CN116462663A

CN116462663A - Pyrimidine bi-deuterated pyrazole compound, pharmaceutical composition and application

Info

Publication number: CN116462663A
Application number: CN202310727481.5A
Authority: CN
Inventors: 刘春河; 靳学健; 郭丽红
Original assignee: Beijing Kexiang Zhongsheng Pharmaceutical Technology Co ltd
Current assignee: Beijing Kexiang Zhongsheng Pharmaceutical Technology Co ltd
Priority date: 2023-06-20
Filing date: 2023-06-20
Publication date: 2023-07-21

Abstract

The invention discloses a compound shown in a formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, a pharmaceutical composition and application. The compound shown in the formula I provided by the invention has good inhibitory activity on EGFR mutants and good therapeutic effect on cancers, especially non-small cell lung cancer.

Description

Pyrimidine bi-deuterated pyrazole compound, pharmaceutical composition and application

Technical Field

The invention belongs to the field of innovative pharmaceutical chemistry, and relates to a pyrimidine-dideutero-pyrazole compound, a pharmaceutical composition and application.

Background

EGFR (Epidermal Growth Factor Receptor) is a transmembrane protein, also known as ErbB-1 or HER1, belonging to the epidermal growth factor receptor family (ErbBs). Up to now, the human ErbB family has found 4 subtypes, erbB1 (EGFR), erbB2 (HER 2/neu), erbB3 (HER 3) and ErbB4 (HER 4), respectively. It contains, like all tyrosine kinases, three region structures, the extracellular, transmembrane and intracellular regions. EGFR and its intracellular signaling pathways are highly expressed in malignant tumors, especially non-small cell lung, breast, colon and ovarian cancers. When the extracellular domain binds to a specific ligand, such as Epidermal Growth Factor (EGF), transforming growth factor alpha (TGF-alpha), cytokines, and epithelial regulatory proteins, EGFR self-aggregates to form homodimers or heterodimers with other ErbB family members, resulting in phosphorylation of residues of critical tyrosine in the cytoplasmic domain, which in turn activates downstream signaling pathways, thereby regulating the growth, proliferation, migration, etc. of cells. Dysregulation of EGFR signaling promotes tumor cell proliferation, angiogenesis, invasion, migration, and metastasis. Thus, EGFR has become an effective target for antitumor drugs.

The first generation EGFR inhibitors, representative drugs including gefitinib and erlotinib, have better efficacy in non-small cell lung cancer patients carrying EGFR activating mutations L858R and Del E746-A750, but the vast majority of patients exhibit varying degrees of resistance after approximately one year of treatment. 50% -60% of the drug resistance occurs due to EGFR T790M mutation in the patient. To address this resistance problem, researchers have developed second generation irreversible EGFR inhibitors, representative drugs including afatinib, but this class of EGFR inhibitors are less selective for wild-type EGFR, leading to serious adverse effects. Thus, researchers have developed third generation highly selective irreversible EGFR inhibitors, representative drugs including octenib and omutinib. Lazertinib is capable of targeting EGFR activation mutants Del E746-a750, L858R and T790M, while having relatively little effect on wild-type EGFR, and is a highly efficient, highly selective EGFR mutant inhibitor.

Deuterated drugs refer to the replacement of part of the hydrogen atoms in the drug molecule with deuterium. Deuterated drugs generally retain the biological activity and selectivity of the original drug due to the shape and volume of deuterium in the drug molecule, which is similar to hydrogen. Because the C-D bond is more stable than the C-H bond, the C-D bond is less likely to break during the chemical reaction of the deuterated drug, and the half-life period of the deuterated drug is prolonged. Since 2000, deuteration strategies have been widely used in drug research.

Disclosure of Invention

The invention provides a compound shown in a formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, which has the following structure:

。

the invention provides an application of a compound shown in a formula I or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof in preparing EGFR mutant inhibitors.

In some embodiments, the EGFR mutant is selected from one or more of Del E746-A750, L858R, or T790M.

In some embodiments, the EGFR mutant is selected from the group consisting of the Del E746-A750/T790M double mutant or the L858R/T790M double mutant.

The invention provides application of a compound shown as I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in preparing a medicament for preventing and/or treating cancer.

In some embodiments, the cancer is lung cancer.

In some embodiments, the lung cancer is non-small cell lung cancer.

In some embodiments, the cancer is a cancer associated with an EGFR mutant.

In some embodiments, the cancer associated with the EGFR mutant is lung cancer associated with the EGFR mutant.

The invention provides a pharmaceutical composition, which contains a compound shown in a formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, and pharmaceutically acceptable carriers or auxiliary materials.

In the pharmaceutical composition, the compound shown in the formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof is used in an amount which is effective in treatment.

The invention provides an application of a pharmaceutical composition in preparing EGFR mutant inhibitor.

The invention provides application of a pharmaceutical composition in preparing medicines for preventing and/or treating cancers.

In some embodiments, the cancer is lung cancer.

In some embodiments, the lung cancer is non-small cell lung cancer.

In some embodiments, the cancer is a cancer associated with an EGFR mutant.

The pharmaceutical excipients can be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent.

Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogenphosphates, dihydrogenphosphates, sulfuric acid (forming sulfates or bisulphates), hydroiodic acid, phosphorous acid, and the like, and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, salts of amino acids (such as arginine and the like), and salts of organic acids such as glucuronic acid.

The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

The term "isomer" refers to compounds of the same chemical formula but having different arrangements of atoms.

The term "metabolite" refers to a pharmaceutically active product of a compound of formula I or a salt thereof produced by in vivo metabolism. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain the metabolites thereof.

Identification of metabolites typically occurs by preparing a radiolabeled isotope of a compound of the invention, parenterally administering it to an animal, such as a rat, mouse, guinea pig, monkey, or human, in a detectable dose (e.g., greater than about 0.5 mg/kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from urine, blood, or other biological samples. These products are easy to isolate because they are labeled (others are isolated by using antibodies that are capable of binding to epitopes present in the metabolite). The metabolite structures are determined in a conventional manner, for example by MS, LC/MS or NMR analysis.

In general, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. So long as the metabolite products are not otherwise undetectable in vivo, they are useful in assays for therapeutic dosing of the compounds of the invention. The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example ³ H) Iodine-125% ¹²⁵ I) Or C-14% ¹⁴ C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxyl group can form a physiologically hydrolyzable ester that acts as a prodrug by hydrolyzing in vivo to give the compound of formula I itself. The prodrugs are preferably administered orally, as hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.

The invention has the positive progress effects that:

(1) The compound has good inhibitory activity on EGFR mutants.

(2) The compound has low toxicity, and the blood concentration is improved, the half-life period is prolonged, and the single administration dosage is reduced.

(3) The compounds of the present invention have good therapeutic effects on cancer.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

Example 1: synthesis of Compound 2

Step one: synthesis of Compound b

To a solution of compound a (81 mg, 0.47 mmol) in N, N-dimethylformamide (15 mL) were added potassium hydroxide (105.5 mg, 1.88 mmol) and elemental iodine (239 mg, 0.94 mmol), the reaction was allowed to react at room temperature for 3 hours, the completion of the reaction was monitored by TLC, a saturated solution of sodium sulfite was added to quench the reaction, the aqueous phase was extracted with ethyl acetate (10 mL ×2), washed with water (20 mL ×2), saturated salt (20 mL) was washed with water and dried over anhydrous sodium sulfate, and the resultant was separated and purified by column chromatography to give iodo compound b (70 mg, 50%). MS (ESI, M/z): 298 (M ⁺ +1).

Step two: synthesis of Compound c

To a deuterated acetic acid solution (8 mL) of the compound b (107 mg, 0.36 mmol) was added sodium acetate (97.9 mg, 0.72 mmol), and after completion of the 2-hour drop, the reaction was performed at room temperature for 24 hours, and the reaction was completed by TLC, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the compound c (63 mg, 62%). MS (ESI, M/z): 174 (M) ⁺ +1).

Step three: synthesis of Compound d

Compound c (173 mg,1 mmol) and compound e (160 mg,1 mmol) were dissolved in NMP (2 mL) and DIPE was added to the above solutionA (0.36 mL, 2 mmol), the reaction was warmed to 120℃and reacted overnight. After the reaction is completed, cooling to room temperature, adding saturated sodium bicarbonate solution to quench the reaction, precipitating, and filtering to obtain the compound d. MS (ESI, M/z): 298 (M ⁺ +1).

Step four: synthesis of Compound 2

Compound d was suspended in (297 mg,1 mmol) dissolved in ethanol and water, and aqueous hydrogen peroxide (0.3 mL, 3 mmol) and a catalytic amount of (NH) ₄ ) ₂ MoO ₄ Stirring is carried out for 2h at room temperature. After completion of the reaction, the reaction was quenched with an excessive amount of sodium thiosulfate, extracted with ethyl acetate (5 mL. Times.3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to give compound 2 (164 mg, 50%).

Example 2: synthesis of Compound I

Step one: synthesis of Compound 3

Compound 1 (109 mg,0.59 mmol) was dissolved in DMF (4 mL), and compound 2 (174 mg,0.53 mmol), potassium tert-butoxide (135 mg,1.18 mmol) was added to the above solution, heated to 50deg.C and reacted under stirring 12 h. The reaction solution was cooled to room temperature, and water was then added to the reaction solution to precipitate a solid, whereby compound 3 (205 mg, 80%) was obtained. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 8.86 (dd, J = 5.3, 4.6 Hz, 2H), 7.73-7.67 (m, 2H), 7.64 (d, J = 5.7 Hz, 1H), 7.55-7.48 (m, 2H), 7.37-7.27 (m, 2H), 6.90 (d, J = 7.9 Hz, 1H), 3.76 (s, 3H).

Step two: synthesis of Compound 4

Compound 3 (174 mg,0.4 mmol) was dissolved in DMAc (8 mL), DIPEA (0.35 mL, 0.8 mmol) and morpholine (0.13 mL,0.6 mmol) were added to the above solution, and the reaction was heated to 80℃and stirred for 2h. The reaction was cooled to room temperature, quenched with water, extracted with DCM (10 mL ×3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 4 (161 mg, 85%).

Step three: synthesis of Compound 5

Compound 4 (51 mg,0.1 mmol) and DIPEA (50. Mu.L, 0.3 mmol) were dissolved in DMAc (2 mL), dimethylamine (0.2 mmol) was added as in the above solution, and after stirring at room temperature for 20min, sodium triacetylborohydride (63 mg,0.3 mmol) was added to the reaction solution, and stirring was continued at room temperature for 24 hours. The reaction was quenched with water, extracted with DCM, washed with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 5 (30 mg, 56%).

Step four: synthesis of Compound 6

Compound 5 (53 mg,0.1 mmol) was dissolved in ethanol/water (2 mL/0.5 mL), and ammonium chloride (269 mg,0.5 mmol) and iron powder (56 mg,1 mmol) were added to the reaction mixture, followed by heating under reflux and stirring for 6h. The reaction solution was cooled to room temperature, an ammonia/methanol solution (2 mL, 2M) was added, the resulting mixture was suction-filtered through celite, the filtrate was concentrated, the resulting residue DCM was dissolved, washed with saturated sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 6 (35 mg, 70%).

Step five: synthesis of Compound I

Compound 6 (51 mg,0.1 mmol) and DIPEA (19. Mu.L, 0.11 mmol) were dissolved in DCM (2 mL) and a solution of acryloyl chloride (8. Mu.L, 0.1 mmol) in DCM (0.2 mL) was slowly added dropwise to the above solution at-20 ℃. After the completion of the dropwise addition, the reaction was continued with stirring for 1 hour, and then quenched with saturated sodium bicarbonate solution, extracted with DCM (10 mL X3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and separated and purified by column chromatography to give Compound I (39 mg, 70%). 1H NMR (500 MHz, DMSO-d) ₆ ) δ 9.64 (s, 1H), 8.86 (d, J = 5.7 Hz, 1H), 7.60 (d, J = 5.7 Hz, 1H), 7.49-7.42 (m, 3H), 7.42-7.35 (m, 2H), 7.35-7.27 (m, 2H), 6.43-6.35 (m, 2H), 6.12 (dd, J = 10.1, 1.8 Hz, 1H), 5.80 (dd, J = 9.9, 1.8 Hz, 1H), 3.89 (s, 2H), 3.83-3.74 (m, 6H), 3.33-3.26 (m, 4H), 2.27 (s, 6H). MS (ESI, m/z): 556 (M ⁺ +1).

Example 3: wild-type EGFR and mutant EGFR enzyme inhibition Activity assay

The experimental method comprises the following steps: the test compounds were diluted with DMSO to a stock solution of 10mM and then with kinase buffer to give 1. Mu.M to 10. Mu.M solutions of the compounds. Serial dilutions (6 μl) of the compounds of the invention were added to 96-well plates. Purified wild-type EGFR proteins and EGFR mutants, del E746-A750, L858R, L858R/T790M and Del E746-A750/T790M were diluted in kinase buffer and added to the test compound solution and incubated for 2h at room temperature. Then, ATP and substrate solution (Ulight-PolyGT) at approximately ATP concentration (1 mM) were added to each well containing compound solution and enzyme (12. Mu.L each) and incubated for 1h. Then, a stop solution (12. Mu.L each) made of EDTA, water and Lanse detection buffer was added to the reaction mixture to stop the phosphorylation, and after shaking for 5min, a detection solution (12. Mu.L each) containing europium-labeled antibody, water and Lanse detection buffer was added to the reaction mixture, and further incubation was performed for 50min. Substrate phosphorylation is a function of the 665nM emission value measured after addition of the detection solution and incubation for 50min.

Table 1 test Compounds have inhibitory Activity (IC) against wild-type EGFR and mutant EGFR enzymes ₅₀ nM）

Names of Compounds	EGFR ^WT	Del E746-A750	L858R	L858R/T790M	Del E746-A750/T790M
						I	90	2.5	6.8	0.11	0.59
Lazertinib	85	5.0	20.6	0.32	1.70
						Erlotinib	＞100	20-200	20-200	＞1000	＞1000
Afatinib	＜20	＜20	＜20	＜20	＜20

As shown in table 1, the enzyme inhibition activity of the EGFR mutant of compound I was significantly enhanced, the selectivity for wild-type EGFR was also significantly improved, and significantly better than the first-generation EGFR inhibitors erlotinib and afatinib, compared to lazertiinib.

Example 4: antiproliferative activity assay

The data of the inhibiting activity of the compound cancer cells are detected by an MTT method, which is also called MTT colorimetric method, and is a method for detecting the survival and growth of the cells. MTT (yellow thiazole blue) can penetrate through cell membranes and enter cells, amber dehydrogenase in mitochondria of living cells can reduce exogenous MTT into bluish purple needle-shaped formalzan crystals which are difficult to dissolve in water and deposit in the cells, the crystals can be dissolved by dimethyl sulfoxide (DMSO), and the light absorption value of the crystals can be detected by an ELISA detector at 490 nm/570 nm wavelength, so that the number of the living cells can be indirectly reflected. Cell lines used included: PC9 carries the mutant Del E746-A750; h1975 cells harbor the L858R/T790M mutation; the specific experimental procedure for the wild type H2073 cells is as follows:

(1) Collecting cells in logarithmic growth phase, regulating the concentration of the cell suspension, and adding 100 mu L of the cell suspension into each well of a 96-well plate; the number of cells per well was about 7000, at 5% CO ₂ ，37 ^◦ Incubating overnight until the cells are fully adherent;

(2) Setting medicine concentration gradients, setting 3 compound holes for each concentration gradient, diluting medicine into corresponding culture medium to required final concentration, sucking out original culture medium in 96 well plate, adding 100 μl of prepared culture medium containing medicine with required final concentration, and adding 5% CO ₂ ，37 ^◦ Incubating; and a blank group (containing only 100. Mu.L of culture medium, no cells, and the subsequent treatment is the same as that of other wells) and a control group (containing cells and culture medium) are simultaneously set;

(3) 10. Mu.L MTT solution (5 mg/ml) was added to each well at 44 hours of drug treatment and incubation was continued for 4 hours (drug treated cells for 48 hours);

(4) The culture medium in the wells was blotted off (if the cells were suspended, the medium was aspirated after centrifugation at 2500 rpm for 5 min). 150 μl of dimethyl sulfoxide was added to each well, and the mixture was shaken until the crystals were sufficiently dissolved. Detecting the absorbance of each well at OD 490 nm on a microplate reader;

(5) Calculating the inhibition rate: inhibition ratio = 1- (dosing OD value-blank OD value)/(control OD value-blank OD value) = (control OD value-dosing OD value)/(control OD value-blank OD value);

(6) Repeating the above experimental steps for three times to obtain average value of three inhibition rates, and using IC ₅₀ IC for calculating medicine by calculator ₅₀ Values.

TABLE 2 anti-cell proliferation Activity of test Compounds

Names of Compounds	PC9	H1975	H2073 (WT)	A431(WT)
					I	1.2	0.8	＞1000	＞1000
Lazertinib	3.6	2.0	＞1000	＞1000
					Erlotinib	20-200	＞1000	＞1000	＞1000
Afatinib	＜20	20-200	20-200	20-200

As shown in table 2, compound I has significant inhibitory activity against PC9 carrying EGFR mutant Del 746-a750 and H1975 carrying double mutant L858R/T790M, while H2073 cells and a431 cells expressing wild-type EGFR have lower inhibitory activity, which suggests that compound I has strong inhibitory activity against tumor cells carrying EGFR mutants, and lower toxic side effects, as well as lazertiinib.

Example 5: test compound pharmacokinetic property detection

Male SD rats were selected for oral (10 mg/kg) or intravenous (2 mg/kg) administration, and after 5min,15min,30min,1h,2 h,4 h,8 h,10 h,24 h administration, blood was continuously taken from the ocular fundus venous plexus and placed in an EP tube containing heparin, centrifuged, and upper plasma was taken for LC-MS/MS analysis, and pharmacokinetic parameters were calculated using WinNonlin software based on the blood concentration-time data obtained from the test, and oral bioavailability was calculated.

The study result shows that the oral bioavailability of lazertiinib in rats is 15% and the half-life is 6.5. 6.5 h; the oral bioavailability of compound I was increased to 45% and the half-life was prolonged to 7.8 h, indicating that the single dose of compound I could be reduced.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, having the structure:

。

2. a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.

3. Use of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 2, for the preparation of an EGFR mutant inhibitor.

4. The use according to claim 3, wherein the EGFR mutant is selected from one or more of Del E746-A750, L858R or T790M.

5. The use according to claim 4, wherein the EGFR mutant is selected from Del E746-A750/T790M double mutant or L858R/T790M double mutant.

6. Use of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 2, for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.

7. The use according to claim 6, wherein the cancer is lung cancer.

8. The use according to claim 7, wherein the lung cancer is non-small cell lung cancer.

9. The use of claim 6, wherein the cancer is a cancer associated with an EGFR mutant.

10. The use of claim 9, wherein the cancer associated with an EGFR mutant is lung cancer associated with an EGFR mutant.