An indolylpyrimidine compound, intermediates thereof, a preparation method and application thereof

Abstract

The application discloses an indole-linked pyrimidine compound, an intermediate thereof, a preparation method and application thereof. The application provides an indole-linked pyrimidine compound shown as formula I or a pharmaceutically acceptable salt thereof, which has a good inhibiting effect on EGFR Del19 / T790M / C797S mutation, and is expected to treat and / or prevent various diseases mediated by EGFR.

Description

Technical Field

[0001] This invention relates to an indolepyrimidine compound, its intermediate, its preparation method, and its application. Background Technology

[0002] Cancer is one of the most significant threats to human health, and lung cancer is one of the most serious malignant tumors threatening people's health and lives. Lung cancer is mainly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with approximately 80% being NSCLC. The most common mutation in NSCLC, and one for which targeted drugs are available, is the epidermal growth factor receptor (EGFR) mutation. Therefore, the use of EGFR inhibitors—EGFR-TKIs—is a major research focus in lung cancer treatment. EGFR (Epidermal Growth Factor Receptor) is the receptor for epidermal growth factor (EGF) cell proliferation and signal transduction. Studies have shown that EGFR is highly expressed or abnormally expressed in many solid tumors. EGFR is associated with the inhibition of tumor cell proliferation, angiogenesis, tumor invasion, metastasis, and apoptosis.

[0003] Currently, marketed EGFR inhibitors are classified into first, second, and third generations. First-generation inhibitors are reversible targeted drugs, such as gefitinib, erlotinib, and icotinib. Second-generation inhibitors are irreversible targeted drugs, such as afatinib and dacomitinib. While first- and second-generation targeted drugs are highly effective, most patients develop resistance after 1-2 years of use. Among patients with EGFR inhibitor resistance, 50% of resistance is related to the T790M mutation. The third-generation EGFR targeted drug osimertinib binds to the T790M mutation site, a sensitive EGFR mutation, inhibiting tumor resistance caused by the T790M mutation. Its advent has brought better survival benefits to more lung cancer patients. However, third-generation targeted drugs inevitably develop resistance, the cause of which is the C797S mutation. The C797S mutation manifests as a cysteine ​​residue mutation to a serine residue. This mutation disrupts the binding of the EGFR protein to third-generation targeted drugs, thus failing to prevent unilateral phosphorylation of EGFR and activation of downstream signaling pathways. Currently, there are no mature treatment options for the two triple mutations that are prone to occur after osimertinib resistance: del19 / T790M / C797S and L858R / T790M / C797S.

[0004] Therefore, overcoming osimertinib resistance to C797S mutations and providing patients with safer and more effective EGFR inhibitors is of great research significance. Summary of the Invention

[0005] The technical problem this invention aims to solve is to overcome the shortcomings of existing EGFR inhibitors, such as their simple structure and poor inhibitory effect on the C797S mutation. This invention provides an indolepyrimidine compound, its intermediate, a preparation method, and its applications. The compound of this invention has a novel structure and exhibits good inhibitory activity against the EGFR Del19 / T790M / C797S mutation, showing promise for the treatment and / or prevention of various EGFR-mediated diseases.

[0006] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0007] This invention provides an indolepyrimidine compound as shown in Formula I, or a pharmaceutically acceptable salt thereof.

[0008]

[0009] Among them, R 1a and R 1b Each independently is H or C 1-4 alkyl;

[0010] R 2a and R 2b Each independently is C 1-4 Alkyl, with one or more R 1-a Replacement C 1-4 Alkyl group; when there are multiple substituents, they may be the same or different;

[0011] R 1-a Independently halogen, -O-(C 1-4 Alkyl), -N(R) a1 (R) a2 ) or -C(=O)-(C 1-4 alkyl);

[0012] R a1 and R a2 Each independently is H or C 1-4 alkyl;

[0013] R 3a and R 3b Each independently is -N(R) b1 (R) b2 );

[0014] R b1 and R b2 Each independently represents H and C. 1-4 Alkyl, -C 1-4 Alkylene-N(R) c1 (R) c2 ) or -C(=O)-R c3 ;

[0015] Rc1 R c2 and R c3 Each independently represents H and C. 1-4 Alkyl groups, C substituted with one or more halogens 1-4 Alkyl, C 2-4 Alkenyl groups or C groups substituted with one or more halogens 2-4 alkenyl;

[0016] R 4a and R 4b Each independently is H or C 1-4 alkyl.

[0017] In certain preferred embodiments of the present invention, certain groups in the indole-pyrimidine compounds represented by Formula I are defined as follows (groups not mentioned are as described in any embodiment of this application, hereinafter referred to as "in a certain embodiment").

[0018] When R 1a and R 1b Each independently is C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl or ethyl.

[0019] In a certain scheme, when R 2a and R 2b Each independently is C 1-4 Alkyl, with one or more R 1-a Replacement C 1-4 When alkyl, the C 1-4 Alkyl and one or more R 1-a Replacement C 1-4 C in alkyl 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl or ethyl.

[0020] In a certain scheme, when R 1-a When there are multiple, the number is 2, 3, 4 or 5; for example, 2 or 3.

[0021] In a certain scheme, when R 1-a When it is a halogen on its own, the halogen is fluorine, chlorine, bromine or iodine on its own; preferably fluorine or chlorine.

[0022] In a certain scheme, when R 1-a Independently for -O-(C 1-4 Alkyl) or -C(=O)-(C 1-4 When alkyl), the -O-(C) 1-4 Alkyl) and -C(=O)-(C 1-4C in alkyl) 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl or ethyl.

[0023] In a certain scheme, when R a1 and R a2 Each independently is C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl or ethyl.

[0024] In a certain scheme, when R b1 and R b2 Each independently is C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl or ethyl.

[0025] In a certain scheme, when R b1 and R b2 Each independently is -C 1-4 Alkylene-N(R) c1 (R) c2 When ), the C 1-4 The alkylene group is -CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH3)CH2- or -C(CH3)2-, for example -CH2- or -CH2CH2-.

[0026] In a certain scheme, when R c1 R c2 R c3 R 4a and R 4b Each independently is C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl or ethyl.

[0027] In a certain scheme, when R c1 R c2 and R c3 Each is an independent C substituted with one or more halogens. 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, such as methyl or ethyl.

[0028] In a certain scheme, when R c1 R c2 and R c3Each independently is C 2-4 Alkenyl groups or C groups substituted with one or more halogens 2-4 When alkenyl, the C 2-4 Alkenyl groups and C groups substituted with one or more halogens 2-4 C in alkenyl 2-4 The alkenyl group can be vinyl, propenyl, or allyl, such as vinyl.

[0029] In a certain scheme, when R 2a and R 2b Each independently of one or more R 1-a Replacement C 1-4 Alkyl, R 1-a When it is halogen, the R 1-a Replacement C 1-4 The alkyl group is trifluoromethyl or -CH2CF3.

[0030] In a certain scheme, when R c1 R c2 and R c3 Each is an independent C substituted with one or more halogens. 1-4 When alkyl, the halogen-substituted C 1-4 The alkyl group is -CH2CH2Cl or -CH2CF3.

[0031] In one particular scheme, R b1 and R b2 Each is independently selected from H, methyl,

[0032] In one particular scheme, R b1 and R b2 One of them is C 1-4 Alkyl, the other is -C 1-4 Alkylene-N(R) c1 (R) c2 ).

[0033] In one particular scheme, R b1 and R b2 One is H, the other is H or -C(=O)-R c3 .

[0034] In one scheme, -N(R) b1 (R) b2 Independently selected from NH2,

[0035] In one particular scheme, R 3a and R 3b One of them is The other is NH2,

[0036] In one embodiment, the indole-pyrimidine compound represented by Formula I may be one of the following compounds.

[0037]

[0038] In one embodiment, the pharmaceutically acceptable salt of the indole-pyrimidine compound represented by Formula I may be the following compound.

[0039]

[0040] In this invention, the indolepyrimidine compounds of Formula I or their pharmaceutically acceptable salts can be synthesized by methods similar to those known in the chemical field, with steps and conditions referencing those of similar reactions in the art, particularly those described herein. Starting materials are typically derived from commercial sources, such as Aldrich, or can be readily prepared using methods known to those skilled in the art (obtained through online databases such as SciFinder and Reaxys).

[0041] In this invention, the indole-pyrimidine compounds of Formula I or their pharmaceutically acceptable salts can also be obtained by peripheral modification of the prepared indole-pyrimidine compounds of Formula I or their pharmaceutically acceptable salts using conventional methods in the art.

[0042] The necessary starting materials or reagents for preparing indolepyrimidine compounds of Formula I or their pharmaceutically acceptable salts are commercially available or prepared by synthetic methods known in the art. The methods described in the Experimental Section below can be used to prepare the compounds of the present invention as free bases or their salts by acid addition. The term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein and possesses all the functions of the parent compound.

[0043] The present invention also provides a method for preparing the indolepyrimidine compound as shown in Formula I or a pharmaceutically acceptable salt thereof, which may be carried out via the following route:

[0044] Route 1

[0045] When R 3b When -NH2 is present, the indole-pyrimidine compounds corresponding to Formula I are shown in Formula I-1, which can be prepared by the following method:

[0046]

[0047] Among them, R 1a R 1b R 2a R2b R 3a R 4a and R 4b The definition is as shown in any of the above schemes; X is a leaving group, such as a halogen, or Cl;

[0048] Step 1: In a solvent, in the presence of a base, mix the compound shown in Formula II-1 with the compound shown in Formula (R) 4a H)NCH2CH2N(HR 4b The compound shown in formula II-2 can be subjected to the addition reaction shown in the formula to obtain the compound shown in formula II-2.

[0049] The operation and conditions of the addition reaction and its post-treatment can be conventional operations and conditions for this type of reaction in the art; for example, the base can be an organic base, such as triethylamine, N,N-diisopropylethylamine or N,N'-dimethylethylenediamine, or triethylamine; the solvent can be tetrahydrofuran, and the reaction can be performed by heating the system to reflux; the compound shown in formula II-1 and the compound shown in formula (R) 4a H)NCH2CH2N(HR 4b The molar ratio of the compound shown in Formula II-1 to the base can be 1:5; the molar ratio of the compound shown in Formula II-1 to the base can be 1:2; the mass-volume ratio of the compound shown in Formula II-1 to the solvent can be from 0.1 kg / L to 0.2 kg / L, for example 0.1 kg / L;

[0050] Step 2: In a solvent and in the presence of a base, the compound shown in Formula II-2 and the compound shown in Formula II-3 or their salts are subjected to the substitution reaction shown to obtain the compound shown in Formula II-4.

[0051] The operation and conditions of the substitution reaction and its post-treatment can be conventional operations and conditions for this type of reaction in the art; for example, the base can be an inorganic base, such as potassium carbonate; the solvent can be DMF or DMSO (e.g., DMF); the reaction temperature can be 30°C to 80°C (e.g., 65°C); the salt of the compound shown in Formula II-3 can be its p-toluenesulfonate; the molar ratio of the compound shown in Formula II-2 and the compound shown in Formula II-3 or their salts can be 0.9:1 to 1:0.9, for example, 1:0.95; the molar ratio of the compound shown in Formula II-2 to the base can be 1:3; the mass-volume ratio of the compound shown in Formula II-2 to the solvent can be 0.1 kg / L to 0.2 kg / L, for example, 0.144 kg / L;

[0052] Step 3: In a solvent, in the presence of a reducing agent, the compound shown in Formula II-4 is subjected to the nitro reduction reaction shown. Optionally, acid is added to promote the reduction reaction to obtain the compound shown in Formula I-1.

[0053] The nitro reduction reaction and its post-treatment operations and conditions can be conventional operations and conditions for this type of reaction in the art; for example, the reducing agent can be sodium hydrosulfite, iron powder, zinc powder, or H2, such as sodium hydrosulfite, wherein the H2 reduction of the compound represented by formula II-4 is carried out in the presence of a catalyst such as Pd / C or Pd(OH)2 / C; the solvent can be tetrahydrofuran and water or ethanol and water (e.g., tetrahydrofuran and water), and the reaction temperature can be 25°C to 50°C (e.g., 35-45°C); the molar ratio of the compound represented by formula II-4 to the reducing agent can be 1:6; the acid can be concentrated hydrochloric acid; the molar ratio of the compound represented by formula II-4 to the acid can be 1:44; the mass-volume ratio of the compound represented by formula II-4 to the solvent can be 0.05 kg / L to 0.1 kg / L, for example, 0.05 kg / L;

[0054] Route 2

[0055] When R 3b -NH-C(=O)-R c3 At that time, the indole-pyrimidine compounds represented by Formula I are as shown in Formula I-2, and can be prepared by the following method:

[0056]

[0057] Among them, R 1a R 1b R 2a R 2b R 3a R c3 R 4a and R 4b The definition is shown in any of the above schemes;

[0058] In a solvent, in the presence of a base, the compound shown in Formula I-1 and the compound of Formula Cl-C(=O)-R are... c3 The compound shown can be subjected to the substitution reaction shown to obtain the compound shown in Formula I-2;

[0059] The substitution reaction and its post-treatment operations and conditions can be conventional operations and conditions for this type of reaction in the art; for example, the base can be an organic base, such as triethylamine or N,N-diisopropylethylamine, or triethylamine for example; the solvent can be dichloromethane or tetrahydrofuran (e.g., dichloromethane); the reaction temperature can be -50°C to 10°C (e.g., -40°C); the compound shown as formula I-1 and the compound shown as Cl-C(=O)-R c3The molar ratio of the compounds shown can be 1:1.5; the molar ratio of the compound shown in Formula I-1 to the base can be 1:2; the mass-volume ratio of the compound shown in Formula I-1 to the solvent can be from 0.05 kg / L to 0.15 kg / L, for example 0.1 kg / L;

[0060] Route 3

[0061] When R 3b When the form is -NH-C(=O)-CH=CH2, the corresponding indole-pyrimidine compounds shown in Formula I are as shown in Formula I-2b, which can be prepared by the following method:

[0062]

[0063] Among them, R 1a R 1b R 2a R 2b R 3a R 4a and R 4b The definition is shown in any of the above schemes;

[0064] In a solvent, in the presence of a base, the compound shown in formula I-2a is subjected to the elimination reaction shown to obtain the compound shown in formula I-2b.

[0065] The elimination reaction and its post-treatment operations and conditions can be conventional operations and conditions for this type of reaction in the art; for example, the base can be an organic base, such as triethylamine or N,N-diisopropylethylamine, or triethylamine for example; the solvent can be acetonitrile or DMSO (e.g., acetonitrile); the reaction temperature can be 50°C to 100°C (e.g., 80°C); the molar ratio of the compound of formula I-2a to the base can be 1:5; the mass-volume ratio of the compound of formula I-2a to the solvent can be 0.05 kg / L to 0.15 kg / L, for example, 0.1 kg / L.

[0066] The present invention also provides a compound as shown below.

[0067]

[0068] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of substance A and a pharmaceutical excipient (or a pharmaceutically acceptable carrier); wherein substance A is an indolepyrimidine compound as shown in Formula I above, or a pharmaceutically acceptable salt thereof.

[0069] This invention also provides the use of substance A in the preparation of EGFR inhibitors, wherein substance A is an indolepyrimidine compound as shown in Formula I or a pharmaceutically acceptable salt thereof, wherein the EGFR includes the EGFR Del19 / T790M / C797S mutation. In the described application, the EGFR inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the effect of EGFR inhibition.

[0070] This invention also provides the use of substance A in the preparation of a drug for treating and / or preventing diseases mediated by EGFR (activating or resistant mutants); wherein substance A is an indolepyrimidine compound as shown in Formula I above, or a pharmaceutically acceptable salt thereof; wherein substance A is a therapeutically effective amount.

[0071] The present invention also provides the use of substance A in the preparation of a medicament for the treatment and / or prevention of cancer; wherein substance A is an indolepyrimidine compound as shown in Formula I or a pharmaceutically acceptable salt thereof; wherein substance A is a therapeutically effective amount.

[0072] The present invention also provides a method for inhibiting EGFR (activating or resistant mutants), comprising administering to a patient a therapeutically effective amount of substance A; said substance A is an indolepyrimidine compound as shown in Formula I above, or a pharmaceutically acceptable salt thereof.

[0073] The present invention also provides a method for treating and / or preventing diseases mediated by EGFR (activating or resistant mutants), comprising administering to a patient a therapeutically effective amount of substance A; said substance A is an indolepyrimidine compound as shown in Formula I above, or a pharmaceutically acceptable salt thereof.

[0074] The present invention also provides a method for treating and / or preventing cancer, comprising administering to a patient a therapeutically effective amount of substance A; said substance A is an indolepyrimidine compound as shown in Formula I above, or a pharmaceutically acceptable salt thereof.

[0075] As mentioned above, EGFR-mediated diseases can be diseases resistant to first-, second-, and third-generation EGFR inhibitors, which can be selected from gefitinib, erlotinib, icotinib, afatinib, dacomitinib, and osimertinib.

[0076] As mentioned above, EGFR-mediated diseases can be diseases mediated by EGFR Del19 / T790M / C797S mutations.

[0077] As mentioned above, EGFR-mediated diseases can be cancerous.

[0078] The cancers mentioned above can be selected from one or more of the following: colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, esophageal cancer, stomach cancer, pancreatic cancer, thyroid cancer, bladder cancer, lymphoma, glioma, glioblastoma, gastrointestinal stromal tumor, bile duct cancer, endometrial cancer, multiple myeloma, leukemia, and melanoma.

[0079] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0080] The term "multiple" refers to 2, 3, 4, or 5.

[0081] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. Pharmaceutically acceptable acids include inorganic acids and organic acids (e.g., methanesulfonic acid). For details, please refer to Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0082] As used herein, compounds of Formula I may contain one or more chiral centers and exist in different optically active forms. When a compound contains one chiral center, the compound comprises enantiomers. This invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of Formula I contains more than one chiral center, diastereomers may be present. This invention includes resolved optically pure specific isomers and mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography. The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers primarily include cis-trans isomers and optical isomers. The compounds described in this invention can exist in stereoisomers, and therefore encompass all possible stereoisomer forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, and trans-isomers. The compounds can also exist in any combination or mixture of the aforementioned stereoisomers, such as a meso compound, a racemic mixture, or an equal mixture of trans-isomers. Examples include a single enantiomer, a single diastereomer or a mixture of more than one, or a single trans-isomer or a mixture thereof. When the compounds of this invention contain an olefin double bond, unless otherwise specified, they include cis and trans isomers, and any combination thereof. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound is not less than 95% relative to all stereoisomers of the compound. Compounds of Formula I have optical isomers derived from asymmetric carbons, axial asymmetry, etc., and if necessary, the single isomer can be obtained by methods known in the art, such as crystallization or chromatography (e.g., chiral chromatography).

[0083] As previously stated, the present invention provides compounds with the structures shown above, or their cis-trans isomers, meso compounds, racemic compounds, enantiomers, diastereomers, septate isomers, or mixtures thereof, wherein “mixtures thereof” includes any form of mixing between any of the aforementioned stereoisomers (e.g., cis-trans isomers, enantiomers, diastereomers, septate isomers) and / or mixtures (meso compounds, racemic compounds), such as mixtures of cis-trans isomers, mixtures of enantiomers and diastereomers, mixtures of diastereomers, mixtures of septate isomers, or mixtures of cis-trans isomers and racemic compounds, mixtures of enantiomers and diastereomers, mixtures of septate isomers and diastereomers, etc.

[0084] The indole-pyrimidine compounds of Formula I of this invention, or pharmaceutically acceptable salts thereof, may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium (D), tritium (… 3 H), Iodine-125 125 I) or C-14 14 C). All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0085] In this application, "pharmaceutical composition" refers to a formulation comprising the compounds of the present invention and a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0086] In this application, "pharmaceutical acceptable" means a substance (such as a pharmaceutical excipient) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to an individual without causing an adverse biological reaction or interacting with any component contained in the composition in an undesirable manner.

[0087] The term "pharmaceutical excipient" or "pharmaceuticalally acceptable carrier" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products. These are all substances contained in a pharmaceutical preparation, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2015 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition). Excipients primarily serve to provide a safe, stable, and functional pharmaceutical composition. They may also provide methods for dissolving the active ingredient at a desired rate after administration to a subject, or for promoting effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipient may be an inert filler or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion agents, flow aids, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0088] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0089] When used as a pharmaceutical, the indolepyrimidine compounds of Formula I or pharmaceutically acceptable salts thereof can be administered in any form of pharmaceutical composition. These compositions can be prepared according to methods well known in the pharmaceutical field and can be administered via various routes, depending on the need for local or systemic treatment and the area to be treated. Administration can be topical (including epidermal and transdermal, ocular and mucous membrane, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or blowing in powder or aerosol, including via nebulizer; intratracheal or intranasal), oral (solid and liquid formulations), or parenteral. Examples of solid oral formulations include, but are not limited to, powders, capsules, tablets, 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 topically applied formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of parenteral administration formulations include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Topical pharmaceutical compositions and formulations may include transdermal patches, ointments, emulsions, creams, gels, drops, suppositories, sprays, liquids, and powders. Other suitable formulations of the pharmaceutical compositions include, but are not limited to, eye drops and other ophthalmic preparations; aerosols, such as nasal sprays or inhalers. Oral administration may include dosage forms formulated for once-daily or twice-daily (BID) dosing. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, injection, or infusion; or intracranial administration such as intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose or may be via a continuous infusion pump. Conventional pharmaceutical carriers, water, powder or oily bases, thickeners, etc., may be necessary or required. Pharmaceutical compositions including those of the present invention may also be controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres).

[0090] The term “treatment” refers to a therapeutic approach or a remission measure. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment; or (4) slowing the progression of the disease or one or more biological manifestations of the condition. “Treatment” can also mean prolonging survival compared to expected survival without treatment.

[0091] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0092] The term "therapeutic effective amount" refers to an amount of compound sufficient to effectively treat the disease or condition described herein when administered to a patient. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but may be adjusted as needed by those skilled in the art.

[0093] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has already received administration of the compound or composition according to embodiments of the invention, with humans being the most preferred. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0094] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this invention, chemical elements are consistent with the CAS edition of the periodic table and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0095] In this specification, groups and their substituents may be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left.

[0096] Certain chemical groups defined in this document are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-C4 alkyl or C 1-4 Alkyl refers to an alkyl group having a total of 1, 2, 3, or 4 carbon atoms as defined below. The total number of carbon atoms in the simplified symbol does not include carbons that may be present in substituents of the group.

[0097] In this paper, the numerical ranges defined in the substituents, such as 0 to 4, 1-4, 1 to 3, etc., indicate the integers within that range, such as 1-6 being 1, 2, 3, 4, 5, 6.

[0098] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0099] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent, provided that the valence state of the particular atom is normal and the substituted compound is stable.

[0100] Generally, the term "substituted" indicates that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise indicated, a substituent can be substituted at each substituted position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.

[0101] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, this invention includes every independent secondary combination of the respective members of these group types and scopes. The term "C" x -C y Alkyl or C x-y "Alkyl" refers to a straight-chain or branched saturated hydrocarbon containing x to y carbon atoms. For example, the terms "C1-C6 alkyl" or "C 1-6 "alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl; "C" 1-4 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl (i.e. propyl, including n-propyl and isopropyl), and C4 alkyl (i.e. butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

[0102] The terms “part,” “structural part,” “chemical part,” “group,” and “chemical group” used in this article refer to specific segments or functional groups within a molecule. A chemical part is generally considered to be a chemical entity embedded in or attached to a molecule.

[0103] When the listed substituents do not specify which atom they are attached to in the general chemical formula (including but not specifically mentioned compounds), such substituents may be bonded to any of their atoms. Combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0104] When any variable (e.g., R) 1-a When a variable appears multiple times in the definition of a compound, the definition at each position is independent of the definitions at the other positions; their meanings are independent and do not affect each other. Therefore, if a group is surrounded by one, two, or three R... 1-a Group substitution, meaning that the group can be replaced by up to 3 R groups. 1-aReplacement, where a certain position R 1-a Definition and other positions R 1-a The definitions are independent of each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0105] When a listed group does not explicitly indicate that it has a substituent, the group refers only to the unsubstituted group. For example, when "C 1-4 When "alkyl" is not preceded by the qualifier "substituted or unsubstituted", it refers only to "C". 1-4 "alkyl" itself or "unsubstituted C" 1-4 alkyl".

[0106] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", then it should be understood that "alkyl" represents a linked alkylene group.

[0107] In some specific structures, when the alkyl group is clearly indicated as a linking group, then the alkyl group represents a linked alkylene group, for example, the group "halogenated-C". 1-4 C in "alkyl" 1-4 Alkyl should be understood as C 1-4 Alkylene.

[0108] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, especially F or Cl.

[0109] In this application, as a group or part of other groups (e.g., used in haloalkyl, deuteralkyl, etc. groups), the term "alkyl" refers to a saturated aliphatic hydrocarbon group comprising branched and straight chains having a specified number of carbon atoms, consisting only of carbon and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, even more preferably 1 to 4) carbon atoms, and connected to the rest of the molecule by single bonds, wherein propyl is a C3 alkyl group (including isomers, such as n-propyl or isopropyl); butyl is a C4 alkyl group (including isomers, such as n-butyl, sec-butyl, isobutyl, or tert-butyl). Butyl); pentyl is a C5 alkyl group (including isomers, such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, tert-pentyl or neopentyl); hexyl is a C6 alkyl group (including isomers, such as n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, nonyl, and decyl, and their similar alkyl groups.

[0110] In this application, as part of a group or other group, the term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group; that is, one hydrogen atom of the alkyl group is substituted, and the definition of alkyl is as described above. Examples of alkylene groups include methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2- or -C(CH3)2-}, and so on.

[0111] In this application, as part of a group or other group, the term "alkenyl" refers to a straight-chain or branched hydrocarbon chain group having at least one double bond, consisting only of carbon and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms, and connected to the rest of the molecule by single bonds, such as including but not limited to vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, 2-methylbutenyl, 2,2-dimethylpropenyl, n-hexenyl, heptenyl, 2-methylhexenyl, 3-methylhexenyl, octenyl, nonenyl, and decenyl.

[0112] It should be understood that the singular form used in this invention, such as "a," includes plural references unless otherwise specified.

[0113] The terms “one or more” or “one or more kinds” refer to 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0114] Unless otherwise stated, this invention employs traditional methods of mass spectrometry and elemental analysis, and the steps and conditions can be referred to conventional operating procedures and conditions in the field.

[0115] Unless otherwise specified, this invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.

[0116] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently" used in this invention should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...independently" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0117] Those skilled in the art will understand that, according to the conventions used in the art, the structural formulas of the descriptive groups described in this application... and This refers to the fact that the corresponding group R is linked to other fragments or groups in the compound through this site.

[0118] Those skilled in the art will understand that, according to the conventions used in the art, the structural formulas of the descriptive groups described in this application... Indicates a single bond or a double bond.

[0119] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail.

[0120] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0121] The reagents and raw materials used in this invention are all commercially available.

[0122] The positive and progressive effects of this invention are as follows: the indolepyrimidine compound has a good inhibitory effect on the EGFR Del19 / T790M / C797S mutation, and is expected to treat and / or prevent a variety of EGFR-mediated diseases, such as diseases resistant to first, second and third generation EGFR inhibitors, and diseases mediated by the EGFR Del19 / T790M / C797S mutation. Detailed Implementation

[0123] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0124] In this invention, room temperature refers to ambient temperature, which is 10℃-35℃. Overnight refers to 8-15 hours. Reflux refers to the solvent reflux temperature under normal pressure.

[0125] Example 1

[0126]

[0127] Preparation of SM-2

[0128] SM-1 (300 g, 1.0 eq), N,N-dimethylethylenediamine (232 g, 5.0 eq), and triethylamine (107 g, 2.0 eq) were added to a four-necked flask, along with tetrahydrofuran (3 L). The mixture was heated to reflux for 24 hours until the reaction was complete. Heating was then stopped, and the mixture was concentrated under reduced pressure to obtain 346 g of crude product with a purity of 97.7% and a yield of 100%.

[0129] MS m / z: 657.5 [M+H] + ;

[0130] 1H NMR (400MHz, DMSO-d6) δ9.97–9.86(m,1H),8.43(d,J=14.9Hz,2H),8.27(d,J=5.4Hz,2H),8.18(s ,1H),7.51(t,J=7.6Hz,1H),7.25(t,J=7.5Hz,1H),7.16(dd,J=14.7,6.3Hz,2H),4.97(q,J=9.1H z,2H),3.32–3.25(m,2H),3.20(dd,J=13.3,6.1Hz,2H),2.95–2.77(m,5H),2.68(dt,J=13.3,6.9 Hz, 3H), 2.57 (t, J = 6.1Hz, 3H), 2.44 (d, J = 3.3Hz, 6H), 2.29–2.17 (m, 10H), 2.12 (d, J = 6.1Hz, 1H).

[0131] Preparation of SM-4

[0132] SM-2 (346 g, 1.0 eq), SM-3 (325 g, 0.95 eq), and potassium carbonate (218 g, 3.0 eq) were added to a four-necked flask, along with DMF (2.4 L). The mixture was heated to 65 °C and maintained at this temperature for 8 hours. The reaction was monitored until the reactants were completely reacted. Heating was then stopped, and the reaction mixture was added to water (12 L). The mixture was stirred, filtered, and the crude product was obtained. The crude product was dissolved in ethyl acetate (5.3 L), washed with saturated ammonium chloride solution (3.5 L), and the organic phase was concentrated to dryness under reduced pressure to obtain 430 g of orange solid with a purity of 88.7% and a yield of 74.3%.

[0133] MS m / z: 1099.6 [M+H] + ;

[0134] 1 H NMR (400MHz, DMSO-d6) δ9.81(s,1H),8.60(d,J=19.6Hz,2H),8.42(d,J=3.8Hz,2H),8.27( dd,J=11.2,6.1Hz,5H),7.49(dd,J=8.2,4.0Hz,2H),7.27–7.18(m,3H),7.18(s,1H),7.17– 7.03(m,3H),5.00(dq,J=26.8,9.0Hz,5H),3.87(d,J=4.9Hz,6H),3.73(t,J=7.0Hz,2H),3. 22(s,2H),2.87(d,J=16.3Hz,6H),2.74(dt,J=11.6,6.8Hz,4H),2.30(s,3H),2.19(s,4H).

[0135] Preparation of Compound 1

[0136] Add SM-4 (430 g, 1.0 eq) to a four-necked flask, add tetrahydrofuran (5.7 L) and water (2.9 L), start stirring, add sodium hydrosulfite (511 g, 6.0 eq) in batches, heat to 35-45℃, keep the reaction at this temperature for 3 hours, monitor the reaction of the starting materials until complete, add concentrated hydrochloric acid (1430 ml, 44.0 eq), keep the reaction at 45℃ overnight, monitor the liquid phase until the intermediate state is completely converted to the product, stop heating, add sodium hydroxide solution to neutralize the system, and adjust the pH to 7-8 with saturated sodium bicarbonate solution, add ethyl acetate (4.3 L) for extraction, concentrate the organic phase under reduced pressure to dryness, and give 419 g of yellow solid (yield 100%), liquid phase purity 80.52%.

[0137] MS m / z: 1070.5 [M+H] + ;

[0138] 1 H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.44(s,1H),8.37–8.21(m,5H),7.49(d, J=8.1Hz,2H),7.27–7.08(m,6H),4.97(q,J=9.1Hz,2H),4.85(q,J=9.2Hz,2H), 3.87(d,J=5.8Hz,6H),3.11(t,J=6.6Hz,2H),2.93(s,5H),2.84(s,3H),2.75( d, J=19.3Hz, 6H), 2.62 (s, 3H), 2.35 (d, J=18.8Hz, 6H), 1.15 (t, J=7.3Hz, 13H).

[0139] Example 2

[0140]

[0141] Preparation of compound 2

[0142] Compound 1 (419 g, 1.0 eq) was added to a four-necked flask, followed by dichloromethane (4.2 L) and triethylamine (80 g, 2.0 eq). The mixture was cooled to -40 °C, and a solution of 3-chloropropionyl chloride (75 g, 1.5 eq) in dichloromethane (2 L) was slowly added dropwise. The reaction was monitored until the reactants were completely reacted. A saturated sodium bicarbonate solution (4 L) was added, and the mixture was stirred and allowed to stand to separate into layers. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (1 L). The organic phases were combined and concentrated under reduced pressure to dryness to obtain 453 g of a brown oily substance.

[0143] MS m / z: 1159.4 [M+H] + .

[0144] Example 3

[0145]

[0146] Preparation of compound 3

[0147] Compound 2 (453 g, 1.0 eq) was added to a four-necked flask, followed by acetonitrile (4.5 L) and triethylamine (198 g, 5.0 eq). The mixture was heated to 80 °C and monitored until the reaction was complete. The mixture was then cooled, filtered, and the crude product was dried. Column chromatography was performed to obtain 133 g of sample. Acetonitrile (1.3 L) and isopropyl ether (1.3 L) were added to the column-passed product, and the mixture was stirred at 70 °C. The mixture was then cooled, filtered, and dried to obtain 110 g of pure product with a purity of 98.5%.

[0148] MS m / z: 1123.6 [M+H] + ;

[0149] 1 H NMR (400MHz, DMSO-d6) δ9.83(s,1H),9.66(s,1H),8.61(s,1H),8.42(d,J=5.2Hz,2H),8.25(dq,J=11.7,5. 2Hz,4H),8.08(d,J=3.3Hz,2H),7.49(d,J=8.1Hz,2H),7.26–7.09(m,7H),6.23(dd,J=17.1,2.1Hz,1H),5.7 1(dd,J=10.0,2.1Hz,1H),4.97(qd,J=9.0,3.6Hz,5H),3.87(d,J=2.1Hz,6H),3.28–3.16(m,5H),2.85(d,J= 11.3Hz, 7H), 2.74 (t, J = 7.1Hz, 2H), 2.61 (t, J = 7.0Hz, 2H), 2.43 (t, J = 6.7Hz, 2H), 2.26 (s, 3H), 2.19 (s, 6H).

[0150] Example 4

[0151]

[0152] Preparation of compound 4

[0153] Compound 3 (43.57 g, 1.0 eq) was added to a four-necked flask, followed by dichloromethane (436 mL). The mixture was stirred at room temperature, and a solution of methanesulfonic acid (3.54 g, 0.99 eq) in dichloromethane (174 mL) was slowly added dropwise. The reaction solution was concentrated to dryness under reduced pressure, and the resulting solid was added to ethyl acetate (871 mL). The mixture was then slurried at 60-65 °C, cooled, and filtered to obtain a wet product. This wet product was then dried under vacuum at 35-40 °C to obtain 39 g of a yellow solid powder with a purity of 98.7%.

[0154] MS m / z: 1123.5 [M+H] + ;

[0155] 1 H NMR(400MHz, DMSO-d6)δ9.73(br,2H),8.52(s,1H),8.47(s,1H),8.39(d,J=8.8Hz,2H),8.29-8.26(m,4 H),8.16(br,1H),8.13(br,1H),7.49(d,J=8.1Hz,2H),7.25–7.13(m,6H),6.57(dd,J=16.8,10.3Hz,1H) ,6.28(d,J=10.7,17.0Hz,1H),5.75(d,J=10.7,17.0Hz,1H),4.99(q,J=8.9Hz,4H),3.86(s,6H),3.56( s,2H),3.40(br,1H),3.16(br,2H),2.98(br,7H),2.85(S,3H),2.83(S,3H),2.74(br,9H),2.42(s,3H).

[0156] Test Example 1: Inhibitory activity against the proliferation of Ba / F3 EGFR-Del19 / T790M / C797S cells

[0157] The inhibitory activity of the compound on the proliferation of mouse original B cells Ba / F3 EGFR-Del19 / T790M / C797S cells stably expressing EGFR protein and possessing the Del19 / T790M / C797S triple mutation was determined in vitro using the PrestoBlue method.

[0158] Cell source: Ba / F3 EGFR-Del19 / T790M / C797S cells were purchased from Crown Bioscience (Beijing) Co., Ltd.

[0159] Ba / F3 EGFR-Del19 / T790M / C797S cells were cultured in RPMI 1640 complete medium containing 10% fetal bovine serum. Ba / F3 EGFR-Del19 / T790M / C797S cells in logarithmic growth phase were seeded at a density of 5000 cells / 135 μl of complete medium / well in 96-well plates and incubated at 37°C with 5% CO2 for 24 hours. Each compound was pre-dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mM stock solution, which was then diluted sequentially with DMSO and complete medium. Remove the 96-well plate inoculated with cells and add 15 μl of different concentrations of compound to each well to achieve final concentrations of 2500, 625, 156.25, 39.06, 9.77, 2.44, 0.61, 0.15, 0.04, and 0.01 nM. Each compound concentration was used in triplicate. A negative control group (containing cell culture medium) and a blank control group (containing no cell culture medium) were also included. The concentration of DMSO in each well was 0.5%. The plates were then incubated at 37°C in a 5% CO2 incubator for 72 hours.

[0160] Remove the 96-well cell culture plate from the CO2 incubator and add Invitrogen to each well. TM PrestoBlue TM 15 μl of HS cell viability assay reagent (catalog number: P50201) was incubated at 37°C in a constant temperature incubator containing 5% CO2 for 3 hours. The 96-well cell culture plate was then removed, and fluorescence was measured at 560 nm excitation and 590 nm emission wavelengths using a microplate reader. The cell inhibition rate of each compound concentration was calculated using the following formula.

[0161] Cell inhibition rate = [(RFU) 72小时阴性对照组 -RFU 给药72小时化合物组 ) / (RFU 72小时阴性对照组 -RFU 72小时空白对照组 )]×100% (RFU is relative fluorescence intensity).

[0162] Data was analyzed using GraphPad Prism 8.3 software. A nonlinear S-curve regression was used to fit the data to derive the dose-response curve, from which the IC was calculated. 50 The values ​​are shown in Table 1.

[0163] Table 1

[0164]

[0165] Test results show that the compound of the present invention has good inhibitory activity against the proliferation of Ba / F3 EGFR-Del19 / T790M / C797S cells.

Claims

1. An indolopyrimidine compound as shown in formula I or a pharmaceutically acceptable salt thereof, characterized in that, ， wherein R 1a and R 1b are each independently H or C 1-4 alkyl; R 2a and R 2b each independently is ethyl substituted by one or more R 1-a substituents. R 1-a independently F; R 3a and one of R 3b is , the other is NH2or ; R 4a and R 4b each independently H or C 1-4 alkyl.

2. The indole-pyrimidine compound of formula I as described in claim 1, characterized in that, the indolopyrimidine compound as shown in formula I or a pharmaceutically acceptable salt thereof meets one or more of the following conditions: (1) when R 1a and R 1b are each independently C 1-4 alkyl, said C 1-4 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl; (2) when R 1-a is multiple, the number thereof is 2, 3, 4 or 5; (3) when R 4a and R 4b are each independently C 1-4 alkyl, said C 1-4 alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl; (4) R 2a and R 2b each independently -CH2CF3.

3. The indole-pyrimidine compound of formula I as described in claim 1, characterized in that, the indolopyrimidine compound as shown in formula I or a pharmaceutically acceptable salt thereof meets one or more of the following conditions: (1) when R 1a and R 1b are each independently C 1-4 alkyl, said C 1-4 alkyl is methyl or ethyl; (2) when R 1-a is multiple, the number thereof is 2 or 3; (3) when R 4a and R 4b are each independently C 1-4 alkyl, said C 1-4 alkyl is methyl or ethyl.

4. The indoloimidazole compound of Formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein the indolopyrimidine compound as shown in formula I is a compound, or ; or the pharmaceutically acceptable salt of the indolopyrimidine compound as shown in formula I is a compound, 。 5. A method for preparing an indolepyrimidine compound of formula I as described in any one of claims 1-4, characterized in that, which is a route as follows: Route one when R 3b is -NH2, the corresponding indolo-pyrimidine compound of formula I is shown as formula I-1, which is prepared by the following method: ， wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 4a and R 4b are as defined in any one of claims 1 to 4; X is a leaving group; Route two when R 3b is -NH-C(=0)-CH=CH2, the corresponding indolopyrimidine of formula I is shown as formula I-2b, which is prepared by the following method: ， wherein R 1a , R 1b , R 2a , R 2b , R 3a , R 4a and R 4b are as defined in any one of claims 1 to 4.

6. A preparation method of the indolopyrimidine compound as shown in formula I or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that, in the route one: Step 1: addition reaction of a compound as shown in Formula II-1 and a compound as shown in Formula (R 4a H)NCH2CH2N(HR 4b ) in a solvent in the presence of a base to obtain a compound as shown in Formula II-2; Step 2: a substitution reaction of a compound as shown in formula II-2 and a compound as shown in formula II-3 or a salt thereof is carried out in a solvent in the presence of a base to obtain a compound as shown in formula II-4; Step 3: a nitro reduction reaction of the compound as shown in formula II-4 is carried out in a solvent in the presence of a reducing agent, and the reduction reaction is optionally promoted by adding an acid to complete the reaction to obtain a compound as shown in formula I-1; in the route two: a compound as shown in formula I-2a is subjected to an elimination reaction in a solvent in the presence of a base to obtain a compound as shown in formula I-2b.

7. A preparation method of the indolopyrimidine compound as shown in formula I or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that, one or more of the following conditions are met in the route one: (1) X is halogen; (2) in step 1, the base is an organic base; (3) in step 1, the solvent is tetrahydrofuran; (4) in step 1, the reaction is heated to reflux the system; (5) In Step 1, the molar ratio of the compound of Formula II-1 and the compound of Formula (R 4a H)NCH2CH2N(HR 4b ) is 1:

5. (6) in step 1, the molar ratio of the compound as shown in formula II-1 to the base is 1:2; (7) in step 1, the mass-volume ratio of the compound as shown in formula II-1 to the solvent is 0.1 Kg / L to 0.2 Kg / L; (8) in step 2, the base is an inorganic base; (9) in step 2, the solvent is DMF or DMSO; (10) in step 2, the reaction temperature is 30°C to 80°C; (11) in step 2, the salt of the compound as shown in formula II-3 is its p-toluenesulfonic acid salt; (12) in step 2, the molar ratio of the compound as shown in formula II-2 to the compound as shown in formula II-3 or a salt thereof is 0.9:1 to 1:0.9; (13) in step 2, the molar ratio of the compound as shown in formula II-2 to the base is 1:3; (14) in step 2, the mass-volume ratio of the compound as shown in formula II-2 to the solvent is 0.1 Kg / L to 0.2 Kg / L; (15) in step 3, the reducing agent is sodium dithionite, iron powder, zinc powder or H2, wherein the reduction of the compound as shown in formula II-4 by H2 is carried out in the presence of a catalyst; (16) in step 3, the solvent is tetrahydrofuran and water or ethanol and water; (17) In step 3, the temperature of the reaction is 25-50 °C; (18) In step 3, the molar ratio of the compound of formula II-4 to the reducing agent is 1:6; (19) In step 3, the mass-volume ratio of the compound of formula II-4 to the solvent is 0.05-0.1 Kg / L; (20) In step 3, the acid is concentrated hydrochloric acid; (21) In step 3, the molar ratio of the compound of formula II-4 to the acid is 1:44; In Route II, one or more of the following conditions is met: (1) The base is an organic base; (2) The solvent is acetonitrile or DMSO; (3) The temperature of the reaction is 50-100 °C; (4) The molar ratio of the compound of formula I-2a to the base is 1:5; (5) The mass-volume ratio of the compound of formula I-2a to the solvent is 0.05-0.15 Kg / L.

8. A method for preparing an indolopyrimidine compound of formula I or a pharmaceutically acceptable salt thereof according to claim 7, wherein, In Route I, one or more of the following conditions is met: (1) X is Cl; (2) In step 1, the base is triethylamine, N,N-diisopropylethylamine or N,N'-dimethylethylenediamine; (3) In step 1, the mass-volume ratio of the compound of formula II-1 to the solvent is 0.1 Kg / L; (4) In step 2, the base is potassium carbonate; (5) In step 2, the temperature of the reaction is 65 °C; (6) In step 2, the molar ratio of the compound of formula II-2 to the compound of formula II-3 or a salt thereof is 1:0.95; (7) In step 2, the mass-volume ratio of the compound of formula II-2 to the solvent is 0.144 Kg / L; (8) In step 3, the reducing agent is sodium dithionite, iron powder, zinc powder or H2, wherein the reduction of the compound of formula II-4 by H2 is carried out in the presence of Pd / C or Pd(OH)2 / C; (9) In step 3, the temperature of the reaction is 35-45 °C; (10) In step 3, the mass-volume ratio of the compound of formula II-4 to the solvent is 0.05 Kg / L; In Route II, one or more of the following conditions is met: (1) The base is triethylamine or N,N-diisopropylethylamine; (2) The temperature of the reaction is 80 °C; (3) The mass-volume ratio of the compound of formula I-2a to the solvent is 0.1 Kg / L.

9. A compound of formula I, or .

10. A pharmaceutical composition, characterized by, which comprises a therapeutically effective amount of substance A and pharmaceutically acceptable adjuvants; the substance A is an indolopyrimidine compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-4.

11. Use of a substance A for the preparation of an inhibitor of EGFR Del19 / T790M / C797S mutations, characterized in that, The substance A is an indolopyrimidine compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-4.

12. Use of a substance A for the manufacture of a medicament, characterized in that The medicament is used for treating and / or preventing a disease mediated by EGFR Del19 / T790M / C797S mutation; the substance A is the indolopyrimidine compound as shown in formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-4; and the substance A is in a therapeutically effective amount.

13. The use according to claim 12, wherein the compound is ###00010### or a pharmaceutically acceptable salt thereof. The disease mediated by EGFR Del19 / T790M / C797S mutation is a disease resistant to a first, second or third generation EGFR inhibitor; the first, second or third generation EGFR inhibitor is selected from gefitinib, erlotinib, icotinib, afatinib, dacomitinib and osimertinib. And / or, the disease mediated by EGFR Del19 / T790M / C797S mutation is a cancer.

14. The use according to claim 13, wherein the compound is ###00010### or a pharmaceutically acceptable salt thereof. The cancer is selected from one or more of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, gastrointestinal stromal tumor, cholangiocarcinoma, endometrial cancer, multiple myeloma and leukemia.

15. The use according to claim 14, wherein the compound is ###00010### 15 The lung cancer is non-small cell lung cancer or small cell lung cancer; the brain cancer is glioma; and the skin cancer is melanoma.

16. The use according to claim 15, wherein the compound is ###00023### 15 The non-small cell lung cancer is lung adenocarcinoma or lung squamous carcinoma; and the glioma is glioblastoma. The non-small cell lung cancer is lung adenocarcinoma or lung squamous carcinoma; and the glioma is glioblastoma.

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