CN112174986A - FGFR4 kinase inhibitor and preparation method and application thereof - Google Patents

Abstract

The invention relates to an FGFR4 kinase inhibitor and a preparation method and application thereof. The present invention relates to compounds of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and their use in the manufacture of a medicament for the treatment of FGFR4 mediated diseases.

Description

FGFR4 kinase inhibitor and preparation method and application thereof

Technical Field

The present invention relates to compounds of formula (I) and pharmaceutical compositions thereof as FGFR4 kinase inhibitors, and the use of the compounds and compositions in the treatment of FGFR4 mediated diseases.

Background

The FGFR (fibroblast growth factor receptor) tyrosine kinase family includes FGFR1, FGFR2, FGFR3 and fgfr4, which consists of an extracellular variant region, a conserved region binding to heparan sulfate proteoglycans, a FGF binding region, a single transmembrane region and an intracellular tyrosine kinase region, most of FGFs form complexes with FGFRs and heparin with the help of the co-receptor Klotho, leading to autophosphorylation of the conformationally altered intracellular kinase region and activation of the STAT3 signaling pathway, autophosphorylated FGFR can also phosphorylate its aptamer protein FRS2 α, activate Grb2/Sos1 complexes to initiate downstream MAPK and PI3K/AKT signaling pathways, furthermore, FGFR activates phospholipase C- γ (PLC- γ) in a FRS2 α -independent manner, RAF differentiates phosphorylates, potentiates MAPK signaling, exerts its function of regulating cell proliferation, MAPK signaling, and metastasis, and PI3 signaling is mainly associated with FGFR mediated cell proliferation and motility metastasis, while PI3 is associated with physiological signal signaling 3K and AKT signaling states, the FGFR4 signaling pathway is tightly controlled, while deregulation of FGFR4 signaling leads to the development, proliferation, survival, and metastasis of cancer.

Fgfr4 inhibitors, in which about 30% of human tumors are abnormally activated in hepatocellular carcinoma patients, show superior potential for treating HCC in both preclinical and clinical trials, and are safe and have a sufficient toxicity/efficacy window.

The small molecule inhibitors of FGFR4 can be divided into pan FGFR and FGFR4 specific small molecule inhibitors, because the kinase domains of FGFR1, FGFR2 and FGFR3 are structurally similar, the inhibitors developed at present for the three kinases have little effect, however, the kinase domain of FGFR4 is different from the kinase domain of FGFR1-3, so that a plurality of inhibitors which can effectively inhibit the FGFR1-3 have poor effect on the FGFR4, and small molecule inhibitors such as CH5183284, BGJ398 and AZD4547 entering the clinical I stage or II stage have selectivity (IC) on the FGFR1-3 (IC)₅₀< 10nmol/L) is much higher than FGFR4, while JNJ-42756493 and LY2874455 are few pan FGFR small molecule inhibitors with equally high inhibitory effect on FGFR1-4, and IC50 reaches single nanomolar level, JNJ-42756493 and LY2874455 show FGFR-dependent antiproliferative effect by inhibiting FGF/FGFR signaling pathway in cells, have strong inhibitory effect on transplanted tumors with abnormal FGFR, and inhibit tumor growth with dose effect.JNJ-42756493 clinical phase I test (NCT01962532) results confirm that its medication dosage (RP2D) directing clinical phase II is 10 mg/day (medication 7 days ), LY2874455 clinical phase I test (NCT 01207) confirms that RP2D is 16 mg/day, 1 day 2 times, AZD4547 clinical phase I test (NCT00979134), AZD4547 shows strong proliferation of small cell cancer cells of squamous cell cancer patients with AZD gene, and is well tolerated at a dose of 80mg, whereas Ponatinib treats FGFR abnormalitiesThe clinical phase II/III trial (NCT01761747) of advanced lung squamous carcinoma patients was terminated by adverse reactions.

Lack of selective FGFR kinase inhibitors have resulted in adverse reactions such as hyperphosphatemia, nail detachment, hair loss, mucositis, taste disturbance and mucosal dryness, conjunctivitis, keratitis, ocular dryness, asymptomatic retinal pigment layer detachment, bone joint pain, myalgia, etc. due to off-target, and have limited clinical applications.

The compound is an FGFR4 protein kinase inhibitor with proprietary intellectual property rights, can inhibit FGFR4 tyrosine kinase with high selectivity, has weak inhibition effect on FGFR1-3, and is expected to treat liver cancer patients with high FGFR4 expression safely and effectively.

Summary of The Invention

In one aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof,

wherein

X is N or CH;

R⁰is-O-C_1-6An alkyl group;

R¹selected from H and halogen;

R²and R³Each independently selected from H and C_1-6An alkyl group;

R⁴selected from H, C_1-6Alkyl and-O-C_1-6An alkyl group;

R¹⁴is selected from

R⁶And R⁸Each independently selected from H and C_1-6An alkyl group; or R⁶And R⁸Joined together to form a key;

R⁷selected from H, C_1-6Alkyl, -O-C_1-6Alkyl and-NR⁹R¹⁰Wherein R is⁹And R¹⁰Each independently selected from H and C_1-6An alkyl group;

R⁵selected from H, halogen, hydroxy, C_1-6Alkyl, -NR¹¹R¹²And- (CH)₂)_n-R¹³；

R¹¹And R¹²Each independently selected from H, C_1-6Alkyl and-C_1-6alkylene-NR¹⁴R¹⁵Wherein R is¹⁴And R¹⁵Each independently selected from H and C_1-6An alkyl group;

R¹³is 3-12 membered heterocycloalkyl, and R¹³Optionally Boc, -SO₂-C_1-6Alkyl, -SO₂-N-(C_1-6Alkyl radical)₂、C_1-6Alkyl, hydroxy, amino, cyano, acetyl, -O-C_1-6Alkyl, - (CH)₂)_n-aryl, - (CH)₂)_n-heteroaryl, - (CH)₂)_n-C_3-8Cycloalkyl, or-C_3-8Heterocycloalkyl substituted, wherein said-C_3-8Heterocycloalkyl optionally substituted by C_1-6Alkyl substitution;

n is independently 0 or 1;

in some embodiments, R⁰Is methoxy;

in some embodiments, R¹Is halogen;

in some embodiments, R²And R³Is H;

in some embodiments, R⁴is-O-C_1-6An alkyl group;

in some embodiments, R⁶And R⁸Is H, or R⁶And R⁸Joined together to form a key;

in some embodiments, R⁷Is H;

in some embodiments, R⁵Is a 3-12 membered heterocycloalkyl group, said 3-12 membered heterocycloalkyl group optionally being Boc, -SO₂-C_1-6Alkyl, -SO₂-N-(C_1-6Alkyl radical)₂、C_1-6Alkyl, acetyl, -C_3-8Cycloalkyl, or-C_3-8Heterocycloalkyl substituted, wherein said-C_3-8Heterocycloalkyl optionally substituted by C_1-6Alkyl substitution;

in some embodiments, the compounds of the present invention are selected from:

or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof;

the compounds of formula (I) of the present invention may be used in the treatment of FGFR4 mediated diseases; in some embodiments, the FGFR 4-mediated disease is non-small cell lung cancer, gastric cancer, multiple myeloma, liver cancer, bile duct cancer, prostate cancer, skin cancer, ovarian cancer, breast cancer, colon cancer, glioma, and rhabdomyosarcoma, preferably liver cancer and bile duct cancer;

yet another aspect of the present invention is directed to a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier;

in another aspect, the present invention provides a method of treating a FGFR4 mediated disease, the method comprising administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or a composition thereof; in some embodiments, the FGFR 4-mediated disease is non-small cell lung cancer, gastric cancer, multiple myeloma, liver cancer, bile duct cancer, prostate cancer, skin cancer, ovarian cancer, breast cancer, colon cancer, glioma, and rhabdomyosarcoma, preferably liver cancer and bile duct cancer;

in some embodiments of the invention, the subject to which the invention relates is a mammal, including a human.

In another aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, in the manufacture of a medicament for the treatment of an FGFR4 mediated disease; in some embodiments, the FGFR 4-mediated disease is non-small cell lung cancer, gastric cancer, multiple myeloma, liver cancer, bile duct cancer, prostate cancer, skin cancer, ovarian cancer, breast cancer, colon cancer, glioma, and rhabdomyosarcoma, preferably liver cancer and bile duct cancer;

Detailed Description

The features and advantages of the present invention may be better understood by referring to the following detailed description of the invention.

It should be understood that the scope of the various aspects of the invention is defined by the claims and that methods and structures within the scope of these claims and their equivalents are intended to be covered thereby.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

Unless otherwise specified, the use of the term "or" means "and/or" unless otherwise specified, and other forms, such as "comprises," "comprising," and "including" are not limiting.

Certain chemical terms

The terms "optionally," "optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.Represents "unsubstituted alkyl" or "substituted alkyl" and the optionally substituted group may be unsubstituted (e.g.: CH)₂CH₃) Fully substituted (e.g.: -CF₂CF₃) Monosubstituted (e.g.: -CH₂CH₂F) Or any level between mono-and fully substituted (e.g.: -CH₂CHF₂、-CF₂CH₃、-CFHCHF₂One skilled in the art will appreciate that any substitution or substitution pattern for any group containing one or more substituents that is not sterically impossible and/or cannot be synthesized is not introduced.

Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, nuclear magnetism, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacological methods, are used unless specifically defined otherwise, the nomenclature for analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry, and the experimental procedures and techniques known in the art, standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients, for example, the instructions for the use of the kits by the manufacturer, or the manner and purification performed as is known in the art or the description of the invention, and the techniques and methods described above can generally be performed according to conventional methods well known in the art as described in the various general and more specific documents cited and discussed in the present specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents as obtained when the formula is written from right to left₂O-is equivalent to-OCH₂-.

As used herein, the terms "group," "chemical group," and "chemical group" refer to a particular moiety or functional group of a molecule.

Some of the chemical groups named herein may beThe total number of carbon atoms is indicated by shorthand notation, e.g. C₁-C₆Alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms the total number of carbon atoms indicated by the shorthand notation does not include carbon atoms on possible substituents.

The terms "halogen", "halo" or "halide" refer to bromine, chlorine, fluorine or iodine.

The terms "aromatic", "aromatic ring", "aromatic" and "aromatic-cyclic" as used herein refer to a planar ring portion of one or more rings having a delocalized electron-conjugated system of 4n +2 electrons, where n is an integer.

The terms "heteroatom" or "hetero", as used herein alone or as part of another ingredient, refer to atoms other than carbon and hydrogen, heteroatoms are independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin.

The terms "fused" or "fused ring" as used herein, alone or in combination, refer to a cyclic structure in which two or more rings share one or more bonds.

The term "spiro" or "spirocyclic" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

The term "alkyl" as used herein alone or as part of another component (e.g., monoalkylamino) refers to an optionally substituted straight or optionally substituted branched chain monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3 methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.

The term "alkylene" as used herein, alone or in combination, refers to a divalent radical derived from a monovalent alkyl radical as defined above₂) Ethylene (-CH)₂CH₂) Propylene (-CH)₂CH₂CH₂) And isopropylidene (-CH (CH)₃)CH₂) And the like.

The term "cycloalkyl" as used herein alone or as part of another ingredient refers to a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms, and may include fused, spiro or bridged ring systems containing 3 to 15 ring-forming carbon atoms, preferably 3 to 10 ring-forming carbon atoms, more preferably 3 to 8 ring-forming carbon atoms, which may or may not be saturated, attached to the rest of the molecule by single bonds non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The terms "heterocyclyl", "heterocycloalkyl", "heterocycle", as used herein alone or as part of another ingredient, refer to a stable 3-18 membered monovalent non-aromatic ring, including 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur unless otherwise specified, a heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can contain fused, spiro or bridged ring systems, the nitrogen, carbon or sulfur in the heterocyclyl group can be selectively oxidized, the nitrogen atom can be optionally quaternized, the heterocyclyl group can be partially or fully saturated, the heterocyclyl group can be attached to the remainder of the molecule by a single bond through a carbon or heteroatom in the ring. The heterocyclic group is preferably a stable 4-to 11-membered monovalent non-aromatic monocyclic or bicyclic ring containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-to 8-membered monovalent non-aromatic monocyclic ring, non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.

The terms "aromatic ring", "aromatic ring radical", "aromatic radical", "aryl" or the prefix "aryl" (as in "aralkyl") as used herein alone or as part of another ingredient refer to a hydrocarbon ring system containing hydrogen, 6 to 18 ring-forming carbon atoms, preferably 6 to 10 ring-forming carbon atoms, and at least one aromatic ring₆-C₁₀More preferably phenyl.

The term "heteroaryl" as used herein alone or as part of another ingredient refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, at least one aromatic ring unless otherwise specified, the heteroaryl may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused or bridged ring systems, provided that the point of attachment to the rest of the molecule is an aromatic ring atom, the nitrogen, carbon and sulfur atoms on the heteroaryl ring may optionally be oxidized, and the nitrogen atom may optionally be quaternized for purposes of this invention, the heteroaryl is preferably a stable 4-11 membered monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5-8 membered monocyclic ring, non-limiting examples of heteroaryl groups comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxolyl, benzofuranonyl, benzofuranyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, furanyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinuclidinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl and the like in the present application, heteroaryl groups are preferably 5-8 membered heteroaryl groups comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridyl, pyrimidyl or thiazolyl.

The term "polymorph" or "polymorph" as used herein refers to a compound of the invention having a plurality of crystal lattice morphologies some compounds of the invention may have more than one crystal form, and the invention encompasses all polymorphs or mixtures thereof.

Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

Unless otherwise specified, the compounds of the present invention contain olefinic double bonds including E and Z isomers.

It is understood that the compounds of the present invention may contain asymmetric centers which may independently be in the R or S configuration, and that some of the compounds of the present invention may also exhibit cis-trans isomerism, as will be apparent to those skilled in the art.

The term "pharmaceutically acceptable salts" as used herein includes both acid and base salts.

"pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological potency and properties of the free base of the compound, are not biologically or otherwise undesirable, and are formed with inorganic acids, such as, but not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like, or organic acids, such as, but not limited to, acetic, 2-dichloroacetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic, benzoic, capric, caproic, carbonic, cinnamic, citric, and the like Lithium salt, ammonium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, aluminum salt, etc. preferred inorganic salts are ammonium salt, sodium salt, potassium salt, calcium salt, and manganese salt.

Salt-forming organic bases include, but are not limited to, primary, secondary, tertiary, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine, and the like.

The term "solvate" as used herein refers to a combination of one or more molecules of a compound of the present invention and one or more molecules of a solvent.

The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may simply be water or a mixture of water and some other solvent may be retained by chance.

The term "pharmaceutical composition" as used herein refers to a formulation mixed with a compound of the present invention and a vehicle generally accepted in the art for delivering biologically active compounds to a mammal, such as a human.

As used herein, the term "acceptable" in reference to a formulation, composition or ingredient means that there is no lasting deleterious effect on the overall health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.

"pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant governmental authorities for use in humans and domestic animals.

The term "subject," "patient," "subject" or "individual" as used herein refers to an individual, including mammals and non-mammals, suffering from a disease, disorder or condition, among others. Humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; in one embodiment of the methods and compositions provided herein, the mammal is a human.

The term "treatment" as used herein refers to the treatment of a disease or condition associated with a mammal, particularly a human, and includes

(i) Preventing the development of a disease or condition in a mammal, particularly a mammal that has previously been exposed to the disease or condition but has not been diagnosed as having the disease or condition;

(ii) inhibiting the disease or disorder, i.e., controlling its development;

(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition;

(iv) relieving symptoms caused by the disease or disorder.

The terms "disease" and "condition" as used herein may be used interchangeably and may have different meanings, as certain specific diseases or conditions have no known causative agent (and therefore the cause of the disease is not yet clear) and therefore are not considered as a disease but can be considered as an unwanted condition or syndrome, with more or less specific symptoms being confirmed by clinical researchers.

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to provide some relief from one or more symptoms of the disease or disorder being treated upon administration.

The terms "administration," "administering," "administration," and the like, as used herein, refer to methods capable of delivering a compound or composition to a desired site for biological action.

Preparation of the Compounds of the invention

The following non-limiting examples are illustrative only and do not limit the invention in any way.

Reagents are commercially available from national pharmaceutical group chemical reagents, Beijing, Inc., Affa Aesar, or Beijing carbofuran technologies, Inc., and these reagents can be used directly without further purification unless otherwise indicated.

Unless otherwise stated, the following reactions are carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or argon, or using a drying tube; glassware was dried and/or heat dried.

Unless otherwise stated, column chromatography purification was performed using 200-300 mesh silica gel from Qingdao oceanic plants; preparation of thin-layer chromatography silica gel precast slab (HSGF254) produced by Nicoti chemical industry research institute was used; MS was measured using a Thermo LCQ fly model (ESI) liquid chromatography-mass spectrometer.

Nuclear magnetic data (¹H NMR) was run at 400MHz using a Varian apparatus the solvent used for nuclear magnetic data was CDCl₃、CD₃OD、D₂O, DMSO-d6, based on tetramethylsilane (0.00ppm) or based on residual solvent (CDCl)₃：7.26ppm；CD₃OD：3.31ppm；D₂O: 4.79 ppm; d 6-DMSO: 2.50ppm) when indicating the diversity of the peak shapes, the following abbreviations indicate the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet triplet).

Example 1:

n- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (2-oxa-8-azaspiro [4.5] decan-8-yl) phenyl) acrylamide

Step 1: synthesis of Compound 3

To a solution of compound 1(2g) in N-methylpyrrolidone (15mL) were added compound 2(2.49g) and potassium carbonate (5.29g), the reaction solution was heated to 100 ℃ to react overnight, the reaction solution was cooled to room temperature and poured into water, and filtered, and the filter cake was washed with distilled water and dried to obtain compound 3(3.58g).

Step 2: synthesis of Compound 4

To a solution of compound 3(3.58g) in THF (100mL) at-20 ℃ was added dropwise sulfuryl chloride (2.3mL), the reaction solution was stirred at that temperature for 2 hours, quenched with saturated aqueous sodium bicarbonate solution, allowed to stand for separation, the organic phase was separated, the resulting aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (dichloromethane/methanol 100/1) to obtain compound 4(3.24g).

And step 3: synthesis of Compound 5

Chloroacetaldehyde (18mL) was added to a solution of compound 4(3.24g) in ethanol (18mL), the reaction was heated to 80 ℃ and reacted overnight, the reaction was poured into water and filtered, and the obtained solid was dried to obtain compound 5(3.1g).

And 4, step 4: synthesis of Compound 7

To a dioxane/water (20mL/5mL) solution of compound 5(1.23g) was added tetrakis (triphenylphosphine) palladium (500mg), compound 6(1.5g) and anhydrous sodium carbonate (1.5g) under nitrogen protection, the reaction was heated to 80 ℃ and reacted overnight, the reaction was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was isolated and purified by flash silica gel column chromatography (dichloromethane/methanol-500/1) to give compound 7(1.12g).

And 5: synthesis of Compound 8

To a solution of compound 7(200mg) in DMF (1mL), anhydrous cesium carbonate (120mg) and morpholine (0.1mL) were added, and the mixture was heated to 60 ℃ to react overnight, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was subjected to separation and purification by flash silica gel column chromatography (dichloromethane/methanol 100/1 to 50/1) to obtain compound 8(120mg).

Step 6: synthesis of Compound 9

To a solution of compound 8(120mg) in tetrahydrofuran (5mL) was added palladium on carbon (50mg), and the system was substituted for hydrogen gas, the reaction system was reacted at room temperature overnight and filtered through celite, and the filtrate was concentrated under reduced pressure to obtain compound 9(71mg).

And 7: synthesis of Compound 10

DIEA (5 μ L) and acryloyl chloride (11 μ L) were added to a dichloromethane (2mL) solution of compound 9(71mg) while cooling on ice, the reaction was stirred for 2h in an ice bath, quenched with methanol and concentrated under reduced pressure, and the resulting residue was isolated and purified by preparative thin layer chromatography (dichloromethane/methanol ═ 30/1) to give compound 10(35mg).¹H NMR(400MHz，CDCl₃)，9.21(1H，s)，9.00(1H，s)，8.35(1H，s)，8.22(1H，s)，8.12(1H，d，J＝1.2Hz)，7.69(1H，d，J＝1.2Hz)，7.50(1H，s)，6.81(1H，s)，6.70(1H，s)，6.42(1H，d，J＝16.8Hz)，6.30(1H，dd，J＝16.8Hz，10.0Hz)，5.77(1H，d，J＝10.0Hz)，3.97(6H，s)，3.91-3.95(5H，m)，3.68(2H，s)，2.85-2.99(4H，m)，1.87(2H，t，J＝7.2Hz)，1.78-1.83(4H，m).

Example 2

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (7-oxa-2-azaspiro [3.5] nonan-2-yl) phenyl) acrylamide

The synthesis method of example 2 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.12(1H，s)，8.41(1H，s)，8.11(1H，s)，8.01(1H，s)，7.68(1H，s)，7.46(1H，s)，7.22(1H，s)，6.70(1H，s)，6.42(1H，d，J＝16.8Hz)，6.31(1H，dd，J＝16.8Hz，10.8Hz)，6.09(1H，s)，5.78(1H，d，J＝10.8Hz)，3.97(6H，s)，3.94(3H，s)，3.77(4H，s)，3.60-3.67(4H，m)，1.77-1.83(4H，m).

Example 3

N- (2- (8-cyclopropyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 3 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.20(1H，s)，8.95(1H，s)，8.42(1H，s)，8.37(1H，s)，8.13(1H，s)，7.69(1H，s)，7.49(1H，s)，7.02-7.13(1H，brs)，6.70(1H，s)，6.45(1H，d，J＝16.8Hz)，6.30(1H，dd，J＝16.8Hz，10.0Hz)，5.78(1H，d，J＝10.0Hz)，3.96(6H，s)，3.88(3H，s)，3.21-3.78(4H，m)，2.79(2H，d，J＝10.4Hz)，2.20-2.38(2H，m)，1.97-2.18(3H，m)，0.81-0.91(2H，m)，0.56-0.70(2H，m).

Example 4

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (tetrahydro-1H-furo [3, 4-c ] pyrrol-5 (3H) -yl) phenyl) acrylamide

The synthesis method of example 4 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.20(1H，s)，8.87(1H，s)，8.37(1H，s)，8.15(1H，s)，8.12(1H，d，J＝1.6Hz)，7.68(1H，d，J＝1.6Hz)，7.49(1H，s)，6.79(1H，s)，6.70(1H，s)，6.43(1H，d，J＝17.2Hz)，6.30(1H，dd，J＝17.2Hz，10.0Hz)，5.76(1H，d，J＝10.0Hz)，3.88-4.01(11H，m)，3.76(2H，d，J＝10.0Hz)，3.17-3.24(2H，m)，2.96-3.07(4H，m).

Example 5

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (4-oxa-7-azaspiro [2.5] oct-7-yl) phenyl) acrylamide

The synthesis method of example 5 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.20(1H，s)，9.01(1H，s)，8.37(2H，s)，8.12(1H，s)，7.69(1H，s)，7.49(1H，s)，6.88(1H，s)，6.70(1H，s)，6.44(1H，d，J＝16.8Hz)，6.29(1H，dd，J＝16.8Hz，10.8Hz)，5.78(1H，d，J＝10.8Hz)，3.90-4.01(11H，m)，3.10(2H.t，J＝7.2Hz)，2.87(2H，s)，0.91-0.99(2H，m)，0.58-0.66(2H，m).

Example 6

N- (2- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 6 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.19(1H，s)，8.85(1H，s)，8.38(1H，s)，8.12(1H，s)，7.84(1H，s)，7.68(1H，s)，7.49(1H，s)，6.70(1H，s)，6.61(1H，s)，6.43(1H，d，J＝16.8Hz)，6.29(1H，dd，J＝16.8Hz，10.4Hz)，5.78(1H，d，J＝10.4Hz)，3.88-3.98(11H，m)，3.75(2H，d，J＝10.8Hz)，3.62-3.65(2H，m)，2.01-2.18(4H，m).

Example 7

N- (2- (8-acetyl-3, 8-diazabicyclo [3.2.1] octan-3-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 7 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.21(1H，s)，8.99(1H，s)，8.36(1H，s)，8.32(1H，s)，8.12(1H，d，J＝1.6Hz)，7.69(1H，d，J＝1.6Hz)，7.50(1H，s)，6.86(1H，s)，6.70(1H，s)，6.46(1H，d，J＝16.8Hz)，6.28(1H，dd，J＝16.8Hz，10.0Hz)，5.80(1H，d，J＝10.0Hz)，4.85-4.90(1H，m)，4.24-4.28(1H，m)，3.97(6H，s)，3.90(3H，s)，3.21(1H，d，J＝9.6Hz)，2.93-3.01(2H，m)，2.85(1H，d，J＝9.6Hz)，1.98-2.28(7H，m).

Example 8

N- (2- (3-cyclopropyl-3, 8-diazabicyclo [3.2.1] octan-8-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 8 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.01(1H，s)，8.41(1H，s)，8.27(1H，s)，8.09(1H，s)，7.49(1H，s)，7.40(1H，s)，6.63(1H，s)，6.51(1H，s)，6.19-6.33(2H，m)，5.67(1H，d，J＝10.0Hz)，3.97(3H，s)，3.86(6H，s)，3.57-3.63(2H，m)，3.19-3.24(1H，m)，2.76(2H，d，J＝10.8Hz)，2.54(2H，d，J＝10.8Hz)，1.68-1.83(4H，m)，0.29-0.36(2H，m)，0.19-0.25(2H，m).

Example 9

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (4, 7-diazaspiro [2.5] oct-7-yl) phenyl) acrylamide trifluoroacetate salt

The synthesis method of example 9 is the same as that of example 1.¹H NMR(400MHz，DMSO)，9.44(2H，s)，9.32(1H，s)，9.28(1H，s)，8.79(1H，s)，8.73(1H，s)，8.34(1H，s)，7.80(1H，s)，7.68(1H，s)，7.08(1H，s)，6.88(1H，s)，6.62(1H，dd，J＝16.8Hz，10.0Hz)，6.23(1H，d，J＝16.8Hz)，5.75(1H，d，J＝10.0Hz)，3.99(6H，s)，3.96(3H，s)，3.39-3.48(2H，m)，3.23-3.32(2H，m)，3.05(2H，s)，1.06-1.12(2H，m)，0.83-0.90(2H，m).

Example 10

N- (2- (4-cyclopropyl-4, 7-diazaspiro [2.5] octan-7-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 10 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.20(1H，s)，8.99(1H，s)，8.47(1H，s)，8.35(1H，s)，8.12(1H，s)，7.69(1H，s)，7.49(1H，s)，6.90(1H，s)，6.70(1H，s)，6.43(1H，d，J＝16.8Hz)，6.29(1H，dd，J＝16.8Hz，10.0Hz)，5.78(1H，d，J＝10.0Hz)，3.97(6H，s)，3.90(3H，s)，3.02-3.21(4H，m)，2.63-2.85(2H，m)，1.95-2.15(1H，m)，1.02-1.16(2H，m)，0.40-0.61(6H，m).

Example 11

N- (2- (4-acetyl-4, 7-diazaspiro [2.5] octan-7-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 11 is the same as that of example 1.¹H NMR(400MHz，DMSO)，9.28(1H，s)，9.22(1H，s)，8.72(1H，d，J＝1.2Hz)，8.70(1H，s)，8.32(1H，s)，7.72(1H，s)，7.60(1H，d，J＝1.2Hz)，7.07(1H，s)，6.95(1H，s)，6.57(1H，dd，J＝16.8Hz，10.4Hz)，6.23(1H，dd，J＝16.8Hz，1.6Hz)，5.75(1H，d，J＝10.4Hz)，3.67-4.05(11H，m)，2.65-3.12(4H，m)，2.13(2.4H，s)，2.03(0.6H，s)，0.78-1.06(4H，m).

Example 12

N- (2- (4-Cyclopropylpiperazin-1-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) vinylsulfonamide

The synthesis method of example 12 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.20(1H，s)，8.39(1H，s)，8.11(2H，s)，7.70(1H，s)，7.49(1H，s)，7.40-7.47(1H，brs)，6.93(1H，s)，6.70(1H，s)，6.66(1H，dd，J＝16.4Hz，9.6Hz)，6.42(1H，d，J＝16.4Hz)，6.01(1H，d，J＝9.6Hz)，3.98(6H，s)，3.89(3H，s)，3.63-3.69(1H，m)，2.84-3.14(4H，m)，1.66-1.92(4H，m)，0.80-0.90(2H，m)，0.56-0.66(2H，m).

Example 13

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -2- (4- (N, N-dimethylsulfonylamino) piperazin-1-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 13 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.21(1H，s)，8.99(1H，s)，8.36(1H，s)，8.12(2H，s)，7.69(1H，s)，7.50(1H，s)，6.84(1H，s)，6.70(1H，s)，6.42(1H，d，J＝16.8Hz)，6.29(1H，dd，J＝16.8Hz，10.4Hz)，5.78(1H，d，J＝10.4Hz)，3.97(6H，s)，3.92(3H，s)，3.43-3.48(4H，m)，3.01-3.06(4H，m)，2.90(6H，s).

Example 14

N- (2- (7-acetyl-2, 7-diazaspiro [3.5] nonan-2-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 14 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.07(1H，s)，8.39(1H，s)，8.10(1H，s)，7.95(1H，s)，7.70-7.82(1H，brs)，7.65(1H，s)，7.43(1H，s)，6.68(1H，s)，6.36-6.44(2H，m)，5.99-6.04(1H，m)，5.70-5.75(1H，m)，3.95(6H，s)，3.90(3H，s)，3.69-3.81(4H，m)，3.48-3.55(2H，m)，3.29-3.38(2H，m)，2.06(3H，s)，1.69-1.80(4H，m).

Example 15

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -2- (7, 7-dioxo-7-thio-2-azaspiro [3.5] nonan-2-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 15 is the same as that of example 1.¹H NMR(400MHz，DMSO)，9.39(1H，s)，9.20(1H，s)，8.67(1H，s)，8.66(1H，s)，7.88(1H，s)，7.66(1H，s)，7.58(1H，s)，7.06(1H，s)，6.46(1H，dd，J＝16.8Hz，10.4Hz)，6.20(1H，dd，J＝16.8Hz，1.6Hz)，6.15(1H，s)，5.69(1H，dd，J＝10.4Hz，1.6Hz)，3.98(6H，s)，3.95(3H，s)，3.80(4H，s)，3.08-3.13(4H，m)，2.17-2.23(4H，m).

Example 16

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (1-oxa-8-azaspiro [4.5] decan-8-yl) phenyl) acrylamide

The synthesis method of example 16 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.20(1H，s)，8.99(1H，s)，8.36(1H，s)，8.31(1H，s)，8.12(1H，s)，7.68(1H，s)，7.49(1H，s)，6.90(1H，s)，6.70(1H，s)，6.41(1H，d，J＝16.8Hz)，6.28(1H，dd，J＝16.8Hz，10.4Hz)，5.75(1H，d，J＝10.4Hz)，3.97(6H，s)，3.91(2H，t，J＝6.8Hz)，3.90(3H，s)，3.07-3.13(2H，m)，2.85-2.92(2H，m)，1.99(2H，qui，J＝6.8Hz)，1.77-1.91(6H，m).

Example 17

N- (2- (7-cyclopropyl-2, 7-diazaspiro [3.5] nonan-2-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 17 was the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.04(1H，s)，9.38(1H，s)，8.24(1H，s)，8.09(1H，s)，7.94(1H，s)，7.63(1H，s)，7.40(1H，s)，6.67(1H，s)，6.49(1H，dd，J＝16.8Hz，10.0Hz)，6.38(1H，d，J＝16.8Hz)，6.01(1H，s)，5.70(1H，d，J＝10.0Hz)，3.93(6H，s)，3.89(3H，s)，3.74(4H，s)，2.62-2.98(4H，m)，1.89-2.06(5H，m)，0.79-0.88(2H，m)，0.55-0.64(2H，m).

Example 18

N- (2- (6-cyclopropyl-2, 6-diazaspiro [3.4] octan-2-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 18 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.10(1H，s)，8.41(1H，s)，8.11(1H，s)，7.99(1H，s)，7.60-7.75(2H，m)，7.44(1H，S)，6.69(1H，s)，6.38-6.45(2H，m)，6.07(1H，s)，5.74-5.77(1H，m)，3.88-4.09(11H，m)，2.92-3.24(4H，m)，2.16-2.25(2H，m)，1.88-2.06(3H，m)，0.80-0.90(2H，m)，0.53-0.62(2H，m).

Example 19

N- (2- (9-cyclopropyl-3, 9-diazaspiro [5.5] undecan-3-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 19 is the same as that of example 1.¹H NMR(400MHz，DMSO)，9.27(1H，s)，9.09(1H，s)，8.70(1H，s)，8.69(1H，s)，8.40(1H，s)，7.70(1H，s)，7.59(1H，s)，7.06(1H，s)，6.85(1H，s)，6.65(1H，dd，J＝16.8Hz，10.4Hz)，6.22(1H，d，J＝16.8Hz)，5.71(1H，d，J＝10.4Hz)，3.98(6H，s)，3.94(3H，s)，2.88-2.96(4H，m)，1.36-2.02(13H，m)，0.96-1.12(2H，m)，0.66-0.86(2H，m).

Example 20

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (2-oxa-6-azaspiro [3.4] oct-6-yl) phenyl) acrylamide

The synthesis method of example 20 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.14(1H，s)，8.41(1H，s)，8.35(1H，s)，8.11(1H，s)，7.68(1H，s)，7.47(1H，s)，7.42(1H，s)，6.70(1H，s)，6.51(1H，s)，6.42(1H，d，J＝16.4Hz)，6.29(1H，dd，J＝16.4Hz，10.0Hz)，5.77(1H，d，J＝10.0Hz)，4.64-4.71(4H，m)，3.97(6H，s)，3.94(3H，s)，3.55(2H，s)，3.33(2H，t，J＝7.2Hz)，2.27(2H，t，J＝7.2Hz).

Example 21

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (3-oxa-9-azaspiro [5.5] undecan-9-yl) phenyl) acrylamide

The synthesis method of example 21 was the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.20(1H，s)，8.99(1H，s)，8.36(1H，s)，8.21(1H，s)，8.12(1H，d，J＝1.6Hz)，7.69(1H，d，J＝1.2Hz)，7.50(1H，s)，6.86(1H，s)，6.70(1H，s)，6.42(1H，d，J＝16.8Hz)，6.30(1H，dd，J＝16.8Hz，10.4Hz)，5.77(1H，d，J＝10.4Hz)，3.97(6H，s)，3.92(3H，s)，3.71-3.75(4H，m)，2.90-2.95(4H，m)，1.74-1.79(4H，m)，1.61-1.66(4H，m).

Example 22

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (7-methyl-2, 7-diazaspiro [4.4] nonan-2-yl) phenyl) acrylamide

The synthesis method of example 22 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.08(1H，s)，8.42(1H，s)，8.11(1H，s)，8.09(1H，s)，7.66(1H，s)，7.44(1H，s)，6.67-6.71(2H，m)，6.49-6.61(1H，m)，6.41(1H，d，J＝16.8Hz)，6.36(1H，s)，5.73(1H，d，J＝10.8Hz)，3.93-4.01(13H，m)，3.37-3.56(4H，m)，2.81(3H，s)，1.99-2.26(4H，m).

Example 23

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (4-methyl-4, 7-diazaspiro [2.5] oct-7-yl) phenyl) acrylamide

The synthesis method of example 23 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.21(1H，s)，9.02(1H，s)，8.44(1H，s)，8.36(1H，s)，8.12(1H，d，J＝1.2Hz)，7.69(1H，d，J＝1.2Hz)，7.50(1H，s)，6.90(1H，s)，6.70(1H，s)，6.44(1H，d，J＝16.8Hz)，6.30(1H，dd，J＝16.8Hz，10.0Hz)，5.78(1H，d，J＝10.0Hz)，3.98(6H，s)，3.93(3H，s)，3.09-3.13(2H，m)，3.02-3.08(2H，m)，2.67-2.78(2H，m)，2.46(3H，s)，0.84-0.90(2H，m)，0.49-0.52(2H，m).

Example 24

N- (2- (5-Cyclopropylhexahydropyrrolo [3, 4-c ] pyrrol-2 (1H) -yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 24 is the same as that of example 1.¹H NMR(400MHz，DMSO)，9.25(1H，s)，9.05(1H，s)，8.70(2H，s)，8.17(1H，s)，7.69(1H，s)，7.59(1H，s)，7.06(1H，s)，6.61-6.74(2H，m)，6.21-6.30(1H，m)，5.69-5.78(1H，m)，3.94-4.01(9H，m)，3.54-3.63(4H，m)，3.06-3.14(4H，m)，2.90-3.02(3H，m)，1.20-1.30(2H，m)，0.74-0.84(2H，m).

Example 25

N- (2- (8-cyclopropyl-2, 8-diazaspiro [4.5] decan-2-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 25 is the same as that of example 1.¹H NMR(400MHz，DMSO)，9.52(1H，s)，9.20(1H，s)，8.68(1H，s)，8.66(1H，s)，7.91(1H，s)，7.66(1H，s)，7.58(1H，s)，7.06(1H，s)，6.38-6.51(2H，m)，6.19(1H，d，J＝16.8Hz)，5.70(1H，d，J＝10.4Hz)，3.99(3H，s)，3.98(6H，s)，3.38-3.54(4H，m)，3.14-3.30(4H，m)，2.76-2.94(1H，m)，1.69-1.91(4H，m)，1.39-1.62(2H，m)，0.96-1.12(2H，m)，0.69-0.87(2H，m).

Example 26

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (2-oxa-7-azaspiro [4.4] nonane 7-yl) phenyl) but-2-ynylamide

The synthesis method of example 26 was the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.15(1H，s)，8.40(1H，s)，8.15(1H，s)，8.11(1H，s)，7.68(1H，s)，7.62(1H，s)，7.46(1H，s)，6.70(1H，s)，6.42(1H，s)，3.89-3.97(11H，m)，3.75(1H，d，J＝8.4Hz)，3.67(1H，d，J＝8.4Hz)，3.44-3.49(2H，m)，3.34(1H，d，J＝9.2Hz)，3.30(1H，d，J＝9.2Hz)，1.88-2.03(7H，m).

Example 27

N- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) but-2-ynylamide

The synthesis method of example 27 was the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.16(1H，s)，8.39(1H，s)，8.26(1H，s)，8.11(1H，s)，7.68(1H，s)，7.53(1H，s)，7.47(1H，s)，6.70(1H，s)，6.49(1H，s)，4.65(1H，s)，4.29(1H，s)，4.10(1H，d，J＝8.0Hz)，3.97(6H，s)，3.93(3H，s)，3.87(1H，d，J＝8.0Hz)，3.49(1H，d，J＝9.2Hz)，3.49(1H，d，J＝9.2Hz)，1.96-2.06(5H，m).

Example 28

N- (2- (3-oxa-8-azabicyclo [3.2.1] oct-8-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) but-2-ynylamide

The synthesis method of example 28 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.19(1H，s)，8.67(1H，s)，8.34(1H，s)，8.11(1H，s)，7.88(1H，s)，7.68(1H，s)，7.49(1H，s)，6.70(1H，s)，6.60(1H，s)，3.93-4.01(8H，m)，3.89(3H，s)，3.76-3.79(2H，m)，3.64-3.68(2H，m)，2.01-2.17(7H，m).

Example 29

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2-morpholinophenyl) but-2-ynylamide

The synthesis method of example 29 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.21(1H，s)，8.80(1H，s)，8.33(1H，s)，8.25(1H，s)，8.12(1H，s)，7.68(1H，s)，7.49(1H，s)，6.84(1H，s)，6.70(1H，s)，3.96(6H，s)，3.89-3.95(7H，m)，2.95-2.98(4H，m)，2.03(3H，s).

Example 30

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -2- (1, 1-dioxothiomorpholine) -4-methoxyphenyl) but-2-ynylamide

The synthesis method of example 30 is the same as that of example 1.¹H NMR(400MHz，CDCl3)，9.22(1H，s)，8.74(1H，s)，8.33(1H，s)，8.12(1H，s)，7.96(1H，s)，7.70(1H，s)，7.51(1H，s)，6.87(1H，s)，6.71(1H，s)，3.98(6H，s)，3.92(3H，s)，3.49-3.53(4H，m)，3.31-3.35(4H，m)，2.05(3H，s).

Example 31

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (4-morpholinepidin-1-yl) phenyl) but-2-ynylamide

The synthesis method of example 31 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.21(1H，s)，8.79(1H，s)，8.32(1H，s)，8.17(1H，s)，8.11(1H，d，J＝1.2Hz)，7.69(1H，d，J＝1.2Hz)，7.49(1H，s)，6.82(1H，s)，6.70(1H，s)，3.97(6H，s)，3.79-3.92(7H，m)，3.18-3.24(2H，m)，2.61-2.84(6H，m)，2.13-2.23(1H，m)，2.04(3H，s)，1.59-1.91(4H，m).

Example 32

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (4-methyl-4, 7-diazaspiro [2.5] oct-7-yl) phenyl) but-2-ynylamide

The synthesis method of example 32 was the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.21(1H，s)，8.79(1H，s)，8.32(2H，s)，8.11(1H，d，J＝1.2Hz)，7.69(1H，d，J＝1.2Hz)，7.49(1H，s)，6.86(1H，s)，6.70(1H，s)，3.98(6H，s)，3.92(3H，s)，3.02-3.28(4H，m)，2.38-2.87(5H，m)，2.04(3H，s)，0.79-0.96(2H，m)，0.61-0.77(2H，m).

Example 33

N- (5- (6- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1 ', 2': 1, 6] pyrido [2, 3-d ] pyrimidin-2-yl) -4-methoxy-2- (4- (oxetan-3-yl) piperazin-1-yl) phenyl) acrylamide

The synthesis method of example 33 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.34(1H，s)，9.07(1H，s)，8.58(1H，s)，8.26(1H，s)，7.68(1H，s)，7.43(1H，s)，6.94(1H，s)，6.71(1H，s)，6.41(1H，d，J＝16.8Hz)，6.28(1H，dd，J＝16.8Hz，10.4Hz)，5.77(1H，d，J＝10.4Hz)，4.66-4.75(4H，m)，3.98(6H，s)，3.93(3H，s)，3.60-3.66(1H，m)，3.02-3.09(4H，m)，2.48-2.64(4H，m).

Example 34

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (5-methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl) phenyl) acrylamide

The synthesis method of example 34 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.07(1H，s)，8.84(1H，s)，8.40(1H，s)，8.35(1H，s)，8.10(1H，s)，7.63(1H，s)，7.42(1H，s)，6.61-6.75(3H，m)，6.39(1H，dd，J＝16.8Hz，1.2Hz)，5.69(1H，d，J＝10.4Hz)，4.44-4.50(1H，m)，4.10-4.20(2H，m)，3.91-3.98(9H，m)，3.64-3.81(1H，m)，3.43-3.52(1H，m)，3.19-3.27(1H，m)，2.87(3H，s)，2.26-2.38(2H，m).

Example 35

N- (2- (4-Cyclopropylpiperazin-1-yl) -5- (6- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1 ', 2': 1, 6] pyrido [2, 3-d ] pyrimidin-2-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 35 is the same as that of example 1.¹H NMR(400MHz，DMSO)，9.55(1H，s)，9.17(1H，s)，8.51(1H，d，J＝1.6Hz)，8.33(1H，s)，7.75(1H，s)，7.64(1H，d，J＝1.6Hz)，7.09(1H，s)，6.87(1H，s)，6.63(1H，dd，J＝16.8Hz，10.4Hz)，6.23(1H，dd，J＝16.8Hz，1.6Hz)，5.73(1H，dd，J＝10.4Hz，1.6Hz)，3.99(6H，s)，3.89(3H，s)，2.92-2.97(4H，m)，2.74-2.79(4H，m)，1.68-1.74(1H，m)，0.42-0.47(2H，m)，0.30-0.36(2H，m).

Example 36

N- (2- ((1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptan-5-yl) -5- (6- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1 ', 2': 1, 6] pyrido [2, 3-d ] pyrimidin-2-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 36 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.31(1H，s)，8.58(1H，s)，8.55(1H，s)，7.69(1H，s)，7.43(1H，s)，7.39(1H，s)，6.72(1H，s)，6.62(1H，s)，6.46(1H，d，J＝16.8Hz)，6.33(1H，dd，J＝16.8Hz，10.0Hz)，5.81(1H，d，J＝10.0Hz)，4.65-4.69(1H，m)，4.27-4.31(1H，m)，4.12(1H，d，J＝8.0Hz)，3.99(6H，s)，3.97(3H，s)，3.88(1H，d，J＝8.0Hz)，3.42-3.46(2H，m)，1.99-2.09(2H，m).

Example 37

N- (2- (4-acetylpiperazin-1-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 37 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.21(1H，s)，8.99(1H，s)，8.39(1H，s)，8.24(1H，s)，8.14(1H，s)，7.70(1H，s)，7.51(1H，s)，6.81(1H，s)，6.71(1H，s)，6.43(1H，d，J＝16.8Hz)，6.30(1H，dd，J＝16.8Hz，10.0Hz)，5.77(1H，d，J＝10.0Hz)，3.97(6H，s)，3.94(3H，s)，3.79-3.87(2H，m)，3.64-3.70(2H，m)，2.94-2.99(4H，m)，2.17(3H，s).

Example 38

(S) -N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (2-methylmorpholine) phenyl) acrylamide

The synthesis method of example 38 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.21(1H，s)，9.01(1H，s)，8.39(1H，s)，8.28(1H，s)，8.14(1H，d，J＝1.2Hz)，7.68(1H，d，J＝1.2Hz)，7.50(1H，s)，6.83(1H，s)，6.70(1H，s)，6.41(1H，d，J＝16.8Hz)，6.29(1H，dd，J＝16.8Hz，10.0Hz)，5.76(1H，dd，J＝10.0Hz，1.2Hz)，4.04(1H，d，J＝11.6Hz)，3.96(6H，s)，3.92(3H，s)，3.77-3.86(2H，m)，2.88-2.95(3H，m)，2.63(1H，t，J＝10.8Hz)，1.24(3H，t，J＝6.4Hz).

Example 39

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (4- (methylsulfonyl) piperazin-1-yl) phenyl) acrylamide

Synthesis of example 39 and Synthesis of example 1The same is true.¹H NMR(400MHz，CDCl₃)，9.19(1H，s)，8.96(1H，s)，8.37(1H，s)，8.11(1H，d，J＝1.6Hz)，8.10(1H，s)，7.68(1H，d，J＝1.2Hz)，7.49(1H，s)，6.83(1H，s)，6.69(1H，s)，6.42(1H，d，J＝16.8Hz)，6.27(1H，dd，J＝16.8Hz，10.0Hz)，5.76(1H，d，J＝10.0Hz)，3.96(6H，s)，3.91(3H，s)，3.42-3.46(4H，m)，3.05-3.08(4H，m)，2.88(3H，s).

Example 40

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -2- (2, 2-dimethylmorpholine) -4-methoxyphenyl) acrylamide

The synthesis method of example 40 was the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.22(1H，s)，8.99(1H，s)，8.39(1H，s)，8.22(1H，s)，8.13(1H，d，J＝1.2Hz)，7.70(1H，d，J＝1.2Hz)，7.51(1H，s)，6.84(1H，s)，6.71(1H，s)，6.46(1H，d，J＝16.8Hz)，6.26(1H，dd，J＝16.8Hz，10.4Hz)，5.78(1H，d，J＝10.4Hz)，3.92-4.02(11H，m)，2.97(2H，t，J＝4.4Hz)，2.71(2H，s)，1.41(6H，s).

EXAMPLE 41

(R) -N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (2-methylmorpholine) phenyl) acrylamide

The synthesis method of example 41 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.21(1H，s)，8.99(1H，s)，8.39(1H，s)，8.27(1H，s)，8.14(1H，d，J＝1.2Hz)，7.69(1H，d，J＝1.2Hz)，7.51(1H，s)，6.84(1H，s)，6.70(1H，s)，6.41(1H，d，J＝16.8Hz)，6.29(1H，dd，J＝16.8Hz，10.0Hz)，5.77(1H，d，J＝10.0Hz)，4.04(1H，d，J＝11.2Hz)，3.96(6H，s)，3.92(3H，s)，3.78-3.87(2H，m)，2.88-2.98(3H，m)，2.63(1H，dd，J＝11.2Hz，10.0Hz)，1.25(3H，d，J＝6.4Hz).

Example 42

N- (2- (4-Cyclopropylpiperazin-1-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) -2-methylimidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 42 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.17(1H，s)，8.97(1H，s)，8.36(1H，s)，8.28(1H，s)，7.86(1H，s)，7.43(1H，s)，6.85(1H，s)，6.68(1H，s)，6.42(1H，d，J＝16.8Hz)，6.32(1H，dd，J＝16.8Hz，10.0Hz)，5.77(1H，d，J＝10.0Hz)，3.96(6H，s)，3.82(3H，s)，2.75-3.05(8H，m)，2.47(3H，s)，1.70-1.81(1H，m)，0.46-0.61(4H，m).

Example 43

Tert-butyl 2- (2-acrylamido-4- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -5-methoxyphenyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate

The synthesis method of example 43 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.11(1H，s)，8.42(1H，s)，8.11(1H，s)，8.04(1H，s)，7.68(1H，s)，7.45(1H，s)，7.03(1H，s)，6.70(1H，s)，6.42(1H，d，J＝16.8Hz)，6.29(1H，dd J＝16.8Hz，10.0Hz)，6.12(1H，s)，5.78(1H，d，J＝10.0Hz)，3.97(6H，s)，3.95(3H，s)，3.76(4H，s)，3.35-3.41(4H，m)，1.72-1.81(4H，m)，1.46(9H，s).

Example 44

N- (2- (8-oxa-3-azabicyclo [3.2.1] oct-3-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide

The synthesis method of example 44 was the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.22(1H，s)，9.01(1H，s)，8.38(1H，s)，8.36(1H，s)，8.13(1H，d，J＝1.2Hz)，7.71(1H，d，J＝1.2Hz)，7.51(1H，s)，6.93(1H，s)，6.72(1H，s)，6.47(1H，d，J＝16.8Hz)，6.30(1H，dd，J＝16.8Hz，10.0Hz)，5.81(1H，d，J＝10.0Hz)，4.52(2H，s)，3.99(6H，s)，3.92(3H，s)，3.19(2H，d，J＝11.2Hz)，2.78(2H，d，J＝11.2Hz)，2.09-2.05(4H，m).

Example 45

N- (5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxy-2- (2, 7-diazaspiro [3.5] nonan-2-yl) phenyl) acrylamide hydrochloride

The synthesis method of example 45 is the same as that of example 1.¹H NMR(400MHz，CD₃OD)，9.49(1H，s)，9.04(1H，s)，9.01(1H，s)，8.22(1H，s)，8.02(1H，s)，7.91(1H，s)，7.08(1H，s)，6.51(1H，dd，J＝16.8Hz，10.0Hz)，6.41(1H，dd，J＝16.8Hz，2.0Hz)，6.27(1H，s)，5.86(1H，dd，J＝10.0Hz，2.0Hz)，4.07(3H，s)，4.04(6H，s)，3.95(4H，s)，3.21-3.24(4H，m)，2.07-2.11(4H，m).

Example 46

N- (2- (((4- (chloromethyl) piperidin-4-yl) methyl) amino) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acrylamide hydrochloride

The synthesis method of example 46 is the same as that of example 1.¹H NMR(400MHz，CD₃OD)，9.59(1H，s)，9.20(1H，d，J＝2.0Hz)，9.09(1H，s)，8.36(1H，s)，8.14(1H，d，J＝2.0Hz)，7.97(1H，s)，7.11(1H，s)，6.75(1H，s)，6.62(1H，dd，J＝16.8Hz，10.4Hz)，6.41(1H，dd，J＝16.8Hz，1.2Hz)，5.85(1H，dd，J＝10.4Hz，1.2Hz)，4.13(3H，s)，4.05(6H，s)，3.83(2H，s)，3.53(2H，s)，3.30-3.36(2H，m)，3.19-3.25(2H，m)，1.90-2.03(4H，m).

Example 47

N- (2- (4-Cyclopropylpiperazin-1-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) but-2-ynylamide

The synthesis method of example 47 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.22(1H，s)，8.82(1H，s)，8.34(1H，s)，8.30(1H，s)，8.13(1H，s)，7.71(1H，s)，7.51(1H，s)，6.88(1H，s)，6.72(1H，s)，3.99(6H，S)，3.89(3H，s)，2.78-3.11(8H，m)，2.06(3H，s)，1.77-1.84(1H，m)，0.44-0.64(4H，m).

Example 48

(Z) -N- (2- (4-cyclopropylpiperazin-1-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) -4-methoxybut-2-enamide

The synthesis method of example 48 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.21(1H，s)，8.89(1H，s)，8.44(1H，s)，8.33(1H，s)，8.11(1H，s)，7.68(1H，s)，7.49(1H，s)，6.85(1H，s)，6.70(1H，s)，6.25(1H，d，J＝6.0Hz)，4.66-4.72(1H，m)，3.98(6H，s)，3.87(3H，s)，3.72(3H，s)，3.24(2H，d J＝7.6Hz)，2.77-3.24(8H，m)，1.78-1.87(1H，m)，0.47-0.59(4H，m).

Example 49

2-chloro-N- (2- (4-cyclopropylpiperazin-1-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acetamide

The synthesis method of example 49 was the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.48(1H，s)，9.22(1H，s)，8.96(1H，s)，8.37(1H，s)，8.12(1H，d，J＝1.2Hz)，7.70(1H，d，J＝1.2Hz)，7.50(1H，s)，6.92(1H，s)，6.71(1H，s)，4.27(2H，s)，3.98(6H，s)，3.84(3H，s)，2.85-3.08(8H，m)，1.76-1.82(1H，m)，0.49-0.63(4H，m).

Example 50

2-cyano-N- (2- (4-cyclopropylpiperazin-1-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) acetamide

The synthesis method of example 50 was the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.28(1H，s)，9.23(1H，s)，8.92(1H，s)，8.37(1H，s)，8.12(1H，s)，7.70(1H，s)，7.51(1H，s)，6.95(1H，s)，6.71(1H，s)，3.98(6H，s)，3.90(3H，s)，3.62(2H，s)，2.86-3.17(8H，m)，1.76-1.95(1H，m)，0.50-0.79(4H，m).

Example 51

N- (2- (4-Cyclopropylpiperazin-1-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) but-3-ynylamide

The synthesis method of example 51 was the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.21(1H，s)，8.92(1H，s)，8.41(1H，s)，8.34(1H，s)，8.11(1H，d，J＝1.6Hz)，7.69(1H，d J＝1.2Hz)，7.49(1H，s)，6.87(1H，s)，6.70(1H，s)，6.03-6.14(1H，m)，5.38-5.43(2H，m)，3.98(6H，s)，3.87(3H，s)，3.25(2H，d，J＝7.6Hz)，2.77-3.02(8H，m)，1.69-1.89(1H，m)，0.48-0.61(4H，m).

Example 52

(E) -N- (2- (4-cyclopropylpiperazin-1-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) but-2-enamide

The synthesis method of example 52 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.33(1H，s)，9.11(1H，s)，8.48(1H，s)，8.23-8.26(2H，m)，7.81(1H，d，J＝1.2Hz)，7.62(1H，s)，7.08-7.17(1H，m)，7.00(1H，s)，6.83(1H，s)，6.12(1H，d，J＝16.8Hz)，4.10(6H，s)，4.01(3H，s)，2.90-3.20(8H，m)，2.07(3H，d，J＝6.8Hz)，1.83-1.96(1H，m)，0.57-0.80(4H，m).

Example 53

N- (2- (4-cyclopropylpiperazin-1-yl) -5- (4- (2, 6-dichloro-3, 5-dimethoxyphenyl) imidazo [1, 2-a ] [1, 6] naphthyridin-8-yl) -4-methoxyphenyl) propynamide

The synthesis method of example 53 is the same as that of example 1.¹H NMR(400MHz，CDCl₃)，9.23(1H，s)，8.85(1H，s)，8.49-8.55(1H，brs)，8.35(1H，s)，8.13(1H，s)，7.71(1H，s)，7.51(1H，s)，6.90(1H，s)，6.72(1H，s)，3.99(6H，s)，3.91(3H，s)，2.85-3.07(9H，m)，1.74-1.83(1H，m)，0.46-0.61(4H，m).

Biological activity test:

1. in vitro protein activity assay of compounds:

the activity of the compounds was determined by establishing a platform for FGFR-4 kinase activity assay by homogeneous time-resolved fluorescence (HTRF) by diluting the compounds 11 times in a 3-fold gradient from 1000. mu.M in 100% DMSO (12 concentrations in total), and adding 4. mu.L of each concentration to 96. mu.L of reaction buffer (50mM HEPES, pH 7.4, 5mM MnCl)₂，0.1mM NaVO₃0.001% Tween-20, 0.01% BAS, 1mM DTT) was mixed well and used as 4-star compound (final concentration 0.017nM to 1000nM) 2-FGFR-4 kinase (final concentration 1nM) was prepared using reaction buffer, 4-substrate (ATP + TK peptide) (TK peptide) was prepared using reaction buffer,

KinEASE^TMTK, purchased from Cisbio, TK peptide, 1. mu.M final concentration, 25. mu.M final concentration of ATP 2.5. mu.L of 4. mu.L compound was added to a 384 well plate (Optiplate-384, purchased from PerkinElmer), then 5. mu.L of 2. mu.L FGFR-4 kinase was added, centrifuged and mixed, then 2.5. mu.L of 4. mu.L substrate mixture was added to initiate the reaction (total reaction volume 10. mu.L). The 384 well plate was placed in an incubator at 23 ℃ and stirred for 60 minutes, then 5. mu.L of Eu was added³⁺ cryptate-labled anti-phosphotyrosine antibody(

KinEASE^TMTK, purchased from Cisbio), 5. mu.L of Streptavidin-XL-665(

KinEASE^TM_TK, purchased from Cisbio) stop the reaction after 1 hour incubation in the incubator the fluorescence values (320nm excitation, detecting 665nm and 620nm emitted light, ratio enzyme activity) were read on Envision (purchased from Perkinelmer). The activity of the enzyme was measured at 12 concentrations for each compound and the data was calculated using GraphPad prism 5.0 software to obtain the IC of the compound₅₀The value is obtained.

2. Determination of cell proliferation activity of compounds:

using Promega corporation

Human liver cancer cell Hep3b (synergetics cell research center) supplemented with 10% fetal calf serum

Is/are as follows

Culturing in a medium at 37 deg.C under 95% air and 5% CO₂Cultured at 25cm²Or 75cm²Plastic tissue culture bottle

And in the middle, subculturing for 2-3 times in a week.

Hep3b cells at 3X 10³Cell/well Density seeded in 96-well cell culture plates

195 mL/well, and at 37 deg.C, 95% air and 5% CO₂After 24 hours, the test compound is added: the compounds were diluted in DMSO in 3-fold gradients starting at 10mM (in DMSO), 4mL of each concentration was added to 96mL of serum-free medium, and 5mL of the diluted compounds were added to the plates inoculated with the cells, the final concentration of DMSO in the cell culture was 0.1%, and the final concentration of the test compound was 0.3nM to 10mM., and the cells were incubated for 3 days at 37 ℃.

After 3 days, Cell viability was determined by Cell Titer-glo (Promega) kit, and finally the half inhibitory concentration of compound on Cell proliferation, IC, was calculated by the GraphPad Prism 5.0 program₅₀The value is obtained.

TABLE 2 FGFR4 inhibitory Effect of the example Compounds

3. Pharmacokinetic data

Male SD rats, from beijing weitongli laboratory animals technologies ltd, were grouped into 3 groups, each of which was orally administered with a single gavage of the sample suspension to be tested (5mg/kg) respectively, animals were fasted overnight before the experiment for a time period ranging from 10 hours before the administration to 4 hours after the administration, blood was taken at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after the administration, 0.3mL of whole blood was taken through the fundus venous plexus after isoflurane anesthesia using a small animal anesthesia machine, placed in a heparin anticoagulation tube, the sample was centrifuged at 4 ℃, 4000rpm for 5min, plasma was transferred to a centrifuge tube and stored at-80 ℃ until analysis, the sample in the plasma was extracted using protein precipitation, and the extract was analyzed by LC/MS.

Claims (10)

1. A compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof,

wherein

X is N or CH;

R⁰is-O-C_1-6An alkyl group;

R¹selected from H and halogen;

R²and R³Each independently selected from H and C_1-6An alkyl group;

R⁴selected from H, C_1-6Alkyl and-O-C_1-6An alkyl group;

R¹⁴is selected from

R⁶And R⁸Each independently selected from H and C_1-6An alkyl group; or R⁶And R⁸Joined together to form a key;

R⁷selected from H, C_1-6Alkyl, -O-C_1-6Alkyl and-NR⁹R¹⁰Wherein R is⁹And R¹⁰Each independently selected from H and C_1-6An alkyl group;

R⁵selected from H, halogen, hydroxy, C_1-6Alkyl, -NR¹¹R¹²And- (CH)₂)_n-R¹³；

R¹¹And R¹²Each independently selected from H, C_1-6Alkyl and-C_1-6alkylene-NR¹⁴R¹⁵Wherein R is¹⁴And R¹⁵Each independently selected from H and C_1-6An alkyl group;

R¹³is 3-12 membered cycloalkyl, and R¹³Optionally Boc, -SO₂-C_1-6Alkyl, -SO₂-N-(C_1-6Alkyl radical)₂、C_1-6Alkyl, hydroxy, amino, cyano, acetyl, -O-C_1-6Alkyl, - (CH)₂)_n-aryl, - (CH)₂)_n-heteroaryl, - (CH)₂)_n-C_3-8Cycloalkyl, and-C_3-8Heterocycloalkyl substituted, wherein said-C_3-8Heterocycloalkyl optionally substituted by C_1-6Alkyl substitution;

n is independently 0 or 1.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R¹Is a halogen, and the halogen is a halogen,R²and R³Is H.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R⁴is-O-C_1-6An alkyl group.

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R⁶And R⁸Is H, or R⁶And R⁸Joined together to form a key;

5. the compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R⁷Is H.

6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R⁵Is a 3-12 membered heterocycloalkyl group, said 3-12 membered heterocycloalkyl group optionally being Boc, -SO₂-C_1-6Alkyl, -SO₂-N-(C_1-6Alkyl radical)₂、C_1-6Alkyl, acetyl, -C_3-8Cycloalkyl, or-C_3-8Heterocycloalkyl substituted, wherein said-C_3-8Heterocycloalkyl optionally substituted by C_1-6Alkyl substitution;

7. a compound selected from:

or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof;

8. a pharmaceutical composition comprising a compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier.

9. Use of a compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a composition according to claim 8, in the manufacture of a medicament for treating an FGFR4 mediated disease.

10. The use of claim 9, wherein the FGFR 4-mediated disease is non-small cell lung cancer, gastric cancer, multiple myeloma, liver cancer, cholangiocarcinoma, prostate cancer, skin cancer, ovarian cancer, breast cancer, colon cancer, glioma, and rhabdomyosarcoma.