CN115322158B - As KRASG12CSubstituted quinazoline compounds of protein inhibitor - Google Patents

As KRASG12CSubstituted quinazoline compounds of protein inhibitor Download PDF

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CN115322158B
CN115322158B CN202210979546.0A CN202210979546A CN115322158B CN 115322158 B CN115322158 B CN 115322158B CN 202210979546 A CN202210979546 A CN 202210979546A CN 115322158 B CN115322158 B CN 115322158B
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carcinoma
pharmaceutically acceptable
kras
acceptable salt
substituted quinazoline
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CN115322158A (en
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范为正
韩忝甫
唐春雷
范懿庆
王杰
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Jiangnan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

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Abstract

The invention discloses a substituted quinazoline compound serving as a KRAS G12C protein inhibitor, belonging to the field of biological medicine. The invention provides a substituted quinazoline compound with a structure shown in a general formula (I), which has good KRAS G12C protein inhibitory activity, and has better targeted inhibition selectivity under the condition of ensuring good KRAS G12C inhibitory activity and metabolic stability.

Description

Substituted quinazoline compounds as KRAS G12C protein inhibitors
Technical Field
The invention relates to a substituted quinazoline compound serving as a KRAS G12C protein inhibitor, belonging to the field of biological medicine.
Background
Mutations in the KRAS gene (KIRSTEN RAT Sarcoma Viral Oncogene Homolog, kirsten rat sarcoma virus oncogene homolog) were first found in NSCLC gene in 1984, which encodes a GTP/GDP-binding protein belonging to the family of small gtpases, consisting of six β -sheets, five α -helices, with a KRAS protein size of 20kda, functioning as a molecular switch to turn on/off transduction in regulating tyrosine kinases and their associated cellular signaling pathways, and the molecules involved in signaling in the cellular signaling pathways in which KRAS protein participates being EGFR, raf, MEK, MAPK, PI3K, akt. Activation of KRAS is achieved after attachment to GTP under the influence of guanine nucleotide exchange factors (including SOS proteins, RAF, PI3K, etc.), inactivation of KRAS proteins being by attachment to GDP. When GTP is linked to KRAS proteins, the conformation of KRAS is altered, which facilitates interactions of KRAS with downstream signaling proteins such as: raf, PI3K, ral-GDS, etc., result in proliferation and growth of cancer cells. The inactivation of KRAS is achieved by the action of KRAS and GAPs (gtpase activating proteins), so that the connection of KRAS and GDP is achieved by enhancing the gtpase action of KRAS proteins, and by this mechanism, KRAS plays an important role in cell proliferation and regulation of cell signal transduction.
The KRAS protein consists of 188 amino acids in total of three domains with significant functional differences, which are respectively an effector region, an allosteric region and a hypervariable region. Wherein the effector region is a KRAS protein substrate binding unit which binds mainly to effector proteins and nucleotides, and is itself divided into three regions: loop area, switch1 area, switch2 area. The hypervariable region has 86% and 15% amino acid sequence homology with the allosteric region relative to the other RAS subtypes, respectively, with respect to the amino acid sequence of the effector region being highly conserved (100% homology among the different RAS subtypes), whereas the hypervariable region is involved in KRAS and recognition of the cell membrane by KRAS.
KRAS mutations are associated with 22% of human cancers, with lung cancer accounting for 17%, colon cancer accounting for 33%, and pancreatic cancer accounting for 61%.80% of KRAS mutations occur at codon 12, resulting in single amino acid substitutions, glycine to cysteine (G12C, 14%), aspartic acid (G12D, 36%), valine (G12V, 23%), wherein the RAS mutation for lung cancer is predominantly KRAS mutation (44%).
Due to the high expression of KRAS G12C mutations in tumor patients, the patients can also develop drug resistance to other targeted drugs, and KRAS G12C protein attracts more and more experts and scholars. However, over the last three decades of effort, the development of small molecule inhibitors directly against KRAS G12C targets for clinical use remains elusive, and thus there is an urgent need in the art for small molecules that target the RAS (e.g., KRAS, HRAS or NRAS) and use thereof to treat a variety of diseases, such as cancer.
Alexach corporation has obtained the first KRAS G12C inhibitor ARS-1620 for the allosteric site of KRAS G12C, followed by many types of KRAS G12C inhibitors built on the parent structure of ARS-1620, currently the only inhibitor of KRAS G12C marketed in bulk is Sotorasib (AMG-510) from Amgen corporation and another KRAS G12C inhibitor marketed in application is Adagrasib (MRTX 849).
Disclosure of Invention
In order to solve the above problems in the prior art, the present invention provides a compound having the general formula (I) (including stereoisomers and tautomers thereof) or pharmaceutically acceptable salts thereof, a pharmaceutical composition and uses thereof. The compound has the characteristic of targeted inhibition of KRAS G12C protein.
The invention aims to provide a substituted quinazoline compound with a structural general formula shown in formula 1, or optical isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:
Wherein:
m is 1 or 2;
r 1 is selected from methoxy, hydroxy, amino, halogen (F, cl, br, I), methylamino, C1-C2 alkyl, C1-C2 alkoxy;
Y is an oxygen atom or a nitrogen atom;
R 2 is selected from aryl or heteroaryl, which may be substituted with 1 to 2 of the following groups: halogen, C1-C2 alkoxy, hydroxy, amino, cyano, C1-C2 alkyl, C3-C6 cycloalkyl;
r 3 is mono-to trisubstituted, selected from hydrogen, methyl, hydroxymethyl, or For/>
R 4 is independently selected from hydrogen, fluorine, methoxy;
R 5 is mono-to trisubstituted selected from hydrogen, methyl, hydroxymethyl; or alternatively For/>
In one embodiment of the invention, R 1 is selected from methoxy or methylamino.
In one embodiment of the invention, R 2 is selected from aryl or heteroaryl, which may be substituted with 1 of the following groups: halogen (fluorine, chlorine, bromine, iodine), C1-2 alkoxy, cyano.
In one embodiment of the present invention,Preferably/>Wherein R 3' and R 3" are each independently selected from hydrogen, methyl, hydroxymethyl; or/>For/>
In one embodiment of the invention, R 3' and R 3" are not both hydrogen.
In one embodiment of the invention, R 4 is hydrogen or fluorine.
In one embodiment of the present invention,R 5 in (B) is preferably methyl, hydroxymethyl, orFor/>
In one embodiment of the invention, Y is oxygen or nitrogen.
In one embodiment of the present invention, aryl refers to a substituted or unsubstituted benzene ring, naphthalene ring.
In one embodiment of the invention, heteroaryl means that the substituted or unsubstituted heteroaryl is a mono-or bicyclic aromatic ring system having 5 to 12 ring atoms, wherein at least one atom in the ring system is a heteroatom selected from N, O and S. The definition also includes ring systems in which heteroaryl groups are fused to a benzene ring. Examples of suitable "heteroaryl rings" or "heteroaryl groups" are furyl, furazanyl, imidazolyl, 1H-indazolyl, indolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridyl, pyrrolyl, thiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl and thienyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazole, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl.
Preferably:
in certain embodiments of the present invention, m is selected to be 1.
In certain embodiments of the invention, Y is oxygen.
In certain embodiments of the invention, R 4 is independently selected from hydrogen.
In certain embodiments of the invention, R 1 is selected from methoxy.
In certain embodiments of the invention, R 2 is selected from halo (chlorofluoro) aryl, alkoxy (C1-C2) aryl, and the inventors have found that such groups result in better protein inhibitory activity due to more favorable hydrophobic interactions.
In certain embodiments of the invention, R 3 is selected from methyl.
In certain embodiments of the invention, R 5 is selected from hydrogen.
In certain embodiments of the invention, the compounds have the following structure and steric configuration:
In certain embodiments of the invention, to obtain better KRAS G12C protein inhibitory activity, the compounds preferably have the following structure and steric configuration:
in one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt, and the inorganic salt includes hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; the organic salt is selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, sulfonate, benzenesulfonate, salicylate.
The invention also provides application of the substituted quinazoline compound or each optical isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof in preparing medicines for preventing or treating KRAS G12C protein-mediated diseases.
The invention also provides a pharmaceutical composition containing the substituted quinazoline compound, or each optical isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof.
In one embodiment of the present invention, the pharmaceutical composition further comprises: a pharmaceutically acceptable carrier, excipient or diluent.
The invention also provides application of the substituted quinazoline compound or each optical isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof in preparing KRAS G12C mutation inhibitor.
The present invention also provides a method of treating cancer comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, or any combination of the foregoing, or a pharmaceutical composition of the foregoing.
The invention also provides a medicine for treating cancers, which comprises the substituted quinazoline compound, or optical isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof.
In one embodiment of the invention, the cancer is pancreatic ductal carcinoma, colorectal carcinoma, multiple myeloma, lung carcinoma, cutaneous melanoma, endometrial carcinoma, uterine sarcoma, thyroid carcinoma, acute myelogenous leukemia, bladder urothelial carcinoma, gastric carcinoma, cervical carcinoma, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal carcinoma, chronic lymphocytic leukemia, lung squamous cell carcinoma, small cell lung carcinoma, renal papillary cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, ovarian serous adenocarcinoma, adrenal cortical carcinoma, prostate carcinoma, neuroblastoma, brain low-grade glioma, glioblastoma, medulloblastoma, esophageal squamous cell carcinoma, renal clear cell carcinoma, osteosarcoma, ovarian small cell carcinoma, rhabdoid tumor, sarcoma, small intestine neuroendocrine tumor, T cell juvenile lymphocytic leukemia.
The beneficial effects are that:
The compound with the structure shown in the general formula (I) provided by the invention has certain selectivity and novel structure under the condition of ensuring good KRAS G12C inhibitory activity and metabolic stability.
Detailed Description
The technical scheme of the present invention will be described in detail with reference to examples.
In the context of the present invention "(1-2C) alkyl" refers to a saturated branched or branched monovalent hydrocarbon radical of 1 to 2 carbon atoms, respectively. Examples include, but are not limited to, methyl, ethyl. "(1-3C) alkyl" is analogically defined, specific examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl.
In the present invention, "halogen" means fluorine, chlorine, bromine and iodine.
In the present invention, "pharmaceutically acceptable salts" refer to those salts which retain the biological effectiveness and properties of the parent compound. The term "salt" refers to any salt of a compound according to the invention prepared from an inorganic or organic acid or base and an internally formed salt. Typically, such salts have a physiologically acceptable anion or cation.
In the present invention, "administering" or "administering" a compound to an individual refers to providing a compound of the present invention to an individual in need of treatment.
Reference throughout this specification to "an embodiment" or "in another embodiment" or "in certain embodiments" or "in some embodiments" means that a particular reference element, structure, or feature described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" or "in some embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.
< Compound or pharmaceutically acceptable salt >
Further, the compounds of formula (I) or their salts may be isolated in the form of solvates, and thus any such solvates are within the scope of the invention.
The compounds of formula (I) also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds of the invention include compounds in which one or more hydrogen atoms are replaced with deuterium or tritium or one or more carbon atoms are replaced with 13C-or 14C-enriched carbon, which are within the scope of the invention.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated as solid formulations for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, and the like. In these solid dosage forms, the compounds of formula (I) according to the invention are mixed as active ingredient with at least one conventional inert excipient (or carrier), for example with sodium citrate or dicalcium phosphate. Or with the following components: (1) Fillers or solubilisers, for example starch, lactose, sucrose, glucose, mannitol, silicic acid and the like; (2) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, acacia, and the like; (3) humectants, for example, glycerin, etc.; (4) Disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and the like; (5) a slow solvent such as paraffin wax or the like; (6) absorption accelerators such as quaternary ammonium compounds and the like; (7) Wetting agents such as cetyl alcohol and glycerol monostearate, and the like; (8) adsorbents such as kaolin and the like; (9) Lubricants, for example, talc, calcium stearate, solid polyethylene glycol, sodium lauryl sulfate, and the like, or mixtures thereof. Buffers may also be included in capsules, tablets, pills.
The solid dosage forms, such as tablets, dragees, capsules, pills and granules, may be provided with coatings and shell materials such as enteric coatings and other materials known in the art in the form of crystalline coatings or microencapsulations. They may contain opacifying agents and the release of the active ingredient in such a composition may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active ingredient may also be in the form of microcapsules with one or more of the above excipients, if desired.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated into liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like. In addition to the compounds of formula (I) or pharmaceutically acceptable salts thereof as active ingredients, liquid dosage forms may contain inert diluents commonly used in the art such as water and other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular cottonseed, groundnut, corn, olive, castor, sesame oils and the like or mixtures of these substances and the like. In addition to these inert diluents, the liquid dosage forms of the present invention can also include conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents and the like.
Such suspending agents include, for example, ethoxylated stearyl alcohol, polyoxyethylene sorbitol, and sorbitan, microcrystalline cellulose, agar-agar, and the like, or mixtures of these.
The compounds of the present invention and pharmaceutically acceptable salts thereof may be formulated in dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be formulated into dosage forms for topical administration, including, for example, ointments, powders, suppositories, drops, sprays, inhalants and the like. The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts as active ingredients are mixed under sterile conditions with physiologically acceptable carriers and optionally with preservatives, buffers and, if appropriate, propellants.
The pharmaceutical composition of the invention comprises a compound of a general formula (I) or pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceutically acceptable carriers, excipients and diluents. In preparing pharmaceutical compositions, the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention are typically admixed with a pharmaceutically acceptable carrier, excipient or diluent, in a unit dosage of formulation comprising from 0.05g to 210mg of a compound of formula (I) or pharmaceutically acceptable salt thereof, preferably from 0.1mg to 100mg of a compound of formula (I).
< Use >
The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of KRAS G12C protein-related cancers.
A method for treating cancer in a mammal, including a human, by maintaining KRAS G12C in an inactive state to close a signal pathway that promotes proliferation of cancer cells, comprising administering to the mammal, including a human, a therapeutically effective amount of a compound of formula (I) above, or a pharmaceutically acceptable salt thereof.
A "therapeutically effective amount" is an amount of a compound of the invention effective to produce a biological or medical response (e.g., reduce or inhibit the activity of an enzymatically active protein, or ameliorate symptoms, alleviate a condition, slow or delay the progression of a disease, or prevent a disease) in an individual.
Cancers contemplated by the present invention include pancreatic ductal carcinoma, colorectal carcinoma, multiple myeloma, lung carcinoma, cutaneous melanoma, endometrial carcinoma, uterine carcinoma sarcoma, thyroid carcinoma, acute myelogenous leukemia, bladder urothelial carcinoma, gastric carcinoma, cervical carcinoma, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal carcinoma, chronic lymphocytic leukemia, lung squamous cell carcinoma, small cell lung carcinoma, renal papillary cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver carcinoma, breast infiltration carcinoma, cervical squamous cell carcinoma, ovarian serous gonadal carcinoma, adrenocortical carcinoma, prostate carcinoma, neuroblastoma, brain low-grade glioma, glioblastoma, neuroblastoma, esophageal squamous cell carcinoma, renal clear cell carcinoma, osteosarcoma, ovarian small cell carcinoma, rhabdoid tumor, sarcoma, small intestine neuroendocrine tumor, T cell juvenile lymphocytic leukemia.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be administered to mammals, including humans, orally, rectally, parenterally (intravenous, intramuscular or subcutaneous), topically (powders, ointments, drops) or intratumorally.
The compounds of the present invention and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions containing such compounds or salts thereof, may be used in combination with other anti-neoplastic agents or therapies such as radiation or chemotherapy.
The following examples illustrate, but do not limit, the synthesis of compounds of formula (I).
The temperatures are in degrees celsius. Reagents were purchased from commercial suppliers and used without further purification, if not otherwise indicated. The structures of the final products, intermediates and starting materials are confirmed by standard analytical methods, such as spectroscopic characterization, MS, NMR, and abbreviations used are conventional in the art.
Preparation of intermediate a:
the preparation method of 4-chloro-2-methoxyquinazoline-7-acetate (intermediate A) comprises the following steps:
Step a, preparation of 4-hydroxy-2-nitrobenzoic acid:
4-methoxy-2-nitrobenzoic acid (20 g,101.5 mmol) was suspended in 100mL of 40% hydrobromic acid and 100mL of acetic acid. The reaction was carried out at 120℃for 20h, and the completion of the reaction was detected by TLC. Cooling the reaction system to room temperature, and concentrating under reduced pressure to obtain a crude product; the crude product was dissolved in 150mL of methylene chloride, saturated aqueous sodium bicarbonate was added, the aqueous phase was separated, the pH was adjusted to about 2 with 1M hydrochloric acid, extracted with ethyl acetate, the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and dried to give 20.2g of crude 2-amino-5-hydroxy 4-methoxybenzoic acid as a yellow solid.
Step b, preparation of 2-amino-4-hydroxybenzoic acid:
A mixture of 2-amino-5-hydroxy 4 methoxybenzoic acid (20.2 g,110.38 mmol) and 2g Pd-C (10%) in 100mL (V 1：V2 =1:1) of a mixed solvent of methanol-tetrahydrofuran was stirred for 3h at room temperature under hydrogen atmosphere, and the reaction was complete by TLC. Filtration, washing with methanol, combining methanol extracts, and evaporation of the solvent under reduced pressure gave the product as a black solid (10.47 g, 62% yield).
Step c, preparation of 2-methoxyquinazoline-4, 7-diol:
To a mixture of 2-amino-5-hydroxy 4 methoxybenzoic acid (10.47 g,68.43 mmol) and 2-methoxyethanol (150 mL) was added oxymethylisourea hydrochloride (15.12 g,136.86 mmol), and the mixture was heated to 125℃and reacted overnight, and the completion of the reaction was detected by TLC. The reaction solution is cooled and distilled under reduced pressure, the residue is poured into 250mL of water, ammonia water is added dropwise to adjust the pH value to 7, the filtration is carried out, a filter cake is washed by water, and the filter cake is dried in vacuum to obtain brown solid 2-methoxyquinazoline-4, 7-diol (8.93 g, yield 68%) for synthesizing the 4-hydroxy-2-methoxyquinazoline-7-yl acetate in the step d:
To a mixture of 2-methoxyquinazoline-4, 7-diol (8.93 g,46.53 mmol) and 65mL of acetic anhydride was added pyridine (7.36 g,93.06 mmol), heated to 80℃and reacted for 1h, and TLC detection was complete. The reaction solution was cooled and distilled under reduced pressure, and the residue was poured into 100mL of water, filtered, and the cake was dried under vacuum to give 4-hydroxy-2-methoxyquinazolin-7-yl acetate (10.57 g, yield 97%) as a gray solid.
Step e, preparation of 4-chloro-2-methoxyquinazolin-7-acetate:
To a mixture of 4-hydroxy-2-methoxyquinazoline-7-acetate (10.57 g,45.13 mmol) and 1, 2-dichloroethane (80 mL) was added dropwise 80mL of thionyl chloride followed by 2 drops of N, N' -dimethylformamide, and after the addition, the reaction was refluxed at 80℃and detected by TLC to be complete. The solvent was distilled off under reduced pressure, the residue was poured into 150mL of water, a saturated aqueous sodium hydrogencarbonate solution was slowly added dropwise to the residue under ice bath, the pH was adjusted to 8-9, filtration was carried out, the cake was washed with water, and the cake was dried under vacuum to give 4-chloro-2-methoxyquinazolin-7-yl acetate (9.89 g, yield 87%) as a white solid.
Preparing an intermediate B:
Preparation method of (S) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (intermediate B):
step f, (S) -preparation of tert-butyl 4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylate:
Pyridine (0.79 g,10.08 mmol) and a solution of tert-butyl (S) -3-methylpiperazine-1-carboxylate (0.67 g,3.36 mmol) in dichloromethane were added dropwise to a mixture of 20mL of anhydrous dichloromethane and trichloromethyl carbonate (1 g,3.36 mmol) at 0deg.C under nitrogen, and after the addition, the mixture was allowed to stand at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give yellow solid B (0.79 g, yield 90%) which was used in the next reaction without further purification.
Preparation of intermediate C:
preparation method of (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (intermediate C):
Step g preparation of (R) -4- (chlorocarbonyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester
Pyridine (0.96 g,12.15 mmol) and a solution of tert-butyl (R) -3-methylpiperazine-1-carboxylate (0.81 g,4.05 mmol) in dichloromethane were added dropwise to a mixture of 20mL of anhydrous dichloromethane and trichloromethyl carbonate (1.2 g,4.05 mmol) at 0deg.C under nitrogen, and the mixture was stirred overnight after the dropwise addition. The reaction mixture was concentrated under reduced pressure to give C (0.98 g, yield 93%) as a yellow solid, which was used in the next reaction without further purification.
Preparation of intermediate D:
Preparation method of (R) -4- (chlorocarbonyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (intermediate D):
Step h preparation of (R) -4- (chlorocarbonyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester
Pyridine (0.79 g,10.08 mmol) and a solution of tert-butyl (R) -2-methylpiperazine-1-carboxylate (0.67 g,3.36 mmol) in dichloromethane were added dropwise to a mixture of 20mL of anhydrous dichloromethane and trichloromethyl carbonate (1 g,3.36 mmol) at 0deg.C under nitrogen, and after the addition, the mixture was allowed to stand at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give yellow solid D (0.78 g, 89% yield) which was used in the next reaction without further purification.
Preparation of intermediate E:
Preparation method of (S) -4- (chlorocarbonyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (intermediate E):
Preparation of step i
Pyridine (0.89 g,11.13 mmol) was added dropwise to a mixture of 20mL of anhydrous dichloromethane and trichloromethyl carbonate (1.1 g,3.71 mmol) at 0℃under nitrogen, followed by dropwise addition of a dichloromethane solution of tert-butyl (S) -2-methylpiperazine-1-carboxylate (0.74 g,3.71 mmol), and the mixture was allowed to stand at room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give yellow oil E (0.88 g, 91% yield), which was used in the next reaction without further purification.
Example 1:4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -4-acryl-2-methylpiperazine-1-carboxylate
The synthetic route is as follows:
the preparation process comprises the following steps:
Step j, preparation of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazoline-7-acetate:
To 4-chloro-2-methoxyquinazoline-7-acetate (500 mg,1.98 mmol) was added 1, 4-dioxane (15 mL), N-diisopropylethylamine (0.27 g,2.15 mmol) was added dropwise in this order with stirring at 40℃and 1- (4-chlorophenyl) piperazine (0.42 g,2.15 mmol) was added and the mixture was stirred at 50℃for 1.5h. TLC monitored complete consumption of starting material. Standing, cooling the reaction system to room temperature, concentrating to dryness, adding 20mL of water, extracting with DCM (2X 10 mL), and combining organic phases. The organic phase was washed with water (1 x 15 ml), saturated sodium chloride (1 x10 ml), dried over anhydrous sodium sulfate, filtered off with suction and distilled under reduced pressure to give 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl acetate as a crude product (0.74 g,1.72mmol, 84% crude yield) which was taken directly to the next step without further treatment.
Step k, preparation of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-ol:
4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazoline-7-acetate (0.74 g,1.79 mmol) was dissolved in anhydrous methanol (10 mL), and anhydrous potassium carbonate solid (0.53 g,3.90 mmol) was added and stirred at room temperature overnight. TLC detection was complete. Distillation under reduced pressure gave a residue which was purified by column chromatography to give 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-ol (0.463 g,1.25mmol, yield 70%).
Step l, preparation of 4- (tert-butyl) 1- (4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl) (R) -2-methylpiperazine-1, 4-dicarboxylic acid ester:
To a reaction system of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-ol (0.463 g,1.25 mmol) and anhydrous potassium carbonate (0.345 g,2.5 mmol) in N, N-dimethylformamide (13 mL) was added (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (0.5 g,2.5 mmol) and the mixture was stirred overnight at room temperature. TLC detects the completion of the starting material reaction. The reaction was added dropwise to 60mL of ice water continuously stirred, stirred for 10min after the addition was completed, left standing for 10min, suction-filtered, and the cake was dried in a vacuum oven at 40℃for 3h to give 4- (tert-butyl) 1- (4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl) (R) -2-methylpiperazine-1, 4-dicarboxylic acid ester (4813 mg,0.81mmol, yield 65.8%).
Step m, preparation of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -2-methylpiperazine-1-carboxylate
To the compound 4- (tert-butyl) 1- (4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl) (R) -2-methylpiperazine-1, 4-dicarboxylic acid ester (481 mg,0.81 mmol) was added 15mL of a 4M hydrogen chloride-methanol solution, and the mixture was stirred at room temperature for 1h, and the reaction was completed by TLC. The compound 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -2-methylpiperazine-1-carboxylate hydrochloride (0.38 g,0.78mmol, 97% yield) was obtained by distillation under reduced pressure, and was directly fed to the next reaction without further treatment.
Step n, preparation of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -4-acryloyl-2-methylpiperazine-1-carboxylate
To the compound 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -2-methylpiperazine-1-carboxylate hydrochloride (0.38 g,0.78 mmol) was added dichloromethane (8.0 mL), N, N-diisopropylethylamine (403 mg,3.12 mmol), after dissolving, a solution of acryloyl chloride (211 mg,2.34 mmol) diluted with dichloromethane (0.5 mL) was added and stirred at-20℃for 30min. After TLC detection of the reaction of the starting materials, the reaction solution was moved to room temperature, 10mL of saturated sodium bicarbonate and 3mL of stirring were added for 30min, the solution was separated, the organic phase was washed with water (2X 10 mL), saturated sodium chloride solution (2X 10 mL) was washed, the organic phase was evaporated to dryness and then directly stirred and passed through a column to give 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -4-acryl-2-methylpiperazine-2-carboxylate (236 mg,0.43mmol, yield 56.3%).
MS(ESI)m/z:551[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.69(s,1H),7.62(s,1H),7.28(d,J＝19.1Hz,1H),6.99(t,J＝8.6Hz,2H),6.92(dd,J＝9.1,4.6Hz,2H),6.56(t,J＝13.6Hz,1H),6.41–6.33(m,1H),5.80–5.73(m,1H),4.64(s,1H),3.96(s,3H),3.90–3.83(m,4H),3.29(s,10H),1.31(s,3H).
The substituted quinazolines corresponding to examples 2-7 were synthesized following procedures similar to the basic procedure of example 1.
Example 2: 2-methoxy-4- (4-phenylpiperazin-1-yl) quinazolin-7-yl (R) -4-acryloyl-2-methylpiperazine-1-carboxylate
Synthesis reference examples of 2-methoxy-4- (4-phenylpiperazin-1-yl) quinazolin-7-yl (R) -4-propenoyl-2-methylpiperazine-1-carboxylate 1.LC-MS(ESI)m/z:517[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),7.75(s,1H),7.35(s,1H),7.24(t,J＝7.9Hz,2H),6.98(d,J＝8.1Hz,2H),6.79(d,J＝7.1Hz,1H),6.22–6.13(m,1H),5.75(s,1H),5.73(d,J＝2.2Hz,1H),4.32(d,J＝38.4Hz,1H),3.94(s,3H),3.83–3.80(m,4H),3.35(s,10H),1.24(s,3H).
Example 3: 2-methoxy-4- (4-phenylpiperazin-1-yl) quinazolin-7-yl (S) -4-acryloyl-2-methylpiperazine-1-carboxylate
Synthesis reference examples of 2-methoxy-4- (4-phenylpiperazin-1-yl) quinazolin-7-yl (S) -4-acryloyl-2-methylpiperazin-1-carboxylate 1.LC-MS(ESI)m/z:517[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),7.64(s,1H),7.31(s,1H),7.24(t,J＝7.9Hz,2H),6.99(d,J＝8.1Hz,2H),6.89(d,J＝7.1Hz,1H),6.22–6.13(m,1H),5.75(s,1H),5.73(d,J＝2.2Hz,1H),4.32(d,J＝38.4Hz,1H),3.94(s,3H),3.83–3.80(m,4H),3.39(s,10H),1.77(s,3H).
Example 4:4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -4-acryloyl-3-methylpiperazine-1-carboxylate
Synthesis of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (R) -4-acryloyl-3-methylpiperazine-1-carboxylate reference examples 1.MS(ESI)m/z:551[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.68(s,1H),7.62(s,1H),7.40(s,1H),7.26–7.21(m,2H),6.87(d,J＝8.9Hz,2H),6.40(s,1H),6.17–6.05(m,1H),5.88–5.82(m,1H),5.80–5.75(m,1H),3.96(s,3H),3.92–3.87(m,4H),3.33(d,J＝9.1Hz,8H),2.94–2.66(m,2H),1.32(s,3H).
Example 5:4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (S) -4-acryloyl-3-methylpiperazine-1-carboxylate
Synthesis of 4- (4- (4-chlorophenyl) piperazin-1-yl) -2-methoxyquinazolin-7-yl (S) -4-acryloyl-3-methylpiperazine-1-carboxylate reference examples 1.MS(ESI)m/z:551[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.70(s,1H),7.62(d,J＝6.6Hz,1H),7.32(s,1H),7.28–7.21(m,2H),6.88(d,J＝8.6Hz,2H),6.58(dd,J＝16.3,10.7Hz,1H),6.35(d,J＝16.6Hz,1H),5.76(d,J＝10.5Hz,1H),4.15(dd,J＝17.6,10.0Hz,1H),3.96(s,3H),3.87(s,4H),3.42–2.99(m,8H),2.05(s,2H),1.37(d,J＝14.9Hz,3H).
Example 6: 2-methoxy-4- (4- (4-methoxyphenyl) piperazin-1-yl) quinazolin-7-yl (R) -4-acryloyl-2-methylpiperazine-1-carboxylate
Synthesis reference examples of 2-methoxy-4- (4- (4-methoxyphenyl) piperazin-1-yl) quinazolin-7-yl (R) -4-acryloyl-2-methylpiperazine-1-carboxylate 1.MS(ESI)m/z:547[M+H]+.1H NMR(400MHz,Chloroform-d)δ8.69(s,1H),7.63(d,J＝6.9Hz,1H),7.32(s,1H),7.29–7.18(m,3H),6.89(d,J＝8.7Hz,2H),6.59(d,J＝16.9Hz,1H),6.35(d,J＝11.5Hz,1H),5.74(d,J＝4.8Hz,1H),3.96(s,6H),3.86(s,4H),3.34(s,10H),1.36(d,J＝19.9Hz,3H).
Example 7: KRAS G12C -SOS1 protein complex inhibition rate test
The test concentration of the test compound was 500nM, diluted to 200-fold final concentration in 100% DMSO in 384 well plates. 50nl 200-fold final concentration of compound was transferred to the destination plate 384-well-plate using a dispenser Echo 550. 50nl of 100% DMSO is added to each of the negative control well and the positive control well, a 4-time final concentration of Tag1-SOS1 solution is prepared by using a reagent buffer, 2.5 μl of a 4-time final concentration of Tag1-SOS1 solution is added to a 384-well plate, and a 4-time final concentration of Tag2-KRAS-G12C solution is prepared by using a reagent buffer; 2.5 μl diluent buffer was added to the negative control wells. The 384-well plate was centrifuged at 1000rpm for 30 seconds, and incubated at room temperature for 15 minutes after shaking and mixing. The Detection buffer was prepared with 1-fold final concentration of Anti-Tag1-TB3+ solution and 1-fold final concentration of Anti-Tag2-XL665 solution, and after mixing the two solutions, 5. Mu.l of Mix solution was added to each well. The 384-well plate was centrifuged at 1000rpm for 30s, mixed with shaking, incubated at room temperature for 120min, and the readings were recorded with an Envision microplate reader. The specific results are shown in Table 1.
Table 1 specific inhibition (500 nM) of the examples and commercial compounds
Examples numbering KRAS G12C -SOS1 protein complex inhibition rate (n=2)
1 60.7％±3.2
2 45.7％±1.2
3 41.2％±0.7
4 63.1％±3.2
5 63.2％±3.5
6 93.8％±4.2
ARS-1620 81.7％±1.2
While the invention has been illustrated by the foregoing specific examples, it should not be construed as being limited thereto; but rather the invention encompasses the generic aspects previously disclosed. Various modifications and embodiments can be made without departing from the spirit and scope of the invention.

Claims (8)

1. A substituted quinazoline compound or pharmaceutically acceptable salt thereof, wherein the structure of the substituted quinazoline compound is as follows:
2. The substituted quinazoline compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an inorganic salt or an organic salt; inorganic salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acid phosphate; the organic salt is selected from acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, sulfonate, benzenesulfonate, salicylate.
3. Use of a substituted quinazoline compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prophylaxis or treatment of a KRAS G12C protein-mediated disease.
4. A pharmaceutical composition comprising a substituted quinazoline compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof.
5. The pharmaceutical composition of claim 4, further comprising: a pharmaceutically acceptable carrier, excipient or diluent.
6. Use of a pharmaceutical composition of a substituted quinazoline compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, in the preparation of a KRAS G12C mutation inhibitor.
7. A medicament for the treatment of cancer comprising a substituted quinazoline compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof.
8. The medicament for treating cancer according to claim 7, wherein the cancer is pancreatic ductal carcinoma, colorectal carcinoma, multiple myeloma, lung carcinoma, cutaneous melanoma, endometrial carcinoma, uterine carcinoma sarcoma, thyroid carcinoma, acute myelogenous leukemia, bladder urothelial carcinoma, gastric carcinoma, cervical carcinoma, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal carcinoma, chronic lymphocytic leukemia, lung squamous cell carcinoma, small cell lung carcinoma, renal papillary cell carcinoma, adenoid cystic carcinoma, chromophobe renal cell carcinoma, liver carcinoma, breast infiltration carcinoma, cervical squamous cell carcinoma, ovarian serous adenocarcinoma, adrenocortical carcinoma, prostate carcinoma, neuroblastoma, brain low-grade glioma, glioblastoma, medulloblastoma, esophageal squamous cell carcinoma, renal clear cell carcinoma, osteosarcoma, ovarian small cell carcinoma, rhabdoid tumor, sarcoma, small intestinal neuroendocrine tumor, T cell juvenile lymphocytic leukemia.
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Publication number Priority date Publication date Assignee Title
CN111848584A (en) * 2020-07-10 2020-10-30 江南大学 Polysubstituted quinazoline compound and application thereof
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Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111848584A (en) * 2020-07-10 2020-10-30 江南大学 Polysubstituted quinazoline compound and application thereof
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CN114656411A (en) * 2022-04-12 2022-06-24 江南大学 Polysubstituted quinazoline compound serving as EGFR/HER2 double-target-point inhibitor and application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KＲASG12C 共价抑制剂AＲS-1620 的 合成工艺研究;韩忝甫，等;《化工时刊》;第35卷(第5期);22-27 *
以SOS1 为靶标的抗肿瘤小分子调节剂研究进展;范懿庆，等;《中国新药杂志》;第31卷(第11期);1072-1079 *

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