WO2021018003A1 - Egfr inhibitor, composition, and preparation method therefor - Google Patents

Abstract

Disclosed are a compound of formula I, a method for using the compound as an EGFR inhibitor, and a pharmaceutical composition containing the compound. The compound can be used to treat, prevent or ameliorate diseases or conditions such as cancers or infections.

Description

EGFR inhibitor, composition and preparation method thereof Technical field

The present invention relates to pharmaceutically active compounds, deuterated compounds (hydrogen replaced by deuterium) and pharmaceutically acceptable salts thereof, which can be used to treat or prevent diseases or medical conditions mediated by certain mutant forms of epidermal growth factor receptor ( For example, L858R activating mutant, Exon19 deletion activating mutant, T790M resistance mutant and C797S resistance mutant). The present invention also relates to a pharmaceutical composition containing the compound and a method of using the compound, deuterated compound and salt thereof to treat diseases mediated by various forms of EGFR mutants.

Background technique

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein belonging to the ErbB family of tyrosine kinase receptors. Activation of EGFR leads to autophosphorylation of receptor tyrosine kinases, which initiates a cascade of downstream signaling pathways involved in regulating cell proliferation, differentiation, and survival. EGFR is abnormally activated by various mechanisms, such as receptor overexpression, mutation, ligand-dependent receptor dimerization, ligand-independent activation, and is associated with the development of a variety of human cancers.

Inhibition of EGFR is one of the key goals of cancer treatment. Although the previous generations of EGFR-TKIs developed rapidly, the problem of drug resistance also appeared along with the development of drugs. Most drug resistance is the T790M mutation of the ATP receptor. Recently developed third-generation irreversible inhibitors against T790M, such as osimertinib, have very good inhibitory activity, but drug resistance will inevitably appear. EGFR-C797S mutation is the most common secondary mutation leading to third-generation TKI resistance. C797S is a missense mutation in which cysteine is replaced by serine at position 797 of exon 20 of EGFR. It is located in the tyrosine kinase region of EGFR. The mutation of C797S prevents osimertinib from continuing to form covalent bonds in the ATP binding domain, thus losing Inhibit the effect of EGFR activation, leading to the occurrence of drug resistance.

Early patent applications WO2018108064, WO2018115218, and WO2018181777 disclosed a series of fourth-generation EGFR inhibitors, but there is still a need for EGFR C797S inhibitors with stronger activity and better PK. In the present invention, the applicant has discovered a small molecule that can act as a fourth-generation EGFR inhibitor, and its activity can be used to treat cancer and/or infectious diseases. It is expected that these small molecules can be used as drugs with better stability, solubility, bioavailability, therapeutic index and toxicity values, which are essential to become effective drugs for promoting human health.

Summary of the invention

The present invention relates to compounds capable of inhibiting EGFR, and these compounds can be used to treat cancer and infectious diseases.

The compound of formula I, or its stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof.

among them,

R _{1 is} selected from -NR ₇ R ₈ , -C _5-6 heterocyclyl and

The -NR ₇ R ₈ and -C _5-6 heterocyclyl are optionally substituted by -C _4-6 cycloalkyl, -C _4-6 heterocyclyl and -NR ₇ R ₈ ;

R _{2 is} selected from halogen, CN, NH ₂ , -C _1-6 alkyl and -C _1-6 haloalkyl;

R _{3 is} selected from hydrogen, halogen, -C _1-6 alkyl and -C _1-6 haloalkyl;

R ₇ , R ₈ and R ₉ are each independently selected from hydrogen, -C _1-6 alkyl and -C _1-6 haloalkyl;

X is selected from CH and N;

s is selected from 1 and 2.

The embodiment compound of formula I is characterized in that R _{1 is} selected from -C _5-6 heterocyclyl.

Example compounds of formula I, characterized in that R _{1 is} selected from

Example compounds of formula I, characterized in that R _{1 is} selected from

Example compounds of formula I, characterized in that R _{1 is} selected from

The example compounds of formula I are characterized in that R ₂ is -C _1-3 alkyl or -C _1-3 haloalkyl.

The example compound of formula I is characterized in that R ₂ is -CH ₃ , -C ₂ H ₅ ,

The example compound of formula I is characterized in that R ₂ is -CH(CH ₃ ) ₂ or

The example compounds of formula I are characterized in that R _{3 is} selected from halogen.

The example compound of formula I is characterized in that R _{3 is} selected from Cl and Br.

Example compounds of formula I are characterized in that R _{3 is} selected from hydrogen.

The example compounds of formula I are characterized in that R ₇ , R ₈ and R ₉ are each independently selected from -C _1-6 alkyl. The example compounds of formula I are characterized in that R ₇ , R ₈ and R ₉ are independently selected from methyl and ethyl.

The embodiment compound of formula I is characterized in that the compound is:

1)(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperazin-1-yl) (Phenyl)amino)pyrimidin-4-yl)amino-2,3-dimethylphenyl)-2,3-dimethylphenyl)dimethylphosphine oxide;

2)(6-((5-Chloro-2-((4-(4-(dimethyl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine- 4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

3) (6-((5-chloro-2-((2-methoxy-5-methyl-4-morpholinphenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethyl (Phenyl) dimethyl phosphine oxide;

4)(6-((5-Chloro-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-methylphenyl)amino )Pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine phosphine oxide;

5)(6-((5-Chloro-2-((2-methoxy-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl )Amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

6)(6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) (Phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

7)(6-((2-((4-([1,4'-Bipiperidine]-1'-yl)-5-ethyl-2-methoxyphenyl)amino)-5-chloro (Pyrimidine-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

8)(6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(pyrrol-1-yl)piperidin-1-yl)phenyl)amino) (Pyrimidine-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

9)(R)-(6-(5-chloro-2-((5-ethyl-4-(hexahydro-1H-pyridine[1,2-a]pyrimidine-2(3H)-yl)-2 -Methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

10)(6-((5-chloro-2-((5-(2-chloroethyl)-2-methoxy-4-(4-(4-methylpiperazine)piperidine)phenyl) Amino)pyrimidine)amino)-2,3-xylyl)dimethylphosphine oxide;

11)(6-((5-chloro-2-((5-(1,1-difluoroethyl)-2-methoxy-4-(4-(4-methylpiperazine)piperidine) (Phenyl)amino)pyrimidine)amino)-2,3-dimethoxyphenyl)dimethylphosphine oxide;

12)(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

13)(6-((2-((4-(([1,4'-Bipiperidine]-1'-yl)-5-ethyl-2-methoxyphenyl)amino)-5- (Bromopyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

14)(6-((5-chloro-2-((5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl )Phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

15)(6-((5-chloro-2-((5-isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl )Phenyl)amino)pyrimidin-4-ylamino)-2,3-dimethylphenyl)dimethylphosphine oxide;

16)(R)-(6-((5-chloro-2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-5-methylphenyl) Amino)pyrimidin-4-yl)amino-2,3-dimethylphenyl)dimethylphosphine oxide;

17)(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-2,3-di (Methylphenyl) dimethyl phosphine oxide;

18)(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )Pyrimidin-4-ylamino)-2,3-dimethylphenyl)dimethylphosphine oxide;

19)(6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl))phenyl)amino)pyrimidine -4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide; or

20)(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)pyridine

(Pyridin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide.

The present invention also provides a pharmaceutical composition, including any one of the compounds of the present invention, or a pharmaceutically acceptable salt or its stereoisomer compound, and at least one pharmaceutically acceptable carrier or excipient .

The present invention additionally provides methods for inhibiting various forms of EGFR, which refer to mutant forms of EGFR, including L858R, Δ19del, T790M, and C797S, and any combination thereof, and the method includes administering the present invention to a patient The compound or pharmaceutically acceptable salt or stereoisomer thereof of any one of the inventions.

The present invention further provides a method for treating EGFR-driven cancer, the method comprising administering a therapeutically effective amount of any compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof to a patient in need thereof.

In some embodiments, the EGFR-driven cancer is characterized by the presence of one or more mutations selected from: (i) C797S, (ii) L858R and C797S, (iii) C797S and T790M, (iv) L858R, T790M , And C797S, or (v) △19del, T790M and C797S.

In some embodiments, the EGFR-driven cancer is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer, or breast cancer.

In some embodiments, the lung cancer is ^{EGFR L858R / T790M /} C797S or ^{EGFR △} 19del ^{/ T790M /} C797S mutant NSCLC.

The present invention provides a method for inhibiting mutant EGFR in a patient, the method comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof to a patient in need thereof.

The invention also provides the use of the compound of the invention or its pharmaceutical composition in the preparation of medicines.

In some embodiments, wherein the drug is used to treat or prevent cancer.

In some embodiments, wherein the cancer is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer, or breast cancer.

In some embodiments, the lung cancer is ^{EGFR L858R / T790M /} C797S or ^{EGFR △} 19del ^{/ T790M /} C797S mutant NSCLC.

The general chemical terms used in the above general formula have their usual meanings. For example, unless otherwise stated, the term "halogen" as used herein refers to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include F, Cl and Br.

Unless otherwise specified, the alkyl group as used herein includes saturated monovalent hydrocarbon groups having linear, branched or cyclic moieties. For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2 -Methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, as in C _1-8 alkyl C _1-8 is defined as the group identified as having a straight-chain or branched 1,2,3,4,5,6,7 or 8 carbon atoms, Chain arrangement.

The alkoxy group is an oxyether formed from the aforementioned linear, branched or cyclic alkyl group.

Unless otherwise specified, the term "aryl" as used herein refers to an unsubstituted or substituted monocyclic or polycyclic ring system containing carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups. The most preferred aryl group is phenyl.

Unless otherwise specified, the term "heteroaryl" as used herein means an unsubstituted or substituted stable five- or six-membered monocyclic aromatic ring system or an unsubstituted or substituted nine- or ten-membered benzo-fused heteroaromatic ring Department or bicyclic heteroaromatic ring system. Preferably, carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein nitrogen or sulfur heteroatoms may be optionally oxidized, and nitrogen heteroatoms may be optionally quaternized. Heteroaryl groups can be attached to any heteroatom or carbon atom to produce a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl , Benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.

The term "cycloalkyl" refers to a cyclic saturated alkyl chain having 3-12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclobutyl, cyclobutyl.

The term "substituted" refers to a group in which one or more hydrogen atoms are each independently substituted with the same or different substituents. Typical substituents include, but are not limited to, halogen (F, Cl, Br or I), C _1-8 alkyl, C _3-12 cycloalkyl, -OR ¹ , SR ¹ , =O, =S, -C( O)R ¹ , -C(S)R ¹ , =NR ¹ , -C(O)OR ¹ , -C(S)OR ¹ , -NR ¹ R ² , -C(O)NR ¹ R ² , cyanide Group, nitro group, -S(O) ₂ R ¹ , -OS(O ₂ )OR ¹ , -OS(O) ₂ R ¹ , -OP(O)(OR ¹ )(OR ² ); where R ¹ and R ^{2 is} independently selected from -H, lower alkyl, and lower haloalkyl. In some embodiments, the substituents are independently selected from -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy , Isobutoxy, t-butoxy, -SCH ₃ , -SC ₂ H ₅ , formaldehyde, -C(OCH ₃ ), cyano, nitro, CF ₃ , -OCF ₃ , amino, dimethyl Amino, methylthio, sulfonyl and acetyl.

As used herein, the term "composition" is intended to encompass products that contain specific ingredients in specific amounts, as well as any product that is directly or indirectly produced by a combination of specific ingredients in specific amounts. Therefore, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods for preparing the compounds of the present invention are also part of the present invention. In addition, some crystalline forms of the compound may exist as polymorphs and are therefore intended to be included in the present invention. In addition, some compounds may form solvates (ie, hydrates) or common organic solvents with water, and these solvates are also included in the scope of the present invention.

Examples of substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.

Examples of substituted alkoxy groups include, but are not limited to, aminomethoxy, tetrafluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.

The compounds of the present invention may also exist in the form of pharmaceutically acceptable salts. For use in medicine, the salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. The pharmaceutically acceptable acid/anionic salt usually takes a form in which the basic nitrogen is protonated with an inorganic acid or an organic acid. Representative organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, apple Acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfamic acid , Salicylic acid, saccharin or trifluoroacetic acid. Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium, and zinc.

The prodrug of the compound of the present invention is included in the protection scope of the present invention. Generally, the prodrug refers to a functional derivative that is easily converted into a desired compound in the body. Therefore, in the treatment method of the present invention, the term "administration" shall include the treatment of various conditions described with specific disclosed compounds or the use of compounds that may not be specifically disclosed, but which are converted into specific compounds in vivo after administration to the subject Compound. The conventional methods for selecting and preparing suitable prodrug derivatives have been described in books such as "Design of Prodrugs" (Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985).

Obviously, the definition of any substituent or variable at a specific position in a molecule is independent of other positions in the molecule. It is easy to understand that a person of ordinary skill in the art can select the substituent or substituted form of the compound of the present invention through the existing technical means and the method described in the present invention to obtain a chemically stable and easy-to-synthesize compound.

The compounds of the present invention may contain one or more asymmetric centers, and may produce diastereomers and optical isomers from this. The present invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.

The above formula I does not exactly define the three-dimensional structure of a certain position of the compound. The present invention includes all stereoisomers of the compound represented by formula I and pharmaceutically acceptable salts thereof. Furthermore, mixtures of stereoisomers and specific isolated stereoisomers are also included in the present invention. In the synthetic process of preparing such compounds, or in the process of racemization or epimerization known to those of ordinary skill in the art, the product obtained may be a mixture of stereoisomers.

When the compound represented by formula I has tautomers, unless otherwise stated, the present invention includes any possible tautomers, pharmaceutically acceptable salts thereof, and mixtures thereof.

When the compound represented by formula I and its pharmaceutically acceptable salt have a solvate or polymorph, the present invention includes any possible solvate and polymorph. The type of solvent that forms the solvate is not particularly limited, as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone and similar solvents can be used.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound provided by the present invention is an acid, the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low prices), ferric, ferrous, lithium, magnesium, manganese (high and low prices), potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium, and sodium salts. Pharmaceutically acceptable non-toxic organic bases capable of being derivatized into salts include primary, secondary and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, haamine, isopropylamine , Lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

When the compound provided by the present invention is a base, the corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , Lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pyruvic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid and p-toluenesulfonic acid. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid. Since the compound of formula I will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% purity, more suitable purity is at least 75%, and particularly suitable purity is at least 98% (% is weight ratio) .

The pharmaceutical composition provided by the present invention includes the compound represented by formula I (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or adjuvants. Although in any given case, the most suitable way of administering the active ingredient depends on the particular subject to be administered, the nature of the subject and the severity of the disease, the pharmaceutical composition of the present invention includes oral, rectal, topical and Pharmaceutical compositions for parenteral administration (including subcutaneous administration, intramuscular injection, and intravenous administration). The pharmaceutical composition of the present invention can be conveniently prepared in a unit dosage form known in the art and prepared by any preparation method known in the pharmaceutical field.

In fact, according to conventional drug mixing technology, the compound of formula I of the present invention, or prodrug, or metabolite, or pharmaceutically acceptable salt, can be used as an active component and mixed with a drug carrier to form a pharmaceutical composition. The pharmaceutical carrier can take various forms, depending on the desired mode of administration, for example, oral or injection (including intravenous injection). Therefore, the pharmaceutical composition of the present invention may adopt a separate unit suitable for oral administration, such as a capsule, cachet or tablet containing a predetermined dose of the active ingredient. Further, the pharmaceutical composition of the present invention may take the form of powder, granule, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition, in addition to the common dosage forms mentioned above, the compound represented by Formula I or a pharmaceutically acceptable salt thereof can also be administered by a controlled release method and/or a delivery device. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. Generally, this method includes the step of bringing into association the active ingredient and the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical composition is prepared by uniformly and intimately mixing the active ingredient with a liquid carrier or a finely divided solid carrier or a mixture of both. In addition, the product can be easily prepared into the desired appearance.

Therefore, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier and a compound represented by formula I or its stereoisomers, tautomers, polymorphs, solvates, and pharmaceutically acceptable salts thereof, Its prodrug. The combination of the compound represented by formula I or its pharmaceutically acceptable salt, and one or more other compounds with therapeutic activity is also included in the pharmaceutical composition of the present invention.

The drug carrier used in the present invention can be, for example, a solid carrier, a liquid carrier or a gas carrier. Solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil and water. The gas carrier includes carbon dioxide and nitrogen. When preparing oral pharmaceutical preparations, any pharmacologically convenient medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, colorants, etc. can be used for oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, Microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc. can be used in oral solid preparations such as powders, capsules and tablets. In view of ease of administration, tablets and capsules are preferred for oral preparations, and solid pharmaceutical carriers are used here. Alternatively, standard aqueous or non-aqueous formulation techniques can be used for tablet coating.

The tablet containing the compound or pharmaceutical composition of the present invention can be compressed or molded, and optionally, can be made into a tablet together with one or more auxiliary components or adjuvants. The active ingredient is in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, surface active agent or dispersant, and compressed in a suitable machine to make compressed tablets. The powdered compound or pharmaceutical composition is soaked with an inert liquid diluent, and then molded in a suitable machine to make a molded tablet. Preferably, each tablet contains about 0.05 mg to 5 g of active ingredient, and each cachet or capsule contains about 0.05 mg to 5 g of active ingredient. For example, a formulation intended for oral administration to humans contains about 0.5 mg to about 5 g of active ingredient, compounded with a suitable and convenient metering auxiliary material, which accounts for about 5% to 95% of the total pharmaceutical composition. The unit dosage form generally contains about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

The present invention provides pharmaceutical compositions suitable for injection, including sterile aqueous solutions or dispersion systems. Further, the above-mentioned pharmaceutical composition can be prepared into a sterile powder form for immediate preparation of sterile injection or dispersion. In any case, the final injection form must be sterile, and for easy injection, it must be easy to flow. In addition, the pharmaceutical composition must be stable during preparation and storage. Therefore, it is preferable that the pharmaceutical composition be stored under conditions of anti-microbial contamination such as bacteria and fungi. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

The pharmaceutical composition provided by the present invention may be in a form suitable for topical administration, for example, aerosol, emulsion, ointment, lotion, dusting or other similar dosage forms. Further, the pharmaceutical composition provided by the present invention can be in a form suitable for use in a transdermal drug delivery device. These preparations can be prepared by using the compound represented by the formula I of the present invention, or a pharmaceutically acceptable salt thereof, through conventional processing methods. As an example, a cream or ointment is prepared by adding about 5 wt% to 10 wt% of a hydrophilic material and water to produce a cream or ointment with the desired consistency.

The pharmaceutical composition provided by the present invention may take a solid as a carrier and is suitable for rectal administration. A unit dose suppository is the most typical dosage form. Suitable auxiliary materials include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by mixing the pharmaceutical composition with softened or melted auxiliary materials, then cooling and molding.

In addition to the above-mentioned adjuvant components, the above formulations may also include, as appropriate, one or more additional adjuvant components, such as diluents, buffers, flavoring agents, binders, surfactants, and additives. Thickeners, lubricants and preservatives (including antioxidants), etc. Further, other adjuvants may also include penetration enhancers that regulate the isotonic pressure between the drug and the blood. The pharmaceutical composition comprising the compound represented by formula I, or a pharmaceutically acceptable salt thereof, can be prepared in the form of powder or concentrate.

In general, to treat the conditions or discomforts shown above, the dosage level of the drug is about 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergies/asthma, diseases and discomforts of the immune system, diseases and discomforts of the central nervous system (CNS), the effective treatment drug dosage level is 0.01mg/kg body weight to 50mg/kg body weight per day, or 0.5mg to 3.5g per patient per day.

However, it is understood that lower or higher dosages than those mentioned above may be required. The specific dosage level and treatment plan for any particular patient will depend on many factors, including the activity of the specific compound used, age, weight, overall health, gender, diet, time of administration, route of administration, excretion rate, drug combination The condition and severity of the specific disease being treated.

These and other aspects will become apparent from the following written description of the invention.

The following examples are provided to better illustrate the present invention. Unless expressly stated otherwise, all parts and percentages are by weight, and all temperatures are in degrees Celsius.

The present invention will be described in more detail through specific examples. The following examples are provided for illustrative purposes, and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to produce substantially the same results. According to at least one assay method described herein, the compounds of the examples have been found to inhibit L858R, Δ19del, T790M and C797S.

Example

It should be understood that the foregoing general description and the following detailed description are only exemplary and illustrative, and do not limit any subject matter claimed. Unless expressly stated otherwise, all parts and percentages are by weight, and all temperatures are in degrees Celsius. The compounds described herein can be obtained from commercial sources or synthesized by conventional methods as shown below using commercially available raw materials and reagents.

The following abbreviations have been used in the examples:

AcOH: acetic acid;

DAST: Diethylaminosulfur trifluoride;

DIEA: N,N-diisopropylethylamine;

DMF: N,N-dimethylformamide;

DMSO: dimethyl sulfoxide;

EtOAc: ethyl acetate;

PE: petroleum ether;

n-BuOH: n-butanol;

TsOH: p-toluenesulfonic acid;

K ₂ CO ₃ : potassium carbonate;

Pd(dppf) ₂ Cl ₂ :1,1'-bis(diphenylphosphine)ferrocene palladium dichloride;

HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid;

LCMS: liquid chromatography-mass spectrometry;

h: hour;

Pd/C: Palladium on carbon;

MeOH: methanol;

NMP: N-methyl-2-pyrrolidone;

TLC: Preparative thin layer chromatography;

Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene;

Example 1 Synthesis of Compound 1

(6-((5-Chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino-2,3-dimethylphenyl)-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 1-1:

Add compound 1-1 (2.0g), HCl (10mL) to the reaction flask, slowly drop NaNO ₂ (996.53mg) in water (5mL) solution into the reaction flask at 0℃, continue to stir for 1h, add A solution of KI (3.00g) in water (10mL), warmed up naturally and continued to stir for 1h. The TLC monitors the end of the reaction and stops the reaction. Water (20mL) was added to the reaction solution, extracted with ethyl acetate (3×20mL), and the organic phase was washed with Na ₂ S ₂ O ₃ (3×20 mL), saturated brine (3×20 mL), and anhydrous sodium sulfate. After drying, separation and purification by column chromatography (n-hexane: ethyl acetate = 8:1), the solvent was removed to obtain the target compound 1-2 (3.0 g) as a yellow solid.

Step 2. Synthesis of compound 1-3:

Add compound 1-2 (3.0g), dimethylphosphine oxide (1.27g), K ₃ PO ₄ (4.60g), Pd(OAc) ₂ (243.10mg), Xantphos (1.25g), Dioxane (20 mL) was heated to 100° C. under N ₂ protection, and heated and stirred for 12 h. LCMS monitored the end of the reaction and stopped the reaction. Water (50 mL) was added to the reaction solution, extracted with dichloromethane (3×50 mL), the organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, and column chromatography (dichloromethane: methanol = 15 1) Isolation and purification, removing the solvent to obtain the target product 1-3 (2.0g) brown solid. MS:228[M+H] ⁺

Step 3. Synthesis of compound 1-4:

Compound 1-3 (2.0g), Pd/C (500mg), MeOH (30mL) were sequentially added to the reaction flask, H _{2 was introduced} , and the reaction solution was stirred at room temperature for 3 hours. LCMS monitored the end of the reaction and stopped the reaction. Filter with suction, rinse with methanol (20 mL), collect the organic phase and remove the solvent to obtain the target product 1-4 (1.2 g) as a light brown solid. MS:198[M+H] ⁺

Step 4. Synthesis of compound 1-6:

Compound 1-4 (1 g), 1-5 (1.40 g), K ₂ CO ₃ (1.40 g) and DMF (20 mL) were sequentially added to the reaction flask, heated to 100° C., heated and stirred for 12 h. LCMS monitored the end of the reaction and stopped the reaction. The reaction solution was poured into water (50 mL), extracted with dichloromethane (3×50 mL), the organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, and column chromatography (dichloromethane: methanol = 15 1) Isolation and purification, the solvent was removed to obtain the target compound 1-6 (1.5 g) as a yellow solid. MS:344[M+H] ⁺

Step 5. Synthesis of compound 1-9:

1-7 (1.0 g), 1-8 (1.48 g), K ₂ CO ₃ (1.49 g) and DMSO (30 mL) were sequentially added to the reaction flask, heated to 90° C., heated and stirred for 12 h. LCMS monitored the end of the reaction and stopped the reaction. The reaction solution was poured into water (100 mL), filtered with suction, the filter cake was washed with water, and dried to obtain the target product 1-9 (1.6 g) as a yellow solid. MS:349[M+H] ⁺

Step 6. Synthesis of compound 1-10:

Compound 1-9 (1.6 g), Pd/C (500 mg) and MeOH (30 mL) were sequentially added to the reaction flask, H _{2 was introduced} , and the reaction solution was stirred at room temperature for 3 hours. LCMS monitored the end of the reaction and stopped the reaction. Suction filtration, elution with methanol (20 mL), collect the organic phase and remove the solvent to obtain the target compound 1-10 (0.9 g) as a light brown solid. MS:319[M+H] ⁺

Step 7. Synthesis of compound 1:

Add compound 1-6 (50mg), compound 1-10 (46.26mg), p-toluenesulfonic acid (37.52mg) and n-butanol (2mL) to the reaction flask in sequence, heat to 120℃, increase to 90℃, heat and stir for 12h . LCMS monitored the end of the reaction and stopped the reaction. The reaction solution was poured into a sodium carbonate water (5mL) solution, extracted with dichloromethane (3×50mL), the organic phase was washed with saturated brine (3×30mL), dried over anhydrous sodium sulfate, and column chromatography (dichloromethane: Methanol=15:1) Isolation, purification, and concentration to obtain compound 1 (80 mg) as a white solid. MS:626[M+H] ⁺

Example 2 Synthesis of Compound 2

(6-((5-Chloro-2-((4-(4-(dimethyl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine-4- (Yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 2-1:

The synthesis method of compound 2-1 is the same as that of compound 1-9, except that the raw material 1-methyl-4-(4-piperidinyl)piperazine dihydrochloride is replaced with 4-dimethylaminopiperidine.

Step 2. Synthesis of compound 2-2:

The synthesis method of compound 2-2 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 2-1.

Step 3. Synthesis of compound 2:

The synthesis method of compound 2 is the same as that of compound 1, except that the raw material compound 1-10 is replaced with compound 2-2. MS of Compound 2: 571[M+H] ⁺

Example 3 Synthesis of Compound 3

(6-((5-Chloro-2-((2-methoxy-5-methyl-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylbenzene Base) dimethyl phosphine oxide

Step 1. Synthesis of compound 3-1:

The synthesis method of compound 3-1 is the same as that of compound 1-9, except that the raw material 1-methyl-4-(4-piperidinyl)piperazine dihydrochloride is replaced with morpholine.

Step 2. Synthesis of compound 3-2:

The synthesis method of compound 3-2 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 3-1.

Step 3. Synthesis of compound 3:

The synthesis method of compound 3 is the same as that of compound 1, except that the raw material compound 1-10 is replaced with compound 3-2. MS of Compound 3: 530[M+H] ⁺

Example 4 Synthesis of Compound 4

(6-((5-chloro-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-methylphenyl)amino)pyrimidine -4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine phosphine oxide

Step 1. Synthesis of compound 4-1:

The synthesis method of compound 4-1 is the same as that of compound 1-9, except that the raw material 1-methyl-4-(4-piperidinyl)piperazine dihydrochloride is replaced with N,N,N'-tri Methyl ethylene diamine.

Step 2. Synthesis of compound 4-2:

The synthesis method of N-(2-(dimethylamine)ethyl)-5-methoxy-N-1,2-dimethylbenzene-1,4-diamine is the same as that of compound 1-10 , Just replace the starting compound 1-9 with compound 4-1.

Step 3. Synthesis of compound 4:

The synthetic method of compound 4 is the same as that of compound 1, except that the raw material compound 1-10 is replaced with compound 4-2. MS of compound 4: 545[M+H] ⁺

Example 5 Synthesis of Compound 5

(6-((5-Chloro-2-((2-methoxy-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino )-2,3-Dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 5-1:

The synthesis method of compound 5-1 is the same as that of compound 1-9, except that the raw material 1-methyl-4-(4-piperidinyl)piperazine dihydrochloride is replaced with N-methylpiperazine.

Step 2. Synthesis of compound 5-2:

The synthesis method of compound 5-2 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 5-1.

Step 3. Synthesis of compound 5:

The synthesis method of compound 5 is the same as that of compound 1, except that the starting material compound 1-10 is replaced with compound 5-2.

Compound 5: ¹ H NMR (500MHz, DMSO-d ₆ ) δ 11.97 (s, 1H), 8.04 (s, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.50 (s, 1H) ,7.20-7.19(m,1H), 6.70(s,1H), 3.78(s,3H), 2.89-2.80(m,4H), 2.66(s,3H), 2.40(s,3H), 2.37(s , 3H), 2.30 (s, 3H), 2.08-2.07 (m, 4H), 1.89-1.86 (m, 6H). MS:543[M+H] ⁺

Example 6 Synthesis of Compound 6

(6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 6-1:

The synthesis method of compound 6-1 is the same as that of compound 1-9, except that the raw material 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene is replaced with 1-fluoro-5-methoxy Base-2-ethyl-4-nitrobenzene.

Step 2. Synthesis of compound 6-2:

The synthesis method of compound 6-2 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 6-1.

Step 3. Synthesis of compound 6:

The synthesis method of compound 6 is the same as that of compound 1, except that the starting material compound 1-10 is replaced with compound 6-2. MS of compound 6: 640[M+H] ⁺

Example 7 Synthesis of Compound 7

(6-((2-((4-([1,4'-Bipiperidine]-1'-yl)-5-ethyl-2-methoxyphenyl)amino)-5-chloropyrimidine- 4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 7-2:

The synthesis method of compound 7-2 is the same as that of compound 6-1, except that compound 1-8 is replaced with compound 7-1.

Step 2. Synthesis of compound 7-2:

The synthesis method of compound 7-3 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 7-2.

Step 3. Synthesis of compound 7:

The synthesis method of compound 7 is the same as that of compound 1, except that the raw material compound 1-10 is replaced with compound 7-3. MS of compound 7: 625[M+H] ⁺

Example 8 Synthesis of Compound 8

(6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(pyrrol-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine- 4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 8-2:

The synthesis method of compound 8-2 is the same as that of compound 6-1, except that compound 1-8 is replaced with compound 8-1.

Step 2. Synthesis of compound 8-3:

The synthesis method of compound 8-3 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 8-2.

Step 3. Synthesis of compound 8:

The synthesis method of compound 8 is the same as that of compound 1, except that the raw material compound 1-10 is replaced with compound 8-3. MS of compound 8: 611[M+H] ⁺

Example 9 Synthesis of Compound 9

(R)-(6-(5-Chloro-2-((5-ethyl-4-(hexahydro-1H-pyridine[1,2-a]pyrimidine-2(3H)-yl)-2-methyl (Oxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 9-2:

The synthesis method of compound 9-2 is the same as that of compound 6-1, except that compound 1-8 is replaced with compound 9-1.

Step 2. Synthesis of compound 9-3:

The synthesis method of compound 9-3 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 6-1.

Step 3. Synthesis of compound 9:

The synthesis method of compound 9 is the same as that of compound 1, except that the starting material compound 1-10 is replaced with compound 9-3. MS of compound 9: 597[M+H] ⁺

Example 10 Synthesis of Compound 10

(6-((5-chloro-2-((5-(2-chloroethyl)-2-methoxy-4-(4-(4-methylpiperazine)piperidine)phenyl)amino) (Pyrimidine) amino)-2,3-xylyl) dimethyl phosphine oxide

Step 1. Synthesis of compound 10-2

Add compound 10-1 (2g) and compound 1A (2.14g) to the reaction flask, dissolved in H ₂ O (4 mL) and dioxane (20 mL), add Pd(dppf)Cl ₂ (653 mg) at room temperature And K ₂ CO ₃ (1.66g), replaced with nitrogen three times, after stirring uniformly, heated to 100°C, and stirred at 100°C for 1.5h. LCMS monitored the end of the reaction. The reaction solution was cooled to room temperature. The concentrated organic phase was mixed with silica gel, and then separated and purified from 0%-50% PE:EtOAc column to obtain 1.5g product.

Step 2. Synthesis of compound 10-3

Add 10-2 (0.5g) and compound 1-8 (460mg), 10mL DMSO to the reaction flask, then add K ₂ CO ₃ (620mg) to it, replace with nitrogen three times, and transfer to 90℃ oil bath for reaction overnight. LCMS monitors that the reaction raw materials are consumed and the main peak is the product, the reaction is stopped and the temperature is reduced to room temperature. The reaction solution was poured into 60 mL of water, extracted three times with 40 mL of ethyl acetate, and the organic phases were combined, dried, and concentrated. The crude product was mixed and purified by silica gel column (petroleum ether: ethyl acetate from 0 to 100%) to obtain 600 mg of product, MS: 361[M+H] ⁺

Step 3. Synthesis of compound 10-4

Add 10-3 (200 mg) to the reaction flask, dissolve it in tetrahydrofuran (10 mL), add borane dimethyl sulfide under an ice water bath, and stir at natural temperature for 3 hours. Then the temperature of the reaction system was lowered to 0 degrees, NaOH and H ₂ O _{2 were added} , and stirring was continued for 2 hours. LCMS monitored the reaction to produce product. The reaction solution was poured into 30 mL of water, extracted three times with 40 mL of ethyl acetate, and the organic phases were combined, dried, and concentrated. The crude product was mixed and purified by silica gel column (petroleum ether: ethyl acetate from 0 to 60%) to obtain 110 mg of product, MS: 379 [M+H] ⁺

Step 4. Synthesis of compound 10-5

Dissolve compound 10-4 (110 mg) in DCM (10 mL) in a reactor equipped with a stir bar and a nitrogen protection device. Add thionyl chloride dropwise under ice bath conditions. After the dropwise addition is completed, the temperature is increased at 60°C for reaction 2 hour. LCMS monitoring showed that the product was produced. The reaction solution was cooled to room temperature, then the reaction solution was poured into water, 20 mL of DCM was added for extraction three times, the organic phase was dried with anhydrous sodium sulfate, then the anhydrous sodium sulfate was filtered off, and concentrated by rotary evaporation. The concentrated organic phase was mixed with silica gel, and then separated and purified from 0%-100% PE:EtOAc column by gradient to obtain 80mg product, MS:397[M+H] ⁺

Step 5. Synthesis of compound 10-6

Compound 10-5 was dissolved in 15 mL of tetrahydrofuran and 5 mL of methanol into a round bottom flask equipped with a stirring device, 0.05 g of Raney Ni was added, hydrogen balloon was replaced with hydrogen three times, and the reaction was carried out at room temperature for 3 hours. LCMS monitors the consumption of reaction raw materials, and the main peak is the product. The reaction was stopped, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated and dried by rotary evaporation. The crude product was not subjected to further purification treatment, and was directly used in the next reaction to obtain 80 mg of crude compound 10-6. MS:367[M+H] ⁺

Step 6. Synthesis of compound 10

In a reactor equipped with a stir bar and a nitrogen protection device, compound 10-6 (80 mg) and compound 1-6 (50 mg) were dissolved in n-BuOH (5 mL), and TsOH (24 mg) was added at room temperature for nitrogen replacement After stirring for three times, transfer to an oil bath and heat to 100°C, and stir at 100°C for 16 hours. LCMS monitoring showed that a product was produced. The reaction solution was cooled to room temperature and concentrated by rotary evaporation. The concentrated organic phase was separated and purified from 0%-30% MeOH: H ₂ O with a gradient to obtain 20 mg of product, MS: 674 [M+H] ⁺

Example 11 Synthesis of Compound 11

(6-((5-chloro-2-((5-(1,1-difluoroethyl)-2-methoxy-4-(4-(4-methylpiperazine)piperidine)phenyl )Amino)pyrimidine)amino)-2,3-dimethoxyphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 11-2:

Concentrated sulfuric acid (15.7g) was added to the flask with stirring to lower the temperature to -20°C, and then compound 11-1 (2.5g) was added in batches, during which the temperature was controlled not to exceed -15°C. Then, fuming nitric acid (1.87g) was slowly added dropwise within 20 minutes, during which the temperature was strictly controlled. After the addition is complete, the reaction solution continues to react for 20 minutes under these conditions. TLC monitors the completion of the reaction. The reaction solution was poured into ice water, stirred for 10 minutes, and an off-white solid appeared, which was filtered. The filter cake was washed with water 5 times and turned into a pale yellow solid. After drying, 2g of product was obtained, MS: 214[M+H] ⁺

Step 2. Synthesis of compound 11-3:

Compound 11-2 (0.4g) was added to a flask with stirring nitrogen protection, dissolved in 10mL DCM, then DAST (1mL) was added thereto, replaced with nitrogen three times, and transferred to an oil bath at 60°C for reaction for 2 hours. LCMS monitors that the reaction raw materials are consumed and the main peak is the product, the reaction is stopped and the temperature is reduced to room temperature. The reaction solution was poured into 60 mL of water, extracted three times with 40 mL of dichloromethane, and the organic phases were combined, dried, and concentrated. The crude product was mixed and purified by silica gel column (petroleum ether: ethyl acetate from 0 to 80%) to obtain 300 mg of product, MS: 236[M+H] ⁺

Step 3. Synthesis of compound 11-4:

Add 11-3 (0.3g) and compound 1-8 (360mg) to a flask with stirring nitrogen protection, dissolve them in 10mL DMSO, then add K ₂ CO ₃ (441mg) to it, replace with nitrogen three times, and transfer to React overnight in an oil bath at 90°C. LCMS monitors that the reaction raw materials are consumed and the main peak is the product, the reaction is stopped and the temperature is reduced to room temperature. The reaction solution was poured into 60 mL of water, extracted three times with 40 mL of ethyl acetate, and the organic phases were combined, dried, and concentrated. The crude product was mixed with samples and purified by silica gel column (petroleum ether: ethyl acetate from 0 to 100%) to obtain 400 mg of product. MS:399[M+H] ⁺

Step 4. Synthesis of compound 11-5:

Compound 11-4 was dissolved in 15 mL of tetrahydrofuran and 5 mL of methanol into a round bottom flask equipped with a stirring device, 0.25 g of Raney Ni was added, hydrogen balloon was replaced with hydrogen three times, and the reaction was carried out at room temperature for 3 hours. LCMS monitors the consumption of reaction raw materials and the main peak is the product. The reaction was stopped, the reaction solution was filtered with diatomaceous earth, and the filtrate was concentrated and dried by rotary evaporation. The crude product was not subjected to further purification treatment and was directly used in the next reaction to obtain 200 mg of crude compound 11-5. MS:369[M+H] ⁺

Step 5. Synthesis of compound 11:

Compounds 11-5 (80 mg) and 1-6 (100 mg) were added to the sealed tube with magnets to dissolve in 10 mL of n-butanol, 30 mg of p-toluenesulfonic acid was added, and the reaction was carried out at 110°C in an oil bath for 16 hours. LCMS monitored that the reaction raw materials were consumed, and the main peak was the product, the reaction was stopped and the temperature was reduced to room temperature. The reaction solution was concentrated and separated with 0-30% MeOH:H ₂ O in reverse phase to obtain 50 mg of the target compound. MS:676[M+H] ⁺

Example 12 Synthesis of compound 12:

(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) (Pyrimidine-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 12-2:

According to the synthesis method of compound 1-6, compound 1-5 is replaced with compound 12-1 to obtain compound 12-2. MS:388[M+H] ⁺

Step 2. Synthesis of compound 12:

The synthesis method of compound 12 is the same as that of compound 6, except that the starting material compound 1-6 is replaced with compound 12-2. MS of compound 12: 684[M+H] ⁺

Example 13 Synthesis of Compound 13

(6-((2-((4-(((1,4'-Bipiperidine)-1'-yl)-5-ethyl-2-methoxyphenyl)amino)-5-bromopyrimidine -4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 13:

The synthesis method of compound 13 is the same as that of compound 7, except that the starting material compound 1-6 is replaced with compound 12-2. MS of compound 13: 669[M+H] ⁺

Example 14 Synthesis of Compound 14

(6-((5-Chloro-2-((5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzene (Yl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 14-1:

The synthetic method of compound 14-1 is the same as that of compound 10-2, except that the raw material 1A is replaced with 14-0.

Step 2. Synthesis of compound 14-2:

The synthesis method of compound 14-2 is the same as that of compound 10-3, except that the raw material 10-2 is replaced with 14-1. MS of compound 14-2: 375[M+H] ⁺

Step 3. Synthesis of compound 14-3:

The synthesis method of compound 14-3 is the same as that of compound 1-10, except that the starting material compound 1-9 is replaced with compound 14-2. MS of compound 14-2: 345[M+H] ⁺

Step 4. Synthesis of compound 14:

The synthetic method of compound 14 is the same as that of compound 1, except that the starting material compound 1-10 is replaced with compound 14-3. MS of compound 14: 652[M+H] ⁺

Synthesis of Example Compound 15

(6-((5-Chloro-2-((5-isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)benzene (Yl)amino)pyrimidin-4-ylamino)-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 15-1:

The synthesis method of compound 15-1 is the same as that of compound 10-2, except that the raw material 10-1 is replaced with isopropenyl boronic acid.

Step 2. Synthesis of compound 15-2:

The synthetic method of compound 15-2 is the same as that of compound 10-3, except that the raw material 10-2 is replaced with 15-1. MS of compound 15-2: 375[M+H] ⁺

Step 3. Synthesis of compound 15-3:

The synthetic method of compound 15-3 is the same as that of compound 1-10, except that the starting material compound 1-9 is replaced with compound 15-2. MS of compound 15-2: 347[M+H] ⁺

Step 4. Synthesis of compound 15:

The synthesis method of compound 15 is the same as that of compound 1, except that the starting material compound 1-10 is replaced with compound 15-3. MS of compound 15: 654[M+H] ⁺

Example 16 Synthesis of compound 16

(R)-(6-((5-chloro-2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-5-methylphenyl)amino) (Pyrimidine-4-yl)amino-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 16-2:

The synthesis method of compound 16-2 is the same as that of compound 1-9, except that the starting material compound 1-8 is replaced with compound 16-1. MS of compound 16-2: 280[M+H] ⁺

Step 2. Synthesis of compound 16-3:

The synthesis method of compound 16-3 is the same as that of compound 1-10, except that the starting material compound 1-9 is replaced with compound 16-2. MS of compound 16-3: 250[M+H] ⁺

Step 3. Synthesis of compound 16:

The synthesis method of compound 16 is the same as that of compound 1, except that the starting material compound 1-10 is replaced with compound 16-3. MS of compound 16: 557[M+H] ⁺

Example 17 Synthesis of Compound 17

(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethyl Phenyl) dimethyl phosphine oxide

Step 1. Synthesis of compound 17-2:

The synthesis method of compound 17-2 is the same as that of compound 6-1, except that compound 1-8 is replaced with compound 17-1. MS 267[M+H] ⁺

Step 2. Synthesis of compound 17-3:

The synthesis method of compound 17-3 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 17-2. MS 237[M+H] ⁺

Step 3. Synthesis of compound 17:

The synthesis method of compound 17 is the same as that of compound 1, except that the starting material compound 1-6 is replaced with compound 17-3, and compound 1-10 is replaced with 12-2. MS of compound 17: 588[M+H] ⁺

Synthesis of Example Compound 18

(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine -4-ylamino)-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 18:

Compound 6 (100 mg), Pd/C (20 mg), and MeOH (10 mL) were sequentially added to the reaction flask, H _{2 was introduced} , and the reaction solution was stirred at room temperature for 3 hours. LCMS monitored the end of the reaction and stopped the reaction. Suction filtration, methanol (20 mL) rinsing, collecting the organic phase and removing the solvent to obtain the target product 18 (10 mg) off-white solid. MS of compound 18: 606[M+H] ⁺

Example 19 Synthesis of Compound 19

(6-((5-Chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl))phenyl)amino)pyrimidine-4 -Amino)-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 19-2:

The synthetic method of compound 19-1 is the same as that of compound 1-9, except that the raw material 1-fluoro-5-methoxy-2-methyl-4-nitrobenzene is replaced with 1-fluoro-5-methoxy 2-ethyl-4-nitrobenzene, starting material 1-8 was replaced with compound 19-1. MS of compound 19-1: 280[M+H] ⁺

Step 2. Synthesis of compound 19-3:

The synthesis method of compound 19-3 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 19-2. MS of compound 19-2: 250[M+H] ⁺

Step 3. Synthesis of compound 19:

The synthesis method of compound 19 is the same as that of compound 1, except that the starting material compound 1-10 is replaced with compound 19-3. MS of compound 19: 557[M+H] ⁺

Example 20 Synthesis of compound 20

(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)pyrimidin-4-yl) (Amino)-2,3-dimethylphenyl)dimethylphosphine oxide

Step 1. Synthesis of compound 20-2:

The synthesis method of compound 20-2 is the same as that of compound 6-1, except that compound 1-8 is replaced with compound 20-1. MS 350[M+H] ⁺

Step 2. Synthesis of compound 20-3:

The synthesis method of compound 20-3 is the same as that of compound 1-10, except that the raw material compound 1-9 is replaced with compound 20-2. MS 320[M+H] ⁺

Step 3. Synthesis of compound 20:

The synthesis method of compound 20 is the same as that of compound 1, except that the starting material compound 1-6 is replaced with compound 20-3, and compound 1-10 is replaced with 12-2. MS of compound 20: 671[M+H] ⁺

Comparative compound A

Step 1. Synthesis of compound A-2:

Add compound A-1 (2.0g), HCl (10mL) to the reaction flask, slowly drop NaNO ₂ (1.09g) in water (5mL) solution into the reaction flask at 0℃, continue stirring for 1h, add A solution of KI (3.27g) in water (10mL) was warmed up naturally and stirred for 1 hour. The TLC monitors the end of the reaction and stops the reaction. Water (20mL) was added to the reaction solution, extracted with ethyl acetate (3×20mL), and the organic phase was washed with Na ₂ S ₂ O ₃ (3×20 mL), saturated brine (3×20 mL), and anhydrous sodium sulfate. After drying, separation and purification by column chromatography (n-hexane: ethyl acetate = 8:1), the solvent was removed to obtain the target compound A-2 (3.0 g) as a yellow solid.

Step 2. Synthesis of compound A-3:

Add compound A-2 (3.0g), dimethyl phosphine oxide (1.38g), K ₃ PO ₄ (5.02g), Pd(OAc) ₂ (265mg), Xantphos (1.37g), dioxane in sequence to the reaction flask (20mL), heated to 100°C under N ₂ protection, heated and stirred for 12 h. LCMS monitored the end of the reaction and stopped the reaction. Water (50 mL) was added to the reaction solution, extracted with dichloromethane (3×50 mL), the organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, and column chromatography (dichloromethane: methanol = 15 1) Isolation and purification, removing the solvent to obtain the target product 1-3 (2.0g) brown solid. MS:214[M+H] ⁺

Step 3. Synthesis of compound A-4:

Compound A-3 (2.0 g), Pd/C (500 mg), and MeOH (30 mL) were sequentially added to the reaction flask, H _{2 was introduced} , and the reaction solution was stirred at room temperature for 3 hours. LCMS monitored the end of the reaction and stopped the reaction. Suction filtration, rinsing with methanol (20 mL), collecting the organic phase, and removing the solvent to obtain the target product A-4 (1.2 g) as a light brown solid. MS:184[M+H] ⁺

Step 4. Synthesis of compound A-6:

Compound A-4 (1 g), 1-5 (1.53 g), K ₂ CO ₃ (1.53 g) and DMF (20 mL) were sequentially added to the reaction flask, heated to 100° C., heated and stirred for 12 h. LCMS monitored the end of the reaction and stopped the reaction. The reaction solution was poured into water (50 mL), extracted with dichloromethane (3×50 mL), the organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, and column chromatography (dichloromethane: methanol = 15 1) Isolation and purification, the solvent was removed to obtain the target compound A-6 (1.5 g) as a yellow solid. MS:330[M+H] ⁺

Step 5. Synthesis of compound 1-9:

1-7 (1.0 g), 1-8 (1.48 g), K ₂ CO ₃ (1.49 g) and DMSO (30 mL) were sequentially added to the reaction flask, heated to 90° C., heated and stirred for 12 h. LCMS monitored the end of the reaction and stopped the reaction. The reaction solution was poured into water (100 mL), filtered with suction, the filter cake was washed with water, and dried to obtain the target product 1-9 (1.6 g) as a yellow solid. MS:349[M+H] ⁺

Step 6. Synthesis of compound 1-10:

Compound 1-9 (1.6 g), Pd/C (500 mg) and MeOH (30 mL) were sequentially added to the reaction flask, H _{2 was introduced} , and the reaction solution was stirred at room temperature for 3 hours. LCMS monitored the end of the reaction and stopped the reaction. Suction filtration, elution with methanol (20 mL), collect the organic phase and remove the solvent to obtain the target compound 1-10 (0.9 g) as a light brown solid. MS:319[M+H] ⁺

Step 7. Comparison of the synthesis of compound A:

Compound A-6 (50mg), compound 1-10 (50mg), p-toluenesulfonic acid (41mg) and n-butanol (2mL) were sequentially added to the reaction flask, heated at 120°C, heated to 90°C, heated and stirred for 12h. LCMS monitored the end of the reaction and stopped the reaction. The reaction solution was poured into a sodium carbonate water (5mL) solution, extracted with dichloromethane (3×50mL), the organic phase was washed with saturated brine (3×30mL), dried over anhydrous sodium sulfate, and column chromatography (dichloromethane: Methanol=15:1) separation, purification, and concentration to obtain a white solid of comparative compound A (60 mg). MS:612[M+H] ⁺

Comparative compound B

The following comparative compound B was prepared according to the method described in Example 41 in WO2019015655.

Pharmacological experiment

Experiment 1 EGFR△19del/T790M/C797S and EGFR wild-type kinase experiment

A mobility variation analysis was performed to determine the affinity of the compound to EGFRΔ19del/T790M/C797S. The enzyme reaction scheme is as follows:

1. Prepare 1* kinase buffer as follows.

1*kinase buffer	Final concentration
HEPES PH7.5(mM)	50
Brij-35	0.0150%
DTT(mM)	2
Mgcl 2 ,Mncl 2 (mM)	10

2. Preparation of compound concentration gradient: the test compound test starting concentration is 3000nM or 100nM, diluted to 100% DMSO solution of 100 times final concentration in 384source plate, and then use Precision to dilute the compound 3 times, 10 concentrations. Use a dispenser Echo 550 to transfer 250 nL 100 times the final concentration of the compound to the target plate OptiPlate-384F.

3. Use 1×Kinase buffer to prepare 2.5 times the final concentration of kinase solution.

4. Add 10 μL of 2.5 times the final concentration of kinase solution to the compound well and the positive control well; add 10 μL of 1×Kinase buffer to the negative control well.

5. Centrifuge at 1000 rpm for 30 seconds, shake and mix the reaction plate and incubate at room temperature for 10 minutes.

6. Use 1×Kinase buffer to prepare a mixed solution of 5/3 times the final concentration of ATP and Kinase substrate.

7. Add 15 μL of a mixed solution of 5/3 times the final concentration of ATP and substrate to start the reaction.

8. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for the corresponding time.

9. Add 30μL of stop detection solution to stop the kinase reaction, centrifuge at 1000rpm for 30 seconds, shake and mix.

10. Use Caliper EZ Reader to read the conversion rate.

11. Calculation formula

_{% Inhibition = ((Conversion% -} max-Conversion% - sample) / (Conversion% - max-Conversion% -min)) * 100

Among them: Conversion%_sample is the conversion rate reading of the sample; Conversion%_min: the average value of the negative control wells, representing the conversion rate readings of the wells without enzyme activity; Conversion%_max: the average value of the positive control wells, representing the conversion rate readings of the wells without compound inhibition.

The fitted dose-response curve takes the log value of the concentration as the X-axis and the percentage inhibition rate on the Y-axis. The log(inhibitor) vs.response–Variable slope of the analysis software GraphPad Prism 5 is used to fit the dose-effect curve to obtain each compound pair IC50 value of enzyme activity.

The calculation formula is Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)).

The results are expressed as IC ₅₀ values, as shown in Table 1. As illustrated in the examples, the compounds of the present invention show IC ₅₀ values within the following range: "A" represents "IC ₅₀ ≤1nM";"B" represents "1nM<IC ₅₀ ≤100nM";"C" represents "IC _50" >100nM".

Table 1

Experiment 2 Ba/F3-△19del/T790M/C797S, Ba/F3-L858R/T790M/C797S and Ba/F3 EGFR WT cell proliferation experiment

1. Cell culture

Cell line:

Cell line: Ba/F3 cell line with stable overexpression of △19del/T790M/C797S or L858R/T790M/C797S mutation gene (named Ba/F3-△19del/T790M/C797S and Ba/F3-L858R/T790M/C797S ), and Ba/F3EGFR wild-type cell line and A431EGFR wild-type cell line.

A. Medium

RPMI 1640 and 10% FBS and 1% PS; DMEM, 10% FBS and 1% PS.

B. Cell recovery

a) Preheat the medium in a 37°C water bath.

b) Take out the freezing tube from the liquid nitrogen tank, quickly put it in a 37°C water bath, and melt it completely within 1 minute.

c) Transfer the cell suspension to a 15 mL centrifuge tube containing 8 mL of medium, and centrifuge at 1000 rpm for 5 minutes.

d) Discard the supernatant, resuspend the cells in 1 mL of medium, transfer to a 75 cm ² culture flask containing 15 mL of medium, and culture in an incubator at 37° C. and 5% CO ₂ .

C. Cell Passaging

a) Preheat the medium in a 37°C water bath.

b) Collect the cells in a 15 mL centrifuge tube and centrifuge at 1000 rpm for 5 minutes. The supernatant was discarded, counted, and the cell density was 1×10 ⁴ cells/mL, and then placed in a 37°C, 5% CO ₂ incubator.

2. Compound preparation

a) The test compound (20mM stock solution) was diluted to 10mM with 100% DMSO as the starting concentration, and then serially diluted 3 times with the "9+0" concentration. In a 96-well dilution plate (Cat#P-05525, Labcyte);

b) Dilute the above compound solution 1:100 times with the culture medium to prepare a 10-fold working solution;

3. Cell plane culture

a) Centrifuge the growth cells in the logarithmic phase at 1000 rpm for 5 minutes, then resuspend the cells in medium, and then count the cells;

b) Inoculate the cells into a 96-well cell culture plate with a density of 2000 cells/well;

4. Compound treatment

a) The compound prepared in step 2 is added to a 15 μL cell plate per well, and the final concentration is 1000, 333, 111.1, 37, 12.3, 4.1, 1.4, 0.5, 0.2 and 0 nM, and the final concentration of DMSO is 0.1%. The blank control well is medium (0.1% DMSO);

b) Incubate the cells in the incubator for another 72 hours.

5. Detection

a) Take out the 96-well cell culture plate and add 50 μl CTG reagent (CellTiter Glo kit, promega, Cat#G7573).

b) Shake the plate for 2 minutes and cool at room temperature for 10 minutes.

c) Use PerkinElmer reader to read the luminous signal value.

Analyze experimental data

GraphPad Prism 6.0 software was used to analyze the data to obtain a fitting curve of compound activity.

Fit compound IC ₅₀ from nonlinear regression equation:

Y=minimum value+(maximum value-minimum value)/(1+10^((LogIC ₅₀ -X)*slope));

X: logarithm of compound concentration; Y: luminescence value.

Cell proliferation assay results are expressed by IC _50, as shown in Table 2. The compounds of the present invention illustrated in the examples show that the IC ₅₀ value is in the following range: "A" represents "IC ₅₀ ≤50nM";"B" represents "50nM<IC ₅₀ <100nM";"C" represents "IC ₅₀ ≥100nM".

Table 2

Note: "/" means not detected.

Experiment 3 Pharmacokinetic experiment

Male SD rats were administered orally, 3 rats in each group. Fasting overnight before the experiment, fasting time from at least 12 hours before administration to 4 hours after administration. Use the orbital vein to take blood. The blood collection time points for oral administration are: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 7 hours and 24 hours, the administration dose is 5 mpk, and the blood collection volume is 300 μL. After anticoagulation with 2.0% EDTA, the blood was centrifuged at 4000 rpm for 5 minutes, and about 100 μL was placed at -20°C for testing. The plasma samples were analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS). Use WinNonlin (V4.1, Pharsight) software with a non-compartmental model to analyze the plasma concentration-time data of individual animals and calculate the pharmacokinetic parameters of the test compound. The PK properties of the compounds in rats are shown in Table 3.

table 3

Claims (24)

1. A compound of formula I, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof,

   

   among them,

   R _{1 is} selected from -NR ₇ R ₈ , -C _5-6 heterocyclyl and

   

   The -NR ₇ R ₈ and -C _5-6 heterocyclyl are optionally substituted by -C _4-6 cycloalkyl, -C _4-6 heterocyclyl and -NR ₇ R ₈ ;

   R _{2 is} selected from halogen, CN, NH ₂ , -C _1-6 alkyl and -C _1-6 haloalkyl;

   R _{3 is} selected from hydrogen, halogen, -C _1-6 alkyl and -C _1-6 haloalkyl;

   R ₇ , R ₈ and R ₉ are each independently selected from hydrogen, -C _1-6 alkyl and -C _1-6 haloalkyl;

   X is selected from CH and N;

   s is selected from 1 and 2.
2. The compound of claim 1, wherein R _{1 is} selected from -C _5-6 heterocyclyl.
3. The compound of claim 1 or 2, wherein R _{1 is} selected from

   

   
4. The compound of claim 1 or 3, wherein R _{1 is} selected from

   

   
5. The compound of claim 1 or 3, wherein R _{1 is} selected from

   

   
6. The compound of any one of claims 1-5, wherein R ₂ is -C _1-3 alkyl or -C _1-3 haloalkyl.
7. The compound according to any one of claims 1-6, wherein R ₂ is -CH ₃ , -C ₂ H ₅ ,

   
8. The compound according to any one of claims 1-6, wherein R ₂ is -CH(CH ₃ ) ₂ or

   
9. The compound according to any one of claims 1-8, wherein R _{3 is} selected from halogen.
10. The compound according to any one of claims 1-9, wherein R _{3 is} selected from Cl and Br.
11. The compound according to any one of claims 1-9, wherein R _{3 is} selected from hydrogen.
12. The compound according to any one of claims 1-11, wherein R ₇ , R ₈ and R ₉ are each independently selected from -C _1-6 alkyl.
13. The compound according to any one of claims 1-12, wherein R ₇ , R ₈ and R ₉ are each independently selected from methyl and ethyl.
14. The compound of any one of claims 1-13, wherein the compound is:

    1)(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperazin-1-yl) (Phenyl)amino)pyrimidin-4-yl)amino-2,3-dimethylphenyl)-2,3-dimethylphenyl)dimethylphosphine oxide;

    2)(6-((5-Chloro-2-((4-(4-(dimethyl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidine- 4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

    3) (6-((5-chloro-2-((2-methoxy-5-methyl-4-morpholinphenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethyl (Phenyl) dimethyl phosphine oxide;

    4)(6-((5-Chloro-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-methylphenyl)amino )Pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine phosphine oxide;

    5)(6-((5-Chloro-2-((2-methoxy-5-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl )Amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

    6)(6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) (Phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

    7)(6-((2-((4-([1,4'-Bipiperidine]-1'-yl)-5-ethyl-2-methoxyphenyl)amino)-5-chloro (Pyrimidine-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

    8)(6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(pyrrol-1-yl)piperidin-1-yl)phenyl)amino) (Pyrimidine-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

    9)(R)-(6-(5-chloro-2-((5-ethyl-4-(hexahydro-1H-pyridine[1,2-a]pyrimidine-2(3H)-yl)-2 -Methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

    10)(6-((5-chloro-2-((5-(2-chloroethyl)-2-methoxy-4-(4-(4-methylpiperazine)piperidine)phenyl) Amino)pyrimidine)amino)-2,3-xylyl)dimethylphosphine oxide;

    11)(6-((5-chloro-2-((5-(1,1-difluoroethyl)-2-methoxy-4-(4-(4-methylpiperazine)piperidine) (Phenyl)amino)pyrimidine)amino)-2,3-dimethoxyphenyl)dimethylphosphine oxide;

    12)(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

    13)(6-((2-((4-(([1,4'-Bipiperidine]-1'-yl)-5-ethyl-2-methoxyphenyl)amino)-5- (Bromopyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

    14)(6-((5-chloro-2-((5-cyclopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl )Phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

    15)(6-((5-chloro-2-((5-isopropyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl )Phenyl)amino)pyrimidin-4-ylamino)-2,3-dimethylphenyl)dimethylphosphine oxide;

    16)(R)-(6-((5-chloro-2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxy-5-methylphenyl) Amino)pyrimidin-4-yl)amino-2,3-dimethylphenyl)dimethylphosphine oxide;

    17)(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)-2,3-di (Methylphenyl) dimethyl phosphine oxide;

    18)(6-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )Pyrimidin-4-ylamino)-2,3-dimethylphenyl)dimethylphosphine oxide;

    19)(6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl))phenyl)amino)pyrimidine -4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide;

    20)(6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)pyrimidine-4- (Yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide.
15. A pharmaceutical composition comprising the compound of any one of claims 1-14 or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
16. A method for inhibiting various forms of EGFR, the different forms of EGFR refer to mutant forms of EGFR, including L858R, Δ19del, T790M and C797S and any combination thereof, the method comprising administering claims 1 to The compound or pharmaceutically acceptable salt of any one of 14.
17. A method for treating EGFR-driven cancer, the method comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof to a patient in need.
18. The method of claim 17, wherein the EGFR-driven cancer is characterized by the presence of one or more mutations selected from the group consisting of (i) C797S, (ii) L858R and C797S, (iii) C797S and T790M, (iv) L858R, T790M and C797S, and (v) Δ19del, T790M and C797S.
19. The method of claim 18, wherein the EGFR-driven cancer is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer, or breast cancer.
20. The method of claim 19, wherein said lung cancer is ^{EGFR L858R / T790M /} C797S or ^{EGFR △} 19del ^{/ T790M /} C797S mutant NSCLC.
21. Use of the pharmaceutical composition of claim 15 or the compound of any one of claims 1-14 in the preparation of a medicine.
22. The use of claim 21, wherein the medicament is used to treat or prevent cancer.
23. The use of claim 22, wherein the cancer is an EGFR-driven cancer, and the EGFR-driven cancer is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, brain cancer, kidney cancer, prostate cancer , Ovarian cancer or breast cancer.
24. The use as claimed in claim 23, wherein said lung cancer is ^{EGFR L858R / T790M /} C797S or ^{EGFR △} 19del ^{/ T790M /} C797S mutant NSCLC.