to that a kind of existence form of compound, the form will not cause organic to being administered The important stimulation of body, and the bioactivity of compound and property will not be made to disappear.It is pharmaceutically acceptable in certain specific aspects Salt be that acquisition is reacted with acid by formula (1) or formula (2) compound, as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, The inorganic acids such as phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, apple The organic acids such as tartaric acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid and aspartic acid, glutamic acid Equal acidic amino acids.

It should be understood that the reference of pharmaceutically acceptable salt includes solvent addition form or crystal form, especially solvate Or polymorphic.Solvate contains stoichiometry or non-stoichiometric solvent, and be with pharmaceutically acceptable solvent such as water, Ethyl alcohol etc., it is selectively formed in crystallisation procedure.Hydrate is formed when solvent is water, or alcohol is formed when solvent is ethyl alcohol Compound.The solvate of formula (1) or formula (2) compound is very easily made or is formed according to method described herein.It illustrates Bright, the hydrate of formula (1) or formula (2) compound is recrystallized from water/organic solvent in the mixed solvent and is easily made, and is used Organic solvent include but is not limited to dioxane, tetrahydrofuran, ethyl alcohol or methanol.In addition, compound as mentioned herein Can exist with non-solvated and solvation form.In short, for the purpose of for Compounds and methods for provided herein, solvation shape Formula is considered being equivalent to nonsolvated forms.

In other specific embodiments, formula (1) or formula (2) compound are prepared to different forms, including but not limited to, It is amorphous, crush shape and millimicro-granularity form.In addition, formula (1) or formula (2) compound include crystal type, polycrystalline can also be used as Type.Polymorphic includes the different crystalline lattice arrangement of the identical element composition of compound.Polymorphic usually has different X-ray diffractions Figure, infrared spectroscopy, fusing point, density, hardness, crystal form, the property of light and electricity, stability and dissolubility.Different factors is as tied again It is leading that brilliant solvent, crystalline rate and storage temperature, which may cause single crystal form,.

On the other hand, formula (1) or formula (2) compound have one or more Stereocenters, and therefore with raceme, outer The form appearance of racemic mixture, single enantiomer, diastereomeric compound and single diastereomer.May exist not Symmetrical centre, the property depending on substituent groups various on molecule.Each this asymmetric center will independently generate two optically-actives Isomers, and all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound are included in this Within the scope of invention.The present invention mean include these compounds all this isomeric forms.

Term

If being used for the present patent application without other explanation, including the term in specification and claims, definition is such as Under.It has to be noticed that in the specification and the appended claims, if Wen Zhongwu is clearly dictated otherwise, singular " one It is a " it include plural references.If using mass spectrum, nuclear-magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA skill without other explanation The conventional method of art and pharmacology.In this application, if referring to "and/or" using "or" or "and" without other explanation.

" alkyl " refers to the aliphatic hydrocarbon group of saturation, straight chain and branched group including 1 to 6 carbon atom.Preferably comprise 1 to The low alkyl group of 4 carbon atoms, such as methyl, ethyl, propyl, 2- propyl, normal-butyl, isobutyl group, tert-butyl.Such as this paper institute With " alkyl " includes unsubstituted and substituted alkyl, especially the alkyl replaced one or more halogens.Preferred alkyl Selected from CH₃, CH₃CH₂, CF₃, CHF₂, CF₃CH₂,ⁱPr,ⁿPr,ⁱBu,^cPr,ⁿBu or^tBu。

" naphthenic base " refers to that 3 to 6 yuan of full carbon monocyclic aliphatic hydrocarbyl groups, wherein one or more rings can contain one or more Double bond, but none ring has the pi-electron system of total conjugated.For example, cyclopropyl, cyclobutyl, cyclopenta, hexamethylene, ring Hexadiene etc..

" alkoxy " refers to the alkyl that molecule rest part is bonded to by ether oxygen atom.Representative alkoxy is with 1- The alkoxy of 6 carbon atoms, as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy and Tert-butoxy.As used herein, " alkoxy " includes unsubstituted and substituted alkoxy, especially by one or more halogen institutes Substituted alkoxy.Preferred alkoxy is selected from OCH₃, OCF₃, CHF₂O, CF₃CH₂O,ⁱPrO,ⁿPrO,ⁱBuO,^cPrO,ⁿBuO or^tBuO。

" aryl " refers to the group at least one aromatic ring structure, that is, has the isocyclic aryl of the pi-electron system of conjugation, such as Phenyl ring and naphthalene nucleus.

" heteroaryl " refers to the aromatic group containing one or more hetero atoms (O, S or N), and heteroaryl is monocycle or polycyclic , for example, bicyclic heteroaryl ring and one or more carbocyclic aromatic radicals or other monocyclic heterocycles base groups it is thick and.Heteroaryl Example includes but is not limited to pyridyl group, pyridazinyl, imidazole radicals, pyrimidine radicals, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinoline Quinoline base, tetrazole radical, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrole radicals, indyl, benzo Imidazole radicals, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzo pyridyl group and pyrrolo-pyrimidine radicals.

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

Term " key " or " singly-bound " refer between two atoms or between two segments (when the atom connected by key is considered as When a part of big structure) chemical bond.On the one hand, when group as described herein is a key, lack with reference to group, allow A key is formed between remaining determining group.

Term " member ring " includes any cyclic structure.Term " member " means the quantity for indicating to constitute the skeletal atom of ring.This Sample, e.g., cyclohexyl, pyridyl group, pyranose, thiapyran base are hexatomic rings, and cyclopenta, pyrrole radicals, furyl and thienyl are five yuan Ring.

Term " segment " refers to specific part or the functional group of molecule.Chemical segment is typically considered to be included in or be attached to point Chemical entities in son.

Specific pharmacy and medical terminology

Term " acceptable " refers to that a prescription component or active constituent are good for general treatment target as used herein The inexcessive adverse effect of health.

Term " treatment ", " therapeutic process " or " therapy " as used herein, including mitigation, inhibition or improve disease symptom Or situation；Inhibit the generation of complication；Improve or prevent potential metabolic syndrome；Inhibit the generation of disease or symptom, such as controls The development of disease or situation；Mitigate disease or symptom；Disease or symptom is set to decline；Mitigate concurrent as caused by disease or symptom Disease, or prevention or the treatment sign as caused by disease or symptom.

As used herein, a certain compound or pharmaceutical composition after administration, can be such that a certain disease, symptom or situation obtains To improvement, espespecially its severity is improved, delayed onset, slows down disease progression, or reduce the state of an illness duration.No matter fix Administration or interim administration are administered continuously or interrupted continuous administration, can be attributed to or the situation related with administration.

" active constituent " refers to the medicine of compound shown in general formula (1) or general formula (2) and general formula (1) or general formula (2) compound Acceptable inorganic or organic salt on.The compound of the present invention can containing one or more asymmetric centers, and therefore with The form appearance of raceme, racemic mixture, single enantiomer, diastereomeric compound and single diastereomer.It can Property with existing asymmetric center, depending on substituent groups various on molecule.Each this asymmetric center is by independent real estate Raw two optical isomers, and all possible optical isomer and non-enantiomer mixture and pure or partial-purified chemical combination Object is included within the scope of the present invention.The present invention mean include these compounds all this isomeric forms.

" compound (compound) ", " composition (composition) ", " medicament (agent) " or " pharmaceuticals The words such as (medicine or medicament) " are used interchangeably herein, and all refer to that (mankind are dynamic when being applied to an individual Object) when, a kind of compound of the pharmacy and/or physiological reaction urgently asked can be induced through part and/or systemic effect Or composition.

" application (administered, administering or administration) " word refers to herein directly to be applied With the compound or composition, or the premedicant (prodrug) of application reactive compound, derivative (derivative), Or the like (analog) etc., and a suitable dosage person of the reactive compound can be formed in vivo in application individual.

Although the numberical range and parameter to define wider range of the present invention are all rough numerical value, herein as far as possible The correlation values in specific embodiment are accurately presented.However, any numerical value is substantially inevitably containing because of individual tests Standard deviation caused by method.Here, " about " typically refer to actual numerical value a certain number value or range positive and negative 10%, 5%, within 1% or 0.5%.Either, " about " word represents actual numerical value and falls within the acceptable standard error of average value, Depending on depending on those skilled in the art the considerations of.Other than experimental example, or unless explicitly stated, when being appreciated that this place All ranges, quantity, numerical value and percentage are (such as to describe material utilization amount, length of time, temperature, operating condition, number Amount ratio and other similar persons) by the modification of " about ".Therefore, unless otherwise opposite explanation, this specification and subsidiary power The sharp revealed numerical parameter of claim is all rough numerical value, and visual demand and change.It at least should be by these numerical parameters It is interpreted as pointed number of significant digit and applies the obtained numerical value of general transfer method.

Unless this specification is defined otherwise, the meaning of science and technology vocabulary used herein and those skilled in the art institute Understand identical as usual meaning.In addition, singular noun used in this specification covers in the case of getting along well context conflict The complex number type of the noun；And also cover the singular type of the noun when used plural noun.Therapeutical uses

It include but is not limited to relate to the present invention provides the method for using the compounds of this invention or the medicine composite for curing patient's condition And the patient's condition (such as cancer) that G12C K-Ras, G12C H-Ras and/or G12C N-Ras are mutated.

In some implementations, method use for cancer treatment is provided, this method includes giving individual in need The pharmaceutical composition of a effective amount of any protection structure (1) above-mentioned or (2) compound.In some embodiments, cancer by K-Ras, H-Ras and/or G12C N-Ras mutation mediate.In other embodiments, which is lung cancer, cancer of pancreas, colon Cancer, MYH associated Polyposis or colorectal cancer.

Administration route

The compound of the present invention and its pharmaceutically acceptable salt can be made into various preparations, wherein comprising safely, effectively measuring The compounds of this invention or its pharmaceutically acceptable salt in range and pharmacologically acceptable excipient or carrier.Wherein " safely, effectively measuring " refers to: the amount of compound is enough to be obviously improved the state of an illness, and is unlikely to generate serious side effect.Chemical combination Safely, effectively measuring according to concrete conditions such as the age for the treatment of object, the state of an illness, the courses for the treatment of for object determines.

" pharmaceutically acceptable excipient or carrier " refers to: one or more biocompatible solids or liquid filler or Gelatinous mass, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " herein means Be in composition each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the medicine of compound Effect.Pharmacologically acceptable excipient or carrier part example have cellulose and its derivates (such as sodium carboxymethylcellulose, second Base sodium cellulosate, cellulose ethanoate etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, plant Object oil (such as soya-bean oil, sesame oil, peanut oil, olive oil), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), cream Agent is (such as), wetting agent (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, Apirogen water etc..

When applying the compounds of this invention, can take orally, rectum, parenteral (intravenous, intramuscular or subcutaneous), part to Medicine.

Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with Following compositions mixing: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example Such as, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates, And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti Pure and mild glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include Buffer.

Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.

Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture. In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances Deng.

Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste Agent, corrigent and fragrance.

In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..

Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.

The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, stock solution and inhalant. Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need Propellant be mixed together.

The compounds of this invention can be administered alone, or be administered in combination with other pharmaceutically acceptable compounds.It uses It is the mammal (such as people) that the compounds of this invention of safe and effective amount is applicable to treatment when pharmaceutical composition, wherein Dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day dosage be usually 1~ 1000mg, preferably 10~500mg.Certainly, specific dosage is also contemplated that the factors such as administration route, patient health situation, these are all Within the scope of being skilled practitioners technical ability.

The feature that the features described above or embodiment that the present invention mentions are mentioned can be in any combination.Disclosed in this case specification All features can be used in combination with any composition form, each feature disclosed in specification, any can provide it is identical, The alternative characteristics of impartial or similar purpose replace.Therefore except there is special instruction, revealed feature is only impartial or similar spy The general example of sign.

Above compound, method, each specific aspect of pharmaceutical composition, spy will be elaborated in the following description Property and advantage, make the contents of the present invention become to be apparent from.Herein it should be understood that following detailed descriptions and example describes specifically Embodiment, be only used for referring to.After having read description of the invention, those skilled in the art can make the present invention each Kind change or modification, these situations of equal value equally fall within range defined herein.

In all embodiments,¹H-NMR is recorded with 400 Nuclear Magnetic Resonance of Vian Mercury, and chemical shift is with δ (ppm) It indicates；It is 200-300 mesh that separation silica gel is undeclared, and the proportion of eluent is volume ratio.

The present invention uses following initialisms: Ar represents argon gas；CDCl₃Represent deuterated chloroform；CDI represents 1,1'- carbonyl two Imidazoles；CD₃OD represents deuterated methanol；CuI represents cuprous iodide；DCM represents methylene chloride；DIPEA represents diisopropyl ethyl Amine；DMF represents dimethylformamide；DMSO represents dimethyl Asia wind；EA represents ethyl acetate；H represents hour；NaOH is represented Sodium hydroxide；LC-MS represents liquid phase-mass spectrum；M-CPBA represents metachloroperbenzoic acid；MeOH represents methanol；Min, which is represented, to be divided Clock；MS represents mass spectrum；NMR represents nuclear magnetic resonance；Pd (dppf) 2Cl2 represents [bis- (diphenylphosphine) ferrocene of 1,1'-] dichloro Change palladium dichloromethane complex；PE represents petroleum ether；Ruphos-Pd-G3 represents methanesulfonic acid (2- dicyclohexyl phosphino- -2', 6'- Diisopropoxy -1,1'- xenyl) (2- amino -1,1'- biphenyl -2- base) palladium (II)；TFA represents trifluoroacetic acid；THF is represented Tetrahydrofuran.

Specific embodiment

Embodiment 1 (S) -4- (4- acryloyl piperazine -1- base) -7- (5- methyl-1 H- indazole -4- base) -1- ((1- methyl pyrrole Cough up alkane -2- base) methyl) -5,6,7,8- tetrahydropyridine simultaneously [3,4-d] pyrimidine -2 (1H) -one (compound 1) synthesis

Compound 1 is prepared according to method A as described below:

4- (4- ((benzyloxy) carbonyl) piperazine -1- base) -2- (first sulfydryl) -5,8- dihydro pyrido [3,4-d] pyrimidine -7 (6H)-t-butyl formate (1-1)

A1 (5.2g, 12.11mmol) is added into 250mL single port bottle, DIPEA (3.2g, 24.22mmol), benzyl -1- piperazine Under piperazine carbonic ester (2.9g, 13.31mmol) and DMF (50mL), Ar protection, it is warming up to 100 DEG C and reacts 1 hour.TLC monitors (PE/ EA=10/1), raw material fully reacting after being cooled to room temperature reaction solution, is added water (100mL), is extracted with EA (50mL*2), closed And organic phase, saturated sodium-chloride are washed, organic phase concentration, column chromatographic purifying (PE/EA=1/0 to 2/1) obtains white solid 1-1 (6.03g, yield 99%), ESI-MS m/z:500.2 [M+H]⁺。

4- (4- ((benzyloxy) carbonyl) piperazine -1- base) -2- (methylsulfonyl) -5,8- dihydro pyrido [3,4-d] pyrimidine -7 (6H)-t-butyl formate (1-2)

It is added into 250mL single port bottle under 1-1 (6.03g, 12.07mmol) and DCM (60mL), Ar protection, ice bath is cooling It to 0-5 DEG C, is added m-CPBA (7.29g, 42.24mmol), is reacted 2 hours under ice bath.TLC monitors (PE/EA=1/10), former Expect fully reacting, saturated sodium bicarbonate solution (60 mL) is added into reaction solution, stirring, liquid separation；Water phase uses DCM (50mL) again Extraction merges organic phase, and saturated sodium-chloride is washed, and organic phase concentration, column chromatographic purifying (PE/EA=1:0 to 1/1) obtains white solid Body 1-2 (4.96g, yield 78%), ESI-MS m/z:532.1 [M+H]⁺。

4- (4- ((benzyloxy) carbonyl) piperazine -1- base) -2- oxo -2,5,6,8- tetrahydropyridine simultaneously [3,4-d] pyrimidine -7 (1H)-t-butyl formate (1-3)

1-2 (4.694g, 8.83mmol) and Isosorbide-5-Nitrae-dioxane (88mL) are added into 250mL single port bottle, is then added Sodium hydroxide solution (44.1mL, 2N), overnight, TLC monitors (PE/EA=1/1), raw material fully reacting, with 2N salt for room temperature reaction Acid adjusts pH to 7, and solid is precipitated, filters to obtain white solid 1-3；Filtrate uses EA (30mL) to extract again, and saturated sodium chloride solution is washed, nothing Aqueous sodium persulfate dries, filters, concentration, and EA (5mL) mashing stirring is added in crude product, filters to obtain white solid 1-3, and merging obtains 1-3 (3.48g, yield 79%), ESI-MS m/z:470.3 [M+H]⁺。

(S) -4- (4- ((benzyloxy) carbonyl) piperazine -1- base) -1- ((1- methylpyrrolidin- 2- yl) methyl) -2- oxo - 2,5,6,8- tetrahydropyridine simultaneously [3,4-d] pyrimidine -7 (1H)-t-butyl formate (1-4)

1-3 (3.2g, 6.74mmol) is added in 100mL tube sealing reaction device, Cs₂CO₃(4.4g, 13.48mmol), (S) -2- (bromomethyl) -1- crassitude (1.8g, 10.1mmol), CuI (257mg, 1.35mmol) and DMSO (30mL), after sealing It rises to 100 DEG C and is stirred to react 20h.System is down to room temperature, and saturated ammonium chloride solution (30mL) is added and is quenched, 30min is stirred at room temperature Afterwards plus EA (50mL*2) extraction, merging organic phase are washed with saturated sodium chloride solution (50mL*2), are concentrated, residue column chromatography (DCM/MeOH=30/0to 20/1) purifies to obtain brown solid 1-4 (2.1g, yield 55%), ESI-MS m/z:567.3 [M+ H]⁺。

(S) -4- (1- ((1- methylpyrrolidin- 2- yl) methyl) -2- oxo -1,2,5,6,7,8- hexahydropyridine simultaneously [3,4- D] -4 base of pyrimidine) piperazine -1- benzyl formate (1-5)

Addition 1-4 (4.66g, 8.22mmol) in 250mL single port bottle, DCM (20mL) and HCl/Dioxane solution (4M, 21mL, 82mmol), reaction 4h is stirred at room temperature in mixed liquor.After LC-MS monitors fully reacting, DCM is added in system concentration, residue Liquid separation after 30min is stirred at room temperature in (50mL), sodium bicarbonate solution (50mL), and water phase uses DCM (50mL) to extract again, merges organic It is mutually washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and is concentrated to dryness to obtain yellowish-brown oily 1-5 (3.96g, yield 100%), ESI-MS m/z:467.3 [M+H]⁺。

4- (7- (5- methyl-1-(tetrahydro-2H- pyrans-2- base)-1H- indazole-4- base)-1- (((S)-1- methylpyrrole Alkane -2- base) methyl) -2- oxo -1,2,5,6,7,8- hexahydropyridine simultaneously -4 base of [3,4-d] pyrimidine) piperazine -1- benzyl formate (1- 6)

1-5 (379mg, 0.812mmol) is added in 100mL single port bottle, the bromo- 5- methyl-1-of 4- (tetrahydro-2H- pyrans-2- Base) -1H- indazole (311mg, 1.056mmol), sodium tert-butoxide (195mg, 2.03mmol), Ruphos-Pd-G3 (134mg, 0.16mmol) and Dioxane (20mL), Ar displacement are warming up to return stirring reaction 20h after protecting.LC-MS monitoring reaction is completed Afterwards, system adds water quenching to go out, and EA (20mL*2) extraction, organic phase is washed with saturated sodium-chloride, dense dry, pre-TLC preparation purifying (DCM/MeOH/NH₄OH=20/1/0.02) pale brown oil object 1-6 (100mg, yield 18%) is obtained, ESI-MS m/z: 481.3[M+H]⁺。

7- (5- methyl-1-(tetrahydro-2H- pyrans-2- base)-1H- indazole-4- base)-1- (((S)-1- methylpyrrolidin- 2- Base) methyl) -4- (piperazine -1- base) -5,6,7,8- tetrahydropyridine simultaneously [3,4-d] pyrimidine -2 (1H) -one (1-7)

Addition 1-6 (100mg, 0.147mmol) in 100mL single port bottle, MeOH (10mL) and 10% Pd/C (20mg, Wet%=50%), H₂It replaces and stirs 20h under rear chamber normal temperature and pressure three times.LC-MS is monitored after the reaction was completed, system filtering, filtrate It is concentrated to dryness, obtains yellow solid 1-7 (80mg, yield 100%), ESI-MS m/z:547.2 [M+H]⁺。

4- (4- acryloylpiperazines-1- base)-7- (5- methyl-1-(tetrahydro-2H- pyrans-2- base)-1H- indazole-4- Base) -1- (((S) -1- methylpyrrolidin- 2- yl) methyl) -4- (piperazine -1- base) -5,6,7,8- tetrahydropyridine is simultaneously [3,4-d] phonetic Pyridine -2 (1H) -one (1-8)

1-7 (80mg, 0.147mmol) is added in 50mL single port bottle, DCM (5mL), DIPEA (38mg, 0.294mmol), Ar protects lower ice bath to be cooled to 0 DEG C, and the DCM solution of acryloyl chloride (16mg, 0.177mmol) is added dropwise afterwards, and drop finishes, and 0-5 DEG C of system Stir 1h.After LC-MS monitors fully reacting, water quenching is added to go out, liquid separation, water phase is extracted with DCM (10mL), merges organic phase saturation Sodium chloride solution (10mL) washing, anhydrous sodium sulfate dry, filter, dense to do to obtain faint yellow solid 1-8 (60mg, yield 68%), ESI-MS m/z: 601.2[M+H]⁺。

(S) -4- (4- acryloyl piperazine -1- base) -7- (5- methyl-1 H- indazole -4- base) -1- ((1- methylpyrrolidin- 2- Base) methyl) -5,6,7,8- tetrahydropyridine simultaneously [3,4-d] pyrimidine -2 (1H) -one (1)

1-8 (60mg, 0.1mmol) is added in 50mL single port bottle, DCM (5mL), TFA (114mg, 1 mmol), under Ar protection 2h is stirred at room temperature, after LC-MS monitors fully reacting, system is concentrated to dryness, and residue pre-TLC purifies (DCM/MeOH/NH₄OH =10/1/0.1) off-white powder compound 1 (25mg, yield 48%) is obtained.

¹H NMR(400MHz,CDCl₃)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]⁺。

2 4- of embodiment (4- acryloylpiperazines -1- base) -6- cyclopropyl -8- methoxyl group -7- (5- methyl-1 H- indazole - 4- yl) -1- (((S) -1- methylpyrrolidin- 2- yl) methyl) quinazoline -2 (1H) -one (compound 53) synthesis

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

4- (the chloro- 8- Fluquinconazole quinoline -4- base of the bromo- 2,6- bis- of 7-) piperazine -1- t-butyl formate (53-1)

B1 (5g, 15.13mmol) is added in 250mL single port bottle, DIPEA (4g, 30.3mmol), N-Boc- piperazine Under (2.96g, 15.89mmol) and DMF (100mL), Ar protection, it is warming up to 80 DEG C and reacts 2 hours.TLC contact plate (PE/EA=5/ 1), raw material fully reacting after being cooled to room temperature reaction solution, is added water (100mL), is extracted with EA (100mL*2), merged organic Phase, saturated sodium-chloride washing, organic phase concentration, column chromatographic purifying (PE/EA=1:0 to 2/1) obtain white solid 53-1 (5.23g, yield 72%), ESI-MS m/z:479.1/481.1 [M+H]⁺。

4- (the fluoro- 2- oxo -1,2- dihydroquinazoline -4- base of the chloro- 8- of the bromo- 6- of 7-) piperazine -1- t-butyl formate (53-2)

53-1 (5.23g, 10.89mmol) and THF (100mL) are added in 250mL single port bottle, it is molten that sodium hydroxide is then added Liquid (2N, 10.5mL, 21mmol), room temperature reaction is overnight.TLC monitors (PE/EA=1/1), raw material fully reacting, with 2N HCl tune PH to 7 adds EA (50mL*2) to extract, and merges organic phase and is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, dense The mashing of EA (5mL)/PE (20mL) room temperature is added in contracting, crude product, filters to obtain white solid 53-2 (2.61g, yield 52%), ESI-MS m/z:462.1/463.1 [M+H]⁺。

4- (the chloro- 8- methoxyl group -2- oxo -1,2- dihydroquinazoline -4- base of the bromo- 6- of 7-) piperazine -1- t-butyl formate (53-3)

DMF (40ml) is added in 250ml there-necked flask, sodium methoxide (485mg, 8.66mmol) is cooled under Ar displacement protection 0-5 DEG C, DMF (10mL) solution of 53-2 (2g, 4.33mmol) is added dropwise afterwards, drop finishes, and system, which is warmed to room temperature, to be stirred to react.LC-MS After the reaction was completed, system adds water (50mL) to be quenched, 1N HCl tune pH to neutrality for monitoring, and EA (50mL*2) extraction merges organic phase It is washed with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and EA (5mL)/PE (20mL) room temperature is added in concentration, residue Mashing, filters to obtain white solid 53-3 (1.68g, 82%), ESI-MS m/z:473.1/475.1 [M+H]⁺。

(S) -4- (the chloro- 8- methoxyl group -1- of the bromo- 6- of 7- ((1- methylpyrrolidin- 2- yl) methyl) -2- oxo -1,2- dihydro Quinazoline -4- base) piperazine -1- t-butyl formate (53-4)

53-3 (840mg, 1.773mmol) is added in 100mL tube sealing reaction device, Cs₂CO₃(1.72g, 5.32 mmol), (S) -2- (chloromethyl) -1- crassitude hydrochloride (600mg, 3.55mmol), CuI (67mg, 0.355mmol) and DMSO (20mL) rises to 100 DEG C and is stirred to react 20h after sealing.LC-MS is monitored after the reaction was completed, and system is down to room temperature, and saturation chlorine is added Change ammonium salt solution (20mL) to be quenched, is stirred at room temperature after 30min plus EA (40mL*2) extraction, merging organic phase saturated sodium-chloride are molten Liquid (40mL*2) washing, concentration, residue column chromatography (DCM/MeOH=50/0to 20/1) purify to obtain off-white powder 53-4 (638mg, yield 63%), ESI-MS m/z:570.0/572.0 [M+H]⁺。

4- (the chloro- 8- methoxyl group-7- of 6- (5- methyl-1-(tetrahydro-2H- pyrans-2- base)-1H- indazole-4- base)-1- (((S) -1- methylpyrrolidin- 2- yl) methyl) -2- oxo -1,2- dihydroquinazoline -4- base) piperazine -1- t-butyl formate (53-5)

53-4 (638mg, 1.118mmol) is added in 100mL single port bottle, 4- bromo- 5- methyl-1-(tetrahydro-2H- pyrans- 2- yl) -1H- indazole (428mg, 1.453mmol), sodium tert-butoxide (268mg, 2.79mmol), Ruphos-Pd-G3 (184mg, 0.22mmol) and Dioxane (20mL), Ar displacement are warming up to return stirring reaction 20h after protecting.LC-MS monitoring reaction is completed Afterwards, system adds water quenching to go out, and EA (20mL*2) extraction, organic phase is washed with saturated sodium-chloride, dense dry, pre-TLC preparation purifying (DCM/MeOH/NH₄OH=20/1/0.02) pale brown oil object 53-5 (371mg, yield 47%) is obtained, ESI-MS m/z: 706.2[M+H]⁺。

4- (6- cyclopropyl -8- methoxyl group -7- (5- methyl-1 H- indazole -4- base) -1- (((S) -1- methylpyrrolidin- 2- Base) methyl) -2- oxo -1,2- dihydroquinazoline -4- base) piperazine -1- t-butyl formate (53-6)

53-5 (371mg, 0.525mmol) is added in 100mL single port bottle, cyclopropylboronic acid (68mg, 0.788 mmol), nothing Pd (dppf) is added after water potassium phosphate (278mg, 1.313mmol) and Dioxane (10mL), Ar displacement protection₂Cl₂(58mg, 0.1mmol), back flow reaction 20h is warming up to after.LC-MS is monitored after the reaction was completed, and mixed liquor is concentrated to dryness, and residue crosses reverse phase Flash preparation purifies to obtain 53-6 (269mg, yield 72%), ESI-MS m/z:712.2 [M+H]⁺。

6- cyclopropyl -8- methoxyl group -7- (5- methyl-1 H- indazole -4- base) -1- (((S) -1- methylpyrrolidin- 2- yl) Methyl) -4- (piperazine -1- base) quinazoline -2 (1H) -one (53-7)

Addition 53-6 (269mg, 0.378mmol) in 50mL single port bottle, DCM (10mL) and HCl/ Dioxane solution (4M, 2mL, 8mmol), reaction 20h is stirred at room temperature in mixed liquor.After LC-MS monitors fully reacting, system is concentrated to dryness to obtain brown solid 53-7 (253mg, yield 100%), ESI-MS m/z:527.2 [M+H]⁺。

4- (4- acryloylpiperazines -1- base) -6- cyclopropyl -8- methoxyl group -7- (5- methyl-1 H- indazole -4- base) -1- (((S) -1- methylpyrrolidin- 2- yl) methyl) quinazoline -2 (1H) -one (53)

53-7 (25mg, 0.039mmol) is added in 25mL single port bottle, DCM (5mL), DIPEA (25mg, 0.196mmol), Under Ar protection, ice bath is cooled to 0 DEG C, and the DCM solution of acryloyl chloride (2.8mg, 0.031mmol) is added dropwise afterwards, and drop finishes, system 0-5 DEG C stirring 1h.The remaining a small amount of raw material of LC-MS monitoring reaction, adds water quenching to go out, and liquid separation, water phase is extracted with DCM (10mL), is merged organic Phase, dense dry, crude product pre-TLC (DCM/MeOH/NH₄OH=20/1/0.02 compound 53 (8mg, yield 35%)) is purified to obtain.

¹H NMR(400MHz,CDCl₃)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]⁺。

3 4- of embodiment ((S) -4- acryloyl group -2- methylpiperazine-1-yl) fluoro- 7- of -6- (the fluoro- 6- hydroxy phenyl of 2-) - The synthesis of 1- (((S) -1- methylpyrrolidin- 2- yl) methyl) pyrido [2,3-d] pyrimidine -2 (1H) -one (compound 74)

Compound 74 is prepared according to method C as described below:

The chloro- 5- fluorine niacinamide (74-1) of 2,6- bis-

CDI (35.6g, 220mmol) is added portionwise in THF (400mL) solution of C1 (42g, 200mmol), is mixed Object stirs 5min, and Ar protection is heated to 50 DEG C, reacts 1h, LC-MS monitoring, and raw material disappears, and reaction solution is dilute with toluene (100mL) Release, be concentrated to the half of initial volume, obtained mixture is cooled to 0 DEG C, be slowly added to ammonium hydroxide (55mL, 400mmol).10min is reacted at room temperature, EA dilutes (200mL), washes (100mL*3).Organic layer anhydrous Na₂SO₄It is dry, rotation It is dry.PE/EA (10/1,200 mL) mashing, filtering by the half of remaining mother liquor concentrations to initial volume, are cooled to 0 DEG C, again Solid, filtering is precipitated.Merge two batches solid, obtain product as light yellow solid 74-1 (22.10g, yield 53%), head product without Purifying is directly used in reacts in next step, ESI-MS m/z:208.9 [M+H]⁺。

(S) the two fluoro- N- of chloro- 5- of -2,6- (((1- methylpyrroline -2- base) methyl) carbamoyl) niacinamide (74-2)

74-1 (5.2g, 25mmol) is dissolved in THF (50mL), is cooled to -78 DEG C under argon gas protection, it is slow by syringe It is slow that oxalic acid chlorine (2M solution D CM, 13mL, 26mmol) is added, it finishes, reaction solution 60 DEG C of reaction 3.5h of heating stop heating, cold But it to -78 DEG C, is added TEA (7.6g, 75mmol), (S)-(1- methylpyrroline -2- base) methylamine (2.85g, 25mmol) adds Finish, be warmed to room temperature stirring 1 hour, add water (120mL) quenching reaction, EA extraction merges organic phase, organic phase anhydrous Na₂SO₄ It is dry, concentration.Column chromatographs (DCM/MeOH=100/1to 20/1), obtains light yellow solid 74-2 (5.20g, yield 60%), ESI-MS m/z:349.1[M+H]⁺。

(S) the fluoro- 1- of the chloro- 6- of -7- ((1- methylpyrroline -2- base) methyl) pyrido [2,3-d] pyrimidine -2,4 (1H, 3H)-diketone (74-3)

74-2 (3.5g, 10mmol) is dissolved in THF (100mL), argon gas protects lower ice bath, is slowly added to KHMDS (1M THF solution, 20mL), it finishes, stirs 10min, remove ice bath, react 30min at room temperature.Saturated ammonium chloride (125mL) is quenched instead It answers, is extracted with EA (250mL).Organic phase is washed with saturated common salt, anhydrous Na₂SO₄It is dry, concentration.Column chromatographs (DCM/MeOH= 100/1to 20/1), obtain light yellow solid 74-3 (1.71g, yield), ESI-MS m/z:313.1 [M+H]⁺。

(S) the two fluoro- 1- of chloro- 6- of -4,7- ((1- methylpyrroline -2- base) methyl) pyrido [2,3-d] pyrimidine -2 (1H) - Ketone (74-4)

74-3 (1.56g, 5.0mmol) is dissolved in acetonitrile (10mL), is added DIPEA (1.9g, 15mmol), POCl₃ (920mg, 6.0mmol), 80 DEG C of heating are stirred to react 30min.LC-MS monitoring, end of reaction, concentration direct plunge into next step Reaction, ESI-MS m/z:331.1 [M+H]⁺。

(S) -4- (the fluoro- 1- of the chloro- 6- of 7- (((S) -1- methylpyrroline -2- base) methyl) -2- oxo -1,2- dihydropyridine And [2,3-d] pyrimidine-4-yl) -3- methyl piperazine -1- t-butyl formate (74-5)

74-4 (theoretical amount 5.0mmol) obtained by upper step is dissolved in DMF (15mL), is added DIPEA (1.9g, 15mmol), (S) -3- methyl piperazine -1- t-butyl formate (1.2g, 6.0mmol) reacts at room temperature 30min clock, LC-MS monitoring, fundamental reaction It finishes, EA is added to dilute, sodium bicarbonate aqueous solution is washed, and dry, concentration, column chromatographs (DCM/MeOH=100/1to 20/1), is obtained To light yellow solid 74-5 (2.01g, yield 20%), ESI-MS m/z:495.2 [M+H]⁺。

(S) -4- (7- (2- hydroxyl -6- aminomethyl phenyl) fluoro- 1- of -6- (((S) -1- methylpyrroline -2- base) methyl) -2- Oxo -1,2- dihydro pyrido [2,3-d] pyrimidine-4-yl) -3- methyl piperazine -1- t-butyl formate (74-6)

By 74-5 (1.2g, 3.0mmol), Pd (dppf) Cl₂(220mg, 0.3mmol), AcOK (2.36g, 24 mmol) are molten It in Isosorbide-5-Nitrae-dioxane (50mL), under argon gas protection, heats up 90 DEG C and reacts 3h, LC-MS monitors end of reaction, is directly concentrated, column It chromatographs (DCM/MeOH=100/1to 20/1), obtains light yellow solid 74-6 (1.10g, yield 65%), ESI-MS m/ z:567.3[M+H]⁺。

4- ((S) -4- acryloyl group -2- methylpiperazine-1-yl) the fluoro- 7- of -6- (the fluoro- 6- hydroxy phenyl of 2-) -1- (((S) - 1- methylpyrroline -2- base) methyl) pyrido [2,3-d] pyrimidine -2 (1H) -one (74)

74-6 (566mg, 1.0mmol) is dissolved in TFA (10mL), 30min is reacted at room temperature, LC-Ms monitoring has been reacted Finish, is directly concentrated.Residue is dissolved in DCM, is added DIPEA (650mg, 5.0mmol), ice bath, dropwise addition acryloyl chloride (100mg, 1.1mmol), it finishes, reacts at room temperature 1h, LC-MS monitoring, end of reaction, reaction solution is diluted with DCM, is washed with water, is concentrated, column layer It analyses (DCM/MeOH=100/1to 20/1), obtains light yellow solid 74 (320mg, yield 61%).

¹H NMR(400MHz,CDCl₃)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]⁺。

4 2- of embodiment ((2S) -1- acryloyl -4- (the chloro- 7- of 6- (the fluoro- 6- hydroxy phenyl of 2-) -1- (((S) -1- methyl pyrrole Cough up alkane -2- base) methyl) -2- oxo -1,2- dihydroquinazoline -4- base) piperazine -2- base) acetonitrile (compound 107) synthesis:

Compound 107 is prepared according to method D as described below:

(S) -4- (the bromo- 2,6- dichloroquinazoline -4- base of 7-) -2- (cyano methyl) piperazine -1- carboxylic acid tert-butyl ester (107-1)

Bromo- 2,4,6- tri- chloro-quinazoline (4.68g, 15.0mmol) of 7-, DIPEA are added into 250mL single port bottle (3.87g, 30mmol), (S) -2- (cyano methyl) piperazine -1- carboxylic acid tert-butyl ester (3.55g, 15.75mmol) and DMF (100mL) under Ar protection, is warming up to 60 DEG C and reacts 20 hours.TLC monitors (PE/EA=10/1), and raw material fully reacting will be anti- It after answering liquid to be cooled to room temperature, is added water (200mL), is extracted with EA (100mL*2), merge organic phase, saturated sodium-chloride is washed, organic It is mutually concentrated, column chromatographic purifying (PE/EA=1/0 to 2/1) obtains white solid 107-1 (5.26g, yield 70%), ESI-MS m/z:500.2/502.2[M+H]⁺。

(S) -4- (the bromo- 6- chloro-2-oxo -1,2- dihydroquinazoline -4- base of 7-) -2- (cyano methyl) piperazine -1- carboxylic acid The tert-butyl ester (107-2)

107-1 (5.26g, 10.5mmol) and Isosorbide-5-Nitrae-dioxane (100mL) are added into 250mL single port bottle, then plus Enter sodium hydroxide solution (51mL, 2N), overnight, TLC monitors (PE/EA=1/1), raw material fully reacting, with 2N salt for room temperature reaction Acid adjusts pH to 7, and solid is precipitated, filters to obtain white solid 107-2；Filtrate uses EA (50mL) to extract again, and saturated sodium chloride solution is washed, Anhydrous sodium sulfate dries, filters, concentration, crude product be added EA (10mL) mashing stirring, filter white solid 1-2, merging obtain 1-2 (3.29g, yield 65%), ESI-MS m/z:482.1/484.1 [M+H]⁺。

(S) -4- (the chloro- 1- of the bromo- 6- of 7- (((S) -1- methylpyrrolidin- 2- yl) methyl) -2- oxo -1,2- dihydro quinoline azoles Quinoline -4- base tert-butyl base) -2- (cyano methyl) piperazine -1- carboxylic acid tert-butyl ester (107-3)

107-2 (3.25g, 6.74mmol) is added in 100mL tube sealing reaction device, Cs₂CO₃(4.4g, 13.48 mmol), (S) -2- (bromomethyl) -1- crassitude (1.8g, 10.1mmol), CuI (257mg, 1.35mmol) and DMSO (30mL), 100 DEG C are risen to after sealing is stirred to react 20h.System is down to room temperature, and saturated ammonium chloride solution (30mL) is added and is quenched, is stirred at room temperature After 30min plus EA (50mL*2) extraction, merging organic phase are washed with saturated sodium chloride solution (50mL*2), are concentrated, residue column Chromatography (DCM/MeOH=30/0to 20/1) purifies to obtain brown solid 107-3 (2.58g, yield 66%), ESI-MS m/z: 579.1/581.1 [M+H]⁺。

(2S) -4- (the chloro- 7- of 6- (the fluoro- 6- of 2- ((tetrahydro -2H- pyrans -2- base) oxygroup) phenyl) -1- (((S) -1- (tertiary fourth Ylmethylpyrrolidine -2- base) methyl) -2- oxo -1,2- dihydroquinazoline -4- base) -2- (cyano methyl) piperazine -1- carboxylic acid uncle Butyl ester (107-4)

107-3 (565mg, 0.974mmol) is added in 100mL single port bottle, 2- (the fluoro- 6- of 2- ((tetrahydro -2H- pyrans -2- Base) oxygroup) phenyl) -4,4,5,5- tetramethyls -1,3,2- dioxaborinate (376mg, 1.17mmol), potassium acetate (239mg, 2, 436mmol), Pd (dppf)₂Cl₂(81mg, 0.1mmol) and Dioxane (20mL), H₂It heats up after O (5ml), Ar displacement protection 6h is reacted to return stirring.LC-MS is monitored after the reaction was completed, and system adds water quenching to go out, EA (20mL*2) extraction, organic phase saturation NaCl, dense dry, column chromatographs (DCM/MeOH=20/1) and obtains pale brown oil object 107-4 (508mg, yield 75%), ESI-MS m/z: 695.1[M+H]⁺。

2- ((2S) -4- (the chloro- 7- of 6- (the fluoro- 6- hydroxy phenyl of 2-) -1- (((S) -1- methylpyrrolidin- 2- yl) methyl) - 2- oxo -1,2- dihydroquinazoline -4- base) piperazine -2- base) acetonitrile (107-5)

107-4 (500mg, 0.719mmol) is added in 50mL single port bottle, EA (10mL), HCl/Diox (3.6mL, 4M, 14.4mmol), 2h is stirred at room temperature under Ar protection, after LC-MS monitors fully reacting, system is concentrated to dryness to obtain light tan solid 107- 5 (370mg, yields 100%).ESI-MS m/z:511.1[M+H]⁺

2- ((2S) -1- acryloyl -4- (the chloro- 7- of 6- (the fluoro- 6- hydroxy phenyl of 2-) -1- (((S) -1- methylpyrrolidin- 2- Base) methyl) -2- oxo -1,2- dihydroquinazoline -4- base) piperazine -2- base) acetonitrile (compound 107)

107-5 (51mg, 0.1mmol) is added in 25mL single port bottle, DCM (5mL), DIPEA (65mg, 0.5mmol), Ar It protects lower ice bath to be cooled to 0 DEG C, the DCM solution of acryloyl chloride (10mg, 0.11mmol) is added dropwise afterwards, drop finishes, and 0-5 DEG C of system is stirred Mix 1h.After LC-MS monitors fully reacting, water quenching is added to go out, liquid separation, water phase is extracted with DCM (10mL), merges organic phase saturation chlorine Change sodium solution (10mL) washing, dense dry, residue pre-TLC purifies (DCM/MeOH/NH₄OH=20/1/0.1 off-white color) is obtained Solid chemical compound 107 (24mg, yield 42.5%).

¹H NMR(400MHz,CDCl₃) 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]⁺。

The detection of 5 compound of embodiment Ras-GTP content intracellular to H358

After growth one day, untested compound (concentration is added in six orifice plates of ultralow absorption in 1000000 H358 cell seedings It is 1 μM), after compound effects 24 hours, after lytic cell, it is added GST-Raf1 (1-149) (millipore 14-863), 4 After degree is incubated overnight, it is added GST beads (millipore, G0924), 4 degree of 2 hours of incubation, is then centrifuged for, takes beads, After beads washes 3 times with IP buffer, SDS lysate is then added, glue is run, with Ras antibody (CST, 3339) western Blot detects the Ras-GTP content pulled down.It is compared with DMSO group, calculates compound and inhibit the active percentage of Ras-GTP, as a result See below list 2.

The inhibitory activity of 2. the compounds of this invention of table Ras-GTP intracellular to H358

+ indicate inhibiting rate at most 50%

++ indicate that inhibiting rate is 50% to 90%

+++ indicate that inhibiting rate is greater than 90%

Antiproliferative activity of 6 compound of embodiment to H358 cell

2500 H358 cell seedings after growth three days, are added in 96 orifice plates (corning, 7007) of ultralow absorption Gradient dilution compound (highest 30uM, 5 times dilute, altogether five dosage), after being added compound four days, is added Cell Titer Glow (Promega, G9681) evaluates the growing state of bead, calculates IC₅₀Value, as a result sees below list 3.

Antiproliferative activity of 3. the compounds of this invention of table to H358 cell

+ indicate to be greater than 30 μM

++ indicate that inhibiting rate is 1 to 30 μM

+++ indicate inhibiting rate less than 1 μM.

Claims

1. a kind of structure such as general formula (1) compound represented or its each optical isomer, each crystal form, pharmaceutically acceptable salt, Hydrate or solvate:

In formula (1):

M is 0,1 or 2；

A is monocycle, bicyclic, bridged ring or the loop coil of 4-12 member saturation or fractional saturation that a divalent contains 1-2 N atom, institute Stating monocycle, bicyclic, bridged ring or loop coil can be optionally by one or more R⁴It is replaced, when by multiple R⁴When substitution, R⁴Can it is identical or It is different；

Y is chemical bond or C1-C6 alkylidene；

R¹For aryl or heteroaryl, the aryl or heteroaryl can be replaced 1-3 following radicals: halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen replace C1-C3 alkyl or halogen to replace C1-C3 Alkoxy；

R²For aminoalkyl, naphthenic base, alkyl substituted amide base, heterocycle, aryl or heteroaryl, the heterocycle, aryl or miscellaneous Aryl can be optionally by one or more R⁵It is replaced, when by multiple R⁵When substitution, R⁵It can be identical or different；

R³Independent choice C1-C3 alkyl or halogenated C1-C3 alkyl；

R⁵Halogen, H, O, CN, OH, alkyl hydroxy, dialkyl amino, C1-C6 alkyl, C3-C6 naphthenic base, halogen is independently selected to take Replace C1-C3 alkoxy for C1-C3 alkyl or halogen；

E is can to form the electrophilic of covalent bond with the cysteine residues of 12 of K-Ras, H-Ras or N-Ras mutant protein Part.

2. compound as described in claim 1, wherein E is one and contains electrophilic carbon-carbon double bond or carbon-carbon triple bond in the formula (1) Group.

3. compound as claimed in claim 2, wherein in the formula (1), E are as follows: Its In, R_aFor H or F, R_bFor H ,-CH₂F、-CHF₂、

4. compound as described in claim 1, wherein in the formula (1), A-E are as follows: Wherein, n is 1 or 2, R⁴C1-C3 alkyl or cyano is replaced to replace C1-C3 alkyl for H, CN, C1-C3 alkyl, halogen.

5. compound as described in claim 1, wherein Y is chemical bond ,-CH in the formula (1)₂,-CH (Me)-or- CH₂CH₂-。

6. compound as described in claim 1, wherein in the formula (1), R¹Are as follows: Wherein R_cAnd R_dIndependently Replace C1-C3 alkane for halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen Base or halogen replace C1-C3 alkoxy.

7. compound as described in claim 1, wherein in the formula (1), R²Are as follows: Wherein n is 1 or 2, R_eAnd R_fSolely It is on the spot H, halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen replace C1-C3 alkyl or halogen replace C1-C3 alkoxy, R_gFor C1-C3 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkyl-alkyl, C1- C3 alkoxyalkyl, halogen replace C1-C3 alkyl, halogen replace C3-C6 naphthenic base or

8. compound or a kind of its pharmaceutically acceptable salt as described in claim 1-7, wherein the compound have with One of flowering structure:

。

9. a kind of structure such as general formula (2) compound represented or its each optical isomer, each crystal form, pharmaceutically acceptable salt, Hydrate or solvate:

In formula (2):

Y is chemical bond or C1-C6 alkylidene；

W is N, C-R⁸Or C-O-R⁶:

Wherein, when W is C-O-R⁶When, R²For aminoalkyl, naphthenic base, alkyl substituted amide base, heterocycle, aryl or heteroaryl, The heterocycle, aryl or heteroaryl can be optionally by one or more R⁵It is replaced, when by multiple R⁵When substitution, R⁵It can be identical Or it is different；

Wherein, when W is N or C-R⁸When, R²For aminoalkyl, alkyl substituted amide base or heterocycle, the heterocycle can optional quilt One or more R⁵It is replaced, when by multiple R⁵When substitution, R⁵It can be identical or different；

R¹For aryl or heteroaryl, the aryl or heteroaryl can be replaced 1-3 following radicals: halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen replace C1-C3 alkyl, halogen to replace C1-C3 alkane Oxygroup；

R⁵Halogen, H, O, CN, OH, alkyl hydroxy, dialkyl amino, C1-C6 alkyl, C3-C6 naphthenic base, halogen is independently selected to take Replace C1-C3 alkyl for C1-C3 alkyl or cyano；

R⁶Replace C1-C3 alkyl or C3-C6 naphthenic base for C1-C3 alkyl, halogen；

R⁷C1-C3 alkyl, halogen is replaced to replace C1- for H, halogen, C1-C3 alkyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen C3 alkoxy or C2-C4 alkenyl；

10. compound as claimed in claim 9, wherein E is one and contains electrophilic carbon-carbon double bond or carbon carbon three in the formula (2) The group of key.

11. compound as claimed in claim 10, wherein in the formula (2), E are as follows: Wherein, R_aFor H or F, R_bFor H ,-CH₂F、-CHF₂、

12. compound as claimed in claim 9, wherein in the formula (2), A-E are as follows: Wherein, n is 1 or 2, wherein R⁴C1-C3 alkyl or cyano is replaced to replace C1-C3 alkyl for H, CN, C1-C3 alkyl, halogen.

13. compound as claimed in claim 9, wherein Y is chemical bond ,-CH in the formula (2)₂,-CH (Me)-or- CH₂CH₂-。

14. compound as claimed in claim 9, wherein in the formula (2), R¹Are as follows: Wherein R_cAnd R_dIndependently Replace C1-C3 alkane for halogen, hydroxyl, amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen Base or halogen replace C1-C3 alkoxy.

15. compound as claimed in claim 9, wherein in the formula (2), W C-O-R⁶, R²Are as follows: Wherein n is 1 or 2, R_eAnd R_fIt independently is halogen, hydroxyl, amino, C1-C3 alkane Base, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen replace C1-C3 alkyl or halogen to replace C1-C3 alkoxy, R_gFor C1-C3 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkyl-alkyl, C1-C3 alkoxyalkyl, halogen replace C1-C3 alkyl, Halogen replace C3-C6 naphthenic base or

16. compound as claimed in claim 9, wherein W is N or C-R in the formula (2)⁸, R²Are as follows: Wherein n is 1 or 2, R_eAnd R_fIndependently be halogen, hydroxyl, Amino, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 naphthenic base, C1-C3 alkoxy, halogen replace C1-C3 alkyl or halogen to replace C1-C3 alkoxy, R_gIt is taken for C1-C3 alkyl, C3-C6 naphthenic base, C3-C6 cycloalkyl-alkyl, C1-C3 alkoxyalkyl, halogen For C1-C3 alkyl, halogen replace C3-C6 naphthenic base or

17. compound or a kind of its pharmaceutically acceptable salt as described in claim 9-16, wherein the compound has With one of flowering structure:

。

18. one kind is for treating, adjusting and/or preventing and K-RAS G12C, H-RAS G12C or N-RAS G12C mutant egg The pharmaceutical composition of the relevant disease of white relevant physiological condition, which is characterized in that it contains pharmaceutically acceptable figuration Agent or carrier, and the described in any item compounds of claim 1-17 or its each optical isomer, medicine as active constituent Acceptable salt, hydrate or solvate on.

19. pharmaceutical composition as claimed in claim 18, which is characterized in that the composition is peroral dosage form.

20. pharmaceutical composition as claimed in claim 18, which is characterized in that the composition is injection type.

21. a kind of described in any item compounds of claim 1-17 or its each optical isomer, can pharmaceutically connect each crystal form The purposes of salt, hydrate or the solvate received, it is characterized in that for treating individual in need by K-RAS G12C, H-RAS The method for the illness that G12C or N-RAS G12C mutation mediates.

22. method as claimed in claim 21, wherein the illness is cancer, the cancer is blood cancer and entity Tumor.