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MULTI-SUBSTITUTED PYRIDONE DERIVATIVES AND MEDICAL USE THEREOF

20210355107 · 2021-11-18

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to multi-substituted pyridone derivatives and therapeutic use thereof. In particular, the present invention relates to a compound of formula (I), a preparation method therefor, a pharmaceutical composition comprising the same, as well as use thereof as a tyrosine kinase inhibitor, in particular, use thereof in treating a disease associated with tyrosine kinase activity. Each substituent in the formula (I) is defined as in the specification.

    ##STR00001##

    Claims

    1. A compound of formula (I), ##STR00140## or a mesomer thereof, a racemate, an enantiomer, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, “custom-character” represents a single bond or a double bond; X and Y are each independently C or N; W and V are each independently CH or N; Z is ##STR00141## A and E are each independently CH or N; G.sub.1, G.sub.2, and G.sub.3 are each independently C, N, O, or S; R.sup.1 is hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally further substituted with one or more groups, each independently selected from halogen, amino, nitro, cyano, hydroxyl, sulfydryl, carboxyl, an ester group, oxo, NR.sup.aR.sup.b, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R.sup.2 is hydrogen, halogen, oxo, hydroxyl, cyano, alkyl, cycloalkyl, heterocyclyl, NR.sup.aR.sup.b, NHC(O)R.sup.a, and NHS(O).sub.mR.sup.a, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted with one or more groups, each independently selected from halogen, hydroxyl, sulfydryl, cyano, alkyl, OR.sup.a, SR.sup.a, NR.sup.aR.sup.b, and C(O)NR.sup.aR.sup.b; R.sup.3 is alkenyl, alkynyl, aryl, or heteroaryl, wherein the alkenyl, alkynyl, aryl, or heteroaryl is optionally further substituted with R.sup.a; R.sup.4 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy; R.sup.5 and R.sup.6 are each independently hydrogen, halogen, cyano, OR.sup.a, SR.sup.a, O(CH.sub.2).sub.pNR.sup.aR.sup.b, O(CH.sub.2).sub.pOR.sup.a, NR.sup.aR.sup.b, C(O)R.sup.a, C(O)OR.sup.a, OC(O)R.sup.a, C(O)NR.sup.aR.sup.b, or OC(O)NR.sup.aR.sup.b, or R.sup.5 and R.sup.6 together with the atoms to which they are attached form oxacycloalkyl, in which the oxygen atom is attached to the phenyl ring; R.sup.7 is hydrogen, halogen, NR.sup.aR.sup.b, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more groups, each independently selected from halogen, amino, nitro, cyano, hydroxyl, sulfydryl, carboxyl, an ester group, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; each R.sup.8 is independently hydrogen, halogen, NR.sup.aR.sup.b, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more groups, each independently selected from halogen, amino, nitro, cyano, hydroxyl, sulfydryl, carboxyl, an ester group, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R.sup.9 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally further substituted with one or more Q groups; each Q is independently halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR.sup.a, SR.sup.a, O(CH.sub.2).sub.pNR.sup.aR.sup.b, O(CH.sub.2).sub.pOR.sup.a, NR.sup.aR.sup.b, C(O)R.sup.a, C(O)OR.sup.a, OC(O)R.sup.a, C(O)NR.sup.aR.sup.b, and OC(O)NR.sup.aR.sup.b, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more groups, each independently selected from halogen, amino, nitro, cyano, hydroxyl, sulfydryl, carboxyl, an ester group, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R.sup.10 is hydrogen, halogen, alkyl, or NR.sup.aR.sup.b, wherein the alkyl is optionally further substituted with one or more halogens; R.sup.11 is hydrogen, halogen, cyano, amino, hydroxyl, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more groups, each independently selected from halogen, amino, nitro, cyano, hydroxyl, sulfydryl, carboxyl, an ester group, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R.sup.a and R.sup.b are each independently hydrogen, halogen, hydroxyl, nitro, cyano, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more groups, each independently selected from halogen, amino, nitro, cyano, hydroxyl, sulfydryl, carboxyl, an ester group, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or R.sup.a and R.sup.b together with the nitrogen atom to which they are attached form nitrogen-containing heterocyclyl, wherein the nitrogen-containing heterocyclyl is optionally further substituted with one or more groups, each independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, sulfydryl, carboxyl, an ester group, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; m is an integer from 1 to 4; n is an integer from 0 to 4; p is an integer from 1 to 6; and any one or more H atoms in the compound of formula (I) are optionally further substituted with D atoms.

    2. The compound of formula (I) according to claim 1, being a compound of formula (II), ##STR00142## or a mesomer, a racemate, an enantiomer, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, custom-character, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.9, R.sup.10, X, Y, W, V, A and n are defined as in claim 1.

    3. The compound of formula (I) according to claim 1, being a compound of formula (III), ##STR00143## or a mesomer, a racemate, an enantiomer, or a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, custom-character, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11, X, Y, W, V, A, E and n are defined as in claim 1.

    4. The compound of formula (I) according to claim 2, wherein W and V are CH, and A is N.

    5. The compound of formula (I) according to claim 4, being a compound of formula (IV), (V), or (VI), ##STR00144## wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.9, R.sup.10 and n are defined as in claim 1.

    6. The compound of formula (I) according to claim 5, wherein R.sup.9 is aryl or heteroaryl, preferably C.sub.6-C.sub.10 aryl or 5-7 membered heteroaryl, wherein the aryl or heteroaryl is optionally further substituted with one or more Q groups; each Q is independently alkyl, cycloalkyl, heterocyclyl, OR.sup.a, SR.sup.a, O(CH.sub.2).sub.pNR.sup.aR.sup.b, O(CH.sub.2).sub.pOR.sup.a, NR.sup.aR.sup.b, OC(O)R.sup.a, or OC(O)NR.sup.aR.sup.b, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted with one or more groups, each independently selected from halogen, amino, nitro, cyano, hydroxyl, sulfydryl, carboxyl, and ester group, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl. and heteroaryl; R.sup.a and R.sup.b are each independently hydrogen or alkyl, wherein the alkyl is optionally further substituted with one or more groups, each independently selected from halogen, cycloalkyl, and heterocyclyl, or R.sup.a and R.sup.b together with the nitrogen atom to which they are attached form nitrogen-containing heterocyclyl, preferably 5-7 membered nitrogen-containing heterocyclyl, wherein the nitrogen-containing heterocyclyl is optionally further substituted with one or more alkyl groups; and p is an integer from 1 to 6.

    7. The compound of formula (I) according to claim 5 or 6, wherein R.sup.10 is amino.

    8. The compound of formula (I) according to claim 3, wherein W and V are CH, E is CH, and A is N.

    9. The compound of formula (I) according to claim 4, being a compound of formula (VII), (VIII), or (IX), ##STR00145## wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11 and n are defined as in claim 1.

    10. The compound of formula (I) according to claim 9, wherein R.sup.5 and R.sup.6 are each independently cyano, OR.sup.a, SR.sup.a, O(CH.sub.2).sub.pNR.sup.aR.sup.b, O(CH.sub.2).sub.pOR.sup.a, NR.sup.aR.sup.b, OC(O)R.sup.a, C(O)NR.sup.aR.sup.b, and OC(O)NR.sup.aR.sup.b, or R.sup.5 and R.sup.6 together with the atoms they are attached form oxacycloalkyl, in which the oxygen atom is attached to the phenyl ring; R.sup.a and R.sup.b are each independently hydrogen or alkyl, wherein the alkyl is optionally further substituted with one or more groups, each independently selected from halogen, cycloalkyl, and heterocyclyl, or R.sup.a and R.sup.b together with the nitrogen atom to which they are attached form nitrogen-containing heterocyclyl, preferably 5-7 membered nitrogen-containing heterocyclyl, wherein the nitrogen-containing heterocyclyl is optionally further substituted with one or more alkyl groups; and p is an integer from 1 to 6.

    11. The compound of formula (I) according to claim 9 or 10, wherein R.sup.11 is hydrogen or amino.

    12. The compound of the formula (I) according to any one of claims 1 to 11, wherein R.sup.1 is halogen, alkyl, alkenyl, cycloalkyl, or heterocyclyl, wherein the alkyl, alkenyl, cycloalkyl, or heterocyclyl is optionally further substituted with one or more groups, each independently selected from halogen, amino, nitro, cyano, hydroxyl, sulfydryl, carboxyl, and ester group, oxo, NR.sup.aR.sup.b, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and R.sup.a and R.sup.b are each independently hydrogen or alkyl, or R.sup.a and R.sup.b together with the nitrogen atom to which they are attached form nitrogen-containing heterocyclyl, wherein the nitrogen-containing heterocyclyl is optionally further substituted with one or more alkyl groups.

    13. The compound of formula (I) according to any one of claims 1 to 12, wherein R.sup.2 is hydrogen, oxo, cyano, hydroxyl, alkyl, cycloalkyl, or heterocyclyl, preferably oxo, cyano, hydroxyl, or alkyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted with one or more groups, each independently selected from halogen, hydroxyl, sulfydryl, cyano, alkyl, OR.sup.a, SR.sup.a, NR.sup.aR.sup.b, and C(O)NR.sup.aR.sup.b; and R.sup.a and R.sup.b are each independently hydrogen or alkyl, wherein the alkyl is optionally further substituted with one or more halogen groups, or R.sup.a and R.sup.b together with the nitrogen atom to which they are attached form nitrogen-containing heterocyclyl, wherein the nitrogen-containing heterocyclyl is optionally further substituted with one or more alkyl groups.

    14. The compound of formula (I) according to any one of claims 1 to 13, wherein R.sup.3 is alkynyl, aryl, or heteroaryl, wherein the alkynyl, aryl, or heteroaryl is optionally further substituted with R.sup.a; and each R.sup.a is independently hydrogen, halogen, cyano, alkyl, alkoxy, or cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl is optionally further substituted with one or more halogen groups.

    15. The compound of formula (I) according to any one of claims 1 to 14, wherein R.sup.4 is hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy, preferably halogen; and n is an integer from 0 to 2.

    16. The compound of formula (I) according to any one of claims 1 to 14, wherein any one or more H atoms in the compound are substituted with D atoms.

    17. The compound of formula (I) according to any one of claims 1 to 16, selected from: ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153## ##STR00154##

    18. A method for preparing the compound of formula (I) according to any one of claims 1 to 17, comprising the step of: ##STR00155## coupling pinacol borate la with aromatic bromide (Br—Z) via the Suzuki reaction in a solvent in the presence of a catalyst and a base to form the compound of formula (I), the catalyst being preferably Pd(dppf).sub.2, the base being preferably K.sub.2CO.sub.3, and the solvent being preferably dioxane and water; wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, Z, X, Y, W, V and n are defined as in claim 1.

    19. A method for preparing the compound of formula (I) according to any one of claims 1 to 17, comprising the step of: ##STR00156## reacting carboxylic acid compound Ig and aromatic amine compound Ic in the presence of a coupling agent and a base to form the compound of formula (I), the coupling agent being preferably HATU, and the base being preferably triethylamine; wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, Z, X, Y, W, V and n are defined as in claim 1.

    20. A method for preparing the compound of formula (I) according to any one of claims 1 to 17, comprising the steps of: when R.sup.2═CN, ##STR00157## step 1: reacting carboxylic acid (Ib) with aromatic amine (Ic) in the presence of a coupling agent and a base to form arylamide intermediate (Id), the coupling agent being preferably HATU, and the base being preferably N,N-diisopropylethylamine; step 2: hydrolyzing arylamide intermediate (Id) in a solvent in the presence of a base to form carboxylic acid intermediate (Ie), the base being preferably LiOH, and the solvent being preferably methanol-water solution; step 3: reacting carboxylic acid intermediate (Ie) and ammonium chloride in the presence of a catalyst and a base to form dicarboxamide intermediate (If), the catalyst being preferably PyBrOP, and the base being preferably DIPEA; and step 4: dehydrating dicarboxamide intermediate (If) in the presence of a dehydrating agent and a base to form the compound of formula (I), the dehydrating agent being preferably trifluoroacetic anhydride, and the base being preferably triethylamine; wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, Z, X, Y, W, V and n are defined as in claim 1.

    21. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 17 and a pharmaceutically acceptable carrier or excipient.

    22. Use of the compound of formula (I) according to any one of claims 1 to 17 or the pharmaceutical composition according to claim 21 as a tyrosine kinase inhibitor, wherein the tyrosine kinase is preferably Axl, Mer, Tyro3, or c-MET.

    23. Use of the compound of formula (I) according to any one of claims 1 to 17 or the pharmaceutical composition according to claim 21 in the manufacture of a medicament for treating a disease associated with tyrosine kinase activity, wherein the disease is preferably bladder cancer, breast cancer, cervical cancer, colorectal cancer, intestinal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, brain cancer, bone cancer, soft tissue cancer, leukemia, or lymph cancer, more preferably leukemia, liver cancer, lung cancer, kidney cancer, breast cancer, or colorectal cancer, and further more preferably leukemia, liver cancer, lung cancer, kidney cancer, breast cancer, gastric cancer, or colorectal cancer.

    Description

    BRIEF DESCRIPTON OF THE DRAWINGS

    [0188] FIG. 1 shows the growth change in tumor volume of mice in the example compound group and the solvent control group in EBC-1 non-small cell lung cancer models.

    [0189] FIG. 2 shows the body weight change of mice as a function of treatment time in the example compound group and the solvent control group in EBC-1 non-small cell lung cancer models.

    EXAMPLES

    [0190] The compounds of the present invention and preparation thereof are further understood by examples which illustrate some methods for preparing or using the compounds. However, it is to be understood that these examples do not limit the present invention. Variations of the present invention, either known already or further developed, are considered to fall within the scope of the present invention as described and claimed herein.

    [0191] The compounds of the present invention are prepared using convenient starting materials and general preparative procedures. Typical or preferential reaction conditions such as reaction temperature, time, solvent, pressure, and molar ratio of reactants are provided in the present invention. However, unless otherwise specified, other reaction conditions can be adopted. The preferential conditions may vary with the particular reactants or solvents used. However, in general, preferential steps and conditions for reaction can be determined.

    [0192] In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are well known to those skilled in the art. For example, Protective Groups in Organic Synthesis (T. W. Greene and G. M. Wuts, 3rd edition, Wiley, New York, 1999 and references therein) describes in detail the protection or deprotection of a number of protective groups.

    [0193] The isolation and purification of the compounds and intermediates may be carried out by any suitable method or procedure depending on the particular requirements, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer plate chromatography, preparative high-performance liquid chromatography or a mixture thereof. The examples described herein may be referred to for specific method for isolation and purification. Of course, other similar means for separation and purification may be employed. They can be characterized using conventional methods, including physical constants and spectral data.

    [0194] The structures of the compounds are determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts are given in 10.sup.−6 (ppm). NMR is determined using a Brukerdps 400 NMR equipment. The solvents for determination are deuterated-dimethyl sulfoxide (DMSO-d.sub.6), deuterated-chloroform (CDCl.sub.3) and deuterated-methanol (CD.sub.3OD), and the internal standard is tetramethylsilane (TMS).

    [0195] MS is determined using an ACQUITY H-Class UPLC mass spectrometer (QDa Detector) (manufacturer: Waters).

    [0196] The liquid phase is prepared using Waters 2545 high performance liquid chromatography (Waters 2489 UV/Visual Detector 2767 sample MGR, single C18, 5 μm, 20 mm×250 mm) (manufacturer: Waters).

    [0197] An initiator and an EU type microwave reactor (manufacturer: Biotage) are used in the microwave reaction.

    [0198] In terms of the thin-layer chromatography silica gel plate, GF254 silica gel plate from Qingdao Ocean Chemical Co., Ltd. is employed. The specification of the silica gel plate used by thin-layer chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the silica gel plate used in the separation and purification of products by thin-layer chromatography is 0.4 mm-0.5 mm.

    [0199] Generally, in the column chromatography, 100-200 mesh and 200-300 mesh silica gels from Qingdao Ocean Chemical Co., Ltd. are used as carriers.

    [0200] Known starting materials of the present invention may be synthesized using or according to methods known in the art, or may be purchased from the companies such as WH Mall, Beijing Ouhe, Sigma, J&K Scientific, Yishiming (Beijing) Biomedical Technology, Shanghai Shuya, Shanghai Innochem, Energy Chemical and Shanghai Bidepharm.

    [0201] Unless otherwise specified in the example, the reaction can be carried out under argon atmosphere or nitrogen atmosphere.

    [0202] The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon balloon or a nitrogen balloon with a volume of about 1 L.

    [0203] The reaction solvent, organic solvent or inert solvent is each considered to be a solvent that, when used, does not participate in the reaction under the reaction conditions described and includes benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, diethyl ether, methanol, nitrogen-methyl pyrroline (NMP), pyridine, and the like. Unless otherwise specified in the example, the solution refers to an aqueous solution.

    [0204] The chemical reactions described herein are generally carried out under normal pressure. The reaction temperature is between −78° C. and 200° C. The reaction time and conditions are, for example, between −78° C. and 200° C. at one atmosphere pressure, completion in about 1 to 24 hours. If the reaction is carried out overnight, the reaction time is generally 16 hours. Unless otherwise specified in the example, the reaction temperature is room temperature (20° C. to 30° C.).

    [0205] The progress of reaction in the examples is monitored by thin layer chromatography (TLC), and the developing agent system used in the reaction includes: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleumether and ethyl acetate system, and D: acetone, wherein the volume ratio of solvents is adjusted according to the polarity of the compound.

    [0206] The eluent system for column chromatography and the developing agent system for thin-layer chromatography used for purifying the compounds include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleumether and ethyl acetate system, wherein the volume ratio of the solvents is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid may also be added for adjustment.

    [0207] Unless otherwise defined, all the professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the described contents can be applied in the method of the present invention.

    [0208] Abbreviations [0209] μL=microliter [0210] μM=micromole [0211] NMR=nuclear magnetic resonance [0212] Boc=tert-butoxycarbonyl [0213] br=broad peak [0214] d=doublet [0215] δ=chemical shift [0216] ° C.=Celsius degree [0217] dd=double doublet [0218] DIPEA=diisopropylethylamine [0219] DMF=N,N-dimethylformamide [0220] DMSO=dimethyl sulfoxide [0221] DCM=dichloromethane [0222] EA=ethyl acetate [0223] HATU=2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate [0224] HPLC=high performance liquid chromatography [0225] Hz=Hertz [0226] IC.sub.50=concentration required for inhibiting activity by 50% [0227] J=coupling constant (Hz) [0228] LC-MS=liquid chromatography-mass spectrometry [0229] m=multiplet [0230] M+H.sup.+=parent compound mass+one proton [0231] mg=milligram [0232] mL=milliliter [0233] mmol=millimole [0234] MS=mass spectrometry [0235] m/z=mass-to-charge ratio [0236] nM=nanomole [0237] NBS=N-bromosuccinimide [0238] PE=petroleumether [0239] ppm=parts per million [0240] PyBrOP=bromo-tris-pyrrolidino-phosphonium hexafluorophosphate [0241] s=singlet [0242] t=triplet [0243] TEA=triethylamine [0244] TBDPS=tert-butyl diphenyl silicon [0245] TFA=trifluoroacetic acid [0246] THF=tetrahydrofuran

    PREPARATION EXAMPLE 1

    Preparation of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (Intermediate a)

    Step 1: Preparation of ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (a1)

    [0247] N,N-dimethylformamide dimethyl acetal (1.72 kg, 14.4 mol) was added dropwise to a reaction flask (with an internal temperature of less than 10° C.) containing ethyl acetoacetate (1.79 kg, 13.75 mol) at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (2.54 kg, red oil),which was directly used in the next step.

    [0248] LC-MS (ESI): m/z 186.2[M+H.sup.+].

    [0249] .sup.1H NMR (400 MHz, Chloroform-d) δ 7.66 (s, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.24-2.84 (m, 6H), 2.31 (s, 3H), 1.31 (t, J=7.1 Hz, 3H).

    ##STR00062## ##STR00063##

    Step 2: Preparation of diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (a2)

    [0250] Ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (150 g, 0.81 mol) and diethyl oxalate (130 g, 0.89 mol) were added to a reaction flask containing anhydrous tetrahydrofuran (700 mL). Sodium hydride (38.8 g, 0.97 mol, 60%) was then slowly added to the reaction mixture at 80° C., and then the resulting reaction mixture was stirred for 30 min after the addition was completed. After the reaction was completed, the reaction mixture was cooled to room temperature, added with 1 N diluted hydrochloric acid (1800 mL) at 0° C. to quench the reaction, and then extracted with ethyl acetate (600 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was slurried with ethanol and petroleumether (1:10) to give diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (140 g, yellow solid, yield: 72%).

    [0251] LC-MS (ESI): m/z 241.1[M+H.sup.+].

    [0252] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.53 (s, 1H), 7.18 (s, 1H), 4.45-4.34 (m, 4H), 1.39 (dd, J=12.8, 7.1 Hz, 6H).

    Step 3: Preparation of diethyl 1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (a3)

    [0253] Diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (300 g, 1.25 mol) was added to a reaction flask containing ethanol (1875 mL), and then the reaction mixture was cooled to 0° C. and added dropwise with isopropylamine (73.8 g, 1.25 mol) while stirring. After the addition was completed, the reaction mixture was warmed to room temperature, stirred for 30 min, and then heated to reflux overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), cooled to 0° C. and then added dropwise with concentrated hydrochloric acid (104 mL). The resulting reaction mixture was stirred for about 30 min and filtered, and the filter cake was washed with ethyl acetate (600 mL). A solid was collected to give diethyl 1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate hydrochloride (307.99 g, white solid, yield: 70%).

    [0254] LC-MS (ESI): m/z 282.12[M+H.sup.+].

    [0255] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.46 (s, 1H), 6.77 (s, 1H), 4.73-4.62 (m, 1H), 4.37 (d, J=7.1 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H), 1.44 (d, J=6.6 Hz, 7H), 1.35-1.21 (m, 6H).

    Step 4: Preparation of diethyl 3-bromo-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (a4)

    [0256] Diethyl 1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate hydrochloride (307 g, 1.09 mol) was added to a reaction flask containing DMF (1500 mL). The reaction mixture was cooled to 0° C. and then added dropwise with liquid bromine (167.5 mL, 3.27 mol) slowly. After the addition was completed, the reaction mixture was stirred for 30 min. After the reaction was completed, the reaction mixture was added dropwise to water containing sodium hydrogen sulfite (7500 mL). The resulting mixture was stirred for 1 h and filtered, and the filter cake was washed with water (2 L). The filter cake was collected and dried to give diethyl 3-bromo-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (236.69 g, white solid, yield: 67.8%).

    [0257] LC-MS (ESI): m/z 360.07/362.07[M+H.sup.+].

    [0258] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.25 (s, 1H), 4.50 (q, J=7.2 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 4.13 (p, J=6.6 Hz, 1H), 1.52 (d, J=6.6 Hz, 6H), 1.41 (dt, J=22.2, 7.1 Hz, 6H).

    Step 5: Preparation of 5-bromo-6-(ethoxycarbonyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a5)

    [0259] Diethyl 3-bromo-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (323.11 g, 0.9 mol) was added to a reaction flask containing ethanol (1600 mL). The reaction mixture was cooled to 0° C., added dropwise with aqueous sodium hydroxide (160 mL of water, 1.06 mol sodium hydroxide), and then stirred for 1 h after the addition was completed. After the reaction was completed, the reaction mixture was added with 1.5 N diluted hydrochloric acid (700 mL) to adjust the pH to 7. After a white solid was precipitated out, the reaction mixture was stirred for 30 min. The reaction mixture was filtered, and the solid was collection and dried to give 5-bromo-6-(ethoxycarbonyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (271.2 g, white solid, yield: 90.8%).

    [0260] LC-MS (ESI): m/z 331.95/333.91[M+H.sup.+].

    [0261] .sup.1H NMR (400 MHz, Chloroform-d) δ 14.71 (s, 1H), 8.59 (s, 1H), 4.56 (q, J=7.1 Hz, 2H), 4.28 (hept, J=6.7 Hz, 1H), 1.58 (d, J=6.6 Hz, 6H), 1.47 (t, J=7.2 Hz, 3H).

    Step 6: Preparation of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (a)

    [0262] 5-bromo-6-(ethoxycarbonyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (43.5 g, 0.13 mol), p-fluorophenylboronic acid (25.18 g, 0.18 mol), potassium carbonate (71.8 g, 0.52 mol) and Pd(dppf)Cl.sub.2(475 mg, 0.065 mmol) were added to a reaction flask containing 1,4-dioxane (400 mL) and water (100 mL) at room temperature. The reaction mixture was sealed in the flask, purged with nitrogen three times, and stirred at 85° C. overnight. After being cooled to room temperature, the reaction mixture was diluted with water (600 mL) and ethyl acetate (200 mL), filtered, and left to stand for liquid separation. The aqueous phase was adjusted to pH 6 with concentrated hydrochloric acid and then filtered after a white precipitate was formed. The filter cake was washed with water and dried to give 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) (31 g, white solid, yield: 68%).

    [0263] LC-MS (ESI): m/z 348.10[M+H.sup.+].

    [0264] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 15.73 (s, 1H), 8.81 (s, 1H), 7.37-7.22 (m, 4H), 4.39 (p, J=6.5 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 1.54 (d, J=6.5 Hz, 6H), 0.93 (t, J=7.1 Hz, 3H).

    PREPARATION EXAMPLE 2

    Preparation of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (Intermediate b)

    [0265] ##STR00064##

    [0266] The same procedures as in Preparation Example 1 were performed, except that aqueous methylamine solution was used in place of isopropylamine, to give 6-(ethoxycarbonyl)-5-(4-fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (grey solid, four-step yield: 38.5%).

    [0267] LC-MS (ESI): m/z 320.1[M+H.sup.+].

    PREPARATION EXAMPLE 3

    Preparation of 1-cyclobutyl-6-(ethoxycarbonyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (Intermediate c)

    [0268] ##STR00065##

    [0269] The same procedures as in Preparation Example 1 were performed, except that cyclobutylamine was used in place of isopropylamine, to give 1-cyclobutyl-6-(ethoxy-carbonyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (white solid, four-step yield: 80.9%).

    [0270] LC-MS (ESI): m/z 360.1[M+H.sup.+].

    PREPARATION EXAMPLE 4

    Preparation of 1-cyclopropyl-6-(ethoxycarbonyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (Intermediate d)

    [0271] ##STR00066##

    [0272] The same procedures as in Preparation Example 1 were performed, except that cyclopropylamine was used in place of isopropylamine, to give 1-cyclopropyl-6-(ethoxycarbonyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (grey solid, four-step yield: 70.8%).

    [0273] LC-MS (ESI): m/z 346.3[M+H.sup.+].

    PREPARATION EXAMPLE 5

    Preparation of 6-cyano-1-cyclopropyl-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (Intermediate e)

    [0274] ##STR00067##

    Step 1: Preparation of ethyl 5-((4-bromo-3-fluorophenyl) carbamoyl)-1-cyclopropyl-3-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-2-carboxylate (e1)

    [0275] 1-cyclopropyl-6-(ethoxycarbonyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (d) (8.0 g, 23.2 mmol), 4-bromo-3-fluoroaniline (4.0 g, 21.1 mmol), HATU (12 g, 31.6 mmol) and DIPEA (5.4 g, 42.1 mmol) were added to a reaction flask containing DMF (100 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction mixture was added with saturated sodium bicarbonate solution to quench the reaction, and then extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=5:1) to give ethyl 5-((4-bromo-3-fluorophenyl)carbamoyl)-1-cyclopropyl-3-(4-fluoro-phenyl)-4-oxo-1,4-dihydropyridine-2-carboxylate (e1) (8.5 g, yellow solid, yield: 78%).

    [0276] LC-MS (ESI): m/z 517.05/519.06 [M+H.sup.+].

    ##STR00068##

    Step 2: Preparation of 5-((4-bromo-3-fluorophenyl)carbamoyl)-1-cyclopropyl-3-(4-fluoro-phenyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid (e2)

    [0277] Ethyl 5-((4-bromo-3-fluorophenyl)carbamoyl)-1-cyclopropyl-3-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-2-carboxylate (e1) (8.5 g, 16.4 mmol), lithium hydroxide monohydrate (1.03 g, 24.6 mmol) and water (25 mL) were added to a reaction flask containing ethanol (100 mL) at room temperature. The reaction mixture was warmed to 70° C. and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give crude 5-((4-bromo-3-fluorophenyl)carbamoyl)-1-cyclopropyl-3-(4-fluorophenyl)-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (e2) (yellow solid), which was directly used in the next step without purification.

    [0278] Step 3: Preparation of N.sup.5-(4-bromo-3-fluorophenyl)-1-cyclopropyl-3-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide (e3)

    [0279] 5-((4-bromo-3-fluorophenyl)carbamoyl)-1-cyclopropyl-3-(4-fluorophenyl)-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (e2) (2.2 g, 4.5 mmol) was added to a reaction flask containing tetrahydrofuran (15 mL) and phosphorus oxychloride (15 mL) at room temperature. The reaction mixture was heated to reflux and stirred for 30 min. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give acyl chloride intermediate, which was directly used in the next step without purification.

    [0280] The acyl chloride intermediate was added to a reaction flask containing tetrahydrofuran (20 mL) and aqueous ammonia (20 mL) at 0° C. After the addition was completed, the reaction mixture was stirred for 20 min. After the reaction was completed, ethyl acetate (30 mL) was added to dilute the reaction mixture. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM=1:20) to give N.sup.5-(4-bromo-3-fluorophenyl)-1-cyclopropyl-3-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide (e3) (1.5 g, yellow solid, yield: 68%).

    Step 4: Preparation of N-(4-bromo-3-fluorophenyl)-6-cyano-1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (e4)

    [0281] N.sup.5-(4-bromo-3-fluorophenyl)-1-cyclopropyl-3-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide (e3) (1.5 g, 3.1 mmol) was added to a reaction flask containing anhydrous tetrahydrofuran (20 mL). The reaction mixture was cooled to 0° C. and then added successively with triethylamine (2.5 g, 24.6 mmol) and trifluoromethanesulfonic anhydride (2.6 g, 12.2 mmol). After the addition was completed, the reaction mixture was stirred for 30 min. After the reaction was completed, ethyl acetate (100 mL) was added to dilute the reaction mixture. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM=1:20) to give N-(4-bromo-3-fluorophenyl)-6-cyano-1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (e4) (1.3 g, yellow solid, yield: 90.3%).

    [0282] Step 5: Preparation of 6-cyano-1-cyclopropyl-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (e)

    [0283] N-(4-bromo-3-fluorophenyl)-6-cyano-1-cyclopropyl-5-(4-fluorophenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxamide (e4) (1.3 g, 2.7 mmol), bis(pinacolato)diboron (1.04 g, 4.1 mmol), potassium acetate (795 mg, 8.1 mmol), Pd.sub.2(dba).sub.3 (275 mg, 0.3 mmol) and X-PHOS (257 mg, 0.54 mmol) were added to a reaction flask containing 1,4-dioxane (16 mL) at room temperature. The reaction mixture was sealed in the flask, purged with nitrogen three times, and subjected to microwave reaction for 30 min (90° C.). After being cooled to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM=1:20) to give 6-cyano-1-cyclopropyl-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (e) (800 mg, grey solid, yield: 55.9%).

    [0284] LC-MS (ESI): m/z 518.14 [M+H.sup.+].

    PREPARATION EXAMPLE 6

    Preparation of 6-cyano-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (Intermediate f)

    [0285] ##STR00069##

    [0286] The same procedures as in Preparation Example 5 were performed, except that 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) was used in place of 1-cyclopropyl-6-(ethoxycarbonyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (d), so as to give 6-cyano-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (grey solid, five-step yield: 25.3%).

    [0287] LC-MS (ESI): m/z 520.21[M+H.sup.+].

    PREPARATION EXAMPLE 7

    Preparation of 6-cyano-1-cyclobutyl-N-(3-fluoro-4-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (Intermediate g)

    [0288] ##STR00070##

    [0289] The same procedures as in Preparation Example 5 were performed, except that 1-cyclobutyl-6-(ethoxycarbonyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (c) was used in place of 1-cyclopropyl-6-(ethoxycarbonyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (d), so as to give 6-cyano-1-cyclobutyl-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (grey solid, five-step yield: 29.6%).

    [0290] LC-MS (ESI): m/z 532.20[M+H.sup.+].

    PREPARATION EXAMPLE 8

    Preparation of 5-bromo-6-(ethoxycarbonyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Intermediate h)

    [0291] ##STR00071##

    Step 1: Preparation of ethyl 3-((4-fluorophenyl)amino)-3-oxopropanoate (h1)

    [0292] 4-fluoroaniline (30 g, 0.27 mol) and triethylamine (28.7 g, 0.28 mol) were added to a reaction flask containing acetone (300 mL). The reaction mixture was cooled to 0° C., and then ethyl 3-chloro-3-oxopropanoate (42.9 g, 0.28 mol) was added dropwise while stirring. After the addition was completed, the reaction mixture was warmed to room temperature and then stirred overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was added with water (500 mL), stirred for 2 h, and then filtered under reduced pressure. The solid was collected to give ethyl 3-((4-fluorophenyl)amino)-3-oxopropanoate (h1) (60 g, yellow solid, yield: 98.8%).

    [0293] LC-MS (ESI): m/z 226.07[M+H.sup.+].

    Step 2: Preparation of 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (h2)

    [0294] Ethyl 3-(4-fluorophenyl)amino)-3-oxopropanoate (h1) (30 g, 0.13 mol), 4,4-dimethoxy-butan-2-one (21.1 g, 0.16 mol) and a solution of 20% sodiumethoxide in ethanol (166 mL, 0.43 mol) were added to a reaction flask containing ethanol (200 mL). The reaction mixture was heated to reflux overnight at 80° C., and then concentrated under reduced pressure after the reaction was completed. The residue was added with 5 M hydrochloric acid to adjust the pH to 4-5, and then dichloromethane (100 mL×3) was added for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was slurried with a mixed solution of petroleumether and ethyl acetate (5:1, 100 mL), and then filtered. The filter cake was washed with petroleumether, and the solid was collected to give the product 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (h2) (24 g, yellow solid, yield: 74.7%).

    [0295] LC-MS (ESI): m/z 248.12[M+H.sup.+].

    ##STR00072## ##STR00073##

    Step 3: Preparation of ethyl 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (h3)

    [0296] 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (h2) (16 g, 64.8 mmol), sodium carbonate (7.6 g, 71.3 mmol) and iodoethane (11.1 g, 71.3 mmol) were added to a reaction flask containing NMP (150 mL), and the reaction mixture was stirred at room temperature for 4 h. After the reaction was completed, the reaction mixture was added with water (300 mL) and then extracted with ethyl acetate (150 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by slurrying with diethyl ether (150 mL) to give ethyl 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (h3) (15 g, yellow solid, yield: 84.2%).

    [0297] LC-MS (ESI): m/z 276.10[M+H.sup.+].

    Step 4: Preparation of ethyl 5-bromo-6-(bromomethyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylate (h4)

    [0298] Ethyl 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (h3) (15 g, 54.5 mmol), NBS (21.4 g, 120 mmol) and BPO (660 mg, 2.72 mmol) were added to a reaction flask containing carbon tetrachloride (150 mL). The reaction mixture was heated to 70° C. and stirred for 24 h. After the reaction was completed, the reaction mixture was added with saturated aqueous sodium thiosulfate solution (200 mL) to quench the reaction, and extracted with dichloromethane (100 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=2:1) to give ethyl 5-bromo-6-(bromomethyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (h4) (16.8 g, yellow solid, yield: 71.2%).

    [0299] LC-MS (ESI): m/z 431.94/433.93 [M+H.sup.+].

    Step 5: Preparation of ethyl 5-bromo-1-(4-fluorophenyl)-6-(hydroxymethyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylate (h5)

    [0300] Ethyl 5-bromo-6-(bromomethyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (h4) (16.8 g, 38.8 mmol) and saturated aqueous sodium bicarbonate solution (150 mL) were added to a reaction flask containing tetrahydrofuran (150 mL). The reaction mixture was heated to 60° C. and stirred overnight. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=1:3) to give ethyl 5-bromo-1-(4-fluorophenyl)-6-(hydroxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (h5) (7.2 g, yellow solid, yield: 50.2%).

    [0301] LC-MS (ESI): m/z 369.95/371.95[M+H.sup.+].

    Step 6: Preparation of ethyl 5-bromo-1-(4-fluorophenyl)-6-formyl-2-oxo-1,2-dihydropyridine-3-carboxylate (h6)

    [0302] Oxalyl chloride (208 mg, 1.64 mmol) was added to a reaction flask containing anhydrous dichloromethane (5 mL). The reaction mixture was sealed in the flask and purged with nitrogen three times. After being cooled to −78° C., the reaction mixture was added dropwise with dimethyl sulfoxide (176 mg, 2.26 mmol) slowly and then stirred at this temperature for 20 min after the addition was completed. Then the resulting mixture was added dropwise with a solution of ethyl 5-bromo-1-(4-fluorophenyl)-6-(hydroxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (h5) (380 mg, 1.03 mmol) in dichloromethane (5 mL) slowly and stirred at this temperature for 30 min after the addition was completed. A solution of triethylamine (520 mg, 5.15 mmol) in dichloromethane was then slowly added dropwise, and then the resulting reaction mixture was stirred at this temperature for 30 min after the addition was completed. After the reaction was completed, the reaction mixture was added dropwise with water to quench the reaction, and then extracted with dichloromethane (10 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give crude ethyl 5-bromo-1-(4-fluorophenyl)-6-formyl-2-oxo-1,2-dihydropyridine-3-carboxylate (h6) (380 mg, yellow solid, yield: 100%).

    [0303] LC-MS (ESI): m/z 367.94/369.95[M+H.sup.+].

    Step 7: Preparation of 5-bromo-6-(ethoxycarbonyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydro pyridine-3-carboxylic acid (h)

    [0304] The crude ethyl 5-bromo-1-(4-fluorophenyl)-6-formyl-2-oxo-1,2-dihydropyridine-3-carboxylate (h6) (7.2 g, 19.6 mmol), sodium dihydrogen phosphate (1.17 g, 9.8 mmol), hydrogen peroxide (20 mL) and sodium chlorite (3.5 g, 39.2 mmol) were added to a reaction flask containing acetonitrile (50 mL). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by slurrying with a mixed solution of petroleumether and ethyl acetate (PE:EA=10:1, 50 mL) to give 5-bromo-6-(ethoxycarbonyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (h) (5.6 g, yellow solid, yield: 74.4%).

    [0305] LC-MS (ESI): m/z 383.99/385.97[M+H.sup.+].

    PREPARATION EXAMPLE 9

    Preparation of 6-cyano-1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (Intermediate i)

    Step 1: Preparation of ethyl 5-bromo-6-carbamoyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylate (i1)

    [0306] 5-bromo-6-(ethoxycarbonyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (h) (500 mg, 1.3 mmol), ammonium chloride (348 mg, 6.5 mmol), PyBrOP (760 mg, 1.6 mmol) and DIPEA (503 mg, 3.9 mmol) were added to a reaction flask containing DMF (8 mL). The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was added with saturated aqueous sodium bicarbonate solution (20 mL) to quench the reaction, and then extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=1:3) to give ethyl 5-bromo-6-carbamoyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylate (i1) (400 mg, white solid, yield: 80.3%).

    [0307] LC-MS (ESI): m/z 383.01/385.03[M+H.sup.+].

    ##STR00074##

    Step 2: Preparation of ethyl 5-bromo-6-cyano-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylate (i2)

    [0308] Ethyl 5-bromo-6-carbamoyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (i1) (100 mg, 0.26 mol) was added to a reaction flask containing acetonitrile (5 mL). After being cooled to 0° C., the reaction mixture was added dropwise with trifluoroacetic anhydride (103 mg, 0.52 mol) and triethylamine (80 mg, 0.78 mol) slowly and successively. The reaction mixture was stirred at 0° C. for 1 h. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give crude ethyl 5-bromo-6-cyano-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylate (12) (96 mg, yellow solid, yield: 100%).

    [0309] LC-MS (ESI): m/z 364.95/366.98[M+H.sup.+].

    Step 3: Preparation of 6-cyano-1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Intermediate i)

    [0310] Ethyl 5-bromo-6-cyano-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (i2) (100 mg, 0.27 mmol), methylboronic acid (164 mg, 2.7 mmol), potassium carbonate (113 mg, 0.82 mmol) and Pd(dppf)Cl.sub.2.DCM (44 mg, 0.055 mmol) were added to a reaction flask containing 1,4-dioxane (9 mL) and water (3 mL) at room temperature. The reaction mixture was sealed in the flask, purged with nitrogen three times, heated to 100° C. in a microwave reactor and then stirred for 30 min. After being cooled to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3), and the organic phase was discarded. The aqueous phase was acidified to pH 3-4 with 1 N aqueous hydrochloric acid solution and then extracted with a mixed solvent of isopropyl alcohol and dichloromethane (15% isopropyl alcohol) (10 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give crude 6-cyano-1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate i) (30 mg, yellow oil, yield: 40.3%).

    [0311] LC-MS (ESI): m/z 273.08[M+H.sup.+].

    PREPARATION EXAMPLE 10

    Preparation of 6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Intermediate j)

    [0312] ##STR00075##

    [0313] The same procedures as in Preparation Example 9 were performed, except that cyclopropylboronic acid was used in place of methylboronic acid, to give 6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate j) (yellow oil, one-step yield: 65.3%).

    [0314] LC-MS (ESI): m/z 299.10[M+H.sup.+].

    PREPARATION EXAMPLE 11

    Preparation of 6-cyano-1-(4-fluorophenyl)-2-oxo-5-(prop-1-en-2-yl)-1,2-dihydropyridine-3-carboxylic acid (Intermediate k)

    [0315] ##STR00076##

    Step 1: Preparation of ethyl 6-cyano-1-(4-fluorophenyl)-2-oxo-5-(prop-1-en-2-yl)-1,2-dihydro-pyridine-3-carboxylate (Intermediate k1)

    [0316] Ethyl 5-bromo-6-cyano-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (i2) (100 mg, 0.27 mmol), pinacol isopropenylborate (230 mg, 1.37 mmol), potassium carbonate (113 mg, 0.82 mmol) and Pd(dppf)Cl.DCM (44 mg, 0.055 mmol) were added to a reaction flask containing 1,4-dioxane (9 mL) and water (3 mL) at room temperature. The reaction mixture was sealed in the flask, purged with nitrogen three times, heated to 100° C. in a microwave reactor and then stirred for 30 min. After being cooled to room temperature, the reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=1:1) to give ethyl 6-cyano-1-(4-fluorophenyl)-2-oxo-5-(prop-1-en-2-yl)-1,2-dihydro-pyridine-3-carboxylate (intermediate k1) (60 mg, yellow oil, yield: 66.7%).

    [0317] LC-MS (ESI): m/z 327.14[M+H.sup.+].

    Step 2: Preparation of 6-cyano-1-(4-fluorophenyl)-2-oxo-5-(prop-1-en-2-yl)-1,2-dihydro-pyridine-3-carboxylic acid (Intermediate k)

    [0318] Ethyl 6-cyano-1-(4-fluorophenyl)-2-oxo-5-(prop-1-en-2-yl)-1,2-dihydropyridine-3-carboxylate (intermediate k1) (60 mg, 0.18 mmol) was added to a reaction flask containing ethanol (3 mL). After being cooled to 0° C., the reaction mixture was added dropwise with aqueous sodium hydroxide solution (1 mL, 10 mg, 0.24 mmol) slowly, and after the addition was completed, the reaction mixture was warmed to room temperature and stirred for 30 min. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give crude 6-cyano-1-(4-fluorophenyl)-2-oxo-5-(prop-1-en-2-yl)-1,2-dihydropyridine-3-carboxylic acid (intermediate k) (60 mg, yellow solid, yield: 100%).

    [0319] LC-MS (ESI): m/z 300.12[M+H.sup.+].

    PREPARATION EXAMPLE 12

    Preparation of 5-bromo-6-(((tert-butoxycarbonyl)(methyl)amino)-methyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Intermediate l)

    [0320] ##STR00077##

    Step 1: Preparation of ethyl 5-bromo-1-(4-fluorophenyl)-6-((methylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (l1)

    [0321] Ethyl 5-bromo-6-(bromomethyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (h4) (300 mg, 0.75 mmol) was added to a reaction flask containing tetrahydrofuran (4 mL). After being cooled to 0° C., the reaction mixture was added dropwise with aqueous methylamine (0.5 mL) slowly, and after the addition was completed, the reaction mixture was warmed to room temperature and stirred for 1 h. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=2:1) to give ethyl 5-bromo-1-(4-fluoro-phenyl)-6-((methylamino)methyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylate (l1) (250 mg, yellow solid, yield: 86.7%).

    [0322] LC-MS (ESI): m/z 383.13/385.10[M+H.sup.+].

    Step 2: Preparation of ethyl 6-(((tert-butoxycarbonyl)methyl)amino) (methyl)-5-bromo-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (l2)

    [0323] Ethyl 5-bromo-1-(4-fluorophenyl)-6-((methylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (l1) (250 mg, 0.65 mmol), Boc.sub.2O (202 mg, 0.94 mmol) and triethylamine (94 mg, 0.94 mmol) were added to a reaction flask containing dichloromethane (4 mL). The reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE:EA=5:1) to give ethyl 6-(((tert-butoxycarbonyl)(methyl)amino) methyl)-5-bromo-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (l2) (230 mg, yellow solid, yield: 73.3%).

    [0324] LC-MS (ESI): m/z 483.15/485.13[M+H.sup.+].

    Step 3: Preparation of 5-bromo-6-(((tert-butoxycarbonyl)(methyl)amino)methyl)-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Intermediate l)

    [0325] Ethyl 6-(((tert-butoxycarbonyl)(methyl)amino)methyl)-5-bromo-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (l2) (230 mg, 0.48 mmol) was added to a reaction flask containing ethanol (4.5 mL). After being cooled to 0° C., the reaction mixture was added dropwise with aqueous sodium hydroxide solution (1.5 mL, 25 mg, 0.62 mmol) slowly, and after the addition was completed, the reaction mixture was warmed to room temperature and stirred for 30 min. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give crude 5-bromo-6-(((tert-butoxycarbonyl)(methyl)amino)methyl)-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (intermediate l) (230 mg, yellow solid, yield: 100%).

    [0326] LC-MS (ESI): m/z 455.12/457.09[M+H.sup.+].

    PREPARATION EXAMPLE 13

    Preparation of 6-((tert-butoxycarbonyl)amino)methyl)-5-bromo-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Intermediate m)

    [0327] ##STR00078##

    [0328] The same procedures as in Preparation Example 12 were performed, except that aqueous ammonia was used in place of aqueous methylamine solution, to give 6-((tert-butoxy-carbonyl)-amino)methyl)-5-bromo-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate m) (yellow solid, three-step yield: 45.3%).

    [0329] LC-MS (ESI): m/z 441.15/443.11[M+H.sup.+].

    PREPARATION EXAMPLE 14

    Preparation of 5-bromo-1-(4-fluorophenyl)-6-(methoxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Intermediate n)

    [0330] ##STR00079##

    Step 1: Preparation of 5-bromo-1-(4-fluorophenyl)-6-(methoxymethyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (Intermediate n)

    [0331] Ethyl 5-bromo-6-(bromomethyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (h4) (500 mg, 1.15 mmol) was added to a reaction flask containing methanol (8 mL). After being cooled to 0° C., the reaction mixture was added dropwise with aqueous lithium hydroxide solution (1.4 mL, 241 mg, 5.75 mmol) slowly, and after the addition was completed, the reaction mixture was warmed to room temperature and stirred for 30 min. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give crude 5-bromo-1-(4-fluoro-phenyl)-6-(methoxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate n) (500 mg, yellow solid, yield: 100%).

    [0332] LC-MS (ESI): m/z 355.95/357.95[M+H.sup.+].

    PREPARATION EXAMPLE 15

    Preparation of tert-butyl 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)-pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Intermediate p)

    [0333] ##STR00080##

    ##STR00081##

    Step 1: Preparation of 3-bromo-5-iodopyridin-2-amine (Intermediate p1)

    [0334] 5-iodopyridin-2-amine (5.0 g, 22.73 mmol) and NBS (4.0 g, 22.73 mmol) were added to a reaction flask containing acetonitrile (100 mL). The reaction mixture was stirred at 50° C. for 12 h, then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=20:1) to give 3-bromo-5-iodopyridin-2-amine (intermediate p1) (2.5 g, yellow solid, yield: 36.8%).

    [0335] LC-MS (ESI): m/z 299.35/301.31[M+H.sup.+].

    Step 2: Preparation of tert-butyl 4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazol-1-yl)-piperidine-1-carboxylate (Intermediate p2)

    [0336] 3-bromo-5-iodopyridin-2-amine (intermediate p1) (2.5 g, 8.36 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Beijing Ouhe Technology, 3.78 g, 10.03 mmol), sodium carbonate (2.66 g, 25.08 mmol) and Pd(PPh.sub.3).sub.4 (483 mg, 0.42 mmol) were added to a reaction flask containing a mixed solution of toluene, ethanol and water (50 mL, 2:2:1) at room temperature. The reaction mixture was sealed in the flask, purged with nitrogen three times, heated to 80° C. and then stirred for 12 h. After the reaction was completed, the reaction mixture was filtered. The filtrate was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=1:1) to give tert-butyl 4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (intermediate p2) (2.8 g, yellow solid, yield: 79.4%).

    [0337] LC-MS (ESI): m/z 422.24/424.21[M+H.sup.+].

    Step 3: Preparation of tert-butyl 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Intermediate p)

    [0338] Tert-butyl 4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (intermediate p2) (2.8 g, 6.64 mmol), 4-amino-2-fluorophenylboronic acid pinacol ester (Shanghai Bidepharm, 1.88 g, 7.96 mmol), potassium carbonate (2.75 g, 19.92 mmol) and Pd(dppf)Cl.sub.2.DCM (538 mg, 0.66 mmol) were added to a reaction flask containing a mixed solution of 1,4-dioxane and water (40 mL, 4:1) at room temperature. The reaction mixture was sealed in the flask, purged with nitrogen three times, heated to 90° C. and then stirred overnight. After the reaction was completed, the reaction mixture was filtered. The filtrate was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=1:2) to give tert-butyl 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)-pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (intermediate p) (2.3 g, yellow solid, yield: 77.1%).

    [0339] LC-MS (ESI): m/z 453.43 [M+H.sup.+].

    PREPARATION EXAMPLE 16

    Preparation of 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (Intermediate q)

    [0340] ##STR00082##

    [0341] The same procedures as in Preparation Example 15 were performed, except that 1-ethyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1H-pyrazole (Beijing Ouhe) was used in place of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, so as to give 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (intermediate q) (yellow solid, two-step yield: 68.8%).

    [0342] LC-MS (ESI): m/z 298.17[M+H.sup.+].

    PREPARATION EXAMPLE 17

    Preparation of 3-(4-amino-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (Intermediate r)

    [0343] ##STR00083##

    [0344] The same procedures as in Preparation Example 15 were performed, except that 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Beijing Ouhe) was used in place of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, so as to give 3-(4-amino-2-fluorophenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (intermediate r) (yellow solid, two-step yield: 72.3%).

    [0345] LC-MS (ESI): m/z 354.31[M+H.sup.+].

    PREPARATION EXAMPLE 18

    Preparation of 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxy-phenyl)pyridin-2-amine (Intermediate s)

    [0346] ##STR00084##

    [0347] The same procedures as in Preparation Example 15 were performed, except that (3,4-dimethoxy-phenyl)boronic acid (Beijing Ouhe) was used in place of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, to give 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (intermediate s) (yellow solid, two-step yield: 79.1%).

    [0348] LC-MS (ESI): m/z 340.22[M+H.sup.+].

    PREPARATION EXAMPLE 19

    Preparation of 3-(4-amino-2-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (Intermediate t)

    [0349] ##STR00085##

    [0350] The same procedures as in Preparation Example 15 were performed, except that 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Beijing Ouhe) was used in place of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-piperidine-1-carboxylate, so as to give 3-(4-amino-2-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (intermediate t) (yellow solid, two-step yield: 75.8%).

    [0351] LC-MS (ESI): m/z 284.15[M+H.sup.+].

    PREPARATION EXAMPLE 20

    Preparation of 3-(4-amino-2-fluorophenyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (Intermediate u)

    [0352] ##STR00086##

    [0353] The same procedures as in Preparation Example 15 were performed, except that 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine (Shanghai Bidepharm) was used in place of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, so as to prepare 3-(4-amino-2-fluorophenyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (intermediate u) (yellow solid, two-step yield: 32.4%).

    [0354] LC-MS (ESI): m/z 367.33[M+H.sup.+].

    PREPARATION EXAMPLE 21

    Preparation of 3-bromo-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v)

    [0355] ##STR00087##

    [0356] The same procedures as steps 1 and 2 in Preparation Examples 15 were performed, except that 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester was used in place of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate, so as to give 3-bromo-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v) (yellow solid, two-step yield: 43%).

    [0357] LC-MS (ESI): m/z 267.01,269.08[M+H.sup.+].

    PREPARATION EXAMPLE 22

    Preparation of 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (w)

    [0358] ##STR00088##

    [0359] The same procedures as steps 1 and 2 in Preparation Examples 15 were performed, except that 1-Methyl-1H-pyrazole-4-boronic acid pinacol ester was used in place of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate, so as to give 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (w) (yellow solid, two-step yield: 36%).

    [0360] LC-MS (ESI): m/z 253.01,255.08[M+H.sup.+].

    PREPARATION EXAMPLE 23

    Preparation of 3-bromo-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-pyridin-2-amine (x)

    [0361] ##STR00089##

    [0362] The same procedures as steps 1 and 2 in Preparation Examples 15 were performed, except that 1-(tetrahydropyran-4-yl)-1H-pyrazole-4-boronic acid pinacol ester was used in place of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate, so as to give 3-bromo-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (x) (yellow solid, two-step yield: 49%).

    [0363] LC-MS (ESI): m/z 323.18/325.14[M+H.sup.+].

    PREPARATION EXAMPLE 24

    Preparation of 6-cyano-N-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (y)

    [0364] ##STR00090##

    [0365] The same procedures as in Preparation Example 5 were performed, except that 6-(ethoxy-carbonyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) was used in place of 1-cyclopropyl-6-(ethoxycarbonyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (d), and 4-bromo-2,5-difluoroaniline was used in place of 4-bromo-3-fluoroaniline, so as to give 6-cyano-N-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (y) (yellow solid, five-step yield: 18%).

    [0366] LC-MS (ESI): m/z 538.25[M+H.sup.+].

    PREPARATION EXAMPLE 25

    Preparation of 3-bromo-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (z)

    [0367] ##STR00091##

    [0368] The same procedures as steps 1 and 2 in Preparation Example 15 were performed, except that 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine (Shanghai Bidepharm) was used in place of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, so as to give 3-bromo-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (z) (yellow solid, two-step yield: 23%).

    [0369] LC-MS (ESI): m/z 336.22/338.18[M+H.sup.+].

    PREPARATION EXAMPLE 26

    Preparation of 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline hydrochloride (Intermediate aa)

    [0370] ##STR00092##

    Step 1: Preparation of 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (Intermediate aa1)

    [0371] 4-chloro-6,7-dimethoxyquinoline (300 g, 1.341 mol) and 2-fluoro-4-nitrophenol (273 g, 1.743 mol) were added to a reaction flask containing diphenyl ether (2000 mL) at room temperature. The reaction mixture was heated to 140° C. and stirred for 24 h, and after the reaction mixture was cooled to room temperature, an off-white solid was precipitated out. The reaction mixture was added with petroleumether (2000 mL), stirred for 2 h, and then filtered. The filter cake was washed with petroleumether (1000 mL), and the solid was collected to give 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (intermediate aa1) (440 g, off-white solid, yield: 95.38%).

    [0372] LC-MS (ESI): m/z 345.23[M+H.sup.+]

    Step 2: Preparation of 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline hydrochloride (Intermediate aa)

    [0373] 4-(2-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (300 g, 0.872 mol), palladium on carbon (30 g, 10%) and concentrated hydrochloric acid (72 mL, 0.872 mol) were added to a reaction flask containing methanol (1500 mL) at room temperature. After being sealed in the flask and purged with nitrogen three times, the reaction mixture was purged with hydrogen three times and then stirred for 36 h. The reaction mixture was added with methanol (1500 mL) and heated to 60° C. until the solid was completely dissolved. The reaction mixture was then filtered, the filtrate was cooled to 0° C. slowly, and a lot of solids were precipitated out. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (1500 mL). The solids were collected to give 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline hydrochloride (intermediate aa) (290 g, light yellow solid, yield: 94.9%).

    [0374] LC-MS (ESI): m/z 315.27[M+H.sup.+].

    PREPARATION EXAMPLE 27

    Preparation of N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (bb)

    [0375] ##STR00093## ##STR00094##

    Step 1: Preparation of diethyl 2-((3-(4-fluorophenyl)ureido)methylene)malonate (bb1)

    [0376] Diethyl aminomethylenemalonate (1.7 g, 9.1 mmol), fluorophenyl isocyanate (1.37 g, 10 mmol) and DIPEA (2.35 g, 18.2 mmol) were added to a reaction flask containing 1,2-dichloroethane (30 mL) at room temperature. The reaction mixture was sealed in the flask, purged with nitrogen three times, and heated to reflux for 6 h. After the reaction was completed, the reaction mixture was cooled to 0° C., and a solid was precipitated out. The reaction mixture was filtered, and the filter cake was washed with diethyl ether. The solid was collected and dried to give diethyl 2-((3-(4-fluorophenyl)ureido)methylene)malonate (bbl) (980 mg, white solid, yield: 33.7%).

    [0377] LC-MS (ESI): m/z 325.1[M+H.sup.+].

    Step 2: Preparation of ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (bb2)

    [0378] Diethyl 2-((3-(4-fluorophenyl)ureido)methylene)malonate (bb1) (980 mg, 3 mmol) and sodium ethoxide (306 mg, 4.5 mmol) were added to a reaction flask containing ethanol (20 mL) at room temperature. The reaction mixture was stirred for 1 h and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL). The organic phase was washed successively with citric acid (200 mL, 1 M) and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM:MeOH=10:1) to give ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (bb2) (780 mg, white solid, yield: 92.7%).

    [0379] LC-MS (ESI): m/z 279.1[M+H.sup.+].

    Step 3: Preparation of ethyl 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylate (bb3)

    [0380] Ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3 ,4-tetrahydropyrimidine-5-carboxylate (bb2) (350 mg, 1.3 mmol), potassium carbonate (538 mg, 4.5 mmol) and 2-iodopropane (660 mg, 3.9 mmol) were added to a reaction flask containing DMF (10 mL) at room temperature. The reaction mixture was warmed to 75° C. and stirred overnight. After being cooled to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL). The organic phase was washed successively with water (100 mL) and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=1:1) to give ethyl 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (bb3) (380 mg, white solid, yield: 94.3%).

    [0381] LC-MS (ESI): m/z 321.1[M+H.sup.+].

    Step 4: Preparation of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid (bb4)

    [0382] Ethyl 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (bb3) (380 mg, 1.2 mmol) and water (0.5 mL) were added to a reaction flask containing a solution of hydrochloric acid in 1,4-dioxane (10 mL, 4 M) at room temperature. The reaction mixture was heated to 70° C. and stirred for 5 h. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure to give 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (bb4), which was directly used in the next step without purification.

    [0383] LC-MS (ESI): m/z 293.1[M+H.sup.+].

    Step 5: Preparation of N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3 ,4-tetrahydropyrimidine-5-carboxamide (bb)

    [0384] 3-(4-fluorophenyl)-1-isopropyl -2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (bb4) (300 mg, 1 mmol), 4-amino-2-fluorophenylboronic acid pinacol ester (244 mg, 1 mmol), HATU (608 mg, 1.6 mmol) and DIPEA (387 mg, 3 mmol) were added to a reaction flask containing DMF (6 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction mixture was added with saturated sodium bicarbonate solution to quench the reaction, and then extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=5:1) to give N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-fluoro-phenyl)-1-isopropyl-2,4-dioxo-1,2,3 ,4-tetrahydropyrimidine-5-carboxamide (bb) (280 mg, yellow solid, yield: 53.3%).

    [0385] LC-MS (ESI): m/z 512.3[M+H.sup.+].

    PREPARATION EXAMPLE 28

    Preparation of 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (Intermediate cc)

    [0386] ##STR00095##

    Step 1: Preparation of methyl 4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)-amino)-2-methoxybenzoate (Intermediate cc1)

    [0387] Methyl 4-amino-2-methoxybenzoate (Shanghai Bidepharm, 5 g, 27.6 mmol) was added to a reaction flask containing ethanol (100 mL) at room temperature. The reaction mixture was warmed to 50° C., stirred for 10 min, and then added with 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (Shanghai Bidepharm, 5.13 g, 27.6 mmol). The reaction mixture was warmed to 80° C. and stirred for 1 h. After being cooled to room temperature, the reaction mixture was filtered, and the solid was collected to give methyl 4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)-amino)-2-methoxybenzoate (intermediate cc1) (8 g, brown solid, yield: 86.5%).

    [0388] LC-MS (ESI): m/z 336.3[M+H.sup.+].

    ##STR00096##

    Step 2: Preparation of methyl 4-hydroxy-7-methoxyquinoline-6-carboxylate (Intermediate cc2)

    [0389] Methyl 4-(((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-methoxy-benzoate (intermediate cc1) (8 g, 23.9 mmol) was added to a reaction flask containing diphenyl ether (100 mL) at room temperature. The reaction mixture was warmed to 200° C. and stirred for 8 h. After being cooled to room temperature, the reaction mixture was filtered, and a solid was collected to give methyl 4-hydroxy-7-methoxyquinoline-6-carboxylate (intermediate cc2) (5.2 g, brown solid, yield: 93.4%).

    [0390] LC-MS (ESI): m/z 234.1[M+H.sup.+].

    Step 3: Preparation of methyl 4-chloro-7-methoxyquinoline-6-carboxylate (Intermediate cc3)

    [0391] Methyl 4-hydroxy-7-methoxyquinoline-6-carboxylate (intermediate cc2) (1 g, 4.29 mmol) and DMF (0.1 mL) were added to a reaction flask containing thionyl chloride (20 mL) at room temperature. The reaction mixture was heated to reflux and stirred for 3 h. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane (30 mL). The organic phase was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give crude methyl 4-chloro-7-methoxyquinoline-6-carboxylate (intermediate cc3) (1.0 g, brown solid, yield: 92.8%).

    [0392] LC-MS (ESI): m/z 237.1/239.1[M+H.sup.+].

    Step 4: Preparation of 4-chloro-7-methoxyquinoline-6-carboxamide (Intermediate cc4)

    [0393] Methyl 4-chloro-7-methoxyquinoline-6-carboxylate (intermediate cc3) (1 g, 3.98 mmol) and aqueous ammonia (33.0%, 5 mL) were added to a reaction flask containing THF (10 mL) at room temperature. The reaction mixture was sealed in the flask, heated to 80° C. and then stirred overnight. After being cooled to room temperature, the reaction mixture was filtered, and the solid was collected to give 4-chloro-7-methoxyquinoline-6-carboxamide (intermediate cc4) (600 mg, brown solid, yield: 63.9%).

    [0394] LC-MS (ESI): m/z 236.2/238.2[M+H.sup.+].

    Step 5: Preparation of 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxamide (Intermediate cc5)

    [0395] 4-chloro-7-methoxyquinoline-6-carboxamide (intermediate cc4) (600 mg, 2.39 mmol) and 2-fluoro-4-nitrophenol (Beijing Ouhe, 750 mg, 4.78 mmol) were added to a reaction flask containing diphenylether (10 mL) at room temperature. The reaction mixture was heated to 140° C. and stirred for 10 h, and after the reaction mixture was cooled to room temperature, an off-white solid was precipitated out. The reaction mixture was filtered, and a solid was collected to give 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxamide (intermediate cc5) (800 mg, off-white solid, yield: 93.7%).

    [0396] LC-MS (ESI): m/z 358.2[M+H.sup.+]

    Step 6: Preparation of 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (Intermediate m)

    [0397] 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline-6-carboxamide (intermediate m5) (800 mg, 2.24 mmol), iron powder (627 mg, 11.2 mmol) and ammonium chloride (1.3 g, 22.7 mmol) were added to a reaction flask containing ethanol (15 mL) and water (5 mL) at room temperature. The reaction mixture was warmed to 80° C. and stirred for 1 h. After being cooled to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM:MeOH=5:1) to give 4-(4-amino-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (intermediate cc) (600 mg, grey solid, yield: 81.7%).

    [0398] LC-MS (ESI): m/z 328.3[M+H.sup.+]

    PREPARATION EXAMPLE 29

    Preparation of 1-(methyl-d.SUB.3.)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)-1H-pyrazole (Intermediate dd)

    [0399] ##STR00097##

    [0400] 4-pyrazoleboronic acid pinacol ester (Shanghai Bidepharm) (1.2 g, 0.5 mmol), deuterated iodomethane (Energy Chemical) (1.7 g, 1 mmol) and potassium carbonate (1.7 g, 1 mmol) were added to a reaction flask containing acetonitrile (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 48 h. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=5:1) to give 1-(methyl-d.sub.3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate dd) (650 mg, white oil, yield: 50%).

    [0401] LC-MS (ESI): m/z 212.23[M+H.sup.+]

    PREPARATION EXAMPLE 30

    Preparation of 3-bromo-5-(1-(methyl-d.SUB.3.)-1H-pyrazol-4-yl)pyridin-2-amine (Intermediate ee)

    [0402] ##STR00098##

    [0403] The same procedure as steps 1 and 2 in Preparation Example 15 were performed, except that 1-(methyl-d.sub.3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used in place of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, so as to prepare 3-bromo-5-(1-(methyl-d.sub.3)-1H-pyrazol-4-yl)pyridin-2-amine (intermediate ee) (yellow solid, two-step yield: 35%).

    [0404] LC-MS (ESI): m/z 256.07/258.05[M+H.sup.+].

    EXAMPLE 1

    Preparation of N-(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluoro-phenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (1)

    Step 1: Preparation of methyl 5-((4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-isopropyl-4-oxoethyl ester-1,4-dihydropyridine-2-carboxylate (1a)

    [0405] 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (intermediate (a) (625 mg, 1.8 mmol), 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)-pyridin-2-amine (s) (500 mg, 1.5 mmol), HATU (875 mg, 2.3 mmol) and DIPEA (387 mg, 3.0 mmol) were added to a reaction flask containing DMF (20 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction mixture was added with saturated sodium bicarbonate solution to quench the reaction, and then extracted with ethyl acetate (60 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM=1:20) to give ethyl 5-((4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-(4-fluoro-phenyl)1-isopropyl-4-oxo-1,4-dihydropyridine-2-carboxylate (1a) (800 mg, yellow solid, yield: 81.2%).

    ##STR00099## ##STR00100##

    [0406] LC-MS (ESI): m/z 669.28[M+H.sup.+].

    Step 2: Preparation of 5-((4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluoro-phenyl)carbamoyl)-3-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1b)

    [0407] Ethyl 5-((4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2-carboxylate (1a) (800 mg, 1.2 mmol), lithium hydroxide monohydrate (67 mg, 1.6 mmol), and water (5 mL) were added to a reaction flask containing ethanol (20 mL) at room temperature. The reaction mixture was stirred at 70° C. overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give crude 5-((4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1b) (yellow solid), which was directly used in the next step without purification.

    [0408] LC-MS (ESI): m/z 641.3[M+H.sup.+].

    Step 3: Preparation of N.SUP.5.-(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluoro-phenyl)-3-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide (1c)

    [0409] 5-((4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1b) (400 mg, 0.6 mmol) was added to a reaction flask containing tetrahydrofuran (8 mL) and phosphorus oxychloride (4 mL) at room temperature. The reaction mixture was heated to reflux for 30 min, and after the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the acyl chloride intermediate, which was directly used in the next step without purification. The acyl chloride intermediate was added dropwise to a reaction flask containing tetrahydrofuran (10 mL) and aqueous ammonia (10 mL) at 0° C. After the addition was completed, the reaction mixture was stirred for 20 min. After the reaction was completed, ethyl acetate (30 mL) was added to dilute the reaction mixture. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent MeOH:DCM=1:10) to give N.sup.5-(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide (1c) (280 mg, yellow solid, yield: 70.2%).

    [0410] LC-MS (ESI): m/z 640.7[M+H.sup.+].

    Step 4: Preparation of N-(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (1)

    [0411] N.sup.5-(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide (6c) (100 mg, 0.16 mol) was added to a reaction flask containing anhydrous tetrahydrofuran (4 mL). The reaction mixture was cooled to 0° C. and then added successively with triethylamine (130 mg, 1.3 mmol) and trifluoromethanesulfonic anhydride (126 mg, 0.6 mol). After the addition was completed, the reaction mixture was stirred for 30 min. After the reaction was completed, the reaction mixture was added with aqueous potassium hydroxide solution (5 M, 0.2 mL), stirred for 1 h, and then diluted with ethyl acetate (50 mL). The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 10%-100%) to give N-(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (1) (30 mg, yellow solid, yield: 31%).

    [0412] LC-MS (ESI): m/z 622.2[M+H.sup.+].

    [0413] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.55 (s, 1H), 8.85 (s, 1H), 8.29 (d, J=2.5 Hz, 1H), 7.90 (dd, J=12.2, 2.0 Hz, 1H), 7.64-7.58 (m, 3H), 7.48-7.36 (m, 4H), 7.18-7.10 (m, 2H), 6.97 (d, J=8.4 Hz, 1H), 5.67 (s, 2H), 4.86 (p, J=6.6 Hz, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 1.63 (d, J=6.6 Hz, 6H).

    EXAMPLE 2

    Preparation of N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (2)

    [0414] ##STR00101##

    Step 1: Preparation of tert-butyl 4-(4-(6-amino-5-(4-(6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamido)-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2a)

    [0415] Tert-butyl 4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (p2) (260 mg, 0.62 mmol), 6-cyano-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (f) (300 mg, 0.62 mmol), potassium carbonate (256 mg, 1.85 mmol) and Pd(PPh.sub.3).sub.4 (285 mg, 0.25 mmol) were added to a reaction flask containing 1,4-dioxane (8 mL) and water (2 mL) at room temperature. The reaction mixture was sealed in the flask, purged with nitrogen three times, heated to 90° C. in a microwave reactor and then stirred for 30 min. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=1:2) to give tert-butyl 4-(4-(6-amino-5-(4-(6-cyano-5-(4-fluoro-phenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamido)-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2a) (290 mg, yellow solid, yield: 68.3%).

    [0416] LC-MS (ESI): m/z 735.4[M+H.sup.+].

    Step 2: Preparation of N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (2)

    [0417] Tert-butyl 4-(4-(6-amino-5-(4-(6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydro-pyridine-3-carboxamido)-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (2a) (100 mg, 0.14 mmol) and hydrochloric acid (1 mL, 4 M) were added to a reaction flask containing DCM (4 mL) at room temperature. The reaction mixture was stirred for 30 min, and after the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 10%-100%) to give N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (2) (25 mg, yellow solid, yield: 29%).

    [0418] LC-MS (ESI): m/z 635.3[M+H.sup.+].

    [0419] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.55 (s, 1H), 8.84 (s, 1H), 8.26 (d, J=2.3 Hz, 1H), 8.14 (s, 1H), 7.90 (dd, J=12.3, 2.1 Hz, 1H), 7.84 (s, 1H), 7.64-7.58 (m, 2H), 7.56 (d, J=2.4 Hz, 1H), 7.46 (dd, J=8.4, 2.1 Hz, 1H), 7.38 (td, J=8.7, 3.5 Hz, 3H), 5.56 (s, 2H), 4.86 (p, J=6.6 Hz, 1H), 4.35 (tt, J=11.0, 4.1 Hz, 1H), 3.24 (s, 2H), 2.92 (td, J=12.5, 3.0 Hz, 2H), 2.16-2.09 (m, 2H), 2.01 (qd, J=12.1, 4.2 Hz, 3H), 1.63 (d, J=6.6 Hz, 6H).

    EXAMPLE 3

    Preparation of N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluoro-phenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (3)

    [0420] ##STR00102##

    Step 1: Preparation of N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluoro-phenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (3)

    [0421] 3-bromo-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v) (80 mg, 0.3 mmol), 6-cyano-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (f) (186 mg, 0.36 mmol), potassium acetate (88 mg, 0.9 mmol), and Pd(PPh.sub.3).sub.4 (69 mg, 0.06 mmol) were added to a reaction flask containing 1,4-dioxane (8 mL) and water (2 mL) at room temperature. The reaction mixture was sealed in the flask, purged with nitrogen three times, heated to 90° C. in a microwave reactor and then stirred for 30 min. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 10%-100%) to give N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (3) (35 mg, yellow solid, yield: 20%).

    [0422] LC-MS (ESI): m/z 580.2[M+H.sup.+].

    [0423] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.55 (s, 1H), 8.84 (s, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.09 (s, 1H), 7.90 (dd, J=12.3, 2.1 Hz, 1H), 7.77 (d, J=0.8 Hz, 1H), 7.63-7.58 (m, 2H), 7.52 (d, J=2.4 Hz, 1H), 7.46 (dd, J=8.4, 2.0 Hz, 1H), 7.38 (tt, J=8.5, 2.3 Hz, 3H), 5.54 (s, 2H), 4.86 (p, J=6.6 Hz, 1H), 4.10 (q, J=7.3 Hz, 2H), 1.63 (d, J=6.6 Hz, 6H), 1.38 (t, J=7.3 Hz, 3H).

    EXAMPLE 4

    Preparation of N-(4-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (4)

    [0424] ##STR00103##

    [0425] The same procedures as in Example 3 were performed, except that 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (w) was used in place of 3-bromo-5-(1-ethyl-1H-pyrazol-4-yl)-pyridin-2-amine (v), so as to give N-(4-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (4) (15 mg, yellow solid, yield: 56%).

    [0426] LC-MS (ESI): m/z 566.23[M+H.sup.+].

    [0427] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.54(s, 1H),8.84 (s, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.02 (d, J=0.8 Hz, 1H), 7.90 (dd, J=12.3, 2.0 Hz, 1H), 7.77 (d, J=0.8 Hz, 1H), 7.63-7.58 (m, 2H), 7.51 (d, J=2.3 Hz, 1H), 7.46 (dd, J=8.4, 2.1 Hz, 1H), 7.38 (td, J=8.7, 2.0 Hz, 3H), 5.55 (s, 2H), 4.88-4.83 (m, 1H), 3.82 (s, 3H), 1.63 (d, J=6.6 Hz, 6H).

    EXAMPLE 5

    Preparation of N-(4-(2-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydro-pyridine-3-carboxamide (5)

    [0428] ##STR00104##

    [0429] The same procedures as in Example 3 were used, except that 3-bromo-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (x) was used in place of 3-bromo-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v), so as to give N-(4-(2-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (5) (22 mg, yellow solid, yield: 42%).

    [0430] LC-MS (ESI): m/z 636.29[M+H.sup.+].

    [0431] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.55 (s, 1H), 8.84 (s, 1H), 8.26 (d, J=2.3 Hz, 1H), 8.17 (s, 1H), 7.90 (dd, J=12.2, 2.0 Hz, 1H), 7.81 (s, 1H), 7.64-7.58 (m, 2H), 7.55 (d, J=2.3 Hz, 1H), 7.46 (dd, J=8.4, 2.1 Hz, 1H), 7.38 (td, J=8.7, 2.4 Hz, 3H), 5.55 (s, 2H), 4.85 (q, J=6.6 Hz, 1H), 4.39-4.32 (m, 1H), 3.99-3.92 (m, 2H), 3.48 (dd, J=11.6, 2.6 Hz, 2H), 2.02-1.90 (m, 4H), 1.63 (d, J=6.6 Hz, 6H).

    EXAMPLE 6

    Preparation of N-(4-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2,5-difluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (6)

    [0432] ##STR00105##

    [0433] The same procedures as in Example 3 were performed, except that 6-cyano-N-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (y) was used in place of 6-cyano-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (f), and 3-bromo-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (w) was used in place of 3-bromo-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v), so as to give N-(4-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-2,5-difluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (6) (14 mg, yellow solid, yield: 39%).

    [0434] LC-MS (ESI): m/z 584.23[M+H.sup.+].

    [0435] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.86 (s, 1H), 8.86 (s, 1H), 8.42 (dd, J=11.6, 6.6 Hz, 1H), 8.24 (d, J=2.3 Hz, 1H), 8.02 (s, 1H), 7.77 (d, J=0.8 Hz, 1H), 7.66-7.58 (m, 2H), 7.54 (d, J=2.4 Hz, 1H), 7.45-7.35 (m, 3H), 5.69 (s, 2H), 4.86 (q, J=6.6 Hz, 1H), 3.82 (s, 3H), 1.63 (d, J=6.6 Hz, 6H).

    EXAMPLE 7

    Preparation of N-(4-(2-amino-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydro-pyridine-3-carboxamide (7)

    [0436] ##STR00106##

    [0437] The same procedures as in Example 3 were performed, except that 3-bromo-5-(1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (z) was used in place of 3-bromo-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v), so as to give N-(4-(2-amino-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (7) (12 mg, yellow solid, yield: 60%).

    [0438] LC-MS (ESI): m/z 649.3[M+H.sup.+].

    [0439] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 12.54 (s, 1H), δ 8.84 (s, 1H), 8.24 (s, 1H), 8.15 (d, J=0.8 Hz, 1H), 7.89 (dd, J=12.2, 2.1 Hz, 1H), 7.79 (d, J=0.7 Hz, 1H), 7.64-7.58 (m, 2H), 7.54 (d, J=2.4 Hz, 1H), 7.46 (dd, J=8.4, 2.0 Hz, 1H), 7.38 (td, J=8.7, 3.3 Hz, 3H), 5.54 (s, 2H), 4.87 (q, J=6.6 Hz, 1H), 4.05 (dq, J=10.1, 5.3, 4.7 Hz, 1H), 2.84 (d, J=11.2 Hz, 2H), 2.20 (s, 3H), 1.99 (dtd, J=22.9, 11.4, 8.4 Hz, 6H), 1.63 (d, J=6.6 Hz, 6H).

    EXAMPLE 8

    Preparation of N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-cyclobutyl-4-oxo-1,4-dihydropyridine-3-carboxamide (8)

    [0440] ##STR00107##

    [0441] The same procedures as in Example 2 were performed, except that 6-cyano-1-cyclobutyl-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (g) was used in place of 6-cyano-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydro-pyridine-3-carboxamide (f), so as to give N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-cyclobutyl-4-oxo-1,4-dihydro-pyridine-3-carboxamide (8) (30 mg, yellow solid, two-step yield: 43.3%).

    [0442] LC-MS (ESI): m/z 647.34[M+H.sup.+].

    [0443] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.52 (s, 1H), 8.75 (s, 1H), 8.27 (dd, J=10.5, 2.0 Hz, 2H), 8.14 (s, 1H), 7.90 (dd, J=12.2, 2.0 Hz, 1H), 7.82 (s, 1H), 7.58 (ddd, J=9.8, 6.0, 3.1 Hz, 3H), 7.46 (dd, J=8.4, 2.0 Hz, 1H), 7.38 (td, J=8.7, 3.1 Hz, 3H), 5.57 (s, 2H), 5.03 (q, J=8.7 Hz, 1H), 4.27 (s, 1H), 3.18 (d, J=12.4 Hz, 3H), 2.79 (t, J=12.1 Hz, 2H), 2.69-2.53 (m, 4H), 2.06 (d, J=13.0 Hz, 2H), 1.86 (td, J=10.2, 5.2 Hz, 3H).

    EXAMPLE 9

    Preparation of N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluoro-phenyl)-6-cyano-5-(4-fluorophenyl)-1-cyclobutyl-4-oxo-1,4-dihydropyridine-3-carboxamide (9)

    [0444] ##STR00108##

    [0445] The same procedures as in Example 3 were performed, except that 6-cyano-1-cyclobutyl-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (g) was used in place of 6-cyano-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydro-pyridine-3-carboxamide (f), so as to give N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-cyclobutyl-4-oxo-1,4-dihydropyridine-3-carboxamide (9) (11 mg, yellow solid, yield: 69%).

    [0446] LC-MS (ESI): m/z 592.27[M+H.sup.+].

    [0447] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.52 (s, 1H), 8.75 (s, 1H), 8.24 (d, J=2.3 Hz, 1H), 8.09 (s, 1H), 7.90 (dd, J=12.2, 2.0 Hz, 1H), 7.78 (s, 1H), 7.61-7.55 (m, 2H), 7.52 (d, J=2.3 Hz, 1H), 7.46 (dd, J=8.4, 2.0 Hz, 1H), 7.42-7.35 (m, 3H), 5.56 (s, 2H), 5.03 (q, J=8.6 Hz, 1H), 4.11 (q, J=7.3 Hz, 2H), 2.67-2.57 (m, 3H), 2.02-1.96 (m, 1H), 1.87 (dq, J=9.9, 5.3 Hz, 2H), 1.38 (t, J=7.3 Hz, 3H).

    EXAMPLE 10

    Preparation of N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-cyclopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (10)

    [0448] ##STR00109##

    [0449] The same procedures as in Example 3 were performed, except that 6-cyano-1-cyclopropyl-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (e) was used in place of 6-cyano-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydro-pyridine-3-carboxamide (I), so as to give N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-cyclopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (10) (60 mg, yellow solid, yield: 46%).

    [0450] LC-MS (ESI): m/z 578.3[M+H.sup.+].

    [0451] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.44 (s, 1H), 8.68 (s, 1H), 8.24 (d, J=2.3 Hz, 1H), 8.09 (s, 1H), 7.88 (dd, J=12.2, 2.0 Hz, 1H), 7.78 (s, 1H), 7.58 (ddd, J=8.6, 5.4, 2.5 Hz, 2H), 7.51 (d, J=2.4 Hz, 1H), 7.46 (dd, J=8.4, 2.1 Hz, 1H), 7.38 (td, J=8.6, 6.3 Hz, 3H), 5.56 (s, 2H), 4.10 (q, J=7.2 Hz, 2H), 3.94 (tt, J=7.3, 3.8 Hz, 1H), 2.92 (td, J=12.5, 3.0 Hz, 2H),1.38 (t, J=7.3 Hz, 4H), 1.27-1.22 (m, 3H).

    EXAMPLE 11

    Preparation of N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-cyclopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (11)

    [0452] ##STR00110##

    [0453] The same procedures as in Preparation Example 2 were performed, except that 6-cyano-1-cyclopropyl-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (e) was used in place of 6-cyano-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (f), so as to give N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-cyclopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (11) (56 mg, yellow solid, two-step yield: 37.6%).

    [0454] LC-MS (ESI): m/z 633.36[M+H.sup.+].

    [0455] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.43 (s, 1H), 8.68 (s, 1H), 8.26 (d, J=2.3 Hz, 1H), 8.14 (s, 1H), 7.88 (dd, J=12.2, 2.0 Hz, 1H), 7.83 (s, 1H), 7.61-7.54 (m, 3H), 7.46 (dd, J=8.4, 2.0 Hz, 1H), 7.38 (td, J=8.7, 6.8 Hz, 3H), 5.55 (s, 2H), 4.33 (s, 1H), 3.96-3.93 (m, 1H), 3.25 (s, 1H), 2.10 (s, 2H), 2.00 (d, J=7.8 Hz, 3H), 1.42 (s, 2H), 1.26-1.21 (m, 3H).

    EXAMPLE 12

    Preparation of N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (12)

    [0456] ##STR00111##

    Step 1: Preparation of tert-butyl 4-(4-(6-amino-5-(4-(6-cyano-5-cyclopropyl-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (12a)

    [0457] 6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate j) (25 mg, 0.084 mmol), tert-butyl 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)-pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (intermediate p) (38 mg, 0.084 mmol), HATU (41 mg, 0.11 mmol) and DIPEA (33 mg, 0.25 mmol) were added to a reaction flask containing DMF (4 mL) at 0° C. The reaction mixture was stirred for 1 h. After the reaction was completed, the reaction mixture was added with saturated sodium bicarbonate solution to quench the reaction, and then extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM=1:20) to give tert-butyl 4-(4-(6-amino-5-(4-(6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenyl)-pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (12a) (25 mg, yellow solid, yield: 40.6%).

    [0458] LC-MS (ESI): m/z 733.41[M+H.sup.+].

    Step 2: Preparation of N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (12)

    [0459] Tert-butyl 4-(4-(6-amino-5-(4-(6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (12a) (25 mg, 0.034 mmol) and a solution of hydrochloric acid in dioxane (4 N, 1.5 mL) were added to a reaction flask containing DCM (3 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 10%400%) to give N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (12) (10 mg, yellow solid, yield: 50.6%).

    [0460] LC-MS (ESI): m/z 633.37[M+H.sup.+].

    [0461] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.93 (s, 1H), 9.06 (d, J=11.4 Hz, 1H), 8.89 (d, J=10.7 Hz, 1H), 8.37 (d, J=2.5 Hz, 2H), 8.19 (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.96 (dd, J=12.2, 2.1 Hz, 1H), 7.74-7.69 (m, 2H), 7.60-7.47 (m, 5H), 4.50-4.44 (m, 1H), 3.08 (d, J=11.9 Hz, 2H), 2.28-2.05 (m, 6H), 2.04-1.95 (m, 1H), 1.19-1.14 (m, 2H), 0.93 (dt, J=7.0, 3.3 Hz, 2H).

    EXAMPLE 13

    Preparation of N-(4-(2-amino-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamide (13)

    [0462] ##STR00112##

    [0463] The same procedures as in Example 12 were performed, except that 3-(4-amino-2-fluoro-phenyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (intermediate u) was used in place of tert-butyl 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (intermediate p), so as to prepare N-(4-(2-amino-5-(1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (13) (yellow solid, one-step yield: 18.4%).

    [0464] LC-MS (ESI): m/z 647.34[M+H.sup.+].

    [0465] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ11.85 (s, 1H), 8.25 (d, J=2.4 Hz, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.87 (dd, J=12.1, 2.1 Hz, 1H), 7.79 (s, 1H), 7.74-7.69 (m, 2H), 7.56-7.46 (m, 4H), 7.38 (t, J=8.4 Hz, 1H), 5.53 (s, 2H), 4.06 (dt, J=10.7, 5.7 Hz, 1H), 2.84 (d, J=11.0 Hz, 2H), 2.20 (s, 3H), 2.09-1.91 (m, 7H), 1.16 (dt, J=8.3, 3.3 Hz, 2H), 0.94 (dt, J=6.9, 4.8 Hz, 2H).

    EXAMPLE 14

    Preparation of N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (14)

    [0466] ##STR00113##

    [0467] The same procedures as in Example 12 were performed, except that 3-(4-amino-2-fluoro-phenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (intermediate q) was used in place of tert-butyl 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (intermediate p), so as to give N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (14) (yellow solid, one-step yield: 20.3%).

    [0468] LC-MS (ESI): m/z 578.36[M+H.sup.+].

    [0469] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ11.85 (s, 1H), 8.24 (d, J=2.3 Hz, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 7.87 (dd, J=12.2, 2.1 Hz, 1H), 7.77 (s, 1H), 7.74-7.69 (m, 2H), 7.50 (ddd, J=10.6, 5.9, 2.5 Hz, 4H), 7.38 (t, J=8.4 Hz, 1H), 5.54 (s, 2H), 4.10 (q, J=7.3 Hz, 2H), 2.10 (td, J=8.3, 4.2 Hz, 1H), 1.38 (t, J=7.3 Hz, 3H), 1.21-1.14 (m, 2H), 0.98-0.92 (m, 2H).

    EXAMPLE 15

    Preparation of N-(4-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (15)

    [0470] ##STR00114##

    [0471] The same procedures as in Example 12 were performed, except that 3-(4-amino-2-fluoro-phenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (intermediate t) was used in place of tert-butyl 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (intermediate p), so as to give N-(4-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamide (15) (yellow solid, one-step yield: 22.4%).

    [0472] LC-MS (ESI): m/z 564.37[M+H.sup.+].

    [0473] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.85 (s, 1H), 8.23 (d, J=2.3 Hz, 1H), 8.11 (s, 1H), 8.02 (s, 1H), 7.87 (dd, J=12.2, 2.1 Hz, 1H), 7.76 (s, 1H), 7.74-7.68 (m, 2H), 7.50 (td, J=7.8, 7.0, 2.2 Hz, 4H), 7.38 (t, J=8.4 Hz, 1H), 5.54 (s, 2H), 3.82 (s, 3H), 2.10 (ddd, J=8.3, 5.1, 3.3 Hz, 1H), 1.20-1.13 (m, 2H), 0.94 (dt, J=6.9, 4.8 Hz, 2H).

    EXAMPLE 16

    Preparation of N-(4-(2-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxamide (16)

    [0474] ##STR00115##

    [0475] The same procedures as in Example 12 were performed, except that 3-(4-amino-2-fluoro-phenyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (intermediate r) was used in place of tert-butyl 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (intermediate p), so as to give N-(4-(2-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-5-cyclopropyl-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (16) (yellow solid, one-step yield: 17.8%).

    [0476] LC-MS (ESI): m/z 634.41[M+H.sup.+].

    [0477] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.85 (s, 1H), 8.25 (d, J=2.4 Hz, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.87 (dd, J=12.2, 2.1 Hz, 1H), 7.80 (s, 1H), 7.74-7.69 (m, 2H), 7.55-7.47 (m, 4H), 7.38 (t, J=8.4 Hz, 1H), 5.54 (s, 2H), 4.34 (dt, J=10.9, 4.7 Hz, 1H), 3.98-3.92 (m, 2H), 3.48 (dd, J=11.6, 2.6 Hz, 2H), 2.12-2.06 (m, 1H), 1.96 (td, J=12.7, 8.0 Hz, 4H), 1.20-1.14 (m, 2H), 0.97-0.92 (m, 2H).

    EXAMPLE 17

    Preparation of N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-1-(4-fluorophenyl)-2-oxo-5-(prop-1-en-2-yl)-1,2-dihydropyridine-3-carboxamide (17)

    [0478] ##STR00116##

    [0479] The same procedures as in Example 12 were performed, except that 6-cyano-1-(4-fluoro-phenyl)-2-oxo-5-(prop-1-en-2-yl)-1,2-dihydropyridine-3-carboxylic acid (intermediate k) was used in place of 6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate j), so as to give N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-1-(4-fluorophenyl)-2-oxo-5-(prop-1-en-2-yl)-1,2-dihydropyridine-3-carboxamide (17) (yellow solid, two-step yield: 9.3%).

    [0480] LC-MS (ESI): m/z 633.38[M+H.sup.+].

    [0481] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.78 (s, 1H), 8.54 (s, 1H), 8.26 (d, J=2.3 Hz, 1H), 8.13 (s, 1H), 7.89 (dd, J=12.2, 2.1 Hz, 1H), 7.81 (s, 1H), 7.76-7.71 (m, 2H), 7.55-7.47 (m, 4H), 7.39 (t, J=8.4 Hz, 1H), 5.55 (s, 2H), 5.51 (t, J=1.6 Hz, 1H), 5.43 (s, 1H), 4.21-4.27 (m, 1H),3.15 (d, J=12.2 Hz, 2H), 2.76 (d, J=12.4 Hz, 2H), 2.18 (s, 3H), 2.02 (t, J=13.8 Hz, 3H), 1.90 (t, J=11.7 Hz, 2H).

    EXAMPLE 18

    Preparation of N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (18)

    [0482] ##STR00117##

    [0483] The same procedures as in Example 14 were performed, except that 6-cyano-1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate i) was used in place of 6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate j), so as to give N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-cyano-1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (18) (yellow solid, one-step yield: 30.1%).

    [0484] LC-MS (ESI): m/z 552.33[M+H.sup.+].

    [0485] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.89 (s, 1H), 8.61 (s, 1H), 8.24 (d, J=2.3 Hz, 1H), 8.08 (s, 1H), 7.88 (dd, J=12.2, 2.1 Hz, 1H), 7.77 (d, J=0.8 Hz, 1H), 7.72-7.67 (m, 2H), 7.54-7.46 (m, 4H), 7.39 (t, J=8.4 Hz, 1H), 5.54 (s, 2H), 4.10 (q, J=7.3 Hz, 2H), 2.45 (s, 3H), 1.38 (t, J=7.3 Hz, 3H).

    EXAMPLE 19

    Preparation of N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-5-bromo-1-(4-fluorophenyl)-6-((methylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (19)

    [0486] ##STR00118##

    [0487] The same procedures as in Example 12 were performed, except that 5-bromo-6-(((tert-butoxycarbonyl)(methyl)amino)methyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate 1) was used in place of 6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate j), and 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (intermediate q) was used in place of tert-butyl 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (intermediate p), so as to give N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluoro-phenyl)-5-bromo-1-(4-fluorophenyl)-6-((methylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (19) (yellow solid, two-step yield: 40.2%).

    [0488] LC-MS (ESI): m/z 634.25/635.21[M+H.sup.+].

    [0489] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.85 (s, 1H), 8.58 (s, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.08 (s, 1H), 7.87 (dd, J=12.2, 2.1 Hz, 1H), 7.77 (s, 1H), 7.55 (ddt, J=8.0, 5.1, 2.6 Hz, 2H), 7.52-7.43 (m, 4H), 7.36 (t, J=8.4 Hz, 1H), 5.53 (s, 2H), 4.09 (t, J=7.3 Hz, 2H), 2.09 (s, 3H), 1.38 (t, J=7.3 Hz, 3H).

    EXAMPLE 20

    Preparation of N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (20)

    [0490] ##STR00119##

    [0491] The same procedures as in Example 2 were performed, except that N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide (bb) was used in place of 6-cyano-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (f), so as to give N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxamide (20) (66 mg, white solid, two-step yield: 37%).

    [0492] LC-MS (ESI): m/z 627.2[M+H.sup.+].

    [0493] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.05 (s, 1H), 8.69 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 8.13 (s, 1H), 7.86 (dd, J=12.3, 2.1 Hz, 1H), 7.80 (s, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.48-7.41 (m, 3H), 7.36 (ddd, J=8.9, 6.6, 2.5 Hz, 3H), 5.53 (s, 2H), 4.78 (p, J=6.8 Hz, 1H), 4.26-4.21 (m, 1H), 3.16-3.11 (m, 2H), 2.72 (td, J=12.4, 2.6 Hz, 3H), 2.06-1.99 (m, 2H), 1.90-1.82 (m, 2H), 1.43 (d, J=6.8 Hz, 6H).

    EXAMPLE 21

    Preparation of 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoro-phenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (21)

    [0494] ##STR00120## ##STR00121##

    Step 1: Preparation of ethyl 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (21a)

    [0495] 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b) (800 mg, 2.51 mmol), 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (aa) (790 mg, 2.51 mmol), HATU (1.43 g, 3.77 mmol) and DIPEA (973 mg, 7.53 mmol) were added to a reaction flask containing DMF (30 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction mixture was added with saturated sodium bicarbonate solution to quench the reaction, and then extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM=1:20) to give ethyl 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (21a) (1.4 g, yellow solid, yield: 90.4%).

    [0496] LC-MS (ESI): m/z 616.3[M+H.sup.+].

    Step 2: Preparation of 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (21b)

    [0497] Ethyl 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3-(4-fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (21a) (1.4 g, 2.27 mmol), lithium hydroxide monohydrate (150 mg, 3.57 mmol) and water (4 mL) were added to a reaction flask containing ethanol (16 mL) at room temperature. The reaction mixture was warmed to 70° C. and stirred for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give crude 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (21b) (1.4 g, grey solid), which was directly used in the next step without purification.

    [0498] LC-MS (ESI): m/z 588.3[M+H.sup.+].

    Step 3: Preparation of N.SUP.5.-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluoro-phenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide (21c)

    [0499] 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (21b) (200 mg, 0.3 mmol) was added to a reaction flask containing tetrahydrofuran (8 mL) and phosphorus oxychloride (4 mL) at room temperature. The reaction mixture was heated to reflux for 30 min, and after the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the acyl chloride intermediate, which was directly used in the next step without purification.

    [0500] The acyl chloride intermediate was added dropwise to a reaction flask containing tetrahydrofuran (10 mL) and aqueous ammonia (10 mL) at 0° C. After the addition was completed, the reaction mixture was stirred for 20 min. After the reaction was completed, ethyl acetate (50 mL) was added to dilute the reaction mixture. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM=1:10) to give N.sup.5-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide (21c) (118 mg, yellow solid, yield: 59.1%).

    [0501] LC-MS (ESI): m/z 587.2[M+H.sup.+].

    Step 4: Preparation of 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (21)

    [0502] N.sup.5-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxamide (21c) (54 mg, 0.1 mol) was added to a reaction flask containing anhydrous tetrahydrofuran (4 mL). The reaction mixture was cooled to 0° C. and then added successively with triethylamine (81 mg, 0.8 mmol) and trifluoromethanesulfonic anhydride (84 mg, 0.4 mol). After the addition was completed, the reaction mixture was stirred for 30 min. After the reaction was completed, ethyl acetate (30 mL) was added to dilute the reaction mixture. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, left to stand overnight and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 10%-100%) to give 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoro-phenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (21) (18.4 mg, yellow solid, yield: 35.2%).

    [0503] LC-MS (ESI): m/z 569.2[M+H.sup.+].

    [0504] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.58 (s, 1H), 8.98 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 8.04 (dd, J=12.9, 2.4 Hz, 1H), 7.60-7.54 (m, 2H), 7.53 (d, J=2.5 Hz, 1H), 7.46 (t, J=8.9 Hz, 1H), 7.42-7.36 (m, 3H), 6.48 (dd, J=5.2, 1.0 Hz, 1H), 4.09 (s, 3H),3.95 (d, 6H).

    EXAMPLE 22

    Preparation of 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoro-phenyl)-5-(4-fluorophenyl)-1-cyclopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (22)

    [0505] ##STR00122##

    [0506] The same procedures as in Example 21 were performed, except that 1-cyclopropyl-6-(ethoxycarbonyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (d) was used in place of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b), so as to give 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoro-phenyl)-5-(4-fluorophenyl)-1-cyclopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (22) (38 mg, yellow solid, four-step yield: 18%).

    [0507] LC-MS (ESI): m/z 595.2[M+H.sup.+].

    [0508] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.43 (s, 1H), 8.67 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.04 (dd, J=12.8, 2.4 Hz, 1H), 7.63-7.50 (m, 4H), 7.49-7.35 (m, 4H), 6.48 (d, J=5.2 Hz, 1H), 3.95 (d, 6H), 3.48 (d, J=11.0 Hz, 1H), 1.41 (d, J=3.9 Hz, 2H), 1.25 (s, 2H).

    EXAMPLE 23

    Preparation of 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoro-phenyl)-5-(4-fluorophenyl)-1-cyclobutyl-4-oxo-1,4-dihydropyridine-3-carboxamide (23)

    [0509] ##STR00123##

    [0510] The same procedures as in Example 21 were performed, except that 1-cyclobutyl-6-(ethoxy-carbonyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (c) was used in place of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b), so as to give 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluoro-phenyl)-1-cyclobutyl-4-oxo-1,4-dihydropyridine-3-carboxamide (23) (25 mg, yellow solid, four-step yield: 21%).

    [0511] LC-MS (ESI): m/z 609.2[M+H.sup.+].

    [0512] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.52 (s, 1H), 8.74 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.06 (dd, J=12.9, 2.4 Hz, 1H), 7.61-7.51 (m, 4H), 7.46 (t, J=8.9 Hz, 1H), 7.43-7.35 (m, 3H), 6.49 (d, J=5.4 Hz, 1H), 5.03 (q, J=8.4 Hz, 1H), 3.95 (d, J=1.8 Hz, 6H), 2.68-2.53 (m, 4H), 1.87 (dq, J=9.9, 5.3 Hz, 2H).

    EXAMPLE 24

    Preparation of 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoro-phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (24)

    [0513] ##STR00124##

    [0514] The same procedures as in Example 21 were performed, except that 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) was used in place of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (b), so as to give 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (24) (38 mg, yellow solid, four-step yield: 23%).

    [0515] LC-MS (ESI): m/z 597.3[M+H.sup.+].

    [0516] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.54 (s, 1H), 8.84 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.06 (dd, J=12.9, 2.4 Hz, 1H), 7.64-7.58 (m, 2H), 7.56-7.51 (m, 2H), 7.45 (t, J=8.9 Hz, 1H), 7.42-7.35 (m, 3H), 6.49 (dd, J=5.2, 1.1 Hz, 1H), 4.85 (h, J=6.6 Hz, 1H), 3.95 (d, J=2.2 Hz, 6H), 1.63 (d, J=6.6 Hz, 6H).

    EXAMPLE 25

    Preparation of 6-cyano-N-(4-((6-cyano-7-methoxyquinolin-4-yl)oxy)-3-fluoro-phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (25)

    [0517] ##STR00125##

    [0518] The same procedures as in Example 21 were performed, except that 4-(4-amino-2-fluoro-phenoxy)-7-methoxyquinoline-6-carboxamide (intermediate cc) was used in place of 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline hydrochloride (intermediate aa), and 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a) was used in place of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (b), so as to give 6-cyano-N-(4-((6-cyano-7-methoxyquinolin-4-yl)-oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (25) (30 mg, yellow solid, four-step yield: 19.3%).

    [0519] LC-MS (ESI): m/z 592.21[M+H.sup.+].

    [0520] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.57 (s, 1H), 8.84 (s, 1H), 8.81 (s, 1H), 8.77 (d, J=5.3 Hz, 1H), 8.08 (dd, J=12.8, 2.3 Hz, 1H), 7.66-7.48 (m, 5H), 7.42-7.35 (m, 2H), 6.63 (dd, J=5.3, 1.1 Hz, 1H), 4.86 (p, J=6.6 Hz, 1H), 4.08 (s, 3H), 1.63 (d, J=6.6 Hz, 6H).

    EXAMPLE 26

    Preparation of 6-(aminomethyl)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydro-1,2-dihydropyridine-3-carboxamide (26)

    Step 1: Preparation of tert-butyl ((3-bromo-5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridin-2-yl)methyl)carbamate (26a)

    [0521] 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (intermediate aa) (77 mg, 0.22 mmol), 6-((tert-butoxycarbonyl)amino)methyl)-5-bromo-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate m) (80 mg, 0.18 mmol), HATU (102 mg, 0.27 mmol) and DIPEA (70 mg, 0.54 mmol) were added to a reaction flask containing DMF (3 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction mixture was added with saturated sodium bicarbonate solution to quench the reaction, and then extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM=1:10) to give tert-butyl ((3-bromo-5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridin-2-yl)methyl)carbamate (26a) (50 mg, yellow solid, yield: 37.7%).

    [0522] LC-MS (ESI): m/z 737.11/739.17[M+H.sup.+].

    ##STR00126## ##STR00127##

    Step 2: Preparation of tert-butyl ((5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-carbamoyl)-1-(4-fluorophenyl)-3-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)carbamate (26b)

    [0523] Tert-butyl ((3-bromo-5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridin-2-yl)methyl)carbamate (26a) (50 mg, 0.07 mmol), methylboronic acid (40 mg, 0.70 mmol), potassium carbonate (28 mg, 0.21 mmol) and Pd(dppf)Cl.sub.2.DCM (10 mg, 0.014 mmol) were added to a reaction flask containing 1,4-dioxane (4 mL) and water (1 mL) at room temperature. The reaction mixture was sealed in the flask, purged with nitrogen three times, heated to 100° C. in a microwave reactor and then stirred for 40 min. After being cooled to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM=1:10) to give tert-butyl ((5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl) carbamoyl)-1-(4-fluorophenyl)-3-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)carbamate (26b) (20 mg, yellow solid, yield: 42.5%).

    [0524] LC-MS (ESI): m/z 673.30[M+H.sup.+].

    Step 3: Preparation of 6-(aminomethyl)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydro-1,2-dihydropyridine-3-carboxamide (26)

    [0525] Tert-butyl ((5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-1-(4-fluorophenyl)-3-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)carbamate (26b) (20 mg, 0.03 mmol) and a solution of hydrochloric acid in dioxane (4 N, 1.5 mL) were added to a reaction flask containing DCM (3 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 10%-100%) to give 6-(aminomethyl)-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydro-1,2-dihydropyridine-3-carboxamide (26) (9 mg, white solid, yield: 52.3%).

    [0526] LC-MS (ESI): m/z 573.25[M+H.sup.+].

    .SUP.1.H NMR (400 MHz, DMSO-d.SUB.6.) δ 12.23 (s, 1H), 8.50-8.45 (m, 2H), 8.04 (dd, J=13.0, 2.5 Hz, 1H), 7.55-7.50 (m, 4H), 7.47-7.40 (m, 4H), 6.47 (dd, J=5.2, 1.1 Hz, 1H), 3.95 (d, J=2.2 Hz, 6H), 2.34 (s, 3H).

    EXAMPLE 27

    Preparation of (4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-methyl-6-((methylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (27)

    [0527] ##STR00128##

    [0528] The same procedures as in Example 26 were performed, except that 5-bromo-6-(((tert-butoxycarbonyl)(methyl)amino)methyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate 1) was used in place of 5-bromo-6-(((tert-butoxycarbonyl)(methyl)-amino-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate m), so as to give (4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-methyl-6-((methylamino)methyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (27) (yellow solid, three-step yield: 16.8%).

    [0529] LC-MS (ESI): m/z 587.35[M+H.sup.+].

    [0530] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.23 (s, 1H), 8.49-8.44 (m, 2H), 8.04 (dd, J=12.9, 2.5 Hz, 1H), 7.58-7.48 (m, 4H), 7.46-7.39 (m, 4H), 6.47 (dd, J=5.3, 1.1 Hz, 1H), 3.95 (d, J=2.4 Hz, 6H), 3.26 (s, 2H), 2.34 (s, 3H), 2.04 (s, 3H).

    EXAMPLE 28

    Preparation of 5-methyl-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-6-(methoxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (28)

    Step 1: Preparation of 5-bromo-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-6-(methoxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (Intermediate 28a)

    [0531] 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline hydrochloride (intermediate aa) (126 mg, 0.40 mmol), 5-bromo-1-(4-fluorophenyl)-6-(methoxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate n) (130 mg, 0.36 mmol), HATU (180 mg, 0.47 mmol) and DIPEA (140 mg, 1.0 mmol) were added to a reaction flask containing DMF (5 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction mixture was added with saturated sodium bicarbonate solution to quench the reaction, and then extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM=1:10) to give 5-bromo-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-6-(methoxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (intermediate 28a) (160 mg, yellow solid, yield: 68.1%).

    [0532] LC-MS (ESI): m/z 652.11/654.08[M+H.sup.+].

    ##STR00129##

    Step 2: Preparation of 5-methyl-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-6-(methoxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (28)

    [0533] 5-bromo-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-6-(methoxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (intermediate 28a) (60 mg, 0.09 mmol), methylboronic acid (30 mg, 0.45 mmol), potassium carbonate (36 mg, 0.27 mmol), and Pd(dppf)Cl.sub.2.DCM (15 mg, 0.018 mmol) were added to a reaction flask containing 1,4-dioxane (8 mL) and water (2 mL) at room temperature. The reaction mixture was sealed in the flask, purged with nitrogen three times, heated to 100° C. in a microwave reactor and then stirred for 40 min. After being cooled to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 10%-100%) to give 5-methyl-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluoro-phenyl)-6-(methoxymethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (28) (15 mg, yellow solid, yield: 28.3%).

    [0534] LC-MS (ESI): m/z 588.20[M+H.sup.+].

    [0535] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.19 (s, 1H), 8.52-8.47 (m, 2H), 8.04 (dd, J=12.9, 2.4 Hz, 1H), 7.53 (s, 2H), 7.46-7.40 (m, 6H), 6.50-6.47 (m, 1H), 4.03 (s, 2H), 3.95 (d, J=2.3 Hz, 6H), 3.01 (s, 3H), 2.33 (s, 3H).

    EXAMPLE 29

    Preparation of 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (29A) and 5-bromo-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-6-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (29B)

    [0536] ##STR00130## ##STR00131## ##STR00132##

    Step 1: Preparation of 5-bromo-6-carbamoyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (Intermediate 29a)

    [0537] Ethyl 5-bromo-6-carbamoyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (i1) (210 mg, 0.55 mmol) was added to a reaction flask containing ethanol (4.5 mL). After being cooled to 0° C., the reaction mixture was added dropwise with aqueous sodium hydroxide solution (1.5 mL, 28.5 mg, 0.71 mmol) slowly, and after the addition was completed, the reaction mixture was warmed to room temperature and stirred for 30 min. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give crude 5-bromo-6-carbamoyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate 29a) (210 mg, yellow solid, yield: 100%).

    [0538] LC-MS (ESI): m/z 355-12/357.08[M+H.sup.+].

    Step 2: Preparation of 3-bromo-N.SUP.5.-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (Intermediate 29b)

    [0539] 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline hydrochloride (intermediate aa) (193 mg, 0.62 mmol), 5-bromo-6-carbamoyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate 29a) (200 mg, 0.56 mmol), HATU (320 mg, 0.84 mmol) and DIPEA (218 mg, 1.68 mmol) were added to a reaction flask containing DMF (5 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction mixture was added with saturated sodium bicarbonate solution to quench the reaction, and then extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM=1:10) to give 3-bromo-N.sup.5-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (intermediate 29b) (260 mg, yellow solid, yield: 71.3%).

    [0540] LC-MS (ESI): m/z 651.21/653.17[M+H.sup.+].

    Step 3: Preparation of 5-bromo-6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (29c)

    [0541] 3-bromo-N.sup.5-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (intermediate 29b) (140 mg, 0.22 mol) was added to a reaction flask containing acetonitrile (5 mL). After being cooled to 0° C., the reaction mixture was added dropwise with trifluoroacetic anhydride (180 mg, 0.84 mol) and triethylamine (130 mg, 0.84 mol) slowly and successively. The reaction mixture was stirred at 0° C. for 1 h. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give crude 5-bromo-6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (29c) (130 mg, yellow solid, yield: 100%).

    [0542] LC-MS (ESI): m/z 633.18/633.14[M+H.sup.+].

    Step 4: Preparation of 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (29A) and 5-bromo-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-6-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (29B)

    [0543] 5-bromo-6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluoro-phenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (28c) (40 mg, 0.065 mmol), methylboronic acid (37 mg, 0.65 mmol), potassium carbonate (30 mg, 0.20 mmol) and Pd(dppf)Cl.sub.2.DCM (10 mg, 0.013 mmol) were added to a reaction flask containing 1,4-dioxane (3 mL) and water (1 mL) at room temperature. The reaction mixture was sealed in the flask, purged with nitrogen three times, heated to 100° C. in a microwave reactor and then stirred for 40 min. After being cooled to room temperature, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 10%-100%) to give 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (29A) (4 mg, yellow solid, yield: 7.1%) and 5-bromo-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-6-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (29B) (by-product) (yellow solid, 15 mg).

    [0544] 29A: LC-MS (ESI): m/z 569.25[M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.89 (s, 1H), 8.60 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.04 (dd, J=12.8, 2.5 Hz, 1H), 7.74-7.66 (m, 2H), 7.59 (ddd, J=8.9, 2.5, 1.1 Hz, 1H), 7.54-7.44 (m, 4H), 7.41 (s, 1H), 6.48 (dd, J=5.2, 1.1 Hz, 1H), 3.95 (d, J=2.4 Hz, 6H), 2.45 (s, 3H).

    [0545] 29B: LC-MS (ESI): m/z 624.07/626.06[M+H.sup.+]. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.23 (s, 1H), 8.72 (d, J=6.2 Hz, 1H), 8.16 (d, J=18.5 Hz, 1H), 8.08 (dd, J=13.6, 2.3 Hz, 1H), 7.70 (s, 1H), 7.48 (s, 1H), 7.44-7.34 (m, 2H), 7.28-7.22 (m, 2H), 7.16 (ddt, J=7.0, 5.1, 2.7 Hz, 2H), 6.84 (d, J=6.1 Hz, 1H), 4.01 (d, J=3.2 Hz, 6H).

    EXAMPLE 30

    Preparation of 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-5-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide (30)

    Step 1: Preparation of diethyl 3-bromo-1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxylate (30a)

    [0546] 5-bromo-6-(ethoxycarbonyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate h) (1.5 g, 3.90 mmol), potassium carbonate (809 mg, 5.86 mmol) and iodoethane (910 mg, 5.86 mmol) were added to a reaction flask containing DMF (10 mL). The reaction mixture was stirred at room temperature for 6 h. After the reaction was completed, the reaction mixture was added with water (50 mL) and then extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=2:1) to give diethyl 3-bromo-1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxylate (30a) (1.3 g, yellow solid, yield: 80.9%).

    [0547] LC-MS (ESI): m/z 412.15/414.11[M+H.sup.+].

    ##STR00133## ##STR00134## ##STR00135##

    Step 2: Preparation of diethyl 1-(4-fluorophenyl)-6-oxo-3-(prop-1-en-2-yl)-1,6-dihydro-pyridine-2,5-dicarboxylate (30b)

    [0548] Diethyl 3-bromo-1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridine-2,5-dicarboxylate (30a) (300 mg, 0.73 mmol), pinacol isopropenylborate (611 mg, 3.64 mmol), potassium carbonate (302 mg, 2.19 mmol) and Pd(dppf)Cl.DCM (60 mg, 0.073 mmol) were added to a reaction flask containing 1,4-dioxane (16 mL) and water (4 mL) at room temperature. The reaction mixture was sealed in the flask, purged with nitrogen three times, heated to 100° C. in a microwave reactor and then stirred for 30 min. After being cooled to room temperature, the reaction mixture was diluted with water (10 mL) and then extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA=1:1) to give diethyl 1-(4-fluorophenyl)-6-oxo-3-(prop-1-en-2-yl)-1,6-dihydropyridine-2,5-dicarboxylate (30b) (220 mg, yellow solid, yield: 80.7%).

    [0549] LC-MS (ESI): m/z 374.27[M+H.sup.+].

    Step 3: Preparation of diethyl 1-(4-fluorophenyl)-3-isopropyl-6-oxo-1,6-dihydropyridine-2,5-dicarboxylate (30c)

    [0550] Diethyl 1-(4-fluorophenyl)-6-oxo-3-(prop-1-en-2-yl)-1,6-dihydropyridine-2,5-dicarboxylate (30b) (220 mg, 0.59 mol), palladium on carbon (55 mg, 25%) and acetic acid (8 mg, 0.12 mol) were added to a reaction flask containing methanol (4 mL). After being sealed in the flask and purged with nitrogen three times, the reaction mixture was purged with hydrogen three times and then stirred for 30 min. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude diethyl 1-(4-fluorophenyl)-3-isopropyl-6-oxo-1,6-dihydropyridine-2,5-dicarboxylate (30c) (200 mg, white solid, yield: 91.4%).

    [0551] LC-MS (ESI): m/z 376.30[M+H.sup.+].

    Step 4: Preparation of 6-(ethoxycarbonyl)-1-(4-fluorophenyl)-5-isopropyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (30d)

    [0552] Diethyl 1-(4-fluorophenyl)-3-isopropyl-6-oxo-1,6-dihydropyridine-2,5-dicarboxylate (30c) (200 mg, 0.53 mmol) was added to a reaction flask containing ethanol (4.5 mL). After being cooled to 0° C., the reaction mixture was added dropwise with aqueous sodium hydroxide solution (1.5 mL, 28.5 mg, 0.71 mmol) slowly, and after the addition was completed, the reaction mixture was warmed to room temperature and stirred for 30 min. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give crude 6-(ethoxycarbonyl)-1-(4-fluorophenyl)-5-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (30d) (200 mg, yellow solid, yield: 100%).

    [0553] LC-MS (ESI): m/z 348.27[M+H.sup.+].

    Step 5: Preparation of ethyl 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-carbamoyl)-1-(4-fluorophenyl)-3-isopropyl-6-oxo-1,6-dihydropyridine-2-carboxylate (30e)

    [0554] 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline hydrochloride (intermediate aa) (193 mg, 0.62 mmol), 6-(ethoxycarbonyl)-1-(4-fluorophenyl)-5-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (30d) (200 mg, 0.56 mmol), HATU (320 mg, 0.84 mmol) and DIPEA (218 mg, 1.68 mmol) were added to a reaction flask containing DMF (5 mL). The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the reaction mixture was added with saturated sodium bicarbonate solution to quench the reaction, and then extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM=1:10) to give ethyl 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-1-(4-fluorophenyl)-3-isopropyl-6-oxo-1,6-dihydropyridine-2-carboxylate (30e) (220 mg, yellow solid, yield: 60.7%).

    [0555] LC-MS (ESI): m/z 644.36 [M+H.sup.+].

    Step 6: Preparation of 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-1-(4-fluorophenyl)-3-isopropyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (30f)

    [0556] Ethyl 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-1-(4-fluorophenyl)-3-isopropyl-6-oxo-1,6-dihydropyridine-2-carboxylate (30e) (220 mg, 0.34 mmol), lithium hydroxide monohydrate (22 mg, 0.51 mmol) and water (1.5 mL) were added to a reaction flask containing ethanol (4.5 mL). The reaction mixture was stirred at 70° C. for 12 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 10%-100%) to give 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-1-(4-fluorophenyl)-3-isopropyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (30f) (80 mg, white solid, yield: 38.2%).

    [0557] LC-MS (ESI): m/z 616.35[M+H.sup.+].

    Step 7: Preparation of N.SUP.5.-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluoro-phenyl)-3-isopropyl-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (30g)

    [0558] 5-((4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)carbamoyl)-1-(4-fluorophenyl)-3-ispropyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (30f) (80 mg, 0.13 mmol), ammonium bicarbonate (103 mg, 1.3 mmol), PyBrOP (91 mg, 0.20 mmol) and DIPEA (50 mg, 0.39 mol) were added to a reaction flask containing DMF (3 mL). The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was added with saturated aqueous sodium bicarbonate solution (10 mL) to quench the reaction, and then extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM:CH.sub.3OH=10:1) to give N.sup.5-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-3-isopropyl-6-oxo-1,6-dihydro-pyridine-2,5-dicarboxamide (30g) (20 mg, white solid, yield: 25.0%).

    [0559] LC-MS (ESI): m/z 615.34[M+H.sup.+].

    Step 8: Preparation of 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide (30)

    [0560] N.sup.5-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-3-isopropyl-6-oxo-1,6-dihydropyridine-2,5-dicarboxamide (30g) (12 mg, 0.02 mol) was added to a reaction flask containing acetonitrile (2 mL). After being cooled to 0° C., the reaction mixture was added dropwise with trifluoroacetic anhydride (11 mg, 0.06 mol) and triethylamine (12 mg, 0.12 mol) slowly and successively. The reaction mixture was stirred at 0° C. for 1 h. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 20%-100%) to give 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluoro-phenyl)-5-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide (30) (8 mg, yellow solid, yield: 67.0%).

    [0561] LC-MS (ESI): m/z 597.33[M+H.sup.+].

    [0562] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.85 (s, 1H), 8.60 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.05 (dd, J=12.8, 2.5 Hz, 1H), 7.75-7.69 (m, 2H), 7.59 (ddd, J=8.8, 2.5, 1.1 Hz, 1H), 7.54-7.45 (m, 4H), 7.41 (s, 1H), 6.49 (dd, J=5.3, 1.1 Hz, 1H), 3.95 (d, J=2.7 Hz, 6H), 2.00 (q, J=7.0, 6.5 Hz, 1H), 1.33 (d, J=6.8 Hz, 6H).

    EXAMPLE 31

    Preparation of 6-cyano-5-cyclopropyl-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (31)

    [0563] ##STR00136##

    [0564] The same synthesis procedure as step 5 in Example 30 was performed, except that 6-cyano-5-cyclopropyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (intermediate j) was used in place of 6-(ethoxycarbonyl)-1-(4-fluorophenyl)-5-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (30d), so as to give 6-cyano-5-cyclopropyl-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (31) (yellow solid, 5.6 mg, yield: 16.5%).

    [0565] LC-MS (ESI): m/z 595.33[M+H.sup.+].

    [0566] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.84 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.10 (s, 1H), 8.03 (dd, J=12.8, 2.5 Hz, 1H), 7.75-7.68 (m, 2H), 7.61-7.56 (m, 1H), 7.55-7.44 (m, 4H), 7.41 (s, 1H), 6.48 (dd, J=5.2, 1.0 Hz, 1H), 3.95 (d, J=3.1 Hz, 6H), 2.10 (td, J=8.3, 4.1 Hz, 1H), 1.19-1.13 (m, 2H), 0.93 (dt, J=6.8, 4.8 Hz, 2H).

    EXAMPLE 32

    Preparation of 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-5-(prop-1-en-2-yl)-1,2-dihydropyridine-3-carboxamide (32)

    [0567] ##STR00137##

    [0568] The same synthesis procedure as step 5 in Example 30 was performed, except that 6-cyano-1-(4-fluorophenyl)-2-oxo-5-(prop-1-en-2-yl)-1,2-dihydropyridine-3-carboxylic acid (intermediate k) was used in place of 6-(ethoxycarbonyl)-1-(4-fluorophenyl)-5-isopropyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (30d), so as to give 6-cyano-N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-5-(prop-1-en-2-yl))-1,2-dihydropyridine-3-carboxamide (32) (yellow solid, 13 mg, yield: 19.8%).

    [0569] LC-MS (ESI): m/z 595.32[M+H.sup.+].

    [0570] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.77 (s, 1H), 8.57-8.50 (m, 2H), 8.06 (dd, J=12.8, 2.5 Hz, 1H), 7.78-7.69 (m, 2H), 7.61 (dt, J=8.9, 1.7 Hz, 1H), 7.57-7.45 (m, 4H), 7.43 (s, 1H), 6.55 (d, J=5.4 Hz, 1H), 5.51 (t, J=1.6 Hz, 1H), 5.44 (s, 1H), 3.96 (d, J=2.8 Hz, 6H), 2.18 (s, 3H).

    EXAMPLE 33

    Preparation of N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-2,5-difluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (33)

    [0571] ##STR00138##

    [0572] The same procedures as in Example 3 were performed, except that 6-cyano-N-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (y) was used in place of 6-cyano-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydro-pyridine-3-carboxamide (f), so as to give N-(4-(2-amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-2,5-difluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (33) (25 mg, yellow solid, yield: 35%).

    [0573] LC-MS (ESI): m/z 598.13[M+H.sup.+].

    [0574] .sup.1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.86 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 8.08 (d, J=0.8 Hz, 1H), 7.77 (d, J=0.8 Hz, 1H), 7.64-7.58 (m, 2H), 7.55 (d, J=2.3 Hz, 1H), 7.45-7.36 (m, 3H), 5.68 (s, 2H), 4.87 (p, J=6.5 Hz, 1H), 4.11 (q, J=7.2 Hz, 2H), 1.63 (d, J=6.6 Hz, 6H), 1.38 (t, J=7.3 Hz, 3H).

    EXAMPLE 34

    Preparation of N-(4-(2-amino-5-(1-methyl-d.SUB.3.-1H-pyrazol-4-yl)pyridin-3-yl)-2,5-difluorophenyl)-6-cyano-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (34)

    [0575] ##STR00139##

    [0576] The same procedures as in Example 3 were performed, except that 6-cyano-N-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (y) was used in place of 6-cyano-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydro-pyridine-3-carboxamide (f), and 3-bromo-5-(1-(methyl-d3)-1H-pyrazol-4-yl)pyridin-2-amine (ee) was used in place of 3-bromo-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v), so as to give N-(4-(2-amino-5-(1-methyl-d.sub.3-1H-pyrazol-4-yl)pyridin-3-yl)-2,5-difluorophenyl)-6-cyano-5-(4-fluoro-phenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxamide (34) (32 mg, yellow solid, yield: 46%).

    [0577] LC-MS (ESI): m/z 587.28[M+H.sup.+].

    [0578] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.86 (s, 1H), 8.86 (s, 1H), 8.42 (dd, J=11.6, 6.6 Hz, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.02 (d, J=0.8 Hz, 1H), 7.77 (d, J=0.8 Hz, 1H), 7.65-7.57 (m, 2H), 7.54 (d, J=2.4 Hz, 1H), 7.47-7.36 (m, 3H), 5.69 (s, 2H), 4.88 (h, J=6.7 Hz, 1H), 1.63 (d, J=6.6 Hz, 6H).

    Biological Evaluation of Compounds Disclosed Herein

    [0579] Test Example 1: Evaluation of Inhibitory Activity (IC.sub.50) of Compounds Disclosed herein against Kinases Axl and c-MET

    [0580] In this test, mobility shift assay was used to test the inhibitory activity of compounds when ATP concentrations correspond to the Km of the kinases. The control substances were staurosporine and cabozantinib.

    [0581] The concentration of test compound was 10-fold diluted from an initial concentration of 10 μM. The test result (IC.sub.50) was the average of two independent experiments.

    [0582] Test Materials:

    [0583] Kinase Axl (Carna, Cat. No. 08-107, Lot. No. 06CBS-3408); kinase c-MET (Carna, Cat. No. 08-151, Lot. No. 10CBS-1118M); substrate peptide FAM-P2 (GL Biochem, Cat. No. 112394, Lot. No. P131014-XP112394); substrate peptide FAM-P22 (GL Biochem, Cat. No. 112393, Lot. No. P130408-ZB112393); ATP (Sigma, Cat. No. A7699-1G, CAS No. 987-65-5); DMSO (Sigma, Cat. No. D2650, Lot. No. 474382); EDTA (Sigma, Cat. No. E5134, CAS No. 60-00-4); HEPES (Sigma, Cat. No. V900477-500G, CAS No. 7365-45-9, Lot. No. WXBC4716V); DTT (Sigma, Cat. No. D0632-25g, CAS No. 3483-12-3, Lot. No. SLBF3964V); Brij-35 (Sigma, Cat. No. B4184, Lot. No. 018K61251); 96-well plate (Corning, Cat. No. 3365, Lot. No. 22008026); 384-well plate (Corning, Cat. No. 3573, Lot. No. 12608008); staurosporine (MCE, Cat. No. HY-15141, Lot. No. 19340); cabozantinib (prepared according to the method disclosed in patent WO 201101763A1).

    [0584] Test Procedures:

    [0585] 1) Preparation of a buffer: 50 mM HEPES, pH 7.5, 0.00015% Brij-35.

    [0586] 2) Preparation of control substance cabozantinib and test samples: cabozantinib and example compounds of the present invention were each serially diluted in 100% DMSO, then diluted to 10% DMSO with the above buffer, and added to a 384-well plate. For example, a compound at an initial concentration of 10 μM was adjusted to 500 μM with 100% DMSO, then serially diluted for 10 concentrations, and then subjected to 10-fold dilution with the buffer to prepare a diluted compound intermediate containing 10% DMSO, 5 μL of which was transferred to the 384-well plate.

    [0587] 3) The Axl and c-MET enzymes were each diluted to optimal concentrations with the following buffer: 50 mM HEPES, pH 7.5, 0.00015% Brij-35, 2 mM DTT. 10 μL of the two enzyme solutions each was added to the 384-well plate and co-incubated with the compound for 10-15 min at room temperature.

    [0588] 4) The substrate was diluted to optimal concentration with the following buffer: 50 mM HEPES, pH 7.5, 0.00015% Brij-35, 10 mM MgCl.sub.2, ATP at Km. 10 μL of the diluted substrate was added to the 384-well plate to initiate the reaction, which lasts for 1 h at 28° C.

    [0589] The reaction concentrations of the reagents in the test are shown in Table 1 below.

    TABLE-US-00002 TABLE 1 Substrate Reaction Km: ATP Peptide Reaction concentration concen- Kinase sequence concentration of kinase tration c-MET Peptide FAM-P2 3 μM 15 nM 35 μM Axl Peptide FAM-P22 3 μM  6 nM 81 μM

    [0590] 5) The conversion rate was read by Caliper Reader (Perkin Elmer) and the inhibition rate was calculated as the average of two tests.

    [0591] 6) IC.sub.50 values were fitted with XL-fit software.

    [0592] The inhibitory activity of the compounds disclosed herein against kinases Axl and c-MET is shown in Table 2 below.

    TABLE-US-00003 TABLE 2 Inhibitory activity (IC.sub.50) of compounds disclosed herein against tyrosine kinases Axl and c-MET IC.sub.50 (nM) Compounds Axl c-MET Example 1 13 133 Example 2 0.46 14 Example 3 2.7 30 Example 4 0.28 3.0 Example 5 2.6 38 Example 6 2.0 26 Example 8 1.1 17 Example 9 4.6 70 Example 10 2.8 23 Example 11 0.95 10 Example 12 2.1 23 Example 14 12 82 Example 15 6.6 20 Example 16 9.8 143 Example 17 1.8 23 Example 18 12 12 Example 20 5.5 14 Example 21 3.2 Example 22 5.9 Example 26 19 19 Example 28 1.0 21 Example 29A 3.1 Example 29B 3.9 30 Cabozantinib 14.0 21

    [0593] As can be seen from Table 2 above, the compounds disclosed herein are effective in inhibiting the activity of kinases Axl and c-MET. Compared with the positive control drug cabozantinib, part of the compounds disclosed herein show higher inhibitory activity.

    [0594] Test Example 2: Evaluation of Inhibitory Activity (IC.sub.50) of Compounds disclosed herein against Tyrosine Kinases Mer and Tyro3

    [0595] In this test, HTRF method was used to test the inhibitory activity of compounds when ATP concentrations correspond to the Km of the kinases. The control substance was RXDX-106. The concentration of test compound was 3-fold diluted from an initial concentration of 10 μM, and two duplicate wells were set.

    [0596] Test Materials:

    [0597] Kinase Mer (Carna, Cat. No. 08-108, Lot. No. 14CBS-0421H); Tyro3 (Carna, Cat. No. 08-109, Lot. No. 08CBS-1186H); HTRF kinase-TK kit (Cisbio, Cat. No. 62TK0PEC), the kit comprising: biotin-TK substrate lyophilized powder (Cisbio, Cat. No. 61TK0BLC, Lot. No. 07A), streptavidin-XL665 (Cisbio, Cat. No. 610SAXLG, Lot. No. 126A), TK antibody-cryptate (Cisbio, Cat. No. 610SAXLG, Lot. No. 04A), and detection buffer (including EDTA) (Cisbio, Cat. No. 62TK0PEC, Lot. No. 12A); ATP (Sigma, Cat. No. A7699-5G, CAS No. 34369-07-8, Lot. No. SLBQ6014V); DMSO (Sigma, Cat. No. D5879-1L, Lot. No. SHBH9944); HEPES (Sigma, Cat. No. V900477-500G, CAS No. 7365-45-9, Lot. No. WXBC4716V); MgCl.sub.2 (Sigma, Cat. No. 208337-1KG, Lot. No. MKBX9508V); EGTA (Sigma, Cat. No. E3889-100g, CAS 67-42-5, CAS No. 7786-30-3, Lot. No. SLBG8546V); NP-40 (Beijing Dingguo, Cat. No. DH218, Lot. No. 36R00160); DTT (Sigma, Cat. No. D0632-25g, CAS No. 3483-12-3, Lot. No. SLBF3964V); compound plate (Labcyte, Cat. No. LP0200, Lot. No. 0006386836); assay plate (Greiner, Cat. No. 784075, Lot. No. E16123HM); control substance RXDX-106 (prepared according to the method disclosed in patent WO2013074633).

    [0598] Test Procedures:

    [0599] 1) Preparation of a buffer: 50 mM HEPES, 10 mM MgCl.sub.2, 1 mM EGTA, 0.01% NP-40, 2 mM DTT.

    [0600] 2) Preparation of control substance and test samples: RXDX-106 and the compounds disclosed herein were each dissolved in DMSO to 10 mM and then diluted to 1 mM or an appropriate concentration with DMSO, and then serial double dilution was performed using BRAVO (Agilent). 100 nL of each was transferred from a compound plate (Labcyte-LP0200) to an assay plate (Greiner-784075) using ECHO 555 (Labcyte). The final concentration of DMSO was 1%.

    [0601] 3) Mer and Tyro3 were each diluted to 0.5 nM and 1.2 nM with the detection buffer (Cisbio, Cat. No. 62TK0PEC, Lot. No. 12A). 5 μL of each was added to a 384-well plate and incubated with the compounds disclosed herein for 30 min at 22-25° C. Final concentrations of Mer and Tyro3 were 0.25 nM and 0.6 nM, respectively.

    [0602] 4) Biotin-TK substrate and ATP were each diluted to a concentration twice the final concentration with 1× kinase buffer made up of HEPES, NaN.sub.3, BSA and orthovanadate. 5 μL of the mixture of substrate and ATP was added to the 384-well plate to initiate the reaction, which lasts for 1 h at 22-25° C.

    [0603] The reaction concentrations of the reagents in the test are shown in Table 3 below.

    TABLE-US-00004 TABLE 3 Enzyme TK substrate ATP concentration, concentration, concentration, Enzyme nM μM μM Mer (80 KD) 0.25 2 30 Tyro3 (76 KD) 0.6 2 50

    [0604] 5) Streptavidin-XL665 and TK antibody-cryptate were diluted to 250 nM and 0.5 nM, respectively, with the detection buffer. 10 μL of each of the two solutions was added to the 384-well plate to initiate the reaction, which lasts for 1 h at 22-25° C. The final concentrations of streptavidin-XL665 and TK antibody-cryptate were 125 nM and 0.25 nM, respectively.

    [0605] 6) The fluorescence intensities at 665 nm and 615 nm were read with an Envision Reader (PerkinElmer) .

    [0606] 7) IC.sub.50 values of the compounds were fitted with XL-fit software.

    [0607] The inhibitory activity of the compounds disclosed herein against the tyrosine kinases Mer and Tyro3 is shown in Table 4 below.

    TABLE-US-00005 TABLE 4 Inhibitory activity (IC.sub.50) of compounds disclosed herein against tyrosine kinases Mer and Tyro3 IC.sub.50 (nM) Example Mer Tyro3 Example 1 4.90 7.51 Example 2 0.62 1.18 Example 3 1.11 2.27 Example 4 0.78 2.67 Example 6 1.17 1.80 Example 7 0.63 1.77 Example 9 1.30 3.00 Example 10 2.17 30.18 Example 24 11.41 15.48 Example 33 0.92 0.50 Example 34 1.16 1.16 RXDX-106 6.40 3.30

    [0608] As can be seen from Table 4 above, the compounds disclosed herein are effective in inhibiting the activity of kinases Mer and Tyro3. Compared with the control substance RXDX-106, part of the compounds disclosed herein show higher inhibitory activity.

    [0609] Test Example 3: Inhibitory Activity of Compounds disclosed herein against EBC-1 Cells

    [0610] Test method: the inhibitory activity of the compounds against EBC-1 cell proliferation was evaluated using CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega).

    [0611] Instruments: Spectramax M3 multi-functional microplate reader (Molecular Devices); Model 311 Series CO.sub.2 incubator (Thermo Scientific); Model 1300 Series A2 biosafety cabinet (Thermo Scientific); CKX41SF inverted microscope (Olympus); IC1000 cell counter (Countstar); KK25E76TI refrigerator (SIEMENS); QB-9001 microporous quick shaker (Kylin-Bell).

    [0612] Test materials: fetal bovine serum FBS (Thermo Fisher, Cat. No. 10099-141, Lot. No. 1966174C); CellTiter-Glo® fluorescent cell viability test reagent (Promega, Cat. No. G7572, Lot. No. 0000310975); 96-well transparent flat-bottom black-wall cell culture plate (Thermo Fisher, Cat. No., Lot. No. 1207365); RPMI1640 culture medium (GE, Cat. No. SH30809.01, Lot. No. AD17321266); MEM culture medium (GE, Cat. No. SH30024.01, Lot. No. AC10232463); NEAA (Thermo Fisher, Cat. No. 11140-050, Lot. No. 1872982); control substance cabozantinib (synthesized according to the method disclosed in WO201101763A1); EBC-1 cells (from Nanjing Cobioer Biotechnology Co., Ltd.; EBC-1 cells are human lung squamous carcinoma cells, which are cultured in complete culture medium (MEM+10% FBS+0.01 mM NEAA) at 37° C./5%CO.sub.2/95% humidity, the doubling time of growth is about 32 h, and the passage ratio is 1:6).

    [0613] Test procedures: when thawing EBC-1 cells, the cell cryopreservation tube was shaken rapidly in a water bath at 37° C. to thaw the cells in 1 min. The cell suspension after thawing was mixed with RPMI1640 culture medium containing 10% FBS and centrifuged for 5 min at 1000 rpm, and the supernatant was discarded. The cell pellet was suspended in 5 mL of complete culture medium. The suspension was placed in a cell culture flask with a bottom area of 25 cm.sup.2, and cultured in a cell incubator at 37° C./95% humidity/5% CO.sub.2. Cell passage was performed when cell confluence reached about 80%. When the cells were passaged, the original cell suspension was directly made uniform by pipetting. 1/6 of the cell suspension was kept, added with 5 mL of new complete culture medium and then made uniform by pipetting. The cell culture flask was then placed in a cell incubator for further culturing. Cell plating was performed when the cell confluence reached about 80% again. With reference to the method for cell passage, 1/6 cell suspension was kept for further culturing when the cells were plated, and the remaining 5/6 of cell suspension was placed in a 15 mL centrifuge tube. Cell viability was detected by trypan blue exclusion using an IC1000 cell counter (Countstar) to ensure that cell viability was above 90%. Cell suspension at a density of 3.33×10.sup.4 viable cells/mL was prepared using complete culture medium, and 90 μL of the cell suspension was added into 96-well cell culture plates, so that the cell density in the cell culture plates (day 0 plate and test compound plate) was 3000 viable cells/well. A control group that contains no cell or compound but only complete culture medium and a control group that contains no compound but cells were set. The cell plates were incubated overnight in a cell incubator. When adding compound, the compounds disclosed herein and the control substance cabozantinib were each dissolved in DMSO and serially diluted to give a 10-fold solution. 10 μL of the above solution was added into a corresponding cell culture plate to ensure that the initial concentration of the compound was 10 μM, the dilution factor of adjacent concentration was 3.16, and the DMSO content in the cell culture plate was 0.1%. The cell plates were then incubated in the cell incubator for 72 h. During detection, CellTiter-Glo reagent (namely CellTiter-Glo® fluorescent cell viability test reagent, Promega, Cat. No. G7572, Lot. No. 0000310975) was melted, and the cell plate was equilibrated at room temperature for 30 min. The cell plate was added with the CellTiter-Glo reagent at 100 μL per well, and then shaken on a QB-9001 microporous quick shaker (Kylin-Bell) for 5 min to fully lyse the cells. The cell plate was left to stand at room temperature for 20 min to stabilize luminescence signals, and the luminescence value of each well was scanned by a Spectramax M3 multi-functional microplate reader (Molecular Devices) at full wavelength.

    [0614] Test samples: example compounds of the present invention and cabozantinib (positive control compound).

    [0615] Data analysis: cell viability was calculated for compounds at various concentrations using the following formula:


    Cell viability(%)=(Lum.sub.test compound−Lum.sub.culture solution control)/(Lum.sub.cell control−Lum.sub.culture solution control)×100%,

    [0616] where Lum refers to the luminescence value of each well of the test compound plate read by the multi-functional microplate reader.

    [0617] The data were analyzed using GraphPad Prism 7.0 software, fitted with nonlinear S-curve regression to give dose-response curves, and IC.sub.50 values were calculated therefrom.

    [0618] The inhibitory activity of the compounds disclosed herein against EBC-1 cells is shown in Table 5 below.

    TABLE-US-00006 TABLE 5 Inhibitory activity (IC.sub.50) of compounds disclosed herein against EBC-1 cells Compounds IC.sub.50 (nM) Example 2 24 Example 3 22 Example 4 30 Example 6 13 Example 7 27 Example 10 208 Example 11 91 Example 12 98 Example 15 190 Example 18 298 Example 20 106 Example 21 109 Example 22 84 Example 23 74 Example 24 45 Example 25 115 Example 26 132 Example 29A 82.7 Cabozantinib 37

    [0619] As can be seen from Table 5 above, the compounds disclosed herein are effective in inhibiting the activity of EBC-1 cells. Compared with the positive control drug cabozantinib, the compounds disclosed herein show similar inhibitory activity. Meanwhile, because EBC-1 is a lung cancer cell line driven by c-MET, the inhibition effect of the compounds disclosed herein against c-MET kinase targets is further verified due to their inhibition against activity of EBC-1 cells.

    [0620] Test Example 4: Inhibitory Activity of Compounds disclosed herein against Ba/F3 Axl Cells

    [0621] Test method: the inhibitory activity of the compounds against Ba/F3 Axl cell proliferation was evaluated using CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega).

    [0622] Instruments: Spectramax M3 multi-functional microplate reader (Molecular Devices); Model 311 Series CO.sub.2 incubator (Thermo Scientific); Model 1300 Series A2 biosafety cabinet (Thermo Scientific); CKX41SF inverted microscope (Olympus); IC1000 cell counter (Countstar); KK25E76TI refrigerator (SIEMENS); QB-9001 microporous quick shaker (Kylin-Bell).

    [0623] Test materials: fetal bovine serum FBS (Thermo Fisher, Cat. No. 10099-141, Lot. No. 1966174C); CellTiter-Glo® fluorescent cell viability test reagent (Promega, Cat. No. G7572, Lot. No. 0000310975); 96-well transparent flat-bottom black-wall cell culture plate (Thermo Fisher, Cat. No., Lot. No. 1207365); RPMI1640 culture medium (GE, Cat. No. SH30809.01, Lot. No. AD17321266); Murine IL-3 (PeproTech, Cat. No. 213-13, Lot. No. 120948); rhGas6 (R&D Systems, Cat. No. 885-GSB, Lot. No. DFGX0417081); control substance bemcentinib (also named BGB324, Shanghai Bidepharm, Cat. No. BD559084, Lot. No. AQU341); Ba/F3 Axl cells (constructed by KYinno Biotechnology Co., Ltd., and cultured in complete culture medium (RPMI1640+10% FBS+100 ng/mL rhGas6) at 37° C./5% CO.sub.2/95% humidity; the doubling time of growth is about 20 h, and the passage ratio is 1:10; see Oncogene. 2009, 28:3442-3455; Oncotarget. FASEB J. 2017, 31(4):1382-1397).

    [0624] Test procedures: when thawing Ba/F3 Axl cells, the cell cryopreservation tube was shaken rapidly in a water bath at 37° C. to thaw the cells in 1 min. The cell suspension after thawing was mixed with RPMI1640 culture medium containing 10% FBS and centrifuged for 5 min at 1000 rpm, and the supernatant was discarded. The cell pellet was suspended in 5 mL of complete culture medium. The suspension was placed in a cell culture flask with a bottom area of 25 cm.sup.2, and cultured in a cell incubator at 37° C./95% humidity/5% CO.sub.2. Cell passage was performed at a cell density of 2×10.sup.6 viable cells/mL. When the cells were passaged, the original cell suspension was directly made uniform by pipetting. 1/10 (namely 0.5 mL) of the cell suspension was kept, added with 4.5 mL of new complete culture medium and then made uniform by pipetting. The cell culture flask was then placed in a cell incubator for further culturing. Cell plating was performed when the cell confluence reached 2×10.sup.6 viable cells/mL again. With reference to the method for cell passage, 1/10 (namely 0.5 mL) of the cell suspension was kept for further culturing when the cells were plated, and the remaining cell suspension was placed in a 15 mL centrifuge tube. The supernatant was discarded after centrifugation, and 5 mL of complete culture medium was used to resuspend the cells. Cell viability was detected by trypan blue exclusion using an IC1000 cell counter (Countstar) to ensure that cell viability was above 90%. Cell suspension at a density of 5.56×10.sup.4 viable cells/mL was prepared using complete culture medium, and 90 μL of the cell suspension was added into 96-well cell culture plates, so that the cell density in the cell culture plates (day 0 plate and test compound plate) was 5000 viable cells/well. A control group that contains no cell or compound but only complete culture medium and a control group that contains no compound but cells were set. The cell plates were incubated overnight in a cell incubator. When adding compound, the compounds disclosed herein and the control substance bemcentinib were each dissolved in DMSO and serially diluted to give a 10-fold solution. 10 μL of the above solution was added into a corresponding cell culture plate to ensure that the initial concentration of the compound was 100 nM, the dilution factor of adjacent concentration was 3.16, and the DMSO content in the cell culture plate was 0.1%. The cell plates were then incubated in the cell incubator for 72 h. During detection, CellTiter-Glo reagent (namely CellTiter-Glo® fluorescent cell viability test reagent, Promega, Cat. No. G7572, Lot. No. 0000310975) was melted, and the cell plate was equilibrated at room temperature for 30 min. The cell plate was added with the CellTiter-Glo reagent at 100 μL per well, and then shaken on a QB-9001 microporous quick shaker (Kylin-Bell) for 5 min to fully lyse the cells. The cell plate was left to stand at room temperature for 20 min to stabilize luminescence signals, and the luminescence value of each well was scanned by a Spectramax M3 multi-functional microplate reader (Molecular Devices) at full wavelength.

    [0625] Test samples: example compounds of the present invention and bemcentinib (positive control compound).

    [0626] Data analysis: cell viability was calculated for compounds at various concentrations using the following formula:


    Cell viability(%)=(Lum.sub.test compound−Lum.sub.culture solution control)/(Lum.sub.cell control−Lum.sub.culture solution control)×100%,

    [0627] where Lum refers to the luminescence value of each well of the test compound plate read by the multi-functional microplate reader.

    [0628] The data were analyzed using GraphPad Prism 7.0 software, fitted with nonlinear S-curve regression to give dose-response curves, and IC.sub.50 values were calculated therefrom.

    [0629] The inhibitory activity of compounds disclosed herein against Ba/F3 Axl cells is shown in Table 6 below.

    TABLE-US-00007 TABLE 6 Inhibitory activity (IC.sub.50) of compounds disclosed herein against Ba/F3 Axl cells Compounds IC.sub.50 (nM) Example 3 0.29 Example 4 0.57 Example 6 0.49 Example 21 0.29 Example 24 0.36 Example 33 0.23 Example 34 0.28 Bemcentinib 26.9

    [0630] As shown in the Table 6 above, compared with the control substance bemcentinib, the compounds disclosed herein show higher inhibitory activity against Ba/F3 Axl cell proliferation.

    [0631] Test Example 5: In Vivo Anti-Tumor Activity of Compounds disclosed herein in Model Mice with Ectopically Grafted Tumor Cells

    [0632] 3×10.sup.6 cells of human non-small cell lung cancer tumor cell strain EBC-1 (ATCC) were inoculated subcutaneously into BALB/c-nude model mice (Beijing AniKeeper Biotech, 10 female mice). When the subcutaneous tumors in mice each grew to 175.5 mm.sup.3, the mice were administered intragastrically with test samples.

    [0633] The mice were divided into a negative control group and an example compound group (compound of Example 3) (30 mg/kg) with 5 mice per group. The mice in the negative control group were administered with 10% solutol HS-15, which was prepared by adding 10 mL of solutol HS-15 to 90 mL of ddH.sub.2O and then mixing well by vortexing. The mice in the example compound group were administered with a compound solution at a concentration of 1 mg/mL which was prepared by dissolving the compound of Example 3 in 10% solutol HS-15. The mice in both the solvent control group and the example compound group were subjected to intragastric administration once daily for 28 days at a dosage of 10 μL per gram of body weight.

    [0634] After the start of the administration, the body weight and tumor size of each mice were measured twice a week. The calculation formula for tumor size is as follows:


    Tumor volume(mm.sup.3)=0.5×(long diameter of tumor×short diameter of tumor).

    [0635] The anti-tumor efficacy was evaluated based on the growth curve of the tumor (i.e., tumor volume per measurement versus its treatment days) and relative tumor volume during treatment. The relative tumor inhibition (TGI) was calculated according to the following formula:


    TGI=1−T/C(%).

    [0636] T/C % is the relative tumor proliferation rate, i.e., the percentage of the relative tumor volume or tumor weight of the example compound group and the solvent control group at a certain time point. T and C are the relative tumor volumes (RTVs) of the example compound group and the solvent control group, respectively, at a particular time point. T/C %=T.sub.RTV/C.sub.RTV×100% (T.sub.RTV: mean RTV of the example compound group; C.sub.RTV: mean RTV of the solvent control group).

    [0637] Relative tumor volume RTV was calculated as follows: RTV=Vt−V0, where V0 is the tumor volume of the animal at the time of grouping, and Vt is the tumor volume of the animal after treatment.

    [0638] FIG. 1 shows the growth change in tumor volume of mice in the example compound group and the solvent control group. As shown in the figure, the compound disclosed herein can effectively inhibit the growth of tumor cells in model mice, and the tumor growth inhibition (TGI) is up to 108%.

    [0639] FIG. 2 shows the change of body weight as a function of treatment time in mice of the example compound group and the solvent control group. As shown in the figure, the body weight of tumor-bearing mice does not change significantly during the experiment, indicating that the compound disclosed herein features good safety and tolerance.

    [0640] In the present invention, it is proved by experiments that the compound disclosed herein can effectively inhibit the activity of tyrosine kinases such as Axl, Mer, Tyro3 or c-MET, and can highly inhibit the growth of tumor cells in mice. Therefore, the compound disclosed herein has wide application prospect in treating diseases related to tyrosine kinases such as Axl, Mer, Tyro3 or c-MET, and particularly in treating cancers.