WO2021088938A1 - Tetrahydropyridopyrimidine-based inhibitor, preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to a tetrahydropyridopyrimidine-based inhibitor, a preparation method therefor and use thereof. Specifically, the compound has a structure represented by formula (I), each of the groups and substituents are defined as described in the description. Also disclosed are a preparation method for the compound and use thereof as a KRAS^G12C inhibitor.

Description

Tetrahydropyridopyrimidine inhibitor and its preparation method and application Technical field

The invention belongs to the field of medicine, and specifically relates to a tetrahydropyridopyrimidine inhibitor and a preparation method and application thereof.

Background technique

Lung cancer is one of the important causes of human cancer deaths. According to the cell type, lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Among them, NSCLC accounts for 85% of all lung cancer patients. According to statistics, the global NSCLC market was approximately US$20.9 billion in 2016, of which the US market accounted for half, followed by Japan, Germany and China. Judging from the current trends, the non-small cell lung cancer market has maintained continuous growth, and the global market is expected to reach 54 billion U.S. dollars in 2023 (Nature, 2018; 553(7689):446-454).

At present, the main treatment drugs for NSCLC are divided into chemotherapy drugs, molecular targeted drugs and tumor immunotherapy. Among them, chemotherapeutic drugs mainly include gemcitabine, paclitaxel and platinum drugs, but these drugs generally have poor selectivity and high toxicity, which leads to relatively strong side effects. In recent years, molecular targeted drugs have gradually become research hotspots due to their high selectivity, relatively small side effects, and their obvious advantages such as precise treatment. Existing NSCLC molecular targeted drugs include EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocarti Ni, etc.), and VEGFR inhibitors (Sorafenib, Regorafenib, Cabozantinib, Sunitinib, Donafenib, etc.) (Current Medicinal Chemistry, 2019, 26, 1-39).

In lung cancer patients, KRAS mutations are frequently monitored, accounting for about 32% of all oncogene mutations. Among them, KRAS ^G12C mutation accounts for 44% of all oncogene mutations in NSCLC. So far, no ^{drugs targeting the KRAS G12C} mutation have been approved on the market.

Since the KRAS ^G12C target protein is pathologically related to a variety of diseases, there is a need for new KRAS ^G12C inhibitors for clinical treatment. Highly selective and active KRAS ^G12C inhibitors have the potential to reduce off-target effects, and therefore have more urgent clinical needs.

Summary of the invention

The purpose of the present invention is to provide a new type of ^compound with selective inhibitory effect on KRAS G12C and/or better pharmacodynamic performance and its use.

The first aspect of the present invention provides a tetrahydropyridopyrimidine compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, and hydrates. Substances, solvates or prodrugs:

Where:

R ^{1 is} selected from: hydrogen or deuterium;

R ^{2 is} selected from: hydrogen, deuterium, -CH ₂ F, -CH ₂ N(Me) ₂ ,

R ^{3 is} selected from: hydrogen, deuterium or fluorine;

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , and R ²⁸ are each independently selected from: hydrogen or deuterium;

R ^{20 is} selected from: CH ₃ , CHD ₂ , CH ₂ D or CD ₃ ;

Ar is selected from:

And the hydrogen atom thereon can be optionally deuterated; the limiting condition is ^{that at least one of R 4} -R ²⁸ or Ar is deuterated or deuterated.

In another preferred embodiment, the compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug having the structure of general formula (I) , Has the structure shown in formula II-A, II-B, II-C, II-D, II-E, II-F, II-G:

Where:

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and Ar are as defined above.

In another preferred embodiment, the compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or pro Medicine, with the structure shown in III-A or III-B:

Where

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ and Ar are as defined above.

In another preferred example, R ⁴ and/or R ⁵ are deuterium atoms or deuterated groups.

In another preferred example, ^{at least one of R 6} , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ¹¹ is a deuterium atom or a deuterated group.

In another preferred embodiment, R ¹² and/or R ¹³ are deuterium atoms or deuterated groups.

In another preferred example, ^{at least one of R 14} , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , and R ²⁰ is a deuterium atom or a deuterated group.

In another preferred embodiment, R ²¹ is a deuterium atom or a deuterated group.

In another preferred embodiment, the compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or pro Medicine, which has the structure shown in formula IV-A or IV-B:

Where

The definitions of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ²⁰ and Ar are as described above.

In another preferred embodiment, the compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or pro Medicine, which has the structure shown by the general formula VA or VB:

Where

The definitions of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹² , R ¹³ , R ²⁰ and Ar are as described above.

In another preferred embodiment, the compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or pro Medicine, which has the structure shown in formula VI-A or VI-B:

Where

The definitions of R ¹² , R ¹³ , R ²⁰ and Ar are as described above.

In another preferred example, in formula I, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and Ar are in the embodiment The specific group corresponding to each specific compound.

In another preferred embodiment, the compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or pro Medicine, the compound is selected from:

In another preferred example, the compound of formula I is selected from the compounds shown in the examples.

The second aspect of the present invention provides a method for preparing the compound of the general formula (I) described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, and solvents. The method of compound or prodrug includes the steps:

(i) Under the action of the first base, compound of formula X-1 and

React, and then react with amino protecting agent to produce compound of formula X-2;

(ii) Under the action of 1-chloroethyl chloroformate, the compound of formula X-2 is deprotected to produce compound of formula X-3;

(iii) Compound of formula X-3 is obtained by coupling reaction to compound of formula X-4;

(iv) The compound of formula X-4 reacts with an oxidizing agent to produce a compound of formula X-5;

(v) Under the action of the second base, the compound of formula X-5 reacts with alcohol to produce compound of formula X-6;

(vi) Under the action of the first acid, the compound of formula X-6 is deprotected to produce compound of formula X-7;

(vii) In an inert solvent, the compound of formula X-7 and

The reaction obtains a compound of formula (I);

Where

Rs and Rs' are amino protecting groups, and the amino protecting groups are selected from: Boc, Bn, Cbz or Fmoc;

R ¹ -R ²⁸ and Ar are as defined above; Y is halogen or OH.

In another preferred embodiment, in the step (vi), the first acid is TFA and the like.

In another preferred example, in the step (i), the first base is selected from TEA or DIPEA.

In another preferred example, in the step (iv), the oxidizing agent is selected from: mCPBA and the like.

In another preferred example, in the step (v), the second base is sodium alkoxide, potassium alkoxide, NaH or LiHNMDS, preferably sodium tert-butoxide or potassium tert-butoxide.

In another preferred embodiment, in the step (v), the alcohol is

R ¹² -R ²¹ are as defined above.

In another preferred embodiment, in the step (i), the amino protecting agent is selected from: (Boc) ₂ O, benzyl chloroformate, di-tert-butyl dicarbonate, phthaloyl chloride, benzyl chloride, triphenyl Methyl chloride, 9-fluorenyl methyl chloroformate, allyl chloroformate.

The third aspect of the present invention provides a pharmaceutical composition comprising one or more compounds of the general formula (I) as described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically Acceptable salts, hydrates, solvates or prodrugs; and pharmaceutically acceptable carriers.

In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the following group:

PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405 , MSB2311 or biological analogues of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab 5 tiFuxetan, etc.) -G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib) , Lorlatinib, okatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (E.g. Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (e.g. Sorafenib, Pazopanib, Regorafenib, Sitravatinib, No. Ni, etc.), HDAC inhibitors (such as Giv inostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (e.g. Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.), MEK inhibitors (e.g. Smet (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), PI3K inhibitors (such as Dactolisib, Idelalisib, Alpelisib, Voxtalisib, Omipalisib, Apitolisib, etc.), Akt inhibitors (such as MK- 2206, Ipatasertib, Capivasertib, Afuresertib, Uprosertib, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.), IGF-1R inhibitors (such as Ceritinib, Ocartib, etc.) Ni, linsitinib, BMS-754807, GSK1838705A, etc.) or a combination thereof.

In another preferred embodiment, a method for preparing a pharmaceutical composition is provided, which includes the steps of combining a pharmaceutically acceptable carrier with the compound of general formula (I), stereoisomers, and tautomers described in the first aspect of the present invention. The structure, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug are mixed to form a pharmaceutical composition.

The fourth aspect of the present invention provides a compound with the structure of general formula (I) as described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, The solvate or prodrug, or the use of the pharmaceutical composition of the third aspect, is used to prepare a pharmaceutical composition for preventing and/or treating diseases related to the activity or expression of ^{KRAS G12C.}

In another preferred embodiment, the disease is a tumor or a disordered disease.

In another preferred embodiment, the disease is selected from the following group: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, gastric cancer, liver cancer, colorectal cancer, melanoma, lymphoma, leukemia , Blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.

The fifth aspect of the present invention provides a ^{method for inhibiting KRAS G12C} , which includes the steps of: administering an effective amount of the compound of general formula (I), its stereoisomers, and tautomers as described in the first aspect to a patient in need Forms, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or administration of the pharmaceutical composition described in the third aspect.

In another preferred embodiment, the method of inhibiting KRAS ^{G12C of the} present invention is in vitro and non-diagnostic.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them here.

Detailed ways

After long-term and in-depth research, the inventors unexpectedly prepared a new type of KRAS ^{G12C compound} with selective inhibition and/or better pharmacodynamic properties. On this basis, the inventor completed the present invention.

the term

In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

The term "halogen" or "halo" refers to chlorine, bromine, fluorine, and iodine.

The term "halo" refers to substitution by halogen.

The term "deuterated" refers to substitution by deuterium.

In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position. Those skilled in the art should understand that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. The substituents such as (but not limited to): halogen, hydroxyl, cyano, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, and C1-C6 ureido and so on.

Unless otherwise stated, it is assumed that any heteroatom with a dissatisfaction valence has enough hydrogen atoms to supplement its valence.

Active ingredient

As used herein, the terms "compounds of the present invention" or "active ingredients of the present invention" are used interchangeably and refer to compounds of formula I, or pharmaceutically acceptable salts, hydrates, solvates, isotopic compounds (such as deuterated Compound) or prodrug. The term also includes racemates and optical isomers.

The compound of formula I has the following structure:

Where

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ The definitions of R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and Ar are as described above.

Preferably, the compound of formula I has the structure shown in formula II-A, II-B, II-C, II-D, II-E, II-F, II-G:

Where:

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and Ar are as defined above.

Preferably, the compound of formula I has the structure shown in III-A or III-B:

Where

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ and Ar are as defined above.

Preferably, the compound of formula I has the structure shown in formula IV-A or IV-B:

Where

The definitions of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ²⁰ and Ar are as described above.

Preferably, in the above formulas, at least one (preferably 2, 3 or 4) of ^{R 6} , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , and R ^{11 is a deuterium atom or a deuterated group.}

Preferably, the compound of formula I has a structure represented by the general formula V-A or V-B:

Where

The definitions of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹² , R ¹³ , R ²⁰ and Ar are as described above.

Preferably, in the above formulas, at least one (preferably 2, 3, or 4) of ^{R 6} , R ⁷ , R ¹² , and R ^{13 is a deuterium atom or a deuterated group.}

Preferably, the compound of formula I has a structure shown in formula VI-A or VI-B:

The definitions of R ¹² , R ¹³ , R ²⁰ and Ar are as described above. Preferably, in the above formulas, R ¹² and/or R ¹³ are deuterium.

Salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise specified, the compounds in the present invention are understood to include their salts. The term "salt" as used herein refers to a salt formed into an acid or basic form with an inorganic or organic acid and a base. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterion ("internal salt") that may be formed is contained in Within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, they can be used in separation or purification steps in the preparation process. The compound of the present invention may form a salt. For example, the compound I can be obtained by reacting with a certain amount of acid or base, such as an equivalent amount of acid or base, and salting out in the medium, or by freeze-drying in an aqueous solution.

The basic fragments contained in the compounds of the present invention, including but not limited to amines or pyridine or imidazole rings, may form salts with organic or inorganic acids. Typical acids that can form salts include acetate (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, and benzoate. , Benzene sulfonate, hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, isethionate (E.g. 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salt, pectinate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, etc.

The acidic fragments that some compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases. Typical salts formed by bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed by organic bases (such as organic amines) such as benzathine and bicyclohexyl. Amine, Hypamine (a salt formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butyl Base amines, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (E.g., dimethyl sulfate, diethyl, dibutyl and dipentyl sulfate), long chain halides (such as chlorides and bromides of decyl, dodecyl, tetradecyl and tetradecyl) And iodides), aralkyl halides (such as benzyl and phenyl bromides) and so on.

The prodrugs and solvates of the compounds of the present invention are also within the scope of coverage. The term "prodrug" herein refers to a compound that undergoes metabolic or chemical transformation to produce the compound, salt, or solvate of the present invention when treating related diseases. The compounds of the present invention include solvates, such as hydrates.

The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imine ethers). All these tautomers are part of the invention.

All stereoisomers of compounds (for example, those asymmetric carbon atoms that may exist due to various substitutions), including their enantiomeric forms and diastereomeric forms, fall within the scope of the present invention. The independent stereoisomers of the compound in the present invention may not coexist with other isomers (for example, as a pure or substantially pure optical isomer with special activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or part of them. The chiral center of the present invention has two configurations, S or R, defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. The racemic form can be resolved by physical methods, such as fractional crystallization, or separation of crystallization by derivatization into diastereomers, or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid and then recrystallization.

In the compound of the present invention, the weight content of the compound obtained by successive preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), as described in the text Listed. Here, such "very pure" compounds of the invention are also part of the invention.

All configuration isomers of the compounds of the present invention are within the scope of coverage, whether in mixture, pure or very pure form. The definition of the compound of the present invention includes two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings.

Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

Specific functional groups and chemical term definitions are described in detail below. For purposes of the present invention, the chemical elements with the Periodic Table of the Elements, CAS version , of Chemistry and Physics, 75 th Ed same as defined in Handbook.. The definition of specific functional groups is also described therein. In addition, the basic principles of organic chemistry and specific functional groups and reactivity are also explained in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and the entire contents are included in the list of references.

Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, and exogenous Spin mixtures and other mixtures. In addition, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and their mixtures are included in the present invention.

According to the present invention, the ratio of the mixture of isomers containing isomers can be varied. For example, a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios, which are easily understood by those skilled in the art, and ratios that are mixtures of more complex isomers are also within the scope of the present invention.

The present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. In practice, however, it usually occurs when one or more atoms are replaced by atoms whose atomic weight or mass number is different. Examples of isotopes that can be classified as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, and ¹⁸ O, respectively. , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention. Certain isotope-labeled compounds of the present invention, such as ^{radioisotopes of 3} H and ¹⁴ C, are also among them, which are useful in tissue distribution experiments of drugs and substrates. Tritium, namely ³ H and carbon-14, namely ¹⁴ C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotopic substitutions such as deuterium, ie ² H, have advantages in certain therapies due to its good metabolic stability, such as increasing the half-life or reducing the dosage in the body, so it can be given priority in some cases. Isotopically-labeled compounds can be prepared by general methods, by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the protocol disclosed in the example.

If you want to design the synthesis of a specific enantiomer of the compound of the present invention, it can be prepared by asymmetric synthesis, or derivatized with a chiral adjuvant, separating the resulting diastereomeric mixture, and then removing the chiral adjuvant. Pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.

As described herein, the compounds of the present invention can be combined with any number of substituents or functional groups to expand their scope of inclusion. Generally, whether the term "substituted" appears before or after the term "optional", the general formula including substituents in the formula of the present invention means that the substituents of the specified structure are substituted for hydrogen radicals. When a plurality of positions in a specific structure are substituted by a plurality of specific substituents, each position of the substituents may be the same or different. The term "substitution" as used herein includes all permissible substitution of organic compounds. Broadly speaking, the permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any permitted organic compound as described above to supplement its valence. In addition, the present invention is not intended to limit the permitted substitution of organic compounds in any way. The present invention believes that the combination of substituents and variable groups is excellent in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases. The term "stable" here refers to a compound that is stable and can be tested for a long enough time to maintain the structural integrity of the compound, preferably for a long enough time to be effective, and is used herein for the above purpose.

The metabolites of the compounds and their pharmaceutically acceptable salts involved in the application, as well as the prodrugs that can be transformed into the structure of the compounds and their pharmaceutically acceptable salts involved in the application, are also included in the claims of the application. in.

Preparation

The preparation methods of the compound of formula (I) of the present invention are described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.

Typically, the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

The compound of general formula (X-1) will generate intermediate formula (X-2) under the action of a base (such as TEA or DIPEA), and then deprotect it under the action of chloroformate-1-chloroethyl to generate intermediate formula (X-3); Compound (X-3) obtains intermediate (X-4) through coupling reaction; Compound (X-4) is oxidized (such as mCPBA) to produce intermediate (X-5); Compound (X- 5) Under the action of a base, it reacts with alcohol to form intermediate (X-6), then deprotects under TFA and other conditions to form intermediate (X-7), and finally obtains the target product general formula (I) through substitution or acylation reaction . Wherein, R ¹ -R ²⁸ and Ar are as described above. Rs and Rs' are protecting groups for amino groups (such as Boc, Bn, Cbz or Fmoc).

Pharmaceutical composition and method of administration

The pharmaceutical composition of the present invention is used to prevent and/or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

The compound of general formula (I) can be used in combination with other drugs known to treat or improve similar conditions. In the case of combined administration, the mode of administration and dosage of the original drug can remain unchanged, while the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is administered with one or more other drugs at the same time, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. The combination of drugs also includes taking the compound of formula I and one or more other known drugs in overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dose of the compound of formula I or the known drug may be lower than the dose of the compound used alone.

The drugs or active ingredients that can be used in combination with the compound of general formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemipilimab, JS-001, SHR-120, BGB- A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001 , KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab) , 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc., CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX- 148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, okatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib) , Buparlisib, etc.), BTK inhibitors (e.g. Ibrutinib, Tirabrutinib, Acalabrutinib, Zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (e.g. Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Riabrutinib, etc.), Etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozan Tinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Trilaciclib, Milciclib, etc.) , Lerociclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 Inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or a combination thereof.

The dosage form of the pharmaceutical composition of the present invention includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment, controlled release or sustained release or nano preparation.

The pharmaceutical composition of the present invention contains a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 10-1000 mg of the compound of the present invention/agent. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid). , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween)

), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .

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 mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into a microcapsule 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 compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.

In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

The composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The dosage forms of the compound of the present invention for topical administration 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 that may be required if necessary.

The treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment. The administered dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.

The present invention also provides a method for preparing a pharmaceutical composition, which includes the steps of combining a pharmaceutically acceptable carrier with the compound of general formula (I), stereoisomers, tautomers, crystal forms, Pharmaceutically acceptable salts, hydrates, solvates or prodrugs are mixed to form a pharmaceutical composition.

The present invention also provides a method of treatment, which includes the steps of: administering the compound of general formula (I), its stereoisomers, tautomers, crystal forms, and pharmaceutically acceptable compounds of the present invention to a subject in need of treatment. Accepted salts, hydrates, solvates or prodrugs, or administration of the pharmaceutical composition of the present invention, are used to selectively inhibit KRAS ^G12C .

Compared with the prior art, the present invention has the following main advantages:

(1) The compound has a selective inhibitory effect ^{on KRAS G12C;}

(2) The compound has better pharmacodynamic properties and lower toxic and side effects.

The present invention will be further explained below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following examples are usually in accordance with the conventional conditions such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or in accordance with the conditions described in the manufacturer The suggested conditions. Unless otherwise stated, percentages and parts are calculated by weight.

Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equal to the content described can be applied to the method of the present invention. The preferred implementation methods and materials described in this article are for demonstration purposes only.

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and liquid mass spectrometry (LC-MS).

NMR is detected by Bruker AVANCE-400 nuclear magnetic instrument. The solvent for determination includes deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated acetone (CD ₃ COCD ₃ ), deuterated chloroform (CDCl ₃ ) and deuterated methanol ( CD ₃ OD), etc., the internal standard uses tetramethylsilane (TMS), and the chemical shift is measured in units of parts per million (ppm).

Liquid chromatography mass spectrometry (LC-MS) is detected by Waters SQD2 mass spectrometer. HPLC measurement uses Agilent1100 high pressure chromatograph (Microsorb 5micron C18 100x 3.0mm chromatographic column).

The thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, the TLC uses 0.15-0.20mm, and the preparative thin layer chromatography uses 0.4mm-0.5mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.

The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by using or according to literature reported in the field.

Except for special instructions, all reactions of the present invention are carried out by continuous magnetic stirring under the protection of dry inert gas (such as nitrogen or argon), and the reaction temperature is all degrees Celsius.

Example 1 2-(1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolin-2-yl)methoxy )-5,6,7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2)piperazin-2-yl)acetonitrile

Step 1: Preparation of ethyl 4-(benzyl(2-ethoxy-2-oxoethyl-1,1-d2)amino)butyrate

4-(benzylamino)butyric acid ethyl ester hydrochloride (2.57g, 10mmol), 2-bromoacetic acid-d2-ethyl ester (16.8g, 10eq) and cesium carbonate (16.5g, 5eq), under nitrogen protection , DMF (40 mL), react at 90°C overnight. Add ethyl acetate and deuterium to the resulting mixture. After the organic phase was separated, it was washed twice with saturated brine, and then dried and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to obtain the target product (1.2 g, yield 40%).

LC-MS: m/z 310(M+H) ⁺ .

Step 2: Preparation of 2-d2-ethyl 1-benzyl-3-oxopiperidine-4-carboxylic acid

Under the protection of nitrogen, NaH (127mg, 3.3mmol) was added to ethyl 4-(benzyl(2-ethoxy-2-oxoethyl-1,1-d2)amino)butyrate in batches at 0°C Ester (500 mg, 1.62 mmol) in anhydrous THF (5 mL), and then the mixture was stirred at 70°C under reflux overnight. After the reaction, the resulting mixture was quenched with a saturated aqueous solution of ammonium chloride and deuterium, and then extracted with ethyl acetate. The organic phases are combined, dried, and filtered. The obtained residue was subjected to silica gel column chromatography to obtain the target product (140 mg, yield 32%).

LC-MS: m/z 264(M+H) ⁺ .

The third step: Preparation of 7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidine-8,8-d2-4-ol

Under the protection of nitrogen, sodium metal (0.44g, 19mmol) was added to deuterated methanol (20mL), stirred for 30 minutes, and then 1-benzyl-3-oxopiperidine-4-carboxylic acid-2,2-d2 was added -Ethyl ester (1 g, 3.8 mmol) and methyl isothiourea disulfate (0.62 g, 8.9 mmol). The reaction solution was reacted overnight at room temperature, and then the pH was adjusted to 6 with a deuterium aqueous solution (2M) of deuterated hydrochloric acid. The resulting mixture was concentrated under reduced pressure, and the residue was slurried with water to obtain the target product (0.95 g). No need to be purified directly for the next reaction

LC-MS: m/z 290(M+H) ⁺ .

The fourth step: Preparation of 7-benzyl-4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyridine [3,4-d]pyrimidine-8,8-d2

7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidine-8,8-d2-4-ol (0.4g, 1.38mmol) A _{solution of POCl 3} (5 mL) was reacted at 80° C. for 3 hr, and then concentrated under reduced pressure to remove POCl ₃ . The resulting residue was dissolved in ethyl acetate (10 mL), and then carefully adjusted to pH 6-7 with saturated sodium bicarbonate solution. The aqueous phase was separated and extracted twice with ethyl acetate, the combined organic phase was dried and filtered, and the filtrate was concentrated. The residue obtained was separated by silica gel column chromatography to obtain the target product (0.23 g, yield 54%).

LC-MS: m/z 308(M+H) ⁺ .

The fifth step: 4-(7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2) Preparation of tert-butyl-2-(cyanomethyl)piperazine-1-carboxylate

Under nitrogen protection, DIPEA (253mg) was added to 7-benzyl-4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidine-8 , 8-d2 (100mg, 0.32mmol) and 2-(piperazin-2-yl)acetonitrile bishydrochloride (78mg, 0.392mmol) in anhydrous DMSO (2mL) and anhydrous 1,4-dioxane (2mL) mixed solvent solution. The reaction solution was reacted at an internal temperature of 80°C for 4 hours, and then (Boc) ₂ O (714 mg, 3.3 mmol) was added. The mixture was reacted at an internal temperature of 80°C for 1 hour, then cooled to room temperature, and then ethyl acetate and deuterium water layer were added. After separation of the aqueous phase, it was extracted twice with ethyl acetate. The organic phases were combined, dried and filtered, and the filtrate was subjected to silica gel column chromatography to obtain the target product (100 mg, yield 63%).

LC-MS: m/z 497(M+H) ⁺ .

The sixth step: 2-(cyanomethyl)-4-(2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8 -d2) Preparation of tert-butyl piperazine-1-carboxylate

Under the protection of nitrogen, the 4-(7-benzyl-2-(methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8- d2) tert-Butyl-2-(cyanomethyl)piperazine-1-carboxylate (500mg, 1mmol) and DIPEA (528uL) were added to anhydrous DCM (10mL), then cooled to 0°C with an ice-salt bath, then 1-chloroethyl chloroformate (272uL) was added dropwise. After the addition, the reaction solution was slowly raised to room temperature, then stirred at room temperature for 3 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in deuterated methanol (10 mL), the resulting mixture was stirred at 70° C. for 1 hour, and then concentrated to dryness under reduced pressure. The resulting residue was purified by preparative liquid phase to obtain the target product (180 mg, yield 44%).

LC-MS: m/z 407(M+H) ⁺ .

The seventh step: 2-(cyanomethyl)-4-(7-(8-methylnaphthalene-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyridine [3 ,4-d)pyrimidin-4-yl-8,8-d2)piperazine-1-carboxylic acid tert-butyl ester

Under the protection of nitrogen, add Ruphos G3Pd (312mg) to 2-(cyanomethyl)-4-(2-(methylthio)-5,6,7,8-tetrahydropyridine [3,4-d] Pyrimidine-4-yl-8,8-d2) piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.2 mmol) and cesium carbonate (1.2 g) in 1,4-dioxane (10 mL). The reaction solution was reacted at 70°C overnight, and then cooled to room temperature, and then layered with deuterium water and ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate. The organic phases were combined and dried and filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to obtain the target product (150 mg, yield 23%).

LC-MS: m/z 547(M+H) ⁺ .

The eighth step: 2-(cyanomethyl)-4-(7-(8-methylnaphthalene-1-yl)-2-(methylsulfoxide)-5,6,7,8-tetrahydropyridine [ 3,4-d)pyrimidin-4-yl-8,8-d2)piperazine-1-carboxylic acid tert-butyl ester

At 0°C, slowly add dropwise an ethyl acetate solution (1.5 mL) containing mCPBA (95 mg) to 2-(cyanomethyl)-4-(7-(8-methylnaphthalene-1-yl)-2 -(Methylthio)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2)tert-butyl piperazine-1-carboxylate (150mg, 0.27 mmol) in ethyl acetate (2.5 mL). After the addition was completed, the reaction solution was reacted at 0° C. for 30 minutes, and then quenched with an aqueous sodium sulfite solution. The aqueous phase was separated and extracted with ethyl acetate, the organic phases were combined, dried and filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to obtain the target product (72 mg, yield 47%).

LC-MS: m/z 563(M+H) ⁺ .

The ninth step: 2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolin-2-yl)methoxy Yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2)piperazine-1-carboxylic acid tert-butyl ester

At 0°C, sodium tert-butoxide (37mg, 3eq) was added to 2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(methylsulfoxide) -5,6,7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2)piperazine-1-carboxylic acid tert-butyl ester (72mg, 0.128mmol) and (S) -(1-Methylpyrrolin-2-yl)methanol (30 mg) in anhydrous toluene (0.8 mL). The reaction solution was reacted at 0°C for 30 minutes, and then deuterium water and ethyl acetate were added for liquid separation. The aqueous phase was separated and extracted with ethyl acetate. After the organic phases were combined, dried and filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to preparative thin layer chromatography to obtain the target product (36 mg, yield 45.8%).

LC-MS: m/z 614(M+H) ⁺ .

The tenth step: 2-(4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolin-2-yl)methoxy)-5, Preparation of 6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2)piperazin-2-yl)acetonitrile

At room temperature, add TFA (0.5 mL) to 2-(cyanomethyl)-4-(7-(8-methylnaphthalene-1-yl)-2-(((S)-1-methylpyrrole) (Alkolin-2-yl)methoxy)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2)piperazine-1-carboxylic acid tert-butyl ester (36 mg, 0.059 mmol) in DCM (1 mL). The resulting reaction solution was reacted at room temperature for 1 hour, and then concentrated in vacuo to obtain the target product. It is directly used in the next reaction without purification.

LC-MS: m/z 514(M+H) ⁺ .

The eleventh step: 2-(1-acryloyl-4-(7-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolin-2-yl)methan Oxy)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2)piperazin-2-yl)acetonitrile

Under the protection of nitrogen, the 2-(4-(7-(8-methylnaphthalene-1-yl)-2-(((S)-1-methylpyrrolin-2-yl)methoxy Yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2)piperazin-2-yl)acetonitrile dissolved in DCM (2mL), then cooled After reaching -40°C, DIPEA (42mg) and acryloyl chloride (10mg) were sequentially added, and the resulting reaction solution was reacted at -40°C for 1 hour, and then quenched by adding deuterated methanol. The obtained mixture was concentrated under reduced pressure, and the obtained residue was purified by preparative liquid phase to obtain the target product (13 mg, yield 37.5%).

LC-MS: m/z 588(M+H) ⁺ .

The following compounds were synthesized according to the method of Example 1 with different starting materials:

Example 2 2-(1-acryloyl-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolin-2-yl)methoxy) -5,6,7,8-Tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2)piperazin-2-yl)acetonitrile

LC-MS: m/z 588(M+H) ⁺ .

Example 3 2-(1-(2-Fluoroacryloyl)-4-(7-(8-methylnaphthalene-1-yl)-2-(((S)-1-methylpyrroline-2- Yl)methoxy)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2)piperazin-2-yl)acetonitrile

LC-MS: m/z 586(M+H) ⁺ .

Example 4 2-(1-(2-Fluoroacryloyl)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolin-2-yl) )Methoxy)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2)piperazin-2-yl)acetonitrile

LC-MS: m/z 606(M+H) ⁺ .

Example 5 2-(1-(2-Fluoroacryloyl)-4-(7-(8-methylnaphthalene-1-yl)-2-(((S)-1-methylpyrroline-2- Yl)methoxy-d2)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

LC-MS: m/z 586(M+H) ⁺ .

Example 6 2-(1-(2-Fluoroacryloyl)-4-(2-(((S)-1-(methyl-d3)pyrrolin-2-yl)methoxy)-7-( 8-methylnaphthalene-1-yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

LC-MS: m/z 587(M+H) ⁺ .

Example 7 2-(1-(2-Fluoroacryloyl)-4-(2-(((S)-1-(methyl-d3)pyrrolin-2-yl)methoxy-d2)-7 -(8-Methylnaphthalene-1-yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

LC-MS: m/z 589(M+H) ⁺ .

Example 8 2-(1-(2-Fluoroacryloyl)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolin-2-yl) )Methoxy-d2)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

LC-MS: m/z 606(M+H) ⁺ .

Example 9 2-(1-(2-Fluoroacryloyl)-4-(2-(((S)-1-(methyl-d3)pyrrolin-2-yl)methoxy)-7-( 8-chloronaphthalene-1-yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

LC-MS: m/z 607(M+H) ⁺ .

Example 10 2-(1-(2-Fluoroacryloyl)-4-(2-(((S)-1-(methyl-d3)pyrrolin-2-yl)methoxy-d2)-7 -(8-Chloronaphthalene-1-yl)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile

LC-MS: m/z 609(M+H) ⁺ .

Example 10A and Example 10B 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-(methyl-d3)pyrroline-2 -Yl)methoxy-d2)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl )Acetonitrile and 2-((R)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-(methyl-d3)pyrrolin-2-yl)methan Oxy-d2)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

In Example 10, two chiral isomers were obtained through chiral resolution:

Example 10A 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-(methyl-d3)pyrrolin-2-yl)methan Oxy-d2)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

LC-MS: m/z 609(M+H) ⁺ .

Example 10B 2-((R)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-(methyl-d3)pyrrolin-2-yl)methan Oxy-d2)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile

LC-MS: m/z 609(M+H) ⁺ .

Example 11 2-(4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-(methyl-d3)pyrrolin-2-yl)methoxy-d2 )-5,6,7,8--Tetrahydropyridine o[3,4-d]pyrimidin-4-yl-8,8-d2)-1-(2-fluoroacryloyl)piperazin-2-yl ) Acetonitrile

LC-MS: m/z 611(M+H) ⁺ .

Example 11 Two chiral isomers were obtained through chiral resolution:

Example 11A 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-(methyl-d3)pyrrolin-2-yl)methan Oxy-d2)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2)-1-(2-fluoroacryloyl)piperazine-2 -Based) acetonitrile

LC-MS: m/z 611(M+H) ⁺ .

Example 11B 2-((R)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-(methyl-d3)pyrrolin-2-yl)methan Oxy-d2)-5,6,7,8-tetrahydropyridine[3,4-d]pyrimidin-4-yl-8,8-d2)-1-(2-fluoroacryloyl)piperazine-2 -Based) acetonitrile

LC-MS: m/z 611(M+H) ⁺

Example 12 Biological Test Evaluation

The following biological test examples further describe and explain the present invention, but these examples are not meant to limit the scope of the present invention.

Cellular experiment of the anti-proliferative activity of the compound against NCI-H358 (KRAS ^{G12C mutation) cells}

Experimental steps

Add 40uL phosphate buffer to the peripheral wells of the 384 microwell plate, then add 40uL test cell suspension to other wells, and then place the microwell plate in a carbon dioxide incubator overnight.

Echo was used to perform a gradient dilution of the test compound, and each compound was diluted in 10 concentration gradients (diluted from 50uM to 0.003uM) and added 100nL to the corresponding wells of the microplate. After adding the drug, add 40uL phosphate buffer to each well in rows A, P and columns 1, 24, and then place the microtiter plate in a carbon dioxide incubator for 5 days.

Add 20uL of Promega CellTiter-Glo reagent to each well of the microtiter plate, then shake at room temperature for 10 minutes to stabilize the luminescence signal, and then use the PekinElmer Envision multi-label analyzer to read.

Finally, GraphPad Prism software was used to calculate the IC ₅₀ value of the compound and draw a fitting curve.

See Table 1 for the anti-proliferative activity of the compound of the examples of the present invention on NCI-H358 (KRAS ^{G12C mutation) cells.}

The reference compound is MRTX1257 (containing a pair of epimers 1:1), the structure is as follows

Table 1 Anti-proliferative activity of the example compounds of the present invention

It can be seen from Table 1:

1) The examples of the present invention show cell anti-proliferation activity ^{on KRAS G12C mutant NCI-H358 cells.}

Pharmacokinetic test evaluation

Male SD rats weighing about 220g, fasted overnight, were given 15 mg/kg of the compound of the present invention or the solution of the control compound MRTX849 [DMSO/PEG400 as carrier]. Blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, 24, 36 and 48 hours after administration, and the concentration of the compound of the present invention or the control compound MRTX849 in plasma was determined by LC/MS/MS. The pharmacokinetic parameters are shown in Table 2.

The structure of the reference compound MRTX849 is as follows:

Table 2 Summary of pharmacokinetic parameters (n=4, mean)

The experimental results show that, compared with the control compound MRTX849, the compound Example 10A obtained in the present invention exhibits better metabolic properties in rats, has a higher plasma exposure AUC, and thus has better efficacy.

All documents mentioned in the present invention are cited as references in this application, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (13)

1. Tetrahydropyridopyrimidine compounds with the structure of general formula (I), their stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs:

   

   Where:

   R ^{1 is} selected from: hydrogen or deuterium;

   R ^{2 is} selected from: hydrogen, deuterium, -CH ₂ F, -CH ₂ N(Me) ₂ ,

   

   R ^{3 is} selected from: hydrogen, deuterium or fluorine;

   R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , and R ²⁸ are each independently selected from: hydrogen or deuterium;

   R ^{20 is} selected from: CH ₃ , CHD ₂ , CH ₂ D or CD ₃ ;

   Ar is selected from:

   

   

   And the hydrogen atom thereon can be optionally deuterated;

   The limiting condition is ^{that at least one of R 4} -R ²⁸ or Ar is deuterated or deuterated.
2. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug having the structure of general formula (I) as claimed in claim 1, characterized in It has the structure shown in formula II-A, II-B, II-C, II-D, II-E, II-F, II-G:

   

   Where:

   R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁸ and Ar are as defined in claim 1.
3. The compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs as claimed in claim 1, which It is characterized by having the structure shown in III-A or III-B:

   

   Where

   R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , Ar are as defined in claim 1 .
4. The compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs as claimed in claim 1, which It is characterized in that it has the structure shown in formula IV-A or IV-B:

   

   Where

   The definitions of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ²⁰ , and Ar are as described in claim 1.
5. The compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs as claimed in claim 1, which It is characterized in that it has the structure shown by the general formula VA or VB:

   

   Where

   The definitions of R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹² , R ¹³ , R ²⁰ , and Ar are as described in claim 1.
6. The compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs as claimed in claim 1, which It is characterized in that it has the structure shown in formula VI-A or VI-B:

   

   Where

   The definitions of R ¹² , R ¹³ , R ²⁰ and Ar are as described in claim 1.
7. The compound having the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs as claimed in claim 1, which It is characterized in that the compound is selected from:

   

   

   

   

   

   
8. A method for preparing a compound of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, characterized in that: Including steps:

   

   (i) Under the action of the first base, compound of formula X-1 and

   

   React, and then react with amino protecting agent to produce compound of formula X-2;

   (ii) Under the action of 1-chloroethyl chloroformate, the compound of formula X-2 is deprotected to produce compound of formula X-3;

   (iii) Compound of formula X-3 is obtained by coupling reaction to compound of formula X-4;

   (iv) The compound of formula X-4 reacts with an oxidizing agent to produce a compound of formula X-5;

   (v) Under the action of the second base, the compound of formula X-5 reacts with alcohol to produce compound of formula X-6;

   (vi) Under the action of the first acid, the compound of formula X-6 is deprotected to produce compound of formula X-7;

   (vii) In an inert solvent, the compound of formula X-7 and

   

   The reaction obtains a compound of formula (I);

   Where

   Rs and Rs' are amino protecting groups, and the amino protecting groups are selected from: Boc, Bn, Cbz or Fmoc;

   R ¹ -R ²⁸ and Ar are as defined in claim 1; Y is halogen or OH.
9. A pharmaceutical composition, characterized in that it contains one or more compounds of the general formula (I) structure of claim 1, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable Salts, hydrates, solvates or prodrugs; and pharmaceutically acceptable carriers.
10. A compound with the structure of general formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs as claimed in claim 1, Or the use of the pharmaceutical composition according to claim 9, characterized in that it is used to prepare a pharmaceutical composition for the prevention and/or treatment of diseases related to the activity or expression of ^{KRAS G12C.}
11. The use according to claim 10, wherein the disease is a tumor or a disordered disease.
12. The use according to claim 10, wherein the disease is selected from the group consisting of lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, and melanin Tumor, lymphoma, leukemia, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer.
13. A method for inhibiting KRAS ^G12C , characterized in that the method comprises the steps of: administering an effective amount of the compound of general formula (I), its stereoisomers, and tautomers as claimed in claim 1 to a desired patient , Crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or administration of the pharmaceutical composition according to claim 9.