CN115141188A - Substituted quinazoline compound, pharmaceutical composition and application thereof - Google Patents
Substituted quinazoline compound, pharmaceutical composition and application thereof Download PDFInfo
- Publication number
- CN115141188A CN115141188A CN202210816370.7A CN202210816370A CN115141188A CN 115141188 A CN115141188 A CN 115141188A CN 202210816370 A CN202210816370 A CN 202210816370A CN 115141188 A CN115141188 A CN 115141188A
- Authority
- CN
- China
- Prior art keywords
- cancer
- pharmaceutically acceptable
- acceptable salt
- substituted quinazoline
- quinazoline compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Abstract
The invention discloses a substituted quinazoline compound, a pharmaceutical composition and application thereof, and belongs to the field of chemical medicines. The invention provides a substituted quinazoline compound shown as a general formula (I) or (II) and a pharmaceutically acceptable salt thereof, and a preparation method thereofThe SOS1 protein has excellent inhibitory activity and excellent pharmacodynamic properties.
Description
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to a substituted quinazoline compound, a pharmaceutical composition and application thereof.
Background
Ras is a highly conserved gene, and its expressed proteins are widely present in eukaryotes. Studies have confirmed that the product of Ras gene expression is a key component of the signaling pathway that controls proliferation, survival and differentiation of eukaryotic cells. Ras is divided into HRas, NRas and KRas, with KRas mutations accounting for 86% of Ras mutations. Because of the high proportion of KRas mutations in cancer patients, KRas is widely recognized as an important target for the treatment of cancers such as colorectal cancer.
After a Receptor Tyrosine Kinase (RTK) mainly composed of an Epidermal Growth Factor Receptor kinase (EGFR) on a cell membrane is activated, a phosphate group is dissociated and then transferred to GRB2, so that the GRB2 is activated. Activated GRB2 recruits and binds SOS to the plasma membrane, activating SOS. Activated SOS binds to Ras-GDP, forming Ras-GTP by nucleotide exchange, thereby activating downstream signaling pathways. RAS-RAF-MAPK is a key signaling pathway, and phosphorylation of extracellular regulated protein kinases (ERKs) negatively feeds on SOS, causing it to switch from an activated state to a self-inhibited state. RAS-PI3K-mTOR is another signaling pathway. In cancer cells, the mutated Ras protein accelerates the nucleotide exchange between its bound GDP and GTP, which results in the excess Ras being in an abnormally activated state of Ras-GTP, abnormal activation of downstream signaling pathways that are closely associated with proliferation and migration of cancer cells.
Sotoria cloth (AMG 510) is a direct targeting KRAS G12C Has been shown to have IC on H358 cells 50 =6nM, half-lives in rats and dogs reach 28h and 34h, respectively; in addition, the medicine is used for treatingThe bed research also shows good curative effect, and in 59 patients with Non-small Cell Lung Cancer (NSCLC), the objective tumor response rate (ORR) reaches 32.2%, the Disease Control Rate (DCR) is 88.1%, the median remission time (DOR) is 10.9 months, and the median progression-free survival time (mPFS) is 6.3 months. Sotolira is also the only KRAS inhibitor currently on the market for use in KRAS G12C A mutant NSCLC patient.
However, over 85% of patients with KRAS non-G12C mutations currently lack targeted specific drug therapy due primarily to the smooth surface of KRAS and lack of pockets for ready drug administration. Therefore, finding alternative approaches to targeting KRAS is an important goal of researchers, one of which is to inhibit Ras-modulating active proteins by inhibiting their activity, such as Guanine nucleotide Exchange Factors (GEFs). The protein expressed by SOS gene is used as GEF and plays a very key role in the activation process of Ras, and the inhibition of SOS protein can effectively reduce the nucleotide exchange speed of KRas protein, thereby weakening the expression level of the protein downstream of the KRas protein. Although SOS is divided into SOS1 and SOS2, and the structures of the SOS1 and the SOS2 are highly homologous, the current research shows that the function of SOS1 is stronger than that of SOS2 in the aspects of controlling cell proliferation, migration and the like, and the SOS1 signal also regulates fibroblast migration, and the absence of SOS1 influences the migration and proliferation of cells.
The SOS1 protein consists of multiple domains: nitrogen terminal region, catalytic and allosteric domain, carbon terminal region. Wherein the nitrogen-terminal region consists of a Histone-like Domain (HD), a Dbl Homology Domain (Dbl Homology, DH), a Pleckstrin Homology Domain (Pleckstrin Homology, PH) and a Helical Linker arm (Helical Linker, HL); catalytic and allosteric domains including the CDC25H catalytic domain and REM (Ras Exchange Motif) domain; the carbon-terminal region includes a Proline-Rich region (PR). Among them, the CDC25H domain is highly conserved, its prominent helical structure inserts into Ras protein and temporarily releases Ras from binding to its encapsulated nucleotide (GDP), and the nucleotide is thus released. Because the intracellular GTP content is higher than that of GDP, the Ras-GDP in the inactive state is largely changed into Ras-GTP in the active state under the catalytic action of SOScat. Experiments demonstrated that the SOS1 catalytic site CDC25H binds much weaker Ras-GTP than Ras-GDP, indicating that SOS1 promotes unidirectional GDP to GTP exchange. And Ras-GDP can not significantly activate the REM structural domain, but can be stimulated by Ras-GTP to be allosterically activated, so that the nucleotide exchange of Ras is further promoted, and the positive feedback channel of Ras-GTP on SOS activation is proved. Most of the current SOS1 inhibitors are designed by taking the SOS1 inhibitors as targets.
SOS1 inhibitors which have been reported at present mainly comprise chromone compounds, pyridopyrimidine compounds, quinazoline compounds, indole compounds and naphthol compounds, and the compounds act on CDC25H catalytic structural domain of SOS 1. In addition, there are some reported compounds that inhibit SOS activation by binding to other well-defined targets, such as the pyrimidine compounds RMC-4550 interfering with SOS 1-mediated Ras-GTP loading by inhibiting SH 2-domain-containing protein-tyrosine phosphatase-2 (SHP2); benzimidazoles inhibit the activation of the SOS 1-mediated signaling pathway by binding to KRas. The covalent inhibitor of SOS1, the maleimide compound, inhibits the expression of Ras-Raf signaling pathway by forming a covalent bond with Cys116 of Ras-SOS 1 complex.
SOS1 inhibitor inhibits the abnormal expression of downstream signal channels by inhibiting the exchange of mutant Ras protein nucleotides, thereby inhibiting the proliferation, migration and invasion of tumor cells. In addition to lung cancer patients, KRas mutations are common in the pancreas, colorectal, small intestine, where KRas mutations occur in the absence of specific frontal-targeted drug therapy, and SOS1 inhibitors may effectively address this problem.
Disclosure of Invention
In the process of researching the SOS1 inhibitor, the inventor discovers a novel substituted quinazoline compound which has excellent inhibitory activity and selectivity on mutated KRas and lower toxic and side effects, provides a feasible treatment scheme for treating patients with KRas mutation and has good safety. The inhibitor is expected to have better curative effect, is expected to overcome the problems of drug resistance and toxic and side effects, and has good development prospect.
The invention provides a substituted quinazoline compound or pharmaceutically acceptable salt thereof, a pharmaceutical composition and application thereof. The compound can be used as SOS1 inhibitor, and has better pharmacodynamic property and metabolic stability.
In one aspect, the present invention provides a compound of the following general formula (I), (II) or a pharmaceutically acceptable salt thereof:
wherein:
Z 1 selected from S, O, NH, Z 2 Is selected from CH; or Z 2 Selected from S, O, NH, Z 1 Is selected from CH;
R 1 selected from hydrogen or halogen; r is 1 ' is selected from R1 is selected from hydrogen, methyl or halogen;
R 2 、R 2 ' are each independently selected from C1-4 alkanyl or C3-6 cycloalkyl; the optical configuration is raceme, R configuration or S configuration;
R 3 、R 3 ' each is independently selected from-OH, -CN, C1-4 alkoxy, -O (CH) 2 ) a NHCH 3 ,-O(CH 2 ) b N(CH 3 ) 2 ,-CH 2 NH(CH 2 ) m OH,-CH 2 NH(CH 2 ) n CH 3 (ii) a Wherein a and b are respectively 1, 2 and 3; m is 2 and 3; n is 0, 1, 2;
R 4 and R 5 Each independently selected from H, halogen, C1-4 alkoxy,orZ a Is selected from CH 2 ,O,NR a ;R a Is H, C 1 -C 4 Alkyl, alkenyl, alkynyl, C 1 -C 4 A carbonyl compound of (a);
R 4 ' is selected from CH 2 (OCH 2 CH 2 O) i CH 2 (ii) a i is 0, 1, 2.
In one embodiment of the present invention, R is 2 、R 2 ' are each independently selected from methyl, ethyl, isopropyl, cyclopropyl.
In one embodiment of the present invention, R is 4 And R 5 Are each independently selected from-OCH 3 。
The compounds described above, or pharmaceutically acceptable salts thereof, in certain embodiments of the invention, the compounds have the following structure:
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, perchlorate, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate. Still further, the pharmaceutically acceptable salt is selected from the hydrochloride, succinate or mesylate salt.
The invention also provides a pharmaceutical composition which comprises the compound or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent.
In preparing the pharmaceutical compositions, the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention are typically mixed with a pharmaceutically acceptable carrier, excipient or diluent. Wherein, in a unit dosage form (e.g., a tablet or capsule), the compound of formula (I) or a pharmaceutically acceptable salt thereof may be present in an amount of 0.01 to 1000mg, e.g., 0.05 to 800mg, 0.1 to 500mg, 0.01 to 300mg, 0.01 to 200mg, 0.05 to 150mg, 0.05 to 50mg, etc.
The composition of the invention can be prepared into conventional pharmaceutical preparations according to conventional preparation methods. Such as tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, tinctures, syrups, ointments, drops, suppositories, inhalants, sprays and the like.
In certain embodiments, 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 one or more ingredients selected from:
(1) Fillers or solubilizers, for example, starch, lactose, sucrose, glucose, mannitol, silicic acid, and the like;
(2) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic and the like;
(3) Humectants, such as glycerol and the like;
(4) Disintegrating agents, 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 and the like;
(6) Absorption accelerators such as quaternary ammonium compounds and the like;
(7) Wetting agents such as cetyl alcohol and glyceryl monostearate and the like;
(8) Adsorbents, for example, kaolin, and the like;
(9) Lubricants, for example, talc, calcium stearate, solid polyethylene glycols, sodium lauryl sulfate, and the like, or mixtures thereof. Capsules, tablets, pills, etc. may also contain buffering agents.
In certain embodiments, the solid dosage forms, e.g., tablets, dragees, capsules, pills, and granules, can be coated or microencapsulated with coating and shell materials such as enteric coatings and other crystalline forms of materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active ingredient may also be in microencapsulated form with one or more of the above excipients.
In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be formulated in 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, the liquid dosage forms may contain inert diluents commonly employed in the art, such as water and other solvents, solubilizing agents and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide as well as oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil and the like or mixtures of these and the like. In addition to these inert diluents, the liquid dosage forms of the present invention may also include conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, perfuming agents and the like.
Such suspending agents include, for example, ethoxylated stearyl alcohols, polyoxyethylene sorbitol, and sorbitan, microcrystalline cellulose, agar, and the like, or mixtures of these materials.
In certain embodiments, the compounds of the present invention and pharmaceutically acceptable salts thereof may be formulated into 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.
In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be formulated in dosage forms for topical administration, including, for example, ointments, powders, suppositories, drops, sprays, inhalants and the like. The compounds of the general formula (I) or pharmaceutically acceptable salts thereof according to the invention as active ingredients are mixed under sterile conditions with a physiologically acceptable carrier and optionally preservatives, buffers, and optionally propellants which may be required.
The compounds of the invention or pharmaceutically acceptable salts thereof may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents, particularly in combination with other antineoplastic agents. Such therapeutic agents include, but are not limited to: antineoplastic acting on DNA chemical structure, such as cisplatin, antineoplastic affecting nucleotide synthesis, such as methotrexate, 5-fluorouracil and the like, antineoplastic affecting nucleic acid transcription, such as adriamycin, epirubicin, aclacinomycin and the like, antineoplastic acting on microscopic protein synthesis, such as taxol, vinorelbine and the like, aromatase inhibitors, such as aminoglutethimide, letrozole, rennin and the like, cell signaling pathway inhibitors, such as mitogen-activated protein kinase inhibitor Qu Meiti ni and the like. The components to be combined may be administered simultaneously or sequentially, in a single formulation or in different formulations. Such combinations include not only combinations of one or other active agents of the compounds of the present invention, but also combinations of two or more other active agents of the compounds of the present invention.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparation of an SOS1 inhibitor.
The invention also provides an application of the compound or the pharmaceutically acceptable salt thereof in the preparation of anti-cancer drugs; the cancer includes pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, sarcoma.
Current SOS1 inhibitors have potential for the treatment of a variety of diseases, including pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, sarcoma.
The invention also provides an application of the compound or the pharmaceutically acceptable salt thereof in medicines for treating RAS.
Furthermore, SOS1 inhibitors are mainly used for the treatment of RAS diseases (preferably selected from neurofibromatosis type I (NF 1), noonan Syndrome (NS), noonan syndrome with multiple plaques (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), costello Syndrome (CS), cardio-facial-skin syndrome (CFC), leges syndrome and hereditary gingival fibromatosis.
Has the advantages that:
most of the compounds of the present invention showed low half inhibitory concentration against SOS1 protein, and most of them showed micromolar activity against K562 cells, so that the compounds of the present invention showed excellent SOS1 inhibitory activity and could be used as SOS1 inhibitors.
Detailed Description
The present invention will be described in detail with reference to examples.
In the present invention, "C 1 -C 4 Alkyl "refers to straight or branched chain saturated hydrocarbon groups as well as saturated cycloalkyl groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl, and cyclopropyl), butyl (e.g., n-butyl, isobutyl, sec-butyl, tert-butyl, and cyclobutyl).
In the present invention, "C 2 -C 4 Alkenyl and alkynyl "refers to straight or branched chain unsaturated alkenyl or alkynyl groups. Examples of alkenyl and alkynyl groups include, but are not limited to, ethenyl, propenyl, allyl, ethynyl, and the like.
In the present invention, "C 1 -C 4 The "carbonyl compound" refers to a straight-chain or branched-chain structure having a carbonyl group (C = O)And (5) forming. Examples of carbonyl compounds include, but are not limited to
In the present invention, halogen means fluorine, chlorine, bromine and iodine.
In the present invention, all pharmaceutically acceptable isotopically-labelled compounds of the compounds of formula I wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for use in the invention include isotopes of hydrogen, such as 2 H and 3 H,“C 1 -C 4 alkyl "includes deuterated methyl (CD) 3 ) And the like.
Compounds with isotopes such as deuterium may be preferred in some circumstances due to their improved metabolic stability.
The following examples are presented to illustrate, but not to limit, the synthesis of the compounds of general formulae (I) and (II).
All temperatures are in degrees Celsius. All reagents were commercially available from commercial reagents and no further purification was required unless otherwise indicated. Abbreviations used are those common in the art.
Preparation of intermediate A
Preparation of 1- (4-bromothien-2-yl) ethyl-1-amine (intermediate A)
Step a: (E) Preparation of (E) -N- ((4-bromothien-2-yl) methylene) -2-methylpropane-2-sulfinamide
To 4-bromo-2-thiophenecarboxaldehyde (4.00g, 21.0mmol) was added tert-butylsulfinamide (3.04g, 25.2mmol), and dissolved with 40mL of ultra-dry tetrahydrofuran at room temperature with stirring, followed by addition of tetraethyl titanate (8.8mL, 42mmol), and stirring at room temperature overnight. TLC detection of the completion of the reaction of the raw material b-1, 40mL of saturated sodium chloride solution was slowly added dropwise to the reaction solution at room temperatureAfter the completion of the dropwise addition, stirring was carried out for 15min, suction filtration was carried out, the filter cake was washed with 40mL of water and then 40mL of dichloromethane, the filtrate was collected, liquid was separated, the aqueous phase was extracted with dichloromethane (2 x 40ml), all the organic phases were combined, the organic phase was washed with water (2 x 50ml), washed with saturated sodium chloride (2 x 50ml), dried over anhydrous sodium sulfate, suction filtration was carried out, and the filtrate was concentrated under reduced pressure to give an orange-yellow solid (5.21 g, yield: 84.3%). MS-ESI (m/z) 294.0[ m ] +H] +
Step b: preparation of N- (1- (4-bromothien-2-yl) ethyl) -2-methylpropane-2-sulfinamide
20mL of ultra-dry tetrahydrofuran was added to (E) -N- ((4-bromothien-2-yl) methylene) -2-methylpropane-2-sulfinamide (2.94g, 10.0mmol) at 0 ℃ and the solution was stirred well, followed by slowly adding dropwise a 3mmol/L methylmagnesium bromide solution in diethyl ether (10mL, 30.0mmol), and after completion of the addition, the mixture was transferred to room temperature for reaction for 1 hour. TLC detection raw material b-2 was completely consumed. The reaction was quenched by slowly adding dropwise to a cold saturated ammonium chloride solution (45 mL), stirring until no more bubbles were formed, extracting with dichloromethane (3 × 40ml), combining the organic phases, washing the organic phase with water (2 × 50ml), washing with saturated sodium chloride (2 × 50ml), drying over anhydrous sodium sulfate, suction filtering, and concentrating the filtrate under reduced pressure to give a tan oil (2.88 g, yield: 92.8%). MS-ESI (m/z) 310.1[ 2 ], [ M + H ]] +
Step c: preparation of 1- (4-bromothien-2-yl) ethyl-1-amine
30mL of a 2mmol/L hydrochloric acid methanol solution was added to N- (1- (4-bromothien-2-yl) ethyl) -2-methylpropane-2-sulfinamide (3.10 g,10.0 mmol), and the mixture was stirred at room temperature for 2 hours. TLC detection raw material b-3 was consumed. The excess solvent was removed by concentration under reduced pressure to give the crude product as a tan solid. The crude product was slurried with 30mL of dichloromethane at room temperature for 5h, allowed to stand for 10min, suction filtered, the filter cake washed with 10mL of dichloromethane, and the filter cake dried to give the hydrochloride of the desired product as an off-white solid (2.04 g, yield: 84.1%). MS-ESI (m/z) 205.9[ 2 ], [ M + H ]] +
Preparation of intermediate B
Preparation of 1- (5-bromothien-2-yl) ethyl-1-amine (intermediate B) reference intermediate A
Preparation of intermediate C
Preparation of (R) -1- (4-bromothien-2-yl) ethan-1-amine (intermediate C)
Step d: preparation of (R, E) -N- ((4-bromothien-2-yl) methylene) -2-methylpropane-2-sulfinamide
To 4-bromo-2-thiophenecarboxaldehyde (4.00g, 21.0mmol), (R) -tert-butylsulfinamide (3.04g, 25.2mmol) was added and dissolved with 40mL of ultra-dry tetrahydrofuran at room temperature with stirring, followed by addition of tetraethyltitanate (8.8mL, 42mmol) and stirring at room temperature overnight. TLC detects that the reaction of the raw material Y-1 is completed, 40mL of saturated sodium chloride solution is slowly dropped into the reaction solution at room temperature, stirring is carried out for 15min after dropping is completed, suction filtration is carried out, the filter cake is washed by 40mL of water and then by 40mL of dichloromethane, the filtrate is collected, liquid separation is carried out, the water phase is extracted by dichloromethane (2 x 40mL), all organic phases are combined, the organic phase is washed by water (2 x 50mL), the saturated sodium chloride (2 x 50mL) is washed, anhydrous sodium sulfate is dried, suction filtration is carried out, and the filtrate is concentrated under reduced pressure to obtain orange yellow solid (5.10 g, yield: 82.5%). MS-ESI (m/z) 293.9[ 2 ], [ M ] +H] +
Step e: preparation of (R) -N- ((R) -1- (4-bromothien-2-yl) ethyl) -2-methylpropane-2-sulfinamide
To (R, E) -N- ((4-bromothien-2-yl) methylene) -2-methylpropane-2-sulfinamide (5.10g, 17.3mmol) was added 35mL of ultra-dry tetrahydrofuran at 0 ℃ and the mixture was thoroughly stirred to dissolve, followed by slowly dropwise addition of a 3mmol/L solution of methylmagnesium bromide in diethyl ether (17.3mL, 51.9mmol), and after completion of the addition, the mixture was transferred to room temperature for reaction for 1 hour. TLC detection raw material consumption is finished. Slowly dropping the reaction solution into a cold saturated ammonium chloride solution (100 mL) for quenching, continuously stirring, and after bubbles are not generated, using dichloromethaneAlkane (3 × 80ml) extraction, organic phase combination, organic phase washing (2 × 150ml), saturated sodium chloride (2 × 150ml) washing, anhydrous sodium sulfate drying, suction filtration, filtrate reduced pressure concentration to get brown yellow oil 2.97g, product through column chromatography purification to get orange yellow solid 1.05g yield: 19.6 percent. MS-ESI (m/z) 310.1[ 2 ], [ M + H ]] + 。 1 H NMR(400MHz,Chloroform-d)δ7.13(d,J=1.5Hz,1H),6.88(t,J=1.1Hz,1H),4.80–4.73(m,1H),3.43(d,J=5.7Hz,1H),1.64(d,J=6.6Hz,3H),1.24(s,9H).
Step f: preparation of (R) -1- (4-bromothien-2-yl) ethan-1-amine (intermediate C)
To (R) -N- ((R) -1- (4-bromothien-2-yl) ethyl) -2-methylpropane-2-sulfinamide (1.03g, 3.3mmol) was added 10mL of 2mmol/L methanol hydrochloride solution, and the mixture was stirred at room temperature for 2 hours. TLC detection raw material consumption is finished. The excess solvent was removed by concentration under reduced pressure to give the crude product as a tan solid. Pulping the crude product with 10mL of dichloromethane for 5h at room temperature, standing for 10min, performing suction filtration, washing a filter cake with 5mL of dichloromethane, and drying the filter cake to obtain a hydrochloride of a target product, which is a white-like solid 630mg and has the yield: 78.7 percent. MS-ESI (m/z) 205.9[ 2 ], [ M + H ]] + 。
Example 1
Synthesis of 2- ((2- (5- (1- ((6,7-dimethoxyquinazolin-4-yl) amino) ethyl) thiophen-3-yl) benzyl) amino) ethan-1-ol:
the synthetic route is as follows:
step g: preparation of 4-chloro-6,7-dimethoxyquinazoline
To 6,7-dimethoxyquinazolin-4-one (5.00g, 24.2mmol) was added thionyl chloride (50 mL) and catalytic amount of DMF (0.1 mL), and stirred at 90 ℃ under reflux for 5h. TLC detection of the raw material after the reaction is finished, decompression concentration is carried out to obtain a brown yellow solid, and then saturated sodium bicarbonate is dissolved at 0 DEG CDropwise adding the solution into a reaction system, continuously stirring to generate bubbles, adjusting the pH of the reaction solution to 7-8, extracting with dichloromethane (3 × 40mL), combining organic phases, washing with organic phase water (2 × 50mL), washing with saturated sodium chloride (2 × 50mL), drying with anhydrous sodium sulfate, performing suction filtration, and concentrating the filtrate under reduced pressure to obtain a light yellow solid, wherein the yield is 4.79 g: 88.1 percent. MS-ESI (m/z) 225.0[ 2 ], [ M + H ]] +
Step h: preparation of N- (1- (4-bromothien-2-yl) ethyl) -6,7-dimethoxyquinazolin-4-amine
Intermediate A (533mg, 2.20mmol), N, N-diisopropylethylamine (775mg, 6.00mmol) and 4.5mL of acetonitrile were added to 4-chloro-6,7-dimethoxyquinazoline (449mg, 2.00mmol), and the mixture was quenched overnight at 120 ℃. Cooling to room temperature, detecting most of raw materials by TLC, adding 15mL of water into reaction liquid, extracting with dichloromethane (3X 15mL), combining organic phases, washing with organic phase water (2X 20mL), washing with saturated sodium chloride (2X 20mL), drying with anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure to obtain brown yellow solid 730mg, purifying crude product by column chromatography to remove residual raw materials to obtain 508mg yellow solid, adding 4mL of anhydrous ether into the solid, pulping for 6h to improve solid properties and remove pigments, filtering, washing filter cake with 2mL of anhydrous ether, and drying the filter cake to obtain off-white solid (407 mg, yield: 51.6%). MS-ESI (m/z) 394.1[ 2 ], [ M + H ]] +
Step i: preparation of 2- (5- (1- ((6,7-dimethoxyquinazolin-4-yl) amino) ethyl) thiophen-3-yl) benzaldehyde
To N- (1- (4-bromothien-2-yl) ethyl) -6,7-dimethoxyquinazolin-4-amine (100.0 mg, 0.254mmol) was added pinacol ester of 2-formylphenylboronic acid (70.6 mg, 0.304mmol), anhydrous potassium carbonate (140.4 mg, 1.02mmol), and palladium tetratriphenylphosphine (29.4 mg, 0.0254mmol) was dissolved well in 3.0mL dioxane under nitrogen, followed by rapid addition to the reaction system, addition of 0.6mL water, and stirring at 110 ℃ under reflux overnight. After TLC detection, 20mL of water was added to precipitate a solid, dichloromethane (3X 20mL) was extracted, the organic phases were combined, washed with water (2X 30mL), washed with saturated sodium chloride (2X 30mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a tan oil, and the crude product was purified by column chromatography to give a yellow solid (76.6 mg, yield:74.2%)。ESI-MS(m/z):420.2[M+H] + 。
step j: preparation of 2- ((2- (5- (1- ((6,7-dimethoxyquinazolin-4-yl) amino) ethyl) thiophen-3-yl) benzyl) amino) ethan-1-ol (example 1)
To 2- (5- (1- ((6,7-dimethoxyquinazolin-4-yl) amino) ethyl) thiophen-3-yl) benzaldehyde (104mg, 0.248mmol) were added ethanolamine (45.4 mg, 0.744mmol), a catalytic amount of glacial acetic acid (1 drop), anhydrous magnesium sulfate (239mg, 1.98mmol) and 2.5mL methanol, stirred at 70 ℃ for 2h, then the reaction temperature was lowered to room temperature, sodium cyanoborohydride (46.8mg, 0.744mmol) was added, and stirred at room temperature overnight. After TLC detection of the end of the consumption of the starting material, 10mL of water was added to quench the reaction, dichloromethane (3X 10mL) was extracted, the organic phases were combined, washed with water (2X 15mL), washed with saturated sodium chloride (2X 15mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a pale yellow oil, and the crude product was purified by column chromatography to give a yellow solid (23.8 mg, 29.3% yield). ESI-MS (m/z) 465.2[ 2 ], [ M + H ]] + 。 1 HNMR(400MHz,DMSO-d 6 )δ8.38(s,1H),8.29(d,J=8.2Hz,1H),7.72(s,1H),7.58–7.51(m,1H),7.47(d,J=1.4Hz,1H),7.34(p,J=3.5,3.1Hz,3H),7.28(d,J=1.5Hz,1H),7.12(s,1H),5.96(p,J=7.1Hz,1H),4.71(s,1H),3.90(s,6H),3.81(s,2H),3.46(s,2H),2.64(t,J=5.6Hz,2H),1.73(d,J=6.9Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ157.82,154.34,153.80,149.10,148.88,146.82,140.47,136.89,130.11,130.04,127.90,127.75,126.09,122.39,108.83,107.51,102.56,59.51,56.65,56.16,55.39,51.17,50.44,45.35,22.10.
Compounds of the structures shown in examples 2-10 (see Table 1) were prepared in a similar procedure as in example 1.
TABLE 1 Structure and map data for examples 2-10
Example 11
Synthesis of 2-methyl-N- (1- (4- (2- ((methylamino) methyl) phenyl) thiophen-2-yl) ethyl) -7,8-dihydro- [1,4] dioxins [2,3-g ] quinazolin-4-amine:
the synthetic route is as follows:
step k: preparation of methyl benzodioxan-6-carboxylate
At 0 ℃, 36mL of anhydrous methanol is added into 2,3-dihydro-1,4-benzodioxane-6-carboxylic acid (3.60g, 20.0mmol), the solution is stirred until the solution is clear, thionyl chloride (4.76g, 40.0mmol) is slowly added dropwise, and the solution is moved to 70 ℃ to reflux and stir for 2 hours after the dropwise addition. TLC detects that the raw material is completely consumed, decompression concentration is carried out to remove all solvents, light brown oil is obtained, saturated sodium bicarbonate solution is added dropwise while stirring under ice bath till the PH of the reaction system is 7-8, ethyl acetate (3 x 40mL) is extracted, organic phases are combined, organic phase is washed by water (2 x 60mL), saturated sodium chloride (2 x 60mL) is washed, anhydrous sodium sulfate is dried, suction filtration is carried out, and filtrate is decompressed and concentrated to obtain orange yellow oil (3.78 g, yield: 97.3%).
Step l: preparation of 7-nitro-1,4-benzodioxan-6-methyl formate
To methyl benzodioxane-6-carboxylate (3.78g, 19.5mmol), 21mL of glacial acetic acid and 7mL of concentrated nitric acid were added, and the mixture was stirred at 70 ℃ for 6 hours. After TLC detection, the reaction solution was added dropwise to 40mL of ice water with continuous stirring to precipitate a light yellow solid, after dropping, the mixture was stirred for 30min, left to stand for 10min, filtered, the filter cake was washed with 15mL of ice water, and dried overnight in a vacuum oven at 40 ℃ to obtain a light yellow powder (4.22 g, yield: 90.5%). 1 H NMR(400MHz,DMSO-d6)δ7.65(s,1H),7.30(s,1H),4.41–4.38(m,4H),3.80(s,3H).
Step m: preparation of methyl 7-amino-2,3-dihydrobenzo [ b ] [1,4] dioxin-6-carboxylate.
Ammonium chloride (5.62g, 105mmol), 30mL of ethanol and 15mL of water were added to 7-nitro-1,4-benzodioxane-6-carboxylic acid methyl ester (3.14g, 15.0mmol), the solution was stirred, reduced iron powder (4.19g, 75.0mmol) was added with stirring, and the mixture was stirred at 80 ℃ overnight under reflux. After TLC detection of the material consumption, the reaction solution was cooled to room temperature with stirring, filtered with celite, and the filter cake was washed with 20mL of water and then 20mL of dichloromethane. The filtrate was collected, the filtrate was extracted with dichloromethane (3 × 30ml), the organic phases were combined, the organic phase was washed with water (2 × 60ml), washed with saturated sodium chloride (2 × 60ml), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give 3.25g of an orange-red oil, and the crude product was purified by column chromatography to give an off-white solid (2.20 g, yield: 70.0%). 1 H NMR(400MHz,DMSO-d6)δ7.14(s,1H),6.25(s,2H),6.24(s,1H),4.26–4.21(m,2H),4.16–4.11(m,2H),3.73(s,3H).
And n: preparation of 7-amino-2,3-dihydrobenzo [ b ] [1,4] dioxin-6-carboxylic acid
In 7-amino-2,3-dihydrobenzo [ b][1,4]To methyl dioxin-6-carboxylate (2.09g, 10.0 mmol) were added tetrahydrofuran and 20mL each of a 2mol/L aqueous solution of lithium hydroxide, and the mixture was stirred at 60 ℃ for 3 hours. TLC detection raw material consumption, decompression concentration to remove tetrahydrofuran, residue added with 10mL water to make the reaction liquid fully dissolved, stirring and dripping glacial acetic acid, pH to 4, stirring for 30min, standing for 10min, suction filtration, filter cake with 15mL water washing, filter cake in 40 degrees C vacuum drying oven overnight drying, get pale yellow solid (1.75 g, yield: 89.7%). ESI-MS (m/z) 196.1[ 2 ], [ M ] +H] + 。
Step o: preparation of 2-methyl-7,8-dihydro- [1,4] dioxins [2,3-g ] quinazolin-4-ol
In 7-amino-2,3-dihydrobenzo [ b][1,4]Ethylamidine hydrochloride (753mg, 8.00mmol), anhydrous sodium acetate (656mg, 8.00mmol) and 15mL of ethylene glycol monomethyl ether were added to dioxin-6-carboxylic acid (780mg, 4.00mmol), and the mixture was stirred at 130 ℃ under reflux for 6 hours. TLC detects that the raw material is completely consumed, and the reaction liquidAfter cooling to room temperature, the reaction mixture was added dropwise to 30mL of ice water, and stirred for 30min after completion of the addition, a solid was precipitated, allowed to stand for 10min, filtered, washed with 10mL of water, and dried overnight in a vacuum oven at 40 ℃ to give a yellowish solid (715 mg, yield: 81.7%). ESI-MS (m/z) 219.1[ 2 ], [ M + H ]] + 。
Step p: preparation of 4-chloro-2-methyl-7,8-dihydro- [1,4] dioxins [2,3-g ] quinazolines
In the presence of 2-methyl-7,8-dihydro- [1,4]Dioxin [2,3-g]Quinazolin-4-ol (655mg, 3.00mmol) was added thionyl chloride (6 mL) and catalytic amount of DMF (2 drops) and stirred at 90 ℃ under reflux for 5h. And (3) performing TLC detection on the raw material, performing reduced pressure concentration to obtain a brown yellow solid, then dropwise adding a saturated sodium bicarbonate solution into the reaction system at 0 ℃ to generate bubbles continuously, adjusting the pH of the reaction solution to 7-8, adding 30mL of dichloromethane, stirring for 30min, performing suction filtration, and drying a filter cake to obtain 150mg of the raw material c-6-1. The filtrates were separated, aqueous phase (2 × 15ml) was extracted, organic phases were combined, organic phase was washed with water (2 × 25ml), washed with saturated sodium chloride (2 × 25ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid (485 mg, yield: 68.3%). ESI-MS (m/z) 237.1[ deg. ] M + H] + 。
And q: preparation of N- (1- (4-bromothien-2-yl) ethyl) -2-methyl-7,8-dihydro- [1,4] dioxine [2,3-g ] quinazolin-4-amine
Step q was performed as in step h to obtain an off-white solid (188 mg yield: 37.9%). ESI-MS (m/z) 406.0[ m ] +H] + 。
Step r: preparation of 2-methyl-N- (1- (4- (2- ((methylamino) methyl) phenyl) thiophen-2-yl) ethyl) -7,8-dihydro- [1,4] dioxins [2,3-g ] quinazolin-4-amine
Step r was performed according to step i to give a pale yellow solid (28.2 mg, yield 33.3%). ESI-MS (m/z): 447.2229[ m ] +H] + 。 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.20(d,J=8.2Hz,1H),7.86(s,1H),7.67(dd,J=6.0,3.1Hz,1H),7.46–7.39(m,3H),7.38–7.34(m,1H),7.20(s,1H),7.00(s,1H),5.91(q,J=7.4Hz,1H),4.34(q,J=4.9Hz,4H),4.04(s,2H),2.45(s,3H),2.41(s,3H),1.70(d,J=6.9Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ161.98,158.06,149.63,149.04,146.46,142.84,139.62,137.32,131.54,130.47,129.82,128.93,128.09,126.00,122.88,112.11,109.02,108.05,64.92,64.51,50.06,45.08,33.59,26.58,21.92.
Compounds of the structures shown in examples 12-18 were prepared in a similar procedure as in example 11 and are shown in Table 2.
TABLE 2 Structure and map data for examples 12-18
Evaluation of biological Activity of the Compound of example 19
1. Evaluation of SOS1 protein inhibitory Activity
(1) Preparation of the compound: each compound was dissolved in 100% DMSO and brought to a volume of 10mM stock solution and stored in a nitrogen cabinet at low temperature in the dark. Immediately before use, the configured compound was diluted by adding it to the assay plate using the dispenser Echo so that the volume fraction of DMSO was 0.25%.
(2) Preparing a Tag1-SOS1 dilution buffer solution: mu.L of Tag1-SOS1 solution was added to the assay plate and 5. Mu.L of dilution buffer was transferred from the low control group.
(3) Preparing a Tag2-KRAS G12C dilution buffer solution: mu.L of Tag2-KRAS G12C solution was added to the assay plate.
(4) Preparing Anti-Tag1-Tb3+ and Anti-Tag2-XL665 detection buffers: mu.L of the test solution was added to the test plate, centrifuged for 1min with a centrifuge 1000, and incubated at room temperature for 30min.
(5) Read with Envision plate reader.
(6) The RFU value was obtained from Envision microplate reader software.
(7) The ratio RFU 665nm/RFU615nm was calculated and converted to a value for percent inhibition. The data were fitted using the following formula and Excel:
(8) Calculating the formula:
Inhibition%=(Max signal-Compound signal)/(Max signal-Min signal)×100%;
min signal: negative control Kong Junzhi; max signal: positive control Kong Junzhi.
The log values of the concentrations were taken as the X axis and the percent inhibition as the Y axis, and the log (inhibitor) vs. response-Variable slope of the GraphPad Prism 5 software was used to fit the dose-effect curves, thereby obtaining the IC50 values of the compounds for the SOS1 protein.
Fitting formula:
Y=Bottom+(Top-Bottom)/(1+IC 50 /X*HillSlope)×100%;
y: inhibition ratio (%); x: the concentration of the compound.
2. Evaluation of cell proliferation inhibitory Activity of K562 (cell line highly expressing KRAS)
(1) Preparation of a culture medium: adding 10mL fetal calf serum into 89mL 164-degree basic culture medium, adding 1mL penicillin/streptomycin solution to prepare culture solution of K562 cells, and storing in a refrigerator at 4 ℃ for later use.
(2) Preparation of the compound: accurately weighing the mass of the compound to be detected by an analytical balance, adding a DMSO solution to prepare a 20mM mother solution, and storing the mother solution in a refrigerator at 4 ℃ for later use.
(3) Subculturing: after the K562 cells were allowed to stand in an incubator (5% carbon dioxide, temperature: 37 ℃) for 4 hours, they were subcultured by the half-liquid-changing method while maintaining the cell culture density at 1X 105 to 1X 106cells/mL. The cells after passaging were further cultured in an incubator containing 5% CO2 at 37 ℃.
(4) Paving a plate and adding medicine: cells were centrifuged, supernatant removed, fresh medium added, plates counted and plated at a seeding density of 1X 105cells/mL in 96-well plates. The test compound was diluted to different concentrations in culture medium for a total of 9 concentrations, 3 replicates, and a blank control group (medium added) and a positive control group (cells and medium added, no drug added) were included. Test compounds of different concentrations were added to the corresponding wells and incubated in an incubator for 72h.
(5) OD value was measured: add 10. Mu.L of CCK-8 solution to the blank, positive control and drug-affected wells and continue incubation in a CO2 incubator for 4h. After shaking the plate (4 min), the OD at 450nm was measured in each well with a microplate reader.
(6) Calculation of IC50 values: the inhibition rate at different concentrations was calculated using GraphPad Prism 5 software, the formula is shown below, and the IC50 values were calculated by fitting a corresponding function according to the inhibition rate curve.
3. EGFR kinase level assessment
(1) Configuring 1 XKinase buffer
(2) Preparation of the compound: test compounds were tested at 10 μ M, single concentration, in duplicate wells. Each compound was dissolved in 100% DMSO and brought to a volume of 10mM stock solution and stored in a nitrogen cabinet at low temperature in the dark. Immediately before use, the prepared compound was added to the assay plate by using the Echo of the dispenser to be diluted to a 100-fold final concentration DMSO solution. 250nL of 100-fold final concentration of compound was transferred to 384-well plates using a dispenser Echo 550. 100% DMSO of 250nL in each of the negative and positive control wells.
(3) Preparing a Kinase solution with 2.5 times of final concentration by using 1 XKinase buffer; mu.L of 1 XKinase buffer was added to the negative control wells.
(4) Add 10. Mu.L of 2.5 fold final concentration kinase solution to the compound well and positive control well, respectively; mu.L of 1 XKinase buffer was added to the negative control wells.
(5) Centrifuged at 1000rpm for 30 seconds, shaken and mixed and incubated at room temperature for 10 minutes.
(6) A mixed solution of ATP and Kinase substrate22 at 25/15 fold final concentration was prepared using a 1 XKinase buffer.
(7) The reaction was initiated by adding 15. Mu.L of a 25/15 fold final ATP and substrate mixture.
(8) The 384 well plates were centrifuged at 1000rpm for 30 seconds, shaken well and incubated at room temperature for 10 minutes.
(9) Add 30. Mu.L of termination detection solution to stop the kinase reaction, centrifuge at 1000rpm for 30 seconds, shake and mix.
(10) Read with a microplate Reader (Caliper EZ Reader).
Formula for calculation
4. Evaluation of proliferation inhibitory Activity of H1975 cells (cell line highly expressing EGFR)
(1) Preparation of a culture medium: to 89mL of 164 ℃ basal medium, 10mL of fetal bovine serum was added, and 1mL of penicillin/streptomycin solution was added to prepare a culture solution for NCI-H1975 cells, which was stored in a refrigerator at 4 ℃ for further use.
(2) Preparation of the compound: accurately weighing the mass of the compound to be detected by an analytical balance, adding a DMSO solution to prepare a 20mM mother solution, and storing the mother solution in a refrigerator at 4 ℃ for later use.
(3) Subculturing: h1975 cells were allowed to stand in an incubator (5% carbon dioxide, temperature: 37 ℃) for 4 hours, and then subcultured by trypsinization while maintaining the cell culture density at 1X 105 to 1X 106cells/mL. The cells after passaging were further cultured in an incubator containing 5% CO2 at 37 ℃.
(4) Plate paving and medicine adding: cells were centrifuged, supernatant removed, fresh medium added, plates counted and plated at a seeding density of 1X 105cells/mL in 96-well plates. The test compound was diluted to different concentrations in culture medium for a total of 9 concentrations, 3 replicates, and a blank control group (medium added) and a positive control group (cells and medium added, no drug added) were present. Test compounds of different concentrations were added to the corresponding wells and incubated in an incubator for 72h.
(5) OD value was measured: to the blank, positive control and drug-affected wells, 10. Mu.L of CCK-8 solution was added and incubation in a CO2 incubator was continued for 4h. After shaking the plate (4 min), the OD at 450nm in each well was measured with a microplate reader.
(6) Calculation of IC50 values: the inhibition rate at different concentrations was calculated using GraphPad Prism 5 software, the formula is shown below, and the IC50 values were calculated by fitting a corresponding function according to the inhibition rate curve.
TABLE 3 Compound on SOS1 protein, K562 cells, EGFR wild type (EGFR) WT ) Biological Activity assay of kinase, H1975 cells
Analyzing the above results can obtain: the compounds of the present invention generally have better activity, with examples 1,3, 7, 10 and 14 showing better activity than BAY-293, especially example 14, on the SOS1 protein IC 50 IC for K562 cells =14.9nM 50 =1.79 μ M, essentially equivalent to BAY-293 (SOS 1 protein IC) 50 =6.90nM, K562 cell IC 50 =1.09 μ M), and example 14 is excellent in selectivity to SOS 1. In addition, all the compounds have no obvious inhibition effect on EGFR and high-expression EGFR cell lines, so that the compounds have a good treatment window when being applied.
Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. Substituted quinazoline compounds with structures shown in general formulas (I) and (II) or pharmaceutically acceptable salts thereof,
wherein:
Z 1 selected from S, O, NH, Z 2 Is selected from CH; or Z 2 Selected from S, O, NH, Z 1 Is selected from CH;
R 1 selected from hydrogen or halogen; r 1 ' is selected from R1 is selected from hydrogen, methyl or halogen;
R 2 、R 2 ' are each independently selected from C1-4 alkanyl or C3-6 cycloalkyl; the optical configuration is raceme, R configuration or S configuration;
R 3 、R 3 ' each is independently selected from-OH, -CN, C1-4 alkoxy, -O (CH) 2 ) a NHCH 3 ,-O(CH 2 ) b N(CH 3 ) 2 ,-CH 2 NH(CH 2 ) m OH,-CH 2 NH(CH 2 ) n CH 3 (ii) a Wherein a and b are respectively 1, 2 and 3; m is 2 and 3; n is 0, 1, 2;
R 4 and R 5 Each independently selected from H, halogen, C1-4 alkoxy, Z a is selected from CH 2 ,O,NR a ;R a Is H, C 1 -C 4 Alkyl, alkenyl, alkynyl, C 1 -C 4 A carbonyl compound of (a);
R 4 ' is selected from CH 2 (OCH 2 CH 2 O) i CH 2 (ii) a i is 0, 1, 2.
2. The substituted quinazoline compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is 2 、R 2 ' are each independently selected from methyl, ethyl, isopropyl, cyclopropyl.
3. The substituted quinazoline compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is 4 And R 5 Are each independently-OCH 3 。
4. The substituted quinazoline compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is an inorganic salt or an organic salt; inorganic salts include hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate.
5. A pharmaceutical composition comprising a substituted quinazoline compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.
6. The pharmaceutical composition of claim 5, further comprising a pharmaceutically acceptable carrier, excipient or diluent.
7. The pharmaceutical composition of claim 5, further comprising a combination of other pharmaceutically acceptable therapeutic agents.
8. Use of a substituted quinazoline compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the preparation of an SOS1 inhibitor.
9. Use of the substituted quinazoline compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the manufacture of an anti-cancer medicament; the cancer includes pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, sarcoma.
10. The substituted quinazoline compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use in a medicament for treating a SOS 1-associated disease; the diseases include: RAS disease, noonan syndrome with multiple plaques, capillary malformation-arteriovenous malformation syndrome, costello syndrome, cardio-facio-cutaneous syndrome, legtis syndrome, and hereditary gingival fibromatosis.
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Citations (2)
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WO2018172250A1 (en) * | 2017-03-21 | 2018-09-27 | Bayer Pharma Aktiengesellschaft | 2-methyl-quinazolines |
WO2022121813A1 (en) * | 2020-12-07 | 2022-06-16 | 北京泰德制药股份有限公司 | Sos1 inhibitor, pharmaceutical composition comprising same, and use thereof |
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WO2018172250A1 (en) * | 2017-03-21 | 2018-09-27 | Bayer Pharma Aktiengesellschaft | 2-methyl-quinazolines |
WO2022121813A1 (en) * | 2020-12-07 | 2022-06-16 | 北京泰德制药股份有限公司 | Sos1 inhibitor, pharmaceutical composition comprising same, and use thereof |
Non-Patent Citations (2)
Title |
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BALTANAS, FERNANDO C. 等: "SOS2 comes to the fore: differential functionalities in physiology and pathology", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 22, no. 12, pages 6613 * |
MARZARO, GIOVANNI 等: "Discovery of Biarylaminoquinazolines as Novel Tubulin Polymerization Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 57, no. 11, pages 4598 - 4605 * |
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