WO2019034075A1 - Fgfr and egfr inhibitor - Google Patents

Abstract

Provided is a FGFR and EGFR inhibitor, a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. Also provided is the application of a drug for treating solid tumors, such as FGFR and EGFR related diseases.

Description

FGFR and EGFR inhibitors

This application claims the following priority:

CN201710698123.0, application date 2017-08-15.

Technical field

The present invention relates to a class of FGFR and EGFR inhibitors and their use in the manufacture of a medicament for the treatment of diseases associated with FGFR and EGFR. Specifically, it relates to a compound of the formula (I) and a pharmaceutically acceptable salt thereof.

Background technique

The fibroblast growth factor receptor (FGFR) is a receptor for fibroblast growth factor (FGF) signaling, and its family consists of four members (FGFR1, FGFR2, FGFR3, FGFR4), which are composed of extracellular immunoglobulins ( Ig) a glycoprotein consisting of a domain, a hydrophobic transmembrane region, and an intracellular portion comprising a tyrosine kinase domain. Fibroblast growth factor (FGF) plays an important role in many physiological regulatory processes such as cell proliferation, cell differentiation, cell migration, and angiogenesis through these receptors (FGFR). There is a lot of evidence that FGF signaling pathway abnormalities (high expression, gene amplification, gene mutation, chromosome recombination, etc.) are directly related to many pathological processes such as tumor cell proliferation, migration, invasion and angiogenesis. Therefore, FGFR has become an important therapeutic target and has attracted a wide range of research and development interests.

Epidermal growth factor receptor (EGFR) is a receptor for epidermal growth factor (EGF) signaling and belongs to the ErbB receptor family, which includes EGFR (ErbB-1), HER2/c-neu (ErbB-2) , HER3 (ErbB-3) and HER4 (ErbB-4). EGFR is widely distributed on the surface of epithelial cells, fibroblasts, glial cells, keratinocytes, etc. EGF plays an important role in regulating the growth, proliferation and differentiation of cells through these receptors. Many studies have shown that there are high expression of EGFR or gene mutation in a variety of solid tumors, which is related to tumor cell proliferation, angiogenesis, tumor invasion, metastasis and inhibition of apoptosis. Studies have also found that activation of the FGFR signaling pathway is one of the reasons for resistance to EGFR inhibitors. Therefore, there is a need for new compounds and methods that simultaneously inhibit FGFR and EGFR for the treatment of value-added conditions such as cancer. The present invention addresses these needs.

Inhibition of EGFR by three compounds (Reference Examples 2-4) is reported in the literature (Angew. Chem. Int. Ed. 2016, 55, 1-5). The kinase spectrum inhibitory activity was characterized for Reference Example 2, and no inhibitory activity against FGFR was exhibited.

A series of compounds having inhibitory activity against FGFR, including reference compound 1, are reported in WO2015008844. A series of compounds having inhibitory activity against FGFR, including the benzothiophene structure used in the present invention, are reported in WO2013124316, WO2013087647, and US20130158000.

Summary of the invention

The present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,

among them,

R _{1 is} selected from the group consisting of H, F, Cl, Br, and I.

R _{2 is} selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ .

R _{3 is} selected from H, halogen, OH, NH ₂ , CN, or selected from C _{1 1-3} alkyl, C _1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;

R _{4 is} selected from H, halogen, OH, NH ₂ , CN, or selected from C _{1 1-3} alkyl, C _1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;

R is selected from the group consisting of: F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ , N(CH ₃ ) ₂ ,

The "hetero" of the C _1-3 heteroalkyl group is independently selected from: -NH-, N, -O-, -S-;

In either case, the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.

In some embodiments of the invention, the above R _{3 is} selected from the group consisting of H, halogen, OH, NH ₂ , CN, or selected from the group consisting of: ₁ , 2 or 3 R: C _1-3 alkyl, C _1-3 Alkoxy, C _1-3 alkylamino, R is as defined in the invention.

In some aspects of the invention, the above R _{3 is} selected from the group consisting of: H, F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ ,

In some embodiments of the invention, the above R _{4 is} selected from the group consisting of H, halogen, OH, NH ₂ , CN, or selected from the group consisting of: ₁ , 2 or 3 R: C _1-3 alkyl, C _1-3 Alkoxy, C _1-3 alkylamino, R is as defined in the invention.

In some embodiments of the invention, the above R _{4 is} selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ ,

In some aspects of the invention, the structural unit

From:

In some embodiments of the invention, the above R _{3 is} selected from the group consisting of H, halogen, OH, NH ₂ , CN, or selected from the group consisting of: ₁ , 2 or 3 R: C _1-3 alkyl, C _1-3 Alkoxy, C _1-3 alkylamino, other variables are as defined above.

In some aspects of the invention, the above R _{3 is} selected from the group consisting of: H, F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ ,

Other variables are as defined above.

In some embodiments of the invention, the above R _{4 is} selected from the group consisting of H, halogen, OH, NH ₂ , CN, or selected from the group consisting of: ₁ , 2 or 3 R: C _1-3 alkyl, C _1-3 Alkoxy, C _1-3 alkylamino, other variables are as defined above.

In some embodiments of the invention, the above R _{4 is} selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ ,

Other variables are as defined above.

In some aspects of the invention, the structural unit

From:

Other variables are as defined above.

In some embodiments of the invention, the above compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

among them,

R ₁ , R ₂ , R ₃ and R _{4 are} as defined above.

Still other aspects of the invention are arbitrarily combined by the above variables.

The present invention also provides a compound of the formula: or a pharmaceutically acceptable salt thereof:

In some embodiments of the invention, the above compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a medicament for treating a disease associated with FGFR.

The present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a medicament for treating diseases associated with FGFR and EGFR.

In some aspects of the invention, the FGFR and EGFR related diseases are referred to as solid tumors.

Technical effect:

One of the corresponding isomers of the present invention exhibits a good inhibitory activity against FGFR, while the other corresponding isomer exhibits a good inhibitory activity against EGFR. The combined use of the racemates of these compounds can simultaneously inhibit FGFR and EGFR, and has a better anti-proliferative effect than inhibition of FGFR or EGFR alone.

Related definition

Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or 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, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.

Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.

As used herein, a "pharmaceutically acceptable salt" is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturaldehyde, propionic acid, salicylic acid, stearic acid, acrylic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, Tartaric acid and p-toluenesulfonic acid.

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

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.

Unless otherwise indicated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of one another.

Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.

Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.

Unless otherwise indicated, "(D)" or "(+)" means dextrorotatory, "(L)" or "(-)" means left-handed, "(DL)" or "(±)" means racemic.

Wedge solid key unless otherwise stated

And wedge-shaped dashed keys

Represents the absolute configuration of a solid center with straight solid keys

And straight dashed keys

Indicates the relative configuration of the stereocenter, using wavy lines

Indicates a wedge solid key

Or wedge-shaped dotted key

Or with wavy lines

Represents a straight solid key

And straight dashed keys

The compounds of the invention may be present in particular. Unless otherwise indicated, the terms "tautomer" or "tautomeric form" mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization. The valence tautomer includes the mutual transformation of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

Unless otherwise indicated, the terms "enriched in one isomer", "isomer enriched", "enriched in one enantiomer" or "enantiomeric enriched" refer to one of the isomers or pairs The content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.

Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .

The optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and then by conventional methods well known in the art. The diastereomers are resolved and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate). The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or ^C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

"Optional" or "optionally" means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of. When the substituent is oxygen (ie, =0), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, the term "hydrocarbyl" or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic. The hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C ₁ -C ₁₂ represents 1 to 12 carbons) , C _{1-12 is} selected from C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ ; C _{3-12 is} selected from C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ .). "Hydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members. An aromatic hydrocarbon group such as benzene, naphthalene or the like. In some embodiments, the term "hydrocarbyl" means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl). A homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl. The unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.

Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl" by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. The hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively. Examples include, but are not limited to, -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S -CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ ,- CH ₂ -CH=N-OCH ₃ and -CH=CH-N(CH ₃ )-CH ₃ . Up to two heteroatoms may be consecutive, for example, -CH ₂ -NH-OCH _3.

Unless otherwise specified, the term "alkyl" is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH ₂ F) or polysubstituted (eg, -CF ₃ ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of the alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.

Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait. Unless otherwise specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

The above-described alkyl groups having the specified number of carbon atoms, "alkoxy" represents attached through an oxygen bridge, unless otherwise specified, C _1-6 alkoxy groups include _{C 1, C 2, C 3} , C 4, C 5 , and C ₆ alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.

The solvent used in the present invention is commercially available. The present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for t-butoxycarbonyl is an amine protecting group; HOAc for acetic acid; NaCNBH ₃ for sodium cyanoborohydride ; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc ₂ O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl ₂ stands for chloride Sulfone; CS ₂ represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n-Bu ₄ NF stands for fluorine Tetrabutylammonium; iPrOH represents 2-propanol; mp mp Representative; Representative LDA lithium diisopropylamide; EGTA representative of EGTA.

Compound by hand or

Software naming, commercially available compounds using the supplier catalog name.

Detailed ways

The invention is described in detail below by the examples, but is not intended to limit the invention. The present invention has been described in detail herein, the embodiments of the present invention are disclosed herein, and various modifications and changes may be made to the embodiments of the present invention without departing from the spirit and scope of the invention. It will be obvious.

Reference Example 1: WXR1

Compound WXR1 was synthesized according to the route reported in patent WO2015008844. ^{1 H NMR (400MHz, DMSO-} d 6) δ8.40 (d, J = 3.0Hz, 1H), 6.93 (d, J = 2.5Hz, 2H), 6.74-6.52 (m, 2H), 6.20-6.16 ( m,1H), 5.74-5.69 (m, 1H), 5.45-5.61 (m, 1H), 4.12-3.90 (m, 2H), 3.90-3.79 (m, 8H), 2.47-2.30 (m, 2H). MS m/z: 419.1 [M+H] ⁺

Reference Example 2:

The synthesis, characterization and biological activity tests of Reference Example 2 are described in the literature (Angew. Chem. Int. Ed. 2016, 55, 1-5).

Reference Example 3: Synthesis of Compound WXR3

Step 1: Synthesis of Compound WXR3-1

Diisopropyl azodicarboxylate (7.8 g, 38 mmol, 7.4 mL, 2.0 eq) was added dropwise to dissolved Compound D (5.0 g, 19 mmol, 1.0 eq), Compound C1 (3.86 g). 19.16 mmol, 1.00 eq.) and a solution of triphenylphosphine (10 g, 38 mmol, 2.0 eq) in anhydrous tetrahydrofurane (100 mL). After the reaction was stirred at room temperature for 16 hr, ethyl acetate (20 mL) was evaporated. The organic phase was dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was removed under reduced pressure to give a crude material. The crude product was separated by chromatography (eluent: methanol / methylene chloride = 0% to 5%) to afford compound WXR3-1 (6.2 g, 14 mmol, yield 73%). ^{1 H NMR (400MHz, DMSO-} d 6) δ: 8.95-8.68 (m, 1H), 5.31-5.13 (m, 1H), 4.20-4.03 (m, 2H), 3.59-3.51 (m, 2H), 2.48 -2.37 (m, 2H), 2.30-2.10 (m, 2H), 2.00 (s, 9H). LCMS (ESI) m/z: 445.1 [M+H] ⁺

Step 2: Synthesis of Compound WXR3-2

WXR3-1 (200 mg, 450 μmol, 1.0 eq), Compound B1 (96 mg, 540 μmol, 1.2 eq), sodium carbonate (95 mg, 900 μmol, 2.0 eq) and tetratriphenylphosphine palladium (52 mg, 45 μmol, 0.1 eq) was sequentially added to a mixed solution of ethylene glycol dimethyl ether/ethanol/water (2.25 mL, 6/2/1). After stirring at 90 ° C for 16 hours under nitrogen atmosphere, the mixture was cooled to room temperature, and the mixture was poured into water (5 mL) and ethyl acetate (5 mL x 3). The organic layer was washed with brine (5 mL) After the desiccant was filtered off, the solvent was evaporated under reduced pressure to give Compound (Del. LCMS (ESI) m / z: 451.1 [M + H] +, 473.2 [M + Na] +

Step 3: Synthesis of Compound WXR3-3

Ethyl hydrogen chloride solution (4M, 2.0 mL) was added to WXR3-2 (150 mg, 333 μmol, 1.0 eq) at room temperature. After stirring for 2 hours, the crude WXR3-3 hydrochloride (90 mg, 233 μmol, crude yield 70%) was obtained by filtration and used directly for the next reaction. ¹ H NMR (400MHz, deuterated methanol) δ: 8.53 (s, 1H ), 8.05-7.95 (m, 2H), 7.86 (s, 1H), 7.55-7.37 (m, 2H), 5.39-5.32 (m, 1H), 3.81-3.69 (m, 2H), 3.51-3.46 (m, 1H), 3.29-3.18 (m, 1H), 2.48-2.29 (m, 2H), 2.26-2.13 (m, 1H), 2.12 1.94 (m, 1H). LCMS (ESI) m/z: 351.0 [M+H] ⁺

Step 4: Synthesis of Compound WXR3

Slowly add propylene to a solution of diisopropylethylamine (50 mg, 388 μmol, 68 μL, 3.0 eq) and crude WXR3-3 hydrochloride (50 mg) in dichloromethane (2.0 mL). A solution of the acid chloride in dichloromethane (0.25 M, 520 uL). After stirring at room temperature for 2 hours, the reaction was diluted with dichloromethane (10 mL) and washed with water The organic phase was dried over anhydrous sodium sulfate, and then filtered and evaporated. The crude product was isolated using a thin-layer preparative plate (ethyl acetate) to afford WXR3 (15 mg, 37 μmol, yield 28%). ^{1 H NMR (400MHz, CHLOROFORM-} d) δ: 8.38-8.37 (m, 1H), 7.98-7.77 (m, 2H), 7.62 (s, 1H), 7.51-7.33 (m, 2H), 6.68-6.49 ( m,1H), 6.37-6.20 (m, 1H), 6.04 (br s, 2H), 5.79-5.56 (m, 1H), 4.62-4.60 (m, 1H), 4.27-3.98 (m, 1H), 3.87 -3.30(m,1H), 3.26-2.76(m,1H), 2.49-2.31(m,1H), 2.29-2.21(m,1H),2.03-1.98(m,1H),1.80-1.61(m, 1H)MS m/z: 405.1 [M+H] ⁺

Reference Example 4: Synthesis of Compound WXR4

Reference Example 4 was synthesized with reference to the synthesis method of Reference Example 3. ^{1 H NMR (400MHz, CHLOROFORM-} d) δ: 8.39 (br s, 1H), 7.94-7.83 (m, 2H), 7.63 (s, 1H), 7.48-7.36 (m, 2H), 6.72-6.47 (m , 1H), 6.33-6.27 (m, 1H), 5.97 (br s, 2H), 5.81-5.61 (m, 1H), 4.99-4.51 (m, 2H), 4.27-3.97 (m, 1H), 3.86- 3.31(m,2H), 3.27-2.80(m,1H), 2.49-2.22(m,1H), 2.04-1.95(m,1H),1.72-1.61(m,1H).MS m/z:405.1[ M+H] ⁺

Intermediate A1:

synthetic route:

Step 1: Synthesis of Compound A1-1

4-Amino-7-bromopyrrolo[2,1-f][1,2,4]triazine (3.00 g, 14.1 mmol, 1.00 eq) was first dissolved in 1,4-dioxane at room temperature. N-Boc-2,5-dihydro-1H-pyrrole-1 quinolol-borate (4.36 g, 14.8 mmol, 1.05 eq) was added to a mixture of the mixture (40 mL) and water (8 mL). Potassium phosphate (8.97 g, 42.2 mmol, 3.00 eq) and 1,1'-bis(diphenylphosphino)ferrocene palladium chloride (1.03 g, 1.41 mmol, 0.10 eq) were added to the mixed solution. The reaction solution was heated to 80 ° C under nitrogen for 2 hours. After the reaction was completed, the reaction liquid was lowered to 25 ° C, poured into 20 mL of water, and a black solid was formed. The black solid was collected by filtration, then dissolved in dichloromethane/methanol (100 mL, 5/1), and filtered again. The organic layer was dried over anhydrous sodium The crude product was slurried with ethyl acetate (30 mL). LCMS (ESI) m / z: 302.1 [M + H] +, 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.05 (s, 1H), 6.98-6.84 (m, 1H), 6.72-6.54 (m, 2H), 4.67-4.49 (m, 2H), 4.44-4.30 (m, 2H).

Step 2: Synthesis of Compound A1-2

Palladium hydroxide (615 mg, 438 μmol) was added to a solution of A1-1 (1.20 g, 3.98 mmol, 1.00 eq) in methanol (30 mL). After replacing the reaction with hydrogen for 3 times, the reaction solution was heated to 50 ° C, and stirred under 50 psi of hydrogen for 2 hours. The reaction solution was cooled to room temperature, and the catalyst was removed by filtration. ¹ H NMR (400MHz, deuterated methanol) δ: 7.80 (s, 1H ), 6.86 (d, J = 4.4Hz, 1H), 6.53 (d, J = 4.4Hz, 1H), 3.96-3.79 (m, 2H ), 3.60-3.51 (m, 1H), 3.49-3.38 (m, 2H), 2.39-2.36 (m, 1H), 2.19 - 2.13 (m, 1H), 1.49 (d, J = 3.6 Hz, 9H).

Step 3: Synthesis of Compound A1

Iodine succinimide (26.7 g, 119 mmol, 3.00 eq) was added portionwise to A1-2 (12.0 g, 39.6 mmol, 1.00 eq) of N,N dimethylformamide (150 mL). In solution. After the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was slowly added to ice water (200 mL), solid was formed, and the solvent was removed by filtration. Compound A1 was chirally resolved (column: IC (250 mm * 50 mm, 10 μm); mobile phase: [0.1% ammonia/ethanol]; B%: 30%-30%) to give compound A1-A (retention time 2.94 minutes) and Compound A1-B (retention time 3.28 minutes).

Intermediate A2:

synthetic route:

Step 1: Synthesis of Compound A2-1

Hydrochloric acid / ethyl acetate (4M, 20.00 mL, 6.87 eq) was slowly added to a solution of A1 (5.00 g, 11.65 mmol, 1.00 eq) in ethyl acetate (30 mL) and stirred for two hours. The reaction solution was filtered, and the filter cake was evaporated under reduced pressure to remove solvent. LCMS (ESI) m / z: 329.9 [M + H] +, 1 H NMR (400MHz, deuterated methanol) δ = 8.11 (s, 1H ), 7.20 (s, 1H), 4.12 (m, 1H), 3.84 (m, 1H), 3.67-3.54 (m, 1H), 3.51-3.37 (m, 2H), 2.71-2.51 (m, 1H), 2.35 - 2.27 (m, 1H).

Step 2: Synthesis of Compound A2

Triethylamine (3.60 g, 35.55 mmol, 4.93 mL, 5.00 eq) and acryloyl chloride (707.88 mg, 7.82 mmol, 1.10 eq) were sequentially added to A2-1 (2.60 g, 7.11 mmol, 1.00 eq) at 0 °C. After stirring for 1 hour in a solution of dichloromethane (20.00 mL), the reaction mixture was poured into a 50 mL aqueous solution. After separation, the aqueous phase was extracted with dichloromethane (20 mL×5) Dry with anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure to give A2. LCMS (ESI) m / z: 384.0 [M + H] +, 406.0 [M + Na] +.

Intermediate A3:

Refer to the intermediate A1 synthesis method.

Intermediate B1:

CAS: 162607-15-0

Intermediate B2:

CAS: 501944-42-9

Intermediate B3:

synthetic route:

Step 1: Synthesis of intermediate B3

A solution of 5-chlorobenzothiophene (1.00 g, 5.93 mmol, 1.00 eq) in tetrahydrofuran (00.00 mL) was cooled to -70 °C. A solution of butyllithium in n-hexane (2.5 M, 4.74 mL, 2.00 eq) was slowly added dropwise to the mixture. Stir for 1 hour after the completion of the dropwise addition. Then triisopropylboronic acid (2.23 g, 11.86 mmol, 2.72 mL, 2.00 eq) was added. After the addition was completed, the mixture was stirred for 1 hour, then slowly warmed to 25 ° C and stirred for 18 hours. After the reaction was completed, water (10 mL) was added dropwise to quench the reaction. The quenched reaction mixture was concentrated to remove tetrahydrofuran. The residue was washed with petroleum ether (50 mL) and then adjusted to pH 5 with dilute hydrochloric acid. Filtration, the filter cake was washed with water (50 mL) and then dried in vacuo to give Intermediate B1. 1H NMR (400 MHz, deuterated methanol) δ= 7.90-7.82 (m, 2H), 7.78 (s, 1H), 7.35-7.29 (m, 1H), 7.36-7.29 (m, 1H)

Intermediate B4:

CAS: 193965-30-9

Intermediate B5:

The synthesis method was carried out by referring to the synthesis method of the intermediate B3 using 2,6-dimethyl basic thiophene as a raw material. ¹ H NMR (400MHz, deuterated methanol) δ = 7.69 (d, J = 8.0Hz, 1H), 7.54 (s, 1H), 7.23-7.11 (m, 1H), 2.53 (s, 3H), 2.48 (s , 3H)

Intermediate B6:

CAS: 912331-30-7

Example 1: Synthesis of Compound WX001A

synthetic route:

Step 1: Synthesis of Compound WX001A-1

Compound B4 (58.16 mg, 279.56 μmol, 1.50 eq), sodium carbonate (39.51 mg, 372.74 μmol, 2.00 eq) and tetrakistriphenylphosphine palladium (21.54 mg, 18.64 μmol, 0.10 eq) were sequentially added at room temperature. Compound A1-B (80.00 mg, 186.37 μmol, 1.00 eq) in a mixed solution of ethylene glycol dimethyl ether (0.9 mL) / ethanol (0.3 mL) / water (0.3 mL), after three times with nitrogen, heated to 90 After stirring at ° C for 16 hours, it was cooled to room temperature, filtered, and the filtrate was evaporated to dryness under reduced pressure to give the crude compound WX001A-1. LCMS (ESI) m / z: 466.2 [M + H] +.

Step 2: Synthesis of Compound WX001A-2

The ethyl acetate solution (4M, 1.00 mL, 21.91 eq) was slowly added dropwise to a solution of WX001A-1 (85.00 mg, 182.57 μmol, 1.00 eq) in ethyl acetate (1 mL) and stirred for 1 hour. The solid was filtered, and the solid was dried under reduced pressure to give the hydrochloride salt of compound WX001A-2. LCMS (ESI) m / z: 366.0 [M + H] +.

Step 3: Synthesis of Compound WX001A

Triethylamine (60.43 mg, 597.15 μmol, 82.77 μL, 4.00 eq) and a solution of acryloyl chloride in dichloromethane (0.25 M, 895.72 μL, 1.50 eq) were added to WX001A-2 hydrochloride ( 60.00 mg, 149.29 μmol, 1.00 eq) in dichloromethane (3.00 mL), stirred for 1 hour, then quenched with methanol, and then quenched and evaporated. The preparation plate (dichloromethane/methanol = 10/1) was purified to give the compound WX001A. LCMS (ESI) m / z: 420.1 [M + H] +, 1 H NMR (400MHz, deuterated methanol) δ = 7.80 (d, J = 2.4Hz, 1H), 7.62 (d, J = 8.8Hz, 1H ), 7.26 (d, J = 2.4 Hz, 1H), 7.20 (s, 1H), 6.94 - 6.87 (m, 1H), 6.62 (d, J = 8.8 Hz, 1H), 6.59-6.48 (m, 1H) , 6.23-6.16 (m, 1H), 5.69-5.62 (m, 1H), 4.21-3.82 (m, 2H), 3.76 (s, 3H), 3.72-3.36 (m, 3H), 2.53-2.30 (m, 1H), 2.27-2.04 (m, 1H)

Example 2: Synthesis of Compound WX001B

Starting from the intermediates A1-A and B4, the synthesis was carried out in accordance with the synthesis method of Example 1. ¹ H NMR (400MHz, deuterated methanol) δ = 7.81 (d, J = 2.4Hz, 1H), 7.36 (d, J = 1.6Hz, 1H), 7.20 (s, 1H), 6.81 (s, 1H), 6.63 (d, J = 8.8 Hz, 1H), 6.59-6.49 (m, 1H), 6.24 - 6.16 (m, 1H), 5.73-5.53 (m, 1H), 4.19 - 3.92 (m, 2H), 3.90 ( s, 3H), 3.82-3.58 (m, 2H), 3.57-3.44 (m, 1H), 2.51-2.31 (m, 1H), 2.27-2.05 (m, 1H)

Example 3: Synthesis of Compound WX002A

Starting from the intermediates A1-B and B5, the synthesis was carried out in accordance with the synthesis method of Example 1. LCMS (ESI) m / z: 418.1 [M + H] +, 1 H NMR (400MHz, deuterated methanol) δ = 7.77 (d, J = 2.8,1H), 7.61 (d, J = 8.0Hz, 1H) , 7.48 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.59-6.42 (m, 2H), 6.24-6.14 (m, 1H), 5.70-5.58 (m, 1H), 4.18-3.98 (m, 1H), 3.97-3.79 (m, 1H), 3.78-3.57 (m, 2H), 3.56-3.42 (m, 1H), 2.49-2.27 (m, 4H), 2.25-2.02 (m, 4H)

Example 4: Synthesis of Compound WX002B

Starting from the intermediates A1-A and B5, the synthesis was carried out in accordance with the synthesis method of Example 1. LCMS (ESI) m/z: 418.2 [M+H] ⁺ , ¹ H NMR (400 MHz, MeOH) δ = 7.77 (d, J = 2.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H) ), 7.48 (s, 1H), 7.14 (d, J = 8.4 Hz, 1H), 6.72-6.41 (m, 2H), 6.24-6.15 (m, 1H), 5.73-5.59 (m, 1H), 4.19- 3.91 (m, 2H), 3.79-3.60 (m, 2H), 3.58-3.38 (m, 1H), 2.50-2.30 (m, 4H), 2.26-2.05 (m, 4H)

Example 5: Synthesis of Compound WX003

The intermediates A3 and B1 were used as starting materials, and were synthesized by referring to the synthesis method of Example 1. LCMS (ESI) m/z: 404.2 [M+H] ⁺ , ¹ H NMR (400 MHz, deuterated methanol) δ=7.91-7.71 (m, 3H), 7.34-7.21 (m, 3H), 6.80-6.66 ( m, 1H), 6.64 (s, 1H), 6.23-5.96 (m, 1H), 5.76-5.56 (m, 1H), 4.46-4.23 (m, 1H), 4.07-4.01 (m, 1H), 3.41 3.29 (m, 1H), 3.28-3.23 (m, 1H), 3.05-2.83 (m, 1H), 2.23-2.10 (m, 1H), 1.88-1.68 (m, 2H), 1.66-1.53 (m, 1H) )

Example 6: Synthesis of Compound WX004

Starting from the intermediates A3 and B2, the synthesis was carried out in accordance with the synthesis method of Example 1. LCMS (ESI) m / z: 444.1 [M + Na] +, 1 H NMR (400MHz, deuterated methanol) δ = 7.87-7.73 (m, 2H ), 7.45-7.42 (m, 1H), 7.25 (s, 1H), 7.09-7.014 (m, 1H), 6.78-6.65 (m, 1H), 6.63 (s, 1H), 6.15-6.03 (m, 1H), 5.70-5.55 (m, 1H), 4.38-4.27 ( m,1H), 4.00-3.96 (m,1H), 3.43-3.27 (m,1H), 3.26-3.22 (m,1H), 3.05-2.83 (m,1H), 2.21-2.05 (m,1H), 1.88-1.70(m,2H),1.63- 1.50(m,1H)

Example 7: Synthesis of Compound WX005

Starting from the intermediates A3 and B5, the synthesis was carried out in accordance with the synthesis method of Example 1. LCMS (ESI) m / z: 432.1 [M + H] +, 1 H NMR (400MHz, deuterated methanol) δ = 7.83-7.72 (m, 1H ), 7.60 (d, J = 8.4Hz, 1H), 7.47 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.82-6.61 (m, 1H), 6.50 (s, 1H), 6.20-5.93 (m, 1H), 5.75-5.53 (m, 1H) ), 5.75-5.53 (m, 1H), 4.34-4.25 (m, 1H), 3.99-3.91 (m, 1H), 3.37-3.25 (m, 1H), 3.20-3.12 (m, 1H), 3.00-2.83 (m,1H), 2.39(s,3H), 2.16(s,3H),2.13-2.06(m,1H),1.86-1.68(m,2H),1.65-1.47(m,1H)

Examples 8 and 9: Synthesis of Compounds WX006A and WX006B

Using the intermediates A2 and B2 as raw materials, the compound WX006 was synthesized by the synthesis method of the step 3 in Example 1, and separated by chirality (column: AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% ammonia methanol]; B% : 35% - 35%) Compound WX006A (retention time: 5.70 minutes) and compound WX006B (retention time: 6.23 minutes)

WX006A: LCMS (ESI) m / z: 408.1 [M + H] +, 1 H NMR (400MHz, deuterated methanol) δ = 7.93 (d, J = 2.4Hz, 1H), 7.91-7.86 (m, 1H) , 7.60-7.55 (m, 1H), 7.38 (s, 1H), 7.21-7.14 (m, 1H), 6.80-6.80 (m, 1H), 6.77 (d, J = 9.2 Hz, 1H), 6.71-6.61 (m, 1H), 6.35-6.28 (m, 1H), 5.81-5.74 (m, 1H), 4.30-3.95 (m, 2H), 3.93-3.72 (m, 2H), 3.70-3.62 (m, 1H) , 2.63-2.44 (m, 1H), 2.40-2.20 (m, 1H)

WX006B: LCMS (ESI) m / z: 408.1 [M + H] +, 1 H NMR (400MHz, deuterated methanol) δ = 7.81 (d, J = 2.4Hz, 1H), 7.79-7.74 (m, 1H) , 7.48-7.42 (m, 1H), 7.26 (s, 1H), 7.09-7.02 (m, 1H), 6.64 (d, J = 9.2 Hz, 1H), 6.59-6.49 (m, 16.9 Hz, 1H), 6.23-6.16(m,1H), 5.69-5.62(m,1H),4.22-3.82(m,2H),3.81-3.59(m,2H),3.55-3.47(m,1H), 2.50-2.31(m , 1H), 2.29-2.05 (m, 1H)

Examples 10 and 11: Synthesis of Compounds WX007A and WX007B

Using the intermediates A2 and B1 as raw materials, the compound WX007 was synthesized by the synthesis method of the step 3 in Example 1, and separated by chirality (column: AS (250 mm * 30 mm, 5 μm); mobile phase: [0.1% aqueous isopropyl alcohol]; B%: 40%-40%) Compound WX007A (retention time: 5.91 minutes) and WX007B (retention time: 6.52 minutes) (column: Chiralpak AS-H 150*4.6 mm ID, 5 μm, mobile phase: A: CO2B: Isopropanol (0.05% diethanolamine), gradient: 5% B for 0.5 minutes, from 5% to 40% in 3.5 minutes, at 2.5% for 2.5 minutes, to 5% B for 1.5 minutes, flow rate: 3 mL/ Min column temperature: 40 ° C)

WX007A: LCMS (ESI) m / z: 390.1 [M + H] +, 412.2 [M + Na] +, 1 H NMR (400MHz, deuterated methanol) δ = 7.82-7.70 (m, 3H ), 7.34-7.21 (m, 3H), 6.63 (d, J = 9.2 Hz, 1H), 6.59-6.48 (m, 1H), 6.24 - 6.15 (m, 1H), 5.69 - 5.61 (m, 1H), 4.26 - 3.98 (m , 1H), 3.90-3.58 (m, 3H), 3.57-3.42 (m, 1H), 2.51-2.30 (m, 1H), 2.26-2.02 (m, 1H), WX007B: LCMS (ESI) m/z: 390.2[M+H] ⁺ , ¹ H NMR (400MHz, deuterated methanol) δ=7.86-7.67 (m, 3H), 7.37-7.14 (m, 3H), 6.73-6.40 (m, 2H), 6.23-6.15 (m, 1H), 5.75-5.53 (m, 1H), 4.21-3.99 (m, 1H), 3.97-3.81 (m, 1H), 3.78-3.59 (m, 2H), 3.56-3.42 (m, 1H) , 2.50-2.29 (m, 1H), 2.24 - 2.02 (m, 1H)

Examples 12 and 13: Synthesis of Compounds WX008A and WX008B

Starting from intermediates A2 and B3, compound WX008 was synthesized by the synthesis method of step 3 in Example 1, and separated by chirality (column: AS (250 mm * 30 mm, 5 μm); mobile phase: [0.1% ammonia methanol]; B% :40%-40%) Compound WX008A (retention time: 5.41 minutes) and WX008B (retention time: 5.92 minutes) (column: Chiralpak AS-3 100×4.6 mm ID, 3 μm, mobile phase: A: CO ₂ B: Methanol (0.05% diethanolamine), gradient: from 5% to 40% in 4.5 minutes, held at 40% for 2.5 minutes, reduced to 5% B for 1 minute, flow rate: 2.8 mL/min, column temperature: 40 °C)

WX008A: LCMS (ESI) m / z: 424.1 [M + H] +, 1 H NMR (400MHz, deuterated methanol) δ = 8.01-7.80 (m, 3H ), 7.52-7.26 (m, 2H), 6.82- 6.74 (m, 1H), 6.71-6.59 (m, 1H), 6.40-6.19 (m, 1H), 5.86-5.68 (m, 1H), 4.35-3.96 (m, 2H), 3.93-3.70 (m, 2H) ), 3.68-3.56 (m, 1H), 2.65-2.40 (m, 1H), 2.37-2.13 (m, 1H)

WX008B: LCMS (ESI) m / z: 424.1 [M + H] +, 1 H NMR (400MHz, deuterated methanol) δ = 7.94 (d, J = 2.0Hz, 1H), 7.90-7.85 (m, 2H) , 7.49-7.26 (m, 2H), 6.77 (d, J = 9.2 Hz, 1H), 6.71-6.61 (m, 1H), 6.36-6.28 (m, 1H), 5.81 - 5.74 (m, 1H), 4.33 -3.97 (m, 2H), 3.93-3.72 (m, 2H), 3.69-3.60 (m, 1H), 2.65-2.43 (m, 1H), 2.39-2.14 (m, 1H)

Examples 14 and 15: Synthesis of compounds WX009A and WX009B

Starting from intermediates A2 and B3, compound WX008 was synthesized by the synthesis method of step 3 in Example 1, and separated by chirality (column: AS (250 mm * 30 mm, 5 μm); mobile phase: [0.1% ammonia methanol]; B% :40%-40%) Compound WX009A (retention time: 6.01 minutes) and WX009B (retention time: 6.67 minutes).

WX009A: LCMS (ESI) m / z: 438.2 [M + H] +, 460.2 [M + Na] +, 1 H NMR (400MHz, deuterated methanol) δ = 8.05-7.76 (m, 3H ), 7.43-7.37 (m, 1H), 6.77-6.58 (m, 2H), 6.35-6.27 (m, 1H), 5.81-5.74 (m, 1H), 4.35-3.96 (m, 2H), 3.94-3.73 (m, 2H) , 3.70-3.55 (m, 1H), 2.67-2.45 (m, 1H), 2.39-2.19 (m, 4H)

WX009B: LCMS (ESI) m / z: 438.2 [M + H] +, 460.3 [M + Na] +, 1 H NMR (400MHz, deuterated methanol) δ = 7.89-7.67 (m, 3H ), 7.29 (d , J=8.8Hz, 1H), 6.67-6.46(m, 2H), 6.30-6.14(m,1H), 5.79-5.53(m,1H), 4.27-3.88(m,2H),3.83-3.67(m , 1H), 3.67-3.54 (m, 1H), 3.54-3.30 (m, 1H), 2.55-2.32 (m, 1H), 2.29-2.11 (m, 4H)

NMR and MS data for each example

Experimental Example 1: In vitro evaluation

The ability of the test compound to inhibit human FGFR1, FGFR4, EGFR (L858R/T790M) was evaluated by measuring the IC ₅₀ value using a ³³ P isotope-labeled kinase activity assay (Reaction Biology Corp).

Buffer conditions: 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO.

Test procedure: The test compound was dissolved in DMSO at room temperature to prepare a 10 mM solution for use. The substrate is dissolved in a freshly prepared buffer, and the kinase to be tested is added thereto and mixed well. A DMSO solution in which the test compound was dissolved was added to the above mixed reaction solution by an acoustic technique (Echo 550). The concentration of the compound in the reaction solution was 10 μM, 3.33 μM, 1.11 μM, 0.370 μM, 0.123 μM, 41.2 nM, 13.7 nM, 4.57 nM, 1.52 nM, 0.508 nM, or 10 μM, 2.50 μM, 0.62 μM, 0.156 μM, 39.1 nM. , 9.8 nM, 2.4 nM, 0.61 nM, 0.15 nM, 0.038 nM. After 15 minutes of incubation, ³³ P-ATP (activity 0.01 μCi/μl, corresponding concentrations listed in Table 1) was added to initiate the reaction. The supplier number, lot number, and concentration information in the reaction solution of FGFR1, FGFR4, EGFR (L858R/T790M) and their substrates are listed in Table 1. After the reaction was allowed to proceed at room temperature for 120 minutes, the reaction solution was spotted on a P81 ion exchange filter paper (Whatman #3698-915). After repeatedly washing the filter paper with a 0.75% phosphoric acid solution, the radioactivity of the phosphorylated substrate remaining on the filter paper was measured. The kinase activity data was expressed as an alignment of the kinase activity of the test compound and the kinase activity of the blank group (DMSO only), and the IC50 value was obtained by curve fitting by Prism4 software (GraphPad), and the experimental results are shown in Table 2.

Table 1

Table 2: In vitro screening test results of the compounds of the present invention

Conclusion: One of the corresponding isomers of the present invention exhibits a good inhibitory activity against FGFR, while the other corresponding isomer exhibits a good inhibitory activity against EGFR. The racemates of these compounds can simultaneously inhibit FGFR and EGFR.

Claims (11)

1. a compound of formula (I) or a pharmaceutically acceptable salt thereof,

   

   among them,

   R _{1 is} selected from the group consisting of H, F, Cl, Br or I.

   R _{2 is} selected from the group consisting of: H, F, Cl, Br, I, OH, NH ₂ ;

   R _{3 is} selected from H, halogen, OH, NH ₂ , CN, or selected from C _{1 1-3} alkyl, C _1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;

   R _{4 is} selected from H, halogen, OH, NH ₂ , CN, or selected from C _{1 1-3} alkyl, C _1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;

   R is selected from the group consisting of: F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ , N(CH ₃ ) ₂ ,

   

   The "hetero" of the C _1-3 heteroalkyl group is independently selected from: -NH-, N, -O-, -S-;

   In either case, the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R _{3 is} selected from H, halogen, OH, NH ₂ , CN, or selected from the group consisting of: 1, 2 or 3, R: C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylamino.
3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R _{3 is} selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ ,

   
4. The compound according to any one of claims 1 to 3, wherein R _{4 is} selected from H, halogen, OH, NH ₂ , CN, or selected from 1, 2 or 3, or a pharmaceutically acceptable salt thereof. R substituted: C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylamino.
5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R _{4 is} selected from the group consisting of H, F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ ,

   
6. The compound according to any one of claims 1, 3 or 5, or a pharmaceutically acceptable salt thereof, wherein the structural unit

   

   From:

   
7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

   

   among them,

   R ₁ , R ₂ , R ₃ and R _{4 are} as defined in claims 1 to 6.
8. A compound of the formula: or a pharmaceutically acceptable salt thereof:

   
9. A compound according to claim 8 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:

   

   
10. The use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of diseases associated with FGFR and EGFR.
11. The use according to claim 10, wherein the FGFR and EGFR-related diseases refer to solid tumors.