WO2022063297A1 - Quinazoline derivative, preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to a quinazoline derivative, a preparation method therefor and use thereof. In particular, the present invention relates to a compound as represented by general formula (1), a preparation method therefor and use of the compound of general formula (1) and each isomer, each crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof as an irreversible inhibitor of G12C mutant K-Ras protein in the preparation of anti-tumor medicaments.

Description

Quinazoline derivatives and their preparation methods and uses

This application claims the priority of Chinese application CN202011036675.3 with a filing date of September 27, 2020. This application cites the full text of the above Chinese application.

technical field

The invention belongs to the field of medicinal chemistry, and more particularly, to a class of quinazoline derivatives, a preparation method thereof, and the use of such compounds as K-Ras G12C inhibitors in the preparation of antitumor drugs.

Background technique

The Ras protein family is an important signal transduction molecule in cells and plays an important role in growth and development. The analysis and research of a large number of in vitro tumor cells, animal models and human tumor samples have shown that the overactivation of Ras family proteins is an early event in the development of human tumors and is one of the important triggers for the occurrence and development of various cancers. Therefore, targeting and inhibiting the activity of Ras protein is an important means to treat related tumors.

Ras protein exists in two forms, which bind to GDP and are in an inactive resting state; and when cells receive signals such as growth factor stimulation, Ras protein binds to GTP and is activated. Activated Ras protein recruits a variety of signal transduction proteins and promotes the phosphorylation of downstream signaling molecules such as ERK and S6, thereby activating the Ras signal transduction pathway and regulating cell growth, survival, migration and differentiation. The GTPase activity of the Ras protein itself can hydrolyze GTP back to GDP. And the existence of GTPase activating proteins (GAPs) in cells interacts with Ras to greatly promote the activity of Ras GTPase, thereby preventing the over-activation of Ras protein.

Mutations in K-Ras, H-Ras and N-Ras proteins in the Ras protein family are one of the common gene mutations in many tumors, and are the main factors leading to the over-activation of Ras proteins in tumors. Compared with wild-type Ras protein, these mutations result in unregulated Ras protein activity, stable binding to GTP, and continuous activation, thereby promoting tumor cell growth, migration, and differentiation. Among them, K-Ras protein mutation is the most common, accounting for 85% of all Ras mutations, while N-Ras (12%) and H-Ras (3%) are relatively rare. K-Ras mutations are extremely common in a variety of cancers, including pancreatic (95%), colorectal (45%), and lung (25%), and are relatively rare in breast, ovarian, and brain cancers (< 2%). The K-Ras mutation sites are mainly concentrated in the G12 position, and the mutation of G12C is the most common. In non-small cell lung cancer (NSCLC), for example, K-Ras G12C accounts for 50% of all K-Ras mutations, followed by G12V and G12D. Genomic studies have shown that K-Ras mutations in non-small cell lung cancer do not coexist with EGFR, ALK, ROS1, RET, and BRAF mutations, but coexist with mutations such as STK11, KEAP1, and TP53, suggesting that K-Ras mutations may coexist with STK11, KEAP1 and TP53 mutations and other synergistic effects are involved in the malignant transformation, proliferation and invasion of cells. In addition to tumors, abnormal activation of Ras protein is also involved in non-tumor diseases including diabetes, neurodegenerative diseases, etc. It can be seen that small molecule compounds targeting Ras protein can make a large number of cancer patients with specific gene mutations and Ras Noncancerous patients with overactivated pathways benefit.

Forty years since the discovery of Ras mutations in tumors, although we have gained a deeper understanding of the pathogenic mechanism of the Ras pathway, there is no effective clinical target for a large number of patients with Ras protein mutations and Ras pathway overactivation. Ras protein therapeutics are on the market. Therefore, the development of highly active small-molecule inhibitors against Ras protein, especially K-Ras G12C protein with high mutation frequency, has important clinical significance.

As a cutting-edge drug target, K-Ras G12C mutant protein has not been studied much, and only a few compounds have entered the clinical research stage, such as Amgen's AMG510 and Mirati's MRTX849. In 2018, Cell reported targeting K- A covalent inhibitor of Ras G12C mutation ARS-1620 [Cell, 2018, 172:578-589]. Patent WO2018/143315 reports that a class of spiro compounds has K-Ras G12C inhibitory activity and anti-tumor activity in mice. Please refer to the patent for the definition):

Patent WO2020/113071 also reported a class of spiro compounds with K-Ras G12C inhibitory activity, the general formula C and the structure of the representative compound D (compound I-6 in the patent) are as follows (for the definitions of the symbols in the formula, please refer to this patent):

The compounds reported in the above-mentioned patents have shortcomings such as stability and activity that are not too strong, so there is an urgent need for research and discovery of compounds with strong inhibition of K-Ras G12C protein activity, good stability, and excellent anti-tumor activity in vivo.

SUMMARY OF THE INVENTION

The present invention provides a compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

In general formula (1):

X is O, N-CN, NC(O)R ⁷ , NS(O) ₂ R ⁷ or NR ⁷ ;

L ¹ is a chemical bond, -O-, -S-, -S(O)-, -S(O) ₂ - or -N(R ⁷ )-;

L ² is a chemical bond, -O-, -S-, -S(O)-, -S(O) ₂ -, -N(R ⁷ )-, -N(R ⁷ )CH ₂ -, -C(O )-, -C(O)N(R ⁷ )-, -N(R ⁷ )C(O)-, -N(R ⁷ )C(O)N(R ⁷ )-, -N(R ⁷ ) C(O)O-, -OC(O)N(R ⁷ )-, -N(R ⁷ )S(O) ₂ -, -S(O) ₂ N(R ⁷ )-, -N(R ⁷ )S(O)-, -S(O)N(R ⁷ )-, -N(R ⁷ )S(O) ₂ N(R ⁷ )-, -N(R ⁷ )S(O)N(R ⁷ )- or alkylene;

L ³ is a chemical bond, -N(R ⁷ )-, -N(R ⁷ )CH ₂ -, -CH ₂ N(R ⁷ )- or alkylene;

A is a divalent 3-12-membered heterocycloalkyl, and the 3-12-membered heterocycloalkyl can be substituted by one or more R ⁸ ;

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

R ¹ is H, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heteroaryl, aryloxy or aryl;

R ² and R ³ are independently H, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl;

R ⁴ is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or 3-6 membered heterocycloalkyl;

R ⁵ and R ⁶ are independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, cyano substituted C1-C6 alkyl, alkoxy substituted C1-C3 alkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, or NR ⁹ R ¹⁰ substituted C1-C6 alkyl, or R ⁵ and R ⁶ form a total of S atoms 4-12-membered heterocycloalkyl, which may be further substituted by the following groups: H, OH, halogen, CN, NR ⁹ R ¹⁰ , C1-C6 alkyl, C1-C6 Alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy substituted C1-C6 alkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, 3-8 membered Heterocycloalkyl substituted C1-C6 alkyl or NR ⁹ R ¹⁰ substituted C1-C6 alkyl;

R ⁷ is H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano substituted C1-C6 alkyl, NR ⁹ R ¹⁰ substituted C1-C6 alkyl or 3-6 membered heterocycloalkyl;

R ⁸ is H, halogen, CN, OH, OMe, NR ⁹ R ¹⁰ , -CO ₂ H, -C(O)H, -C(O)NH ₂ , -C(O)NHC1-C6 alkyl, - C(O)N(C1-C6 alkyl) ₂ , -C(O)C1-C6 alkyl, -NHC(O)-(C1-C6 alkyl), -N(C1-C6 alkyl)C( O)-(C1-C6 alkyl), C1-C6 alkoxy, C3-C8 cycloalkyl or C1-C10 alkyl, said C1-C10 alkyl may be selected from one or more of the following groups Substitution: CN, OH, OMe, NR ⁹ R ¹⁰ , -CO ₂ H, -C(O)H, -C(O)NH ₂ , -C(O)NHC1-C6 alkyl, -C(O)N (C1-C6 alkyl) ₂ , -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl) C(O)C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl;

R ⁹ and R ¹⁰ are independently H, C1-C6 alkyl or R ⁹ and R ¹⁰ have a total of N atoms to form a 3-8 membered heterocycloalkyl.

In another preferred example, in the compound of the general formula (1), L ¹ is a chemical bond or -O-, and L ¹ is preferably -O-.

In another preferred example, in the compound of general formula (1), L ² is a chemical bond, -O-, -CH ₂ -, -NH- or -N(Me)-, and L ² is preferably a chemical bond.

In another preferred example, in the compound of general formula (1), L ³ is a chemical bond, -CH ₂ -, -NH- or -N(Me)-, and L ³ is preferably a chemical bond.

In another preferred embodiment, wherein in the compound of general formula (1), A is:

Wherein, "*" represents the position connected to L ³ , n is 1 or 2, R ⁸ is H, F, OH, OMe, CN, -CO ₂ H, -C(O)H, -C(O)NH ₂ , -C(O)NHMe, -C(O)NHEt, -C(O)N(Me) ₂ , -C(O)N(Et) ₂ , -C(O)Me, -C(O) Et, -NHC(O)Me, -NHC(O)Et, -N(Me)C(O)Me, Me, Et, cyclopropyl, cyclobutyl, cyclopropylmethyl or CH ₂ CN; A is preferred for

Wherein "*" represents the position connected to L ³ , n is preferably 1, R ⁸ is preferably H or F; A is more preferably

Wherein "*" represents the position connected to L ³ , and R ⁸ is more preferably H.

In another preferred example, wherein the compound of general formula (1), its representative structure is shown in general formula (1A):

In general formula (1A):

X is O, N-CN, NC(O)R ⁷ , NS(O) ₂ R ⁷ or NR ⁷ ;

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

R ¹ is H, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heteroaryl, aryloxy or aryl;

R ² and R ³ are independently H, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl;

R ⁴ is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or 3-6 membered heterocycloalkyl;

R ⁵ and R ⁶ are independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, cyano substituted C1-C6 alkyl, alkoxy substituted C1-C3 alkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, or NR ⁹ R ¹⁰ substituted C1-C6 alkyl, or R ⁵ and R ⁶ form a total of S atoms 4-12-membered heterocycloalkyl, which may be further substituted by the following groups: H, OH, halogen, CN, NR ⁹ R ¹⁰ , C1-C6 alkyl, C1-C6 Alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy substituted C1-C6 alkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, 3-8 membered Heterocycloalkyl substituted C1-C6 alkyl or NR ⁹ R ¹⁰ substituted C1-C6 alkyl;

R ⁷ is H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano substituted C1-C6 alkyl, NR ⁹ R ¹⁰ substituted C1-C6 alkyl or 3-6 membered heterocycloalkyl;

R ⁹ and R ¹⁰ are independently H, C1-C6 alkyl or R ⁹ and R ¹⁰ have a total of N atoms to form a 3-8 membered heterocycloalkyl.

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

In another preferred example, in the general formula (1) and general formula (1A), E is:

Wherein, R ¹¹ is H or F, and R ¹² is H, Me, Et, CN, -CONH ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -CH ₂ OH, CH ₂ OMe,

R ¹³ is H, F, Me or Et; E is preferably

R ¹¹ is preferably H; R ¹² is preferably H, -CH ₂ F, CH ₂ OMe,

More preferably H; R ¹³ is preferably H.

In another preferred embodiment, wherein the compound of the general formula (1) and the general formula (1A), R ¹ is

wherein R ^a is H or F, R ^b is H, F, Cl or Me, R ^c is H, F, Cl, Me or CF ₃ , R ^d is F, Cl, NH ₂ , Me or cyclopropyl, R ^e , ^Rf , ^Rg , ^Rh , ^{Ri, Rj and Rk are independently} H, F, Cl, OH, OMe, _NH2 , _CF3 , C1-C3 alkyl or C3-C6 cycloalkyl.

In another preferred embodiment, wherein the compound of the general formula (1) and the general formula (1A), R ¹ is

R ¹ is preferably

R ¹ is more preferably

In another preferred embodiment, wherein the compounds of the general formula (1) and the general formula (1A), R ² is H, F, Cl, CN, Me, Et, isopropyl, vinyl, ethynyl or Cyclopropyl, R ² is preferably vinyl or cyclopropyl, and R ² is more preferably cyclopropyl.

In another preferred embodiment, wherein the compounds of the general formula (1) and the general formula (1A), R ³ is H, F, Cl, CN, Me, Et, isopropyl, vinyl, ethynyl or Cyclopropyl, R ³ is preferably H or F, and R ³ is more preferably H.

In another preferred embodiment, wherein the compound of the general formula (1) and the general formula (1A), R ⁴ is CH ₃ , CH ₃ CH ₂ , CF ₃ CH ₂ , (CH ₃ ) ₂ CH , CHF ₂ CH ₂ or CF ₃ (CH ₃ )CH, R ⁴ is preferably CH ₃ CH ₂ , CF ₃ CH ₂ or CHF ₂ CH ₂ , and R ³ is more preferably CF ₃ CH ₂ .

In another preferred example, in general formula (1) and general formula (1A), R ⁵ and R ⁶ are independently Me, Et,

Or R ⁵ and R ⁶ have a total of S atoms to form a 4-12-membered heterocycloalkyl group, which can be further substituted by the following groups: H, OH, F, CN, Me, Et,

OMe, OEt,

In another preferred embodiment, wherein in the general formula (1) and general formula (1A),

for:

preferably

more preferably

more preferably

In various embodiments, representative compounds of the present invention have one of the following structures:

The present invention also provides a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the general formula (1) of the present invention, or each isomer, each crystal form, A pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.

The present invention also provides the compound represented by the general formula (1) of the present invention, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition for preparation Use in medicaments for the treatment, modulation or prevention of RAS mutation-related diseases.

The present invention also provides a method for treating, regulating or preventing RAS mutation-related diseases, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or each of its isomers and crystals Form, pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition.

In one embodiment, the RAS mutation-related disease is a RAS mutation-mediated disease.

In one embodiment, the RAS mutation-related disease is cancer.

In one embodiment, the cancer is a hematological cancer or a solid tumor.

In one embodiment, the cancer is leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelial cancer tumor or all cancer metastases.

In one embodiment, the cancer is lung cancer, pancreatic cancer, colon cancer, MYH-associated polyposis, or colorectal cancer.

A variety of new compounds involving the inhibition of K-RAS G12C have been synthesized and carefully studied, and these compounds have the structures of sulfoximine and sulfanediimine. The inventors found that among these compounds, especially when X is O or -N(Me)-, and R ⁵ and R ⁶ form a ring with S atoms, the compounds have a strong inhibitory effect on the tumor cell H358 carrying K-RAS G12C mutation. Proliferative activity, in the evaluation of antitumor activity in mice, also showed strong antitumor activity in vivo, in addition, the compound was stable.

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

compound synthesis

The preparation method of the compound of the general formula (1) of the present invention is specifically described below, but these specific methods do not constitute any limitation to the present invention.

The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or well-known techniques combined with methods incorporated herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds with various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 ^th Ed., Vols. A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS ^3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by the use of appropriate reagents and conditions for the introduction of various groups into the formulae provided herein.

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

General Reaction Scheme 1

Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 1, wherein X, A, E, L ¹ , L ² , L ³ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ As defined above, PG represents a protecting group and Y represents a boronic acid, boronic ester or trifluoroborate. As shown in the general reaction scheme 1, compound A1 and compound R ¹ -Y undergo coupling reaction under basic conditions to obtain compound A2, compound A2 reacts with CSCl ₂ in aprotic solvent to form compound A3, compound A3 and compound A4 in base Compound A5 is formed under neutral conditions, compound A5 and compound A6 are coupled to obtain compound A7, compound A7 is deprotected to obtain compound A8, and compound A8 is further reacted to obtain target compound A9.

further forms of compounds

"Pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, ie, administered to a subject, does not cause undesired biological effects or Interacts in a detrimental manner with any of the components it contains.

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

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

In other specific embodiments, compounds of general formula (1) are prepared in various forms including, but not limited to, amorphous, comminuted and nano-particle size forms. In addition, the compound of the general formula (1) includes a crystalline form and can also be a polymorph. Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.

In another aspect, compounds of general formula (1) may exist in chiral centers and/or axial chirality and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds Enantiomeric forms, and cis-trans isomers occur. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), and C-14 ( ¹⁴ C). For another example, a deuterated compound can be formed by replacing a hydrogen atom with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. It has the advantages of stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All alterations in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

the term

Unless otherwise stated, terms used in the present application, including the specification and claims, are defined as follows. It must be noted that, in the specification and the appended claims, the singular form "a" includes the plural unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology were used unless otherwise stated. In this application, the use of "or" or "and" means "and/or" unless stated otherwise.

Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from _CH3 , _CH3CH2 , _CF3 , _CHF2 , _CF3CH2 , _CF3 ( _{CH3 ) CH} , ^iPr , ^nPr , ^iBu , ^nBu or ^tBu .

Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched chain groups of 1 to 14 carbon atoms. Preference is given to lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methpropenyl.

Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, are preferred.

Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), and if the carbocyclic ring contains at least one double bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkyl" alkenyl", or if the carbocycle contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl". Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spiro rings. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. The ring-forming carbon atoms of a cycloalkyl group can optionally be oxidized to form oxo or thiol groups. Cycloalkyl also includes cycloalkylene. In some embodiments, the cycloalkyl group contains 0, 1 or 2 double bonds. In some embodiments, cycloalkyl groups contain 1 or 2 double bonds (partially unsaturated cycloalkyl groups). In some embodiments, cycloalkyl groups can be fused to aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused to aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused to aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and cycloalkyl groups. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinyl, norcarbenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexane and the like.

Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom. Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens. Preferred alkoxy groups are selected from _OCH3 , OCF3, _CHF2O , _CF3CH2O , ⁱ _- PrO, ^n- _PrO , ^i- BuO, ^n- BuO or ^t- BuO.

Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group that is monocyclic or polycyclic, eg, a monocyclic aryl ring fused with one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthryl.

Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the remainder of the molecule through an ether oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy.

Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S, or N), which is monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene pyridyl, pyrrolopyrimidinyl, 1H-pyrro[3,2-b]pyridyl, 1H-pyrro[2,3-c]pyridyl, 1H-pyrro[3,2-c]pyridyl, 1H- Pyrro[2,3-b]pyridyl,

Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one independently selected from boron, phosphorus , nitrogen, sulfur, oxygen and phosphorus heteroatom ring members. A partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl" if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond May be referred to as "heterocycloalkynyl". Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic, or polycyclic (eg, having two fused or bridged rings) ring systems. In some embodiments, a heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (eg C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. A heterocycloalkyl group can be attached via a ring carbon atom or a ring heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (ie, sharing a bond with) the heterocycloalkyl ring, such as piperidine, morpholine, azacyclotriene or Benzo derivatives of thienyl and the like. A heterocycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom, including a ring-forming atom of a fused aromatic ring. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolamine, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidine, butyrolactone Amido, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, pyrimidine-2,4(1H,3H)-dione, 1 ,4-dioxane, morpholinyl, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, pyranyl , pyridone, 3-pyrroline, thiopyranyl, pyranone, tetrahydrothienyl, 2-azaspiro[3.3]heptyl, indolinyl,

Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen-substituted") appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted with F, Cl, Br or I in any combination, preferably replaced by F or Cl.

"Optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.

Substituent "-O-CH ₂ -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:

When the number of a linking group is 0, such as -(CH ₂ ) ₀ -, it means that the linking group is a single bond.

When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in X-L-Y represents a chemical bond, it means that the structure is actually X-Y.

Use solid wedge keys unless otherwise specified

and wedge-dotted keys

Indicate the absolute configuration of a stereocenter, using a straight solid key

and straight dashed keys

Indicate the relative configuration of the stereocenter, with a wavy line

Represents a solid wedge key

or wedge-dotted key

or with wavy lines

Represents a straight solid key

or straight dashed key

Unless otherwise specified, use

Indicates a single or double bond.

Certain Pharmacy and Medical Terms

The term "acceptable", as used herein, refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.

The terms "treatment", "course of treatment" or "therapy" as used herein include alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating symptoms caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, the conditions attributable to or associated with the administration.

"Active ingredient" refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds in the form of enantiomers. The number of asymmetric centers that can exist depends on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

The terms "compound," "composition," "agent," or "medicine or medicament" are used interchangeably herein, and all refer to when administered to an individual (human or animal), a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.

The term "administered, administering or, administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.

Notwithstanding that the numerical ranges and parameters setting forth the broader scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains the standard deviation resulting from individual testing methods. As used herein, "about" generally means within plus or minus 10%, 5%, 1%, or 0.5% of the actual value of a particular value or range. Alternatively, the word "about" means that the actual value lies within an acceptable standard error of the mean, as considered by those skilled in the art. Except for the experimental examples, or unless expressly stated otherwise, all ranges, quantities, values and percentages used herein (for example, to describe material amounts, time durations, temperatures, operating conditions, quantity ratios and the like) should be understood ) are modified by "about". Accordingly, unless stated to the contrary, the numerical parameters disclosed in this specification and the appended claims are approximations that can be modified as required. At a minimum, these numerical parameters should be construed to mean the number of significant digits indicated and the numerical values obtained using ordinary rounding.

Unless otherwise defined in this specification, scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless contradicting the context, the singular noun used in this specification covers the plural form of the noun; and the plural noun used also covers the singular form of the noun.

therapeutic use

The present invention provides methods of treating diseases, including but not limited to, conditions involving mutations in G12C K-Ras, G12CH H-Ras and/or G12C N-Ras (eg, cancer) using the compounds or pharmaceutical compositions of the present invention of general formula (1) .

In some embodiments, methods for cancer treatment are provided, the methods comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of general structural formula (1). In some embodiments, the cancer is mediated by K-Ras, H-Ras and/or G12C N-Ras mutations. In other embodiments, the cancer is blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer , head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases. In other embodiments, the cancer is lung cancer, pancreatic cancer, colon cancer, MYH-associated polyposis, or colorectal cancer.

Route of administration

The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective amount. . The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective dose of the compound is determined according to the age, disease condition, course of treatment and other specific conditions of the object to be treated.

"Pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gelling substances, which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity . "Compatibility" as used herein means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmacologically acceptable excipients or carrier moieties are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween)

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

The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato 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, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed 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, and the like.

Besides these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.

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

Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is The administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.

The above features mentioned in the present invention or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in this specification can be used in combination with any composition, and each feature disclosed in the specification can be replaced by any alternative features that serve the same, equivalent or similar purpose. Therefore, unless otherwise stated, the disclosed features are only general examples of equivalent or similar features.

detailed description

In the following description, various specific aspects, properties and advantages of the above-described compounds, methods, and pharmaceutical compositions will be set forth in detail so that the content of the present invention will become apparent. It should be understood herein that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined by the present application.

In all the examples, ¹ H-NMR was recorded with a Varian Mercury 400 nuclear magnetic resonance apparatus, and chemical shifts were expressed in δ (ppm); the silica gel used for separation was 200-300 mesh not specified, and the proportions of eluents were all volume ratios.

The following abbreviations are used in the present invention: CSCl ₂ for thiophosgene; Cs ₂ CO ₃ for cesium carbonate; DCM for dichloromethane; DIPEA for diisopropylethylamine; Dioxane for 1,4-dioxane ; DMF for dimethylformamide; EA for ethyl acetate; h for hours _; K2CO3 for potassium carbonate _{; K3PO4} for potassium phosphate _; min for minutes; MeOH for methanol; MS for mass spectrometry; MTBE for methyl N ₂ for nitrogen; NaH for sodium hydride; NaHCO ₃ for sodium bicarbonate; NMR for nuclear magnetic resonance; Pd ₂ (dba) ₃ for tris(dibenzylideneacetone)dipalladium; Pd(dppf) Cl ₂ represents 1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride; Pd-Ruphos-G3 represents (2-dicyclohexylphosphino-2',6'-dichloromethanesulfonic acid) Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II); TFA(CF ₃ COOH) for trifluoroacetic acid; Tf ₂ O stands for trifluoromethanesulfonic anhydride; TLC stands for thin layer chromatography; THF stands for tetrahydrofuran; Ru-phos stands for 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl; Xantphos stands for 4,5-Bis(diphenylphosphine)-9,9-dimethylxanthene.

Example 1 1-(7-(6-Cyclopropyl-7-(5-methyl-1H-indazol-4-yl)-2-((1-tetrahydro-2H-1λ ⁶ -thiopyran -1-ylidene)amino)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl) Synthesis of Prop-2-en-1-one (Compound 1)

Step 1: Synthesis of Compounds 1-3

In dioxane (800 mL) solution were added compounds 1-1 (78.0 g, 0.25 mol, 1.0 eq) and 1-2 (125.0 g, 0.30 mol), Pd-Ruphos-G3 (21.1 g, 25.3 mmol, 0.1 eq) and Ru _- phos (11.8 g, 25.3 mmol), under argon, then _K3PO4 in water (160 mL) was added. Stir at reflux for 16 h under argon. Water was added, extracted with EA, washed with brine, dried and concentrated to obtain product 1-3 (90.0 g, yield 64%) through column chromatography and recrystallization, MS (ESI): 559 [M+1] ⁺ .

Step 2: Synthesis of Compounds 1-4

Under nitrogen protection, thiophosgene (18.3 mL, 2.2 eq) was added to a solution of compound 1-3 (60.8 g, 0.109 mol, 1.0 eq) in THF (600 mL) at room temperature, and stirred at 40 °C for 1 hour. After the reaction was complete, Beating with PE gave the product 1-4 as a light yellow solid (57.8 g, 88% yield), MS (ESI): 603 [M+1] ⁺ .

Step 3: Synthesis of Compounds 1-5

Under argon, compound 1-4 (57.8g, 95.8mmol, 1.0eq) was dissolved in DCM (400mL) and cooled to -70°C, DIPEA (50.2mL, 0.287mol, 3.0eq) was added, then - A solution of Tf ₂ O (21 mL, 0.124 mmol, 1.3 eq) in DCM (100 mL) was added dropwise at 60 °C. Stir at -60°C for 20 minutes, then add dropwise a solution of 2-Boc-2,7-diazaspiro[3.5]nonane (32.5 g, 0.143 mol, 1.5 eq) in DCM (100 mL). After stirring for 30 minutes, TLC detected that the reaction was complete. Quench by adding MeOH (100 mL) and water (100 mL) and return to room temperature. Column chromatography and beating gave 1-5 as a pale yellow solid (61 g, 78% yield), MS (ESI): 811 [M+1] ⁺ .

Step 4: Synthesis of Compounds 1-6

1-5 (800mg, 1eq), _{1-aminoidenetetrahydro-2H-thiopyran-1-oxide (157.6mg, 1.2eq), Pd2(dba)3 (} 90.3mg, 0.1eq), Xantphos (114mg, 0.2eq), _Cs2CO3 ( _643mg , 2eq) was suspended in dioxane (40mL), under _N2 , heated to 100°C, stirred overnight, TLC detected the reaction was complete, added water, extracted with EA, concentrated to the next step , MS(ESI): 908[M+1] ⁺ .

Step 5: Synthesis of Compounds 1-7

The crude product 1-6 obtained in the previous step was dissolved in methanol (20 mL), K ₂ CO ₃ (0.5 g, 3 eq) was added, stirred at 60° C. for 30 min, the reaction was complete by TLC, concentrated, added DCM, washed with water in the organic phase, saturated with common salt After washing with water once, drying, the product 1-7 (600 mg, two-step yield 81%) was obtained by column chromatography, MS (ESI): 754[M+1] ⁺ .

MS(ESI): 747[M+1] ⁺ .

Step 6: Synthesis of Compounds 1-8

1-7 (300 mg, 1 eq) was dissolved in DCM (6 mL), TFA (2 mL) was added at room temperature, stirred at room temperature for 1 h, LC-MS showed that the reaction was complete. Concentrate until the system is viscous, add MTBE (20 mL) to make slurry, filter, and the crude product is directly put into the next step, MS(ESI): 654[M+1] ⁺ .

Step 7: Synthesis of Compound 1

1-8 (209mg, 0.32mmol, 1eq) was suspended in DCM (5mL), DIPEA (206mg, 5eq) was added, stirred until the solution was clear, cooled to 0°C, and slowly added dropwise acrylic anhydride (40mg, 1eq, dissolved in 2mL of DCM), stirred for 5min, LC-MS showed that the reaction was complete, added saturated NaHCO ₃ solution, stirred for 10min, separated the layers, washed the organic phase with saturated brine once, dried, concentrated, and column chromatography gave white solid compound 1 (130mg, yield 58%).

¹ H NMR (400MHz, DMSO-d ₆ )δ: 12.93(s, 1H), 7.46(d, J=10.9Hz, 2H), 7.32(d, J=8.5Hz, 1H), 7.16(s, 1H) ,6.35(dd,J＝17.0,10.3Hz,1H),6.12(dd,J＝17.0,2.1Hz,1H),5.68(dd,J＝10.3,2.1Hz,1H),4.99-4.81(m,1H) ), 4.61-4.43(m, 1H), 4.03(s, 2H), 3.90(s, 1H), 3.84-3.40(m, 11H), 2.11(s, 3H), 1.97(d, J=17.0Hz, 8H), 1.61(s, 2H), 1.28(d, J=31.9Hz, 3H), MS(ESI): m/z=708.

Example 2-132 Synthesis of Compound 2-132

Using different starting materials, the target compound 2-132 was obtained according to the synthetic method similar to that in Example 1.

Table 1

Example 133 Chiral Resolution of Compound 1

The compounds of the present application may have axial chirality. Compounds with axial chirality can be resolved into two chiral isomers. Using chiral column separation and purification, two chiral isomers 1-a and 1-b of compound 1 can be obtained:

Sampling, the sample was dissolved in ethanol, the concentration was 25 mg/mL, and the injection volume was 2000 μL. Preparative chromatography conditions: chromatographic column is UniChiral CMD-5H (30×250mm, 5μm); mobile phase: ethanol-n-hexane (50:50); flow rate: 30mL/min; detection wavelength: 254nm. The fractionated liquid was concentrated by rotary evaporation and dried to obtain products 1-a (1st eluting isomer) and 1-b (2nd eluting isomer).

Other compounds of the present invention are also resolved by similar resolution methods to obtain two axial chiral isomers. 77, 78, 79, 131 and 132 were subjected to chiral resolution, and each obtained its two chiral isomers 13-a/13-b, 22-a/22-b, 65-a/65-b, 66-a/66-b, 67-a/67-b, 68-a/68-b, 71-a/71-b, 72-a/72-b, 73-a/73-b, 74- a/74-b, 75-a/75-b, 76-a/76-b, 77-a/77-b, 78-a/78-b, 79-a/79-b, 131-a/ 131-b and 132-a/132-b:

Antiproliferative activity of the compound of Example 134 on H358 cells

2500 H358 cells were seeded in an ultra-low adsorption 96-well plate (corning, 7007). After one day of growth, a series of dilutions of the compound (up to 5 μM, 5-fold dilution, a total of five doses) were added. Three days after the compound was added, the Cell Titer was added. Glow (Promega, G9681) evaluated the growth of the pellets and calculated _IC50 values, the results are shown in Table 2 below.

Table 2. Antiproliferative activity of compounds of the invention on H358 cells

compound	IC50	compound	IC50	compound	IC50
1	4.85nM	2	+++	3	+++
4	+++	5	+++	6	++
7	++	8	++	9	++
10	++	11	+++	12	+++

13	+++	14	+++	15	+++
16	+++	17	+++	18	+++
19	+	20	++	twenty one	++
twenty two	+++	twenty three	+++	twenty four	++
25	++	26	++	27	++
28	+++	29	+++	30	+++
31	+++	32	+++	33	++
34	+++	35	++	36	++
37	++	38	++	39	+++
40	+++	41	+++	42	+++
43	+++	44	++	45	++
46	++	47	++	48	++
49	+++	50	+++	51	+++
52	+++	53	+++	54	+++
55	+++	56	+++	57	++
58	++	59	++	60	+++
61	+++	62	+++	63	+++
64	++	65	5.89nM	66	++
67	+++	68	+++	69	++
70	++	71	+++	72	+++
73	+++	74	+++	75	+++
76	+++	77	+++	78	+++
79		80	+++	81	+++
82	+++	83	+++	84	+++
85	+++	86	+++	87	+++
88	+++	89	+++	90	+++
91	+++	92	+++	93	++
94	++	95	++	96	++
97	++	98	++	99	+++
100	+++	101	+++	102	+++
103	+++	104	+++	105	+++

106	+++	107	+++	108	+++
109	+++	110	+++	111	+++
112	+++	113	+++	114	+++
115	+++	116	+++	117	+++
118	++	119	+++	120	++
121	+++	122	+++	123	+++
124	++	125	++	126	++
127	+++	128	++	129	++
130	++	131	+++	132	+++
B	8.42nM	D	36.5nM

+ indicates a compound with an _IC50 greater than 1 μM

++ indicates that the compound has an _IC50 of 0.3 to 1 μM

+++ indicates that the compound has an _IC50 of less than 0.3 μM.

From the data in Table 2, it can be seen that the antiproliferative activity of the compounds of the present invention on H358 cells is less than 0.3 μM, especially when X is -O- or -N(Me)-, and R ⁵ and R ⁶ form a total of S atoms When the six-membered ring is used, the compound has a strong inhibitory activity against the proliferation of H358 tumor cells carrying K-RAS G12C mutation. For example, the anti-proliferative activity _IC50 of compound 1 and 65 on H358 cells is 4.85nM and 5.89nM, respectively, while the control compound B and D were 8.42 nM and 36.5 nM, respectively.

Example 135 Evaluation of antitumor activity in mice

Human pancreatic cancer Mia PaCa-2 cells were routinely cultured with 1640 containing 10% fetal bovine serum in a 37°C, 5% _CO2 incubator, and after passage, when the cells reached the required amount, the cells were collected. 1×10 ⁷ Mia PaCa-2 cells were injected into the left back of each nude mouse. After the tumor grew to 150 mm ³ , the animals were randomly divided into groups and started to be administered. They were 1) solvent control group, with 8 animals; 2) compound 1 group, compound 13 group, compound 22 group, compound 71 group and compound 72 group, with 8 animals in each group. The solvent control group was intragastrically administered 0.5% CMC-Na once a day; the compound administration group was intragastrically administered compound 0.5% CMC-Na suspension once a day. The tumor volume was measured every Tuesday and Thursday, and the body weight of the mice was measured. Nude mice were sacrificed on the 21st day of administration. The test results are shown in Table 3 below.

Table 3. Experimental therapeutic effects of compounds on human pancreatic cancer Mia PaCa-2 xenografts in nude mice

compound

Dosage (mg/kg)

dosing regimen

Tumor inhibition rate (%)

1	20	qd*21	142%
13	20	qd*21	124%
twenty two	20	qd*21	154%
71	20	qd*21	152%
72	20	qd*21	148%

From the data in the above table, it can be seen that the compound of the present invention has strong anti-tumor activity in vivo. After continuous administration of 20 mg/kg/day for 21 days, the compound of the present invention can further regress the tumor.

Stability test of the compound of Example 136

Accurately weigh three parts of the test compound (2-3 mg each), the purity of the first sample was measured by high performance liquid chromatography on the day of the experiment, as the data of day 0, the second sample and the third sample were placed at 60 ℃ , and its purity was determined by high performance liquid chromatography after 7 days and 14 days, respectively.

Table 4. Stability of compounds after exposure to elevated temperature (60°C) for 7 and 14 days

From the stability data of the compounds in Table 4, it can be seen that the compounds of the present invention have good stability, and the liquid phase purity decreases by no more than 0.3% after being placed at a high temperature of 60°C for 7 days and 14 days, while the stability of the compounds B and D is poor compared to the control compounds. , the purity of the liquid phase decreased by more than 3% after being placed at a high temperature of 60 °C for 7 days, and the purity of the liquid phase decreased by more than 7% after being placed for 14 days. It can be seen that the compound of the present invention has good stability, which is of great significance to the process synthesis, quality control and druggability of the compound.

Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes may be made to these embodiments without departing from the principle and essence of the present invention. Revise. Accordingly, the scope of protection of the present invention is defined by the appended claims.

Claims (20)

1. A compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

   

   In general formula (1):

   X is O, N-CN, NC(O)R ⁷ , NS(O) ₂ R ⁷ or NR ⁷ ;

   L ¹ is a chemical bond, -O-, -S-, -S(O)-, -S(O) ₂ - or -N(R ⁷ )-;

   L ² is a chemical bond, -O-, -S-, -S(O)-, -S(O) ₂ -, -N(R ⁷ )-, -N(R ⁷ )CH ₂ -, -C(O )-, -C(O)N(R ⁷ )-, -N(R ⁷ )C(O)-, -N(R ⁷ )C(O)N(R ⁷ )-, -N(R ⁷ ) C(O)O-, -OC(O)N(R ⁷ )-, -N(R ⁷ )S(O) ₂ -, -S(O) ₂ N(R ⁷ )-, -N(R ⁷ )S(O)-, -S(O)N(R ⁷ )-, -N(R ⁷ )S(O) ₂ N(R ⁷ )-, -N(R ⁷ )S(O)N(R ⁷ )- or alkylene;

   L ³ is a chemical bond, -N(R ⁷ )-, -N(R ⁷ )CH ₂ -, -CH ₂ N(R ⁷ )- or alkylene;

   A is a divalent 3-12-membered heterocycloalkyl, and the 3-12-membered heterocycloalkyl can be substituted by one or more R ⁸ ;

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

   R ¹ is H, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heteroaryl, aryloxy or aryl;

   R ² and R ³ are independently H, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl;

   R ⁴ is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or 3-6 membered heterocycloalkyl;

   R ⁵ and R ⁶ are independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, cyano substituted C1-C6 alkyl, alkoxy substituted C1-C3 alkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, or NR ⁹ R ¹⁰ substituted C1-C6 alkyl, or R ⁵ and R ⁶ form a total of S atoms 4-12-membered heterocycloalkyl, which may be further substituted by the following groups: H, OH, halogen, CN, NR ⁹ R ¹⁰ , C1-C6 alkyl, C1-C6 Alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy substituted C1-C6 alkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, 3-8 membered Heterocycloalkyl substituted C1-C6 alkyl or NR ⁹ R ¹⁰ substituted C1-C6 alkyl;

   R ⁷ is H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano substituted C1-C6 alkyl, NR ⁹ R ¹⁰ substituted C1-C6 alkyl or 3-6 membered heterocycloalkyl;

   R ⁸ is H, halogen, CN, OH, OMe, NR ⁹ R ¹⁰ , -CO ₂ H, -C(O)H, -C(O)NH ₂ , -C(O)NHC1-C6 alkyl, - C(O)N(C1-C6 alkyl) ₂ , -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl)C(O)C1 -C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl or C1-C10 alkyl, the C1-C10 alkyl may be substituted by one or more groups selected from the group consisting of CN, OH, OMe, NR ⁹ R ¹⁰ , -CO ₂ H, -C(O)H, -C(O)NH ₂ , -C(O)NHC1-C6 alkyl, -C(O)N(C1-C6 alkyl ) ₂ , -C(O)C1-C6 alkyl, -NHC(O)C1-C6 alkyl, -N(C1-C6 alkyl) C(O)C1-C6 alkyl, C1-C6 alkoxy , C3-C8 cycloalkyl;

   R ⁹ and R ¹⁰ are independently H, C1-C6 alkyl or R ⁹ and R ¹⁰ have a total of N atoms to form a 3-8 membered heterocycloalkyl.
2. The compound according to claim 1 or each of its isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), L ¹ is a chemical bond or -O -.
3. The compound according to claim 1 or each of its isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), L ² is a chemical bond, -O -, _-CH2- , -NH- or -N(Me)-.
4. The compound according to claim 1 or each of its isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), L ³ is a chemical bond, -CH _2- , -NH- or -N(Me)-.
5. The compound according to any one of claims 1-4, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), A for:

   

   

   Wherein, "*" represents the position connected to L ³ , n is 1 or 2, R ⁸ is H, F, OH, OMe, CN, -CO ₂ H, -C(O)H, -C(O)NH ₂ , -C(O)NHMe, -C(O)NHEt, -C(O)N(Me) ₂ , -C(O)N(Et) ₂ , -C(O)Me, -C(O) Et, -NHC(O)Me, -NHC(O)Et, -N(Me)C(O)Me, Me, Et, cyclopropyl, cyclobutyl, cyclopropylmethyl or _CH2CN .
6. The compound of general formula (1) as claimed in claim 1 or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate, its structure is shown in (1A):

   

   In general formula (1A):

   X is O, N-CN, NC(O)R ⁷ , NS(O) ₂ R ⁷ or NR ⁷ ;

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

   R ¹ is H, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, heteroaryl, aryloxy or aryl;

   R ² and R ³ are independently H, halogen, CN, OH, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl;

   R ⁴ is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl or 3-6 membered heterocycloalkyl;

   R ⁵ and R ⁶ are independently C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, cyano substituted C1-C6 alkyl, alkoxy substituted C1-C3 alkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, or NR ⁹ R ¹⁰ substituted C1-C6 alkyl, or R ⁵ and R ⁶ form a total of S atoms 4-12-membered heterocycloalkyl, which may be further substituted by the following groups: H, OH, halogen, CN, NR ⁹ R ¹⁰ , C1-C6 alkyl, C1-C6 Alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C1-C6 alkoxy substituted C1-C6 alkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, 3-8 membered Heterocycloalkyl substituted C1-C6 alkyl or NR ⁹ R ¹⁰ substituted C1-C6 alkyl;

   R ⁷ is H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano substituted C1-C6 alkyl, NR ⁹ R ¹⁰ substituted C1-C6 alkyl or 3-6 membered heterocycloalkyl;

   R ⁹ and R ¹⁰ are independently H, C1-C6 alkyl or R ⁹ and R ¹⁰ have a total of N atoms to form a 3-8 membered heterocycloalkyl.
7. The compound of any one of claims 1-6, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the general formula (1) and the general formula In (1A), E is a group containing an electrophilic carbon-carbon double bond or a carbon-carbon triple bond.
8. The compound according to claim 7, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1) and general formula (1A), E for

   

   Wherein, R ¹¹ is H or F, and R ¹² is H, Me, Et, CN, -CONH ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -CH ₂ OH, CH ₂ OMe,

   

   

   R ¹³ is H, F, Me or Et.
9. The compound of any one of claims 1-8, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the general formula (1) and the general formula In (1A), R ¹ is

   

   

   

   wherein R ^a is H or F, R ^b is H, F, Cl or Me, R ^c is H, F, Cl, Me or CF ₃ , R ^d is F, Cl, NH ₂ , Me or cyclopropyl, R ^e , ^Rf , ^Rg , ^Rh , ^{Ri, Rj and Rk are independently} H, F, Cl, OH, OMe, _NH2 , _CF3 , C1-C3 alkyl or C3-C6 cycloalkyl.
10. The compound according to claim 9, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1) and general formula (1A), R ¹ for

    

    

    
11. The compound of any one of claims 1-10, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the general formula (1) and the general formula In (1A), R ² is H, F, Cl, CN, Me, Et, isopropyl, vinyl, ethynyl or cyclopropyl.
12. The compound of any one of claims 1-11, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the general formula (1) and the general formula In (1A), R ³ is H, F, Cl, CN, Me, Et, isopropyl, vinyl, ethynyl or cyclopropyl.
13. The compound of any one of claims 1-12, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the general formula (1) and the general formula In (1A), R ⁴ is CH ₃ , CH ₃ CH ₂ , CF ₃ CH ₂ , (CH ₃ ) ₂ CH, CHF ₂ CH ₂ or CF ₃ (CH ₃ )CH.
14. The compound of any one of claims 1-13, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the general formula (1) and the general formula In (1A), R ⁵ and R ⁶ are independently Me, Et,

    

    

    

    

    Or R ⁵ and R ⁶ have a total of S atoms to form a 4-12-membered heterocycloalkyl group, and the 4-12-membered heterocycloalkyl group may be further substituted by the following groups: H, OH, F, CN, Me, Et,

    

    OMe, OEt,

    

    
15. The compound of any one of claims 1-14, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the general formula (1) and the general formula (1A),

    

    for:

    

    

    
16. The compound of claim 1 or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound has one of the following structures:

    

    

    

    

    

    

    

    

    

    
17. A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1-16, or each isomer, each crystal form, A pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.
18. A compound as claimed in any one of claims 1-16, or each of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the drug of claim 17 Application of the composition in the preparation of a medicine for treating RAS mutation-related diseases.
19. The use of claim 18, wherein the RAS mutation-related disease is cancer.
20. The use according to claim 19, wherein the cancer is hematological cancer or solid tumor.