CN114835640B - Fibroblast growth factor receptor inhibitor, preparation method and application - Google Patents

Fibroblast growth factor receptor inhibitor, preparation method and application Download PDF

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CN114835640B
CN114835640B CN202210569981.6A CN202210569981A CN114835640B CN 114835640 B CN114835640 B CN 114835640B CN 202210569981 A CN202210569981 A CN 202210569981A CN 114835640 B CN114835640 B CN 114835640B
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CN114835640A (en
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孙丽萍
王敏
王雨薇
张谨阳
兰丽
王晨艳
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention discloses a fibroblast growth factor receptor inhibitor, a preparation method and application thereof. A compound of formula (i), stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein the substituents are as defined in the specification and claims. The compound has the function of FGFR4 kinase inhibitor, and can be used for preparing medicines for treating tumor diseases, in particular medicines for treating hepatocellular carcinoma, breast cancer, colon cancer, prostatic cancer, pancreatic cancer or rhabdomyosarcoma.

Description

Fibroblast growth factor receptor inhibitor, preparation method and application
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a fibroblast growth factor receptor inhibitor, a preparation method and application thereof.
Background
Fibroblast growth factor receptor 4 (Fibroblast Growth Factor Receptor, FGFR 4) is a receptor tyrosine kinase (Receptor Tyrosine Kinases, RTK), a subtype belonging to the FGFR family. The human FGFR family includes four typical subtypes FGFR1, FGFR2, FGFR3, and FGFR 4. Under physiological conditions, they can specifically bind to corresponding fibroblast growth factors (Fibroblast Growth Factors, FGFs) with high affinity, resulting in dimerization and activation of two neighboring FGFR molecules, thereby mediating cell signaling, involved in a number of important physiological processes such as embryonic development, organogenesis, angiogenesis, tissue homeostasis, tissue repair and inflammatory responses (Haugsten E M et al Molecular Cancer Research,2010,8 (11): 1439-1452; brooks A N et al Clinical Cancer Research,2012,18 (7): 1855-1862; turner N et al Nature Reviews Cancer,2010,10 (2): 116-129).
FGF19 is an important metabolic regulator under normal physiological conditions; FGF19 may be associated with the development and progression of a variety of cancers under pathological conditions. FGFR4 is currently thought to be the only receptor for FGF19 that shows specificity, and FGF19 can bind to FGFR4 and activate downstream signaling using β -Klotho as a cofactor (Goetz R et al Nature Reviews Molecular Cell Biology,2013,14 (3): 166-180). FGFR4 was found to be aberrantly activated in a variety of tumors, including over-expression of FGFR4 in a variety of human cancers such as breast cancer, liver cancer, colon cancer, prostate cancer, rhabdomyosarcoma (Levine K M et al: pharmacology & Therapeutics,2020, 214:107590); N535K and V550E mutations found in FGFR4 kinase domains in rhabdomyosarcoma (Sherm J F et al Cancer Discovery,2014,4 (2): 216-231; taylor J G T et al Journal of Clinical Investigation,2009,119 (11): 3395-3407); FGFR4-G388R is associated with the occurrence, progression and prognosis of a variety of cancers such as breast, colorectal, prostate, lung, soft tissue sarcomas and head and neck squamous cell carcinoma (Bange J et al Cancer Research,2002,62 (3): 840-847; morimoto Y et al Cancer 2003,98 (10): 2245-2250); overexpression of FGF19 is found in hepatocellular carcinoma (Miura S et al BMC Cancer 2012, 12:56).
Disclosure of Invention
The invention designs a series of fibroblast growth factor receptor inhibitors with brand new structures by utilizing a computer aided drug design means.
It is another object of the present invention to provide a method for preparing the fibroblast growth factor receptor inhibitor.
It is a further object of the present invention to provide the use of the fibroblast growth factor receptor inhibitor.
The aim of the invention can be achieved by the following technical scheme:
a compound of formula (I), a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,
wherein:
a is C 6-8 Aryl, 5-to 8-membered heteroaryl, C 3-8 Cycloalkyl, 3-to 8-membered heterocycloalkyl or C 3-8 A cycloalkenyl group;
b is phenyl or heteroaryl;
x is selected from one of-O-, -NH-or none;
y is selected from one of-NHCONH-, -NHCO or-CONH-;
l is a moiety capable of forming a covalent bond with a nucleophile selected from the group consisting of:
wherein the method comprises the steps ofRepresents a double bond or a single bond;
R 1 、R 2 and R is 3 Each independently selected from hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted heterocyclylalkyl;
R 4 and R is 5 Selected from hydrogen, halogen, cyano, mercapto, hydroxy, amino, amido, ester, amido, sulfonyl, sulfinyl, and optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 An alkoxy group;
R 6 a group selected from a chlorine atom, a cyano group or from the following structures:
R 7 selected from hydrogen, hydroxy, cyano, optionally substituted C 1-4 Alkyl or optionally substituted heterocyclylalkyl;
m is 1 or 2; n is 0,1,2,3 or 4; p is 0,1,2,3 or 4
As a preferred aspect of the present invention, the compounds of formula (I), stereoisomers, tautomers or pharmaceutically acceptable salts thereof,
wherein:
a is a pyridine ring;
b is selected from phenyl, pyridyl or pyrazinyl;
x is one of-O-or none;
y is-NHCONH-;
l is selected fromWherein R is 1 、R 2 Each independently selected from hydrogen, C1-3 alkyl, R 3 Selected from hydrogen, halogen;
R 4 selected from hydrogen, C1-3 alkyl, C1-3 alkoxy, halogen;
R 5 is trifluoromethyl;
R 6 selected from chlorine atom, 4-methylpiperazino-1-methylene, 4-ethylpiperazino-1-methylene, morpholin-1-methylene, pyrrole-1-methylene;
n is 1 or 2.
As a further preferred aspect of the invention, the compounds of formula (I), stereoisomers, tautomers or pharmaceutically acceptable salts thereof,
wherein:
a is a pyridine ring;
b is selected from phenyl, pyridyl or pyrazinyl;
x is one of-O-or none;
y is-NHCONH-;
l is selected from acrylamide, chloroacetamide, butenamide, butynamide, 2-fluoroacrylamide or propionyl;
R 4 selected from hydrogen, methyl, fluoro, chloro, methoxy;
R 5 is trifluoromethyl;
R 6 selected from the group consisting of4-methylpiperazino-1-methylene, 4-ethylpiperazino-1-methylene;
n is 1.
As a still further preferred aspect of the present invention, the compound of formula (I) is selected from any one of the following:
the preparation method of the compound of the formula (I) disclosed by the invention has the following reaction route selected from any one of the following:
route one:
firstly, raw material a and BTC react under the catalysis of pyridine to generate phenyl isocyanate, then a commercial raw material or a laboratory prepared intermediate b is added, an aryl urea intermediate c is obtained through condensation reaction, and simultaneously, raw material d is added in Pd (dppf) Cl 2 Miyaura boronation reaction is carried out with the pinacol ester of the biboronate under the catalysis of the catalyst to obtain the pinacol ester intermediate e of the phenylboronate, and the further intermediate c and the intermediate e are prepared in Pd (PPh) 3 ) 4 Carrying out Suzuki coupling reaction under the catalysis of (a) to obtain an intermediate f; finally, intermediate f is condensed with the corresponding carboxylic acid and acid chloride to give compound of general formula (Ia).
Route two:
firstly, nucleophilic substitution is carried out on raw materials g and h under alkaline conditions to generate an intermediate i, the intermediate i and BTC react under the catalysis of pyridine to generate phenyl isocyanate, then a commercial raw material or a laboratory preparation raw material b is added, and an aryl urea intermediate j is obtained through condensation reaction; reducing the nitro group of the intermediate j into an amino intermediate k through palladium carbon and hydrogen; finally, condensing the intermediate k with the corresponding carboxylic acid and acyl chloride to obtain the compound (Ib).
Methods for enantiomeric and diastereomeric mixtures are familiar to the person skilled in the art. The invention includes any isolated racemic or optically active form of formula (I) having FGFR4 kinase inhibitory activity.
A pharmaceutical composition comprising a compound of formula (i), a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable receptor, adjuvant or diluent.
The invention relates to application of a compound shown in a formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof in preparing medicines for treating diseases related to FGFR4 abnormal activation.
Preferably, the disease associated with aberrant FGFR4 activation is selected from hepatocellular carcinoma, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, rhabdomyosarcoma, lung cancer, soft tissue sarcoma, head and neck squamous cell carcinoma, or cervical cancer.
The administration mode is as follows:
the compounds of the invention may be administered to a mammal, preferably a human, alone or in combination with pharmaceutically acceptable receptors, adjuvants or diluents in pharmaceutical compositions; the compounds may be administered orally or subcutaneously, by intramuscular injection, intraperitoneally, intravenously, rectally, topically, ocularly, pulmonary, nasal, and parenterally.
Drug metabolism and prodrugs:
metabolites of the compounds and pharmaceutically acceptable salts thereof, as well as prodrugs that can be converted in vivo to structures of the compounds and pharmaceutically acceptable salts thereof, are also encompassed by the claims of this application.
The invention relates to application of a compound shown in a formula (I), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof in preparing a fibroblast growth factor receptor inhibitor.
The beneficial effects of the invention are as follows: the invention designs a small molecular compound with the structural characteristics of a formula (I), which can effectively inhibit the activity of fibroblast growth factor receptor 4 and has obvious antiproliferative activity on FGFR 4-mediated liver cancer cell lines.
The compounds of the invention and the corresponding preparation methods are further explained and exemplified below by examples and preparations. It should be appreciated that while typical or preferred reaction conditions (e.g., reaction temperature, time, molar ratios of reactants, reaction solvents, and pressures, etc.) are given in the specific examples, other reaction conditions may be used by those skilled in the art. The optimum reaction conditions can vary with the particular Van-tone fifth or solvent used, but such conditions can be determined by one of ordinary skill in the art by routine experimentation.
The structures of the compounds of the examples below were characterized by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The compound was dissolved in the appropriate deuterating reagent using Bruker AV-300 (300 MHz) nuclear magnetic resonance, and 1H-NMR analysis was performed at ambient temperature using TMS as an internal standard. NMR chemical shift (δ) is in ppm and is abbreviated as follows: s, unimodal; d, double peaks; t, triplet; q, quartet; m, multiple peaks; brs, broad unimodal. MS was determined by Water Q-TOF Micros TM mass spectrometer.
The starting materials, intermediates and compounds of the examples may be isolated and purified by conventional techniques such as precipitation, filtration, recrystallization, evaporation, distillation and chromatography (e.g., column chromatography, TLC analytical purification, etc.).
The invention will now be further described with reference to examples. It is to be understood that the invention is not limited to these examples, which are provided solely for practicing the invention and do not in any way limit the scope of the invention.
Detailed Description
EXAMPLE 1 Synthesis of N- (5- (3-methyl-4- (3- (4- (4-methylpiperazin-1-ylidene) -3- (trifluoromethyl) benzene) Group) ureido) phenyl) pyridine-2-yl) acrylamide (W-1)
Step 1, preparing an intermediate 4-nitro-2-trifluoromethyl bromobenzyl
The starting material 2-methyl-5-nitrobenzotrifluoride (3.20 g,15.6 mmol) was dissolved in 1, 2-dichloroethane (40 mL), N-bromosuccinimide (3.04 g,17.1 mmol) and azobisisobutyronitrile (256 mg,1.56 mmol) were added with stirring at room temperature, and then heated to 80℃for reaction. After TLC monitoring the reaction was completed, the reaction mixture was diluted with water (100 mL), extracted with dichloromethane (100 ml×3), and the organic phase was washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent PE: ea=400:1 to 50:1) to give a pale yellow liquid (3.32 g, yield 75.8%).
1 H NMR(300MHz,Chloroform-d)δ(ppm):8.54(d,J＝2.3Hz,1H),8.42(dd,J＝8.6,2.4Hz,1H),7.84(d,J＝8.6Hz,1H),4.67(s,2H).
Step 2, preparing intermediate 4- (4-methylpiperazine-1-methylene) -3-trifluoromethyl-1-nitrobenzene
4-nitro-2-trifluoromethyl benzyl bromide (3.29 g,11.7 mmol) was dissolved in dichloromethane (50 mL) and anhydrous potassium carbonate (1.62 g,11.7 mmol) was added with stirring at room temperature. Subsequently, a solution of N-methylpiperazine (2.6 mL,23.4 mmol) in methylene chloride (5 mL) was added dropwise to the reaction solution under ice bath, and the reaction was stirred while the dropwise addition was continued until the temperature reached room temperature. After TLC monitoring the reaction was complete, the reaction was diluted with water (100 mL), extracted with dichloromethane (100 ml×3), the organic phase was washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (meoh=80:1, 1% tea elution) to give a pale yellow liquid (3.23 g, 89.8% yield).
1 H NMR(300MHz,Chloroform-d)δ(ppm):8.51(d,J＝2.3Hz,1H),8.38(dd,J＝8.6,2.4Hz,1H),8.11(d,J＝8.6Hz,1H),3.75(s,2H),2.54(s,8H),2.32(s,3H).
Step 3, preparing intermediate 4- (4-methylpiperazine-1-methylene) -3-trifluoromethyl aniline
4- (4-methylpiperazine-1-methylene) -3-trifluoromethyl-1-nitrobenzene (3.03 g,10 mmol) was dissolved in methanol (40 mL), 10% palladium on carbon (300 mg) and 85% hydrazine hydrate (4.9 mL,100 mmol) were added with stirring at room temperature, and then the temperature was raised to 65℃for reaction. After the completion of the TLC monitoring reaction, the reaction solution was suction-filtered through celite, the filtrate was concentrated under reduced pressure, the reaction solution was diluted with water (100 mL), dichloromethane (100 mL. Times.3) was extracted, the organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and dried after the solvent was distilled off under reduced pressure to give a pale yellow solid (2.14 g, yield 78.5%).
1 H NMR(300MHz,Chloroform-d)δ(ppm):7.47(d,J＝8.3Hz,1H),6.92(d,J＝2.5Hz,1H),6.79(dd,J＝8.2,2.4Hz,1H),3.76(s,2H),3.53(s,2H),2.46(s,8H),2.29(s,3H).
Step 4, preparation of intermediate 1- (4-bromo-2-methylphenyl) -3- (4- (4-methylpiperazin-1-ylidene) -3- (tri) Fluoromethyl) phenyl) urea
Triphosgene (302 mg,1.02 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) under nitrogen. A solution of pyridine (943. Mu.L, 18 mmol) and 2-methyl-4-bromoaniline (578 mg,3 mmol) in tetrahydrofuran (3 mL) was slowly added dropwise to the reaction system at-5℃and the mixture was allowed to react at room temperature for 30 minutes. A solution of the compound 4- (4-methylpiperazine-1-methylene) -3-trifluoromethylaniline (727 mg,2.7 mmol) in tetrahydrofuran (2 mL) was then added dropwise and the reaction continued at room temperature. After the completion of the TLC monitoring reaction, the reaction mixture was filtered off with suction, and the cake was washed three times with tetrahydrofuran and dried. A pink solid (1.11 g, 84.8% yield) was obtained.
1 H NMR(300MHz,DMSO-d 6 )δ(ppm):9.51(s,1H),8.14(s,1H),7.97(s,1H),7.82(d,J＝8.7Hz,1H),7.63(d,J＝8.6Hz,1H),7.56(d,J＝8.4Hz,1H),7.40(s,1H),7.32(d,J＝8.7Hz,1H),3.53(s,2H),2.39(s,8H),2.25(s,3H),2.20(s,3H).
Step 5, preparation of intermediate 2-aminopyridine-5-boronic acid pinacol ester
2-amino-5-bromopyridine (2.60 g,15 mmol), pinacol diboronate (4.57 g,18 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (268 mg,0.75 mmol) and potassium acetate (4.42 g,45 mmol) were successively introduced into a dry two-necked flask, and after adding anhydrous dioxane (30 mL), nitrogen was replaced three times, and the temperature was raised to 100℃to stir the reaction. After the completion of the TLC monitoring reaction, the filtrate was dried by suction filtration through celite, and the filtrate was dried under reduced pressure, slurried with petroleum ether, and dried after suction filtration to give a pale brown solid (3.25 g, yield 98.5%).
Step 6, preparation of intermediate 1- (4- (6-aminopyridin-3-yl) -2-methylphenyl) -3- (4- (4-methylpiperazine) 1-methylene) -3- (trifluoromethyl) phenyl) urea
2-aminopyridine-5-boronic acid pinacol ester (660 mg,3 mmol), 1- (4-bromo-2-methylphenyl) -3- (4- (4-methylpiperazine-1-methylene) -3- (trifluoromethyl) phenyl) urea (970 mg,2 mmol), tetrakis (triphenylphosphine) palladium (115 mg,0.01 mmol) and cesium carbonate (1.30 g,4 mmol) were successively introduced into a Shi Linke tube, toluene/ethanol/water (9/6/3 mL) was added, and then nitrogen was replaced three times, and the temperature was raised to 100℃and the mixture was stirred. After TLC monitoring the reaction was complete, celite was filtered off with suction, concentrated under reduced pressure, and purified by column chromatography (eluent DCM: meoh=100:1 to 40:1,1% tea) to give a pale yellow solid (511 mg, 51.3% yield).
1 H NMR(300MHz,DMSO-d 6 )δ(ppm):9.32(s,1H),8.22(d,J＝2.5Hz,1H),8.01(s,1H),7.98(d,J＝2.1Hz,1H),7.83(d,J＝8.4Hz,1H),7.69–7.64(m,1H),7.61(s,1H),7.59–7.54(m,1H),7.41(d,J＝2.2Hz,1H),7.35(dd,J＝8.4,2.3Hz,1H),6.51(d,J＝8.6Hz,1H),5.99(s,2H),3.53(s,2H),2.38(s,8H),2.29(s,3H),2.18(s,3H).
Step 7, preparation of N- (5- (3-methyl-4- (3- (4- (4-methylpiperazine-1-methylene) -3- (trifluoromethyl) benzene) Yl) ureido) phenyl) pyridin-2-yl acrylamide (W-1)
1- (4- (6-Aminopyridin-3-yl) -2-methylphenyl) -3- (4- (4-methylpiperazin-1-ylidene) -3- (trifluoromethyl) phenyl) urea (99.7 mg,0.2 mmol) was dissolved in anhydrous dichloromethane (3 mL) and triethylamine (83. Mu.L, 0.6 mmol) was added with stirring at room temperature. Subsequently, a solution of acryloyl chloride (20. Mu.L, 0.25 mmol) in dichloromethane (1 mL) was slowly added dropwise under ice bath, and the mixture was stirred overnight at room temperature after the dropwise addition. After completion of the TLC detection reaction, the reaction was quenched with water (20 mL), extracted with dichloromethane (20 ml×3), and the organic phase was washed with saturated aqueous ammonium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM: meoh=60:1, 1% tea solution elution). The mixed solvent of methylene chloride and n-hexane was slurried, suction-filtered and dried to obtain a white solid (46.7 mg, yield 42.3%).
1 H NMR(300MHz,DMSO-d6)δ(ppm):10.82(s,1H),9.43(s,1H),8.66(d,J＝2.4Hz,1H),8.26(d,J＝8.6Hz,1H),8.10(d,J＝8.5Hz,2H),7.98(d,J＝8.8Hz,2H),7.64(d,J＝8.6Hz,1H),7.59(s,2H),7.53(d,J＝9.7Hz,1H),6.64(dd,J＝17.0,10.1Hz,1H),6.33(d,J＝17.1Hz,1H),5.84–5.77(m,1H),3.53(s,2H),2.38(s,8H),2.33(s,3H),2.17(s,3H).
HRMS(ESI)m/z calcd for C 29 H 31 F 3 N 6 O 2 [M+H] + ,553.2533；found,553.2531.
EXAMPLE 2 Synthesis of N- (5- (3-methyl-4- (3- (4- (4-methylpiperazine-1-methylene) -3- (trifluoromethyl)) benzene Radical) ureido) phenoxy) pyridin-2-yl acrylamide (W-23)
Step 1, preparation of intermediate 2-methyl-4- ((6-nitropyridin-3-yl) oxy) aniline
The starting 3-methyl-4-aminophenol (1.60 g,13 mmol) was dissolved in anhydrous N, N-dimethylformamide (20 mL) under nitrogen protection, cesium carbonate (9.45 g,29 mmol) was added, and stirred at room temperature for 30 minutes. A solution of 2-nitro-5-chloropyridine (2.30 g,14.5 mmol) in DMF (5 mL) was then slowly added dropwise to the reaction mixture and the mixture was allowed to react at 90 ℃. After TLC monitored the completion of the reaction, diluted with water (50 mL), extracted with ethyl acetate (50 ml×3), washed with saturated aqueous sodium chloride (50 ml×2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent PE: ea=8:1) to give a yellow solid (1.71 g, 53.7% yield).
1 H NMR(300MHz,Chloroform-d)δ(ppm):8.28(d,J＝2.9Hz,1H),8.19(d,J＝8.9Hz,1H),7.33(dd,J＝9.0,2.9Hz,1H),6.84–6.77(m,2H),6.71(d,J＝8.3Hz,1H),3.67(s,2H),2.19(s,3H).
Step 2, preparation of intermediate 1- (2-methyl-4- ((6-nitropyridin-3-yl) oxy) phenyl) -3- (4- (4-methyl) Piperazine-1-methylene) -3- (trifluoromethyl) phenyl) urea
Triphosgene (164 mg,0.55 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) under nitrogen. A solution of pyridine (785. Mu.L, 9.72 mmol) and 2-methyl-4- ((6-nitropyridin-3-yl) oxy) aniline (412 mg,1.62 mmol) in tetrahydrofuran (2 mL) was slowly added dropwise to the reaction system in ice-bath, and the mixture was allowed to react at room temperature for 30 minutes. A solution of 4- (4-methylpiperazine-1-methylene) -3-trifluoromethylaniline (390 mg,1.46 mmol) in tetrahydrofuran (2 mL) was then added dropwise thereto, and the reaction was continued at room temperature. After TLC monitoring the reaction was complete, concentrated directly under reduced pressure, and purified by column chromatography (eluent DCM: meoh=100:1, 1% tea) to give a yellow solid (625 mg, 78.7% yield).
Step 3, preparation of intermediate 1- (4- ((6-aminopyridin-3-yl) oxy) -2-methylphenyl) -3- (4- (4-methyl) Piperazine-1-methylene) -3- (trifluoromethyl) phenyl) urea
1- (2-methyl-4- ((6-nitropyridin-3-yl) oxy) phenyl) -3- (4- (4-methylpiperazin-1-ylidene) -3- (trifluoromethyl) phenyl) urea (1.50 g,2.76 mmol) was dissolved in ethanol: water (10:5 mL), iron powder (1.21 g,22 mmol), ammonium chloride (1.47 g,27.6 mmol) were added with stirring at room temperature, and then heated to 85℃for reaction. After completion of the TLC detection reaction, the reaction solution was suction-filtered through celite, and after the filtrate was dried under reduced pressure, diluted with water (30 mL), extracted with methylene chloride (50 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure and dried to give a white solid (1.26 g, yield 88.7%).
Step 4, preparation of N- (5- (3-methyl-4- (3- (4- (4-methylpiperazine-1-methylene) -3- (trifluoromethyl) benzene) Radical) ureido) phenoxy) pyridin-2-yl acrylamide (W-23)
1- (4- ((6-Aminopyridin-3-yl) oxy) -2-methylphenyl) -3- (4- (4-methylpiperazin-1-ylidene) -3- (trifluoromethyl) phenyl) urea (98 mg,0.2 mmol) was dissolved in anhydrous dichloromethane, triethylamine (83.4 ul,0.6 mmol) was added with stirring at room temperature, then a solution of acryloyl chloride (25 ul,0.25 mmol) in dichloromethane was slowly added dropwise under ice-bath, and the mixture was warmed to room temperature with stirring overnight. After completion of the TLC detection reaction, the reaction was quenched with water (20 mL), extracted with dichloromethane (20 ml×3), and the organic phase was washed with saturated aqueous ammonium chloride (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM: meoh=60:1, 1% tea solution elution). The mixed solvent of methylene chloride and n-hexane was slurried, suction-filtered and dried to obtain a white solid (41.6 mg, yield 38.5%).
1 H NMR(300MHz,DMSO-d 6 )δ(ppm):10.77(s,1H),9.39(s,1H),8.22(d,J＝9.0Hz,1H),8.12(d,J＝2.9Hz,1H),8.08(s,1H),7.97(d,J＝2.2Hz,1H),7.73(d,J＝8.8Hz,1H),7.62(d,J＝8.6Hz,1H),7.56(dd,J＝8.6,2.2Hz,1H),7.50(dd,J＝9.0,3.0Hz,1H),6.94(d,J＝2.9Hz,1H),6.87(dd,J＝8.7,2.9Hz,1H),6.60(dd,J＝17.0,10.1Hz,1H),6.30(dd,J＝17.0,2.1Hz,1H),5.78(dd,J＝10.2,2.0Hz,1H),3.53(s,2H),2.41(s,8H),2.23(d,J＝2.9Hz,6H).
HRMS(ESI)m/z calcd for C 29 H 31 F 3 N 6 O 3 [M+H] + ,569.2482；found,569.2494.
Examples and summary of structural characterization information are shown in table 1:
the synthesis method is as in example 1 or example 2:
table 1, examples and structural characterization information:
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biological testing
1. In vitro kinase Activity assay
All compounds were completely dissolved in DMSO to prepare a mother liquor at a concentration of 10 mM. Then, diluted to 50 times the desired maximum concentration. 100. Mu.L of dilution was added to the 96-well plate, while 100. Mu.L of DMSO was added to both wells as a compound-free control and an enzyme-free control, and the plate was labeled as a source plate. Transfer 10 μl of compound from the source plate to a new 96-well plate as an intermediate plate, add 90 μl of 1x kinase base buffer per well, shake mix for 10 minutes. mu.L of liquid from each well of the intermediate plate was transferred to 384 well plates in duplicate. A kinase solution with a final concentration of 2.5x is prepared by using a 1x kinase base buffer, and FAM labeled peptide and ATP are added into the 1x kinase base buffer to prepare a 2.5x polypeptide solution. 10. Mu.L of 2.5 Xkinase solution was added to each well of 384-well assay plates, incubated at room temperature for 10 minutes, then 10. Mu.L of 2.5 Xpolypeptide solution was added to each well, incubated at 28℃for a period of time, and 30. Mu.L of stop buffer was added to stop the kinase reaction. The conversion was read with a microplate reader. Data analysis inhibition (%) = (max-conversion)/(max-min) 100
Where conversion is a conversion reading of a compound; max is positive control well, representing conversion reading for no compound well; min is a negative control well representing a conversion reading for the enzyme-free well. The results are shown in Table 2.
TABLE 2 inhibition of FGFR4 kinase by Compounds at a test concentration of 1. Mu.M
The data show that the compound has remarkable inhibition effect on FGFR4 and deserves further research.
2. In vitro tumor cell antiproliferation experiments
Firstly, cells are digested and counted to prepare the cell culture material with the density of 4.5X10 4 mu.L of cell suspension was added per well to a 96-well cell culture plate, and the 96-well cell culture plate was then placed at 37℃with 5% CO 2 Culturing in an incubator for 24 hours. Diluting the drug with the medium to the desired concentration, adding 100. Mu.L of the corresponding to each wellWhile setting up a negative control group, placing 96-well cell culture plate at 37deg.C, 5% CO 2 The incubator continues to incubate for 72 hours. Then, 10. Mu.L of CCK-8 was added to each well, and the culture was continued in an incubator for 2 to 3 hours. Gently mixing the mixture for 10 minutes on a shaker to remove bubbles in a 96-well plate; the absorbance of each well at a wavelength of 450nm was measured on a microplate reader (BioTek), and the inhibition was calculated. Inhibition (%) = (negative control OD value-experimental OD value)/negative control OD value 100%. The results are shown in Table 3.
Table 3, in vitro tumor cell antiproliferative activity results for compounds:
the data show that the compound has remarkable inhibition effect on the liver cell cancer strain Hep3B and HuH 7.

Claims (5)

1. A compound of formula (I), a tautomer or a pharmaceutically acceptable salt thereof,
wherein:
a is a pyridine ring;
b is selected from phenyl, pyridyl or pyrazinyl;
x is one of-O-or none;
y is-NHCONH-;
l is selected from acrylamide, chloroacetamide, butenamide, butynamide, 2-fluoroacrylamide or propionyl; r is R 4 Selected from hydrogen, methyl, fluoro, chloro, methoxy;
R 5 is trifluoromethyl;
R 6 selected from 4-methylpiperazino-1-methylene, 4-ethylpiperazino-1-methylene;
p is 1;
n is 1.
2. A compound of formula (i), tautomer or pharmaceutically acceptable salt according to claim 1, wherein the compound of formula (i) is selected from any one of the following:
3. a pharmaceutical composition comprising a compound of formula (i), tautomer or pharmaceutically acceptable salt according to claim 1 and a pharmaceutically acceptable adjuvant.
4. Use of a compound of formula (i), tautomer or pharmaceutically acceptable salt according to claim 1 for the manufacture of a medicament for the treatment of a disease associated with aberrant FGFR4 activation; the diseases related to the abnormal activation of FGFR4 are selected from hepatocellular carcinoma, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, rhabdomyosarcoma, lung cancer, soft tissue sarcoma, head and neck squamous cell carcinoma or cervical cancer.
5. Use of a compound of formula (i), tautomer or pharmaceutically acceptable salt according to claim 1 for the preparation of a fibroblast growth factor receptor inhibitor.
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CN110022900A (en) * 2016-09-08 2019-07-16 蓝图药品公司 The combination of fibroblast growth factor receptor 4 inhibitor and cell cycle protein dependent kinase inhibitor
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