CN103435553A - Piperazine structure-based aryl formamide Raf kinase inhibitor and preparation method as well as application thereof - Google Patents
Piperazine structure-based aryl formamide Raf kinase inhibitor and preparation method as well as application thereof Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to a diaryl urea compound (A), wherein the definitions of R1-R13, Ar and X are shown in the specification. The invention also discloses a preparation method of the compounds of the general formula (A), medicinal compositions containing the compounds and medical application thereof, particularly application as the Raf kinase inhibitor.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a class piperazine compounds, their preparation method, the medicinal compositions that contains these compounds and their medical use, particularly as the purposes of Raf kinase inhibitor.
Background technology
The Raf kinases has become the important drug target of a treatment tumour.The important composition composition of Ras/Raf/MEK/ERK signal transduction pathway.This signal transduction pathway plays an important role in growth and the differentiation of cell.If the Raf kinases is undergone mutation, may cause the activation of this signal transduction pathway allostery and cause the uncontrollable growth of cell and propagation.2005, by Onyx Pharmaceuticals (Emeryville, CA, USA) and Bayer (Leverkusen, Germany) the Raf-1 inhibitor Sorafenib (BAY43-9006) of company's R & D Cooperation by FDA approval listing, is used for the treatment of advanced renal cell cancer; FDA in 2007 ratifies again it and is used for the treatment of liver cancer.Sorafenib is a kind of substituted bisarylurea compound, thereby can block the Ras/Raf/MAPK/ERK signal transduction pathway by potent inhibition Raf-1 kinases, clinical data shows that Sorafenib is to kidney, prostate cancer, the rectum cancer, the tumor diseases such as minicell and nonsmall-cell lung cancer all have therapeutic action preferably.The substituted bisarylurea compound that comprises in addition Sorafenib usually has other kinase whose inhibition activity in the tumor signal Signal Transduction Pathways, and these kinases comprise VEGF R2/3 (VEGFR-2, VEGFR-3), platelet derived growth factor receptor β (PDGFR-β), KIT, FLT-3, RET.Make this type of medicine not only can the inhibition tumor cell hyperplasia, can also stop tumor neovasculature generation.This has further strengthened clinical effectiveness and the researching value of this compounds inhibition tumour.
Summary of the invention
The present invention has studied a large amount of substituted bisarylurea compounds that comprise Sorafenib, utilize the homology mould to build Raf-1 kinase protein, Docking, COMFA/COMSIA, the Computer-Aided Drug Design means such as structure Pharmacophore Model have tentatively been built structure activity relationship model and the medicine virtual screening model of substituted bisarylurea compound, have designed on this basis the compound of a series of brand news.Calculation by computer shows that with the preliminary pharmacological tests result designed compound and lead compound have the similar mechanism of action, may retain the effect of Sorafenib to target.Activity level surpasses or is similar to Sorafenib.By these work, it is strong that expectation obtains selectivity, good drug efficacy, the lead compound that toxic side effect is little.
Compound general formula A of the present invention is as follows:
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12or R
13independently mean separately hydrogen, hydroxyl, nitro, amino, methyl, ethyl, methoxyl group, trifluoromethyl, fluorine, chlorine, bromine, iodine, cyano group;
Ar means five yuan of aromatic rings or fragrant heterocycle, benzene or substituted benzene, indoles, benzoglyoxaline;
Mean-NHC of X (O) NH-,-NHC (O)-or-C (O) NH-;
Preferred compound is R
1, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11or R
13mean hydrogen;
R
2mean hydrogen, trifluoromethyl;
R
3mean hydrogen, halogen;
R
12mean hydrogen, methyl, halogen;
Ar means 2-pyrryl, 2-pyrazolyl, 2-aminophenyl, 2-hydroxy phenyl, 2-indyl, 2-benzimidazolyl-;
Mean-NHC of X (O) NH-.
The compound of above-mentioned general formula and pharmacy acceptable salt thereof can be:
N-[4-[4-(1H-benzimidazolyl-2 radicals-Ji formyl radical) piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5a),
N-[4-[4-(1H-benzimidazolyl-2 radicals-carbonyl) piperazine-1-yl]-the 2-aminomethyl phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5b),
N-[4-[4-(1H-benzimidazolyl-2 radicals-carbonyl) piperazine-1-yl]-the 2-chloro-phenyl-]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5c),
N-[4-[4-(1H-indole-2-carbonyl) piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5d),
N-[4-[4-(1H-indole-2-carbonyl) piperazine-1-yl]-the 2-aminomethyl phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5e),
The N-[4-[4-[(2-amino benzoyl) piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5f),
The N-[4-[4-[(2-amino benzoyl)] piperazine-1-yl]-the 2-chloro-phenyl-]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5g),
The N-[4-[4-[(2-hydroxy benzoyl)] piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5h),
N-[4-[4-(1H-pyrroles-2-carbonyl) piperazine-1-yl] phenyl]-3-(the chloro-3-trifluoromethyl of 4-) urea (5i),
N-[4-[4-(1H-pyrroles-2-carbonyl) piperazine-1-yl]-the 2-chloro-phenyl-]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5j),
N-[4-[4-(1H-pyrazoles-3-carbonyl) piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5k),
N-[4-[4-(1H-pyrazoles-3-carbonyl) piperazine-1-yl]-the 2-aminomethyl phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (51).
Part of compounds preparation method of the present invention is as follows:
The compounds of this invention can prepare by above-mentioned preparation method, according to the difference of substituent difference and substituting group position, selects corresponding raw material to get final product.
The pharmacology test result shows, the compounds of this invention has the Raf kinase inhibiting activity, can be used for prevention or the treatment clinical disease relevant with the Raf kinase inhibitor, these diseases can be: melanoma, liver cancer, kidney, acute leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, cancer of the stomach or mesothelioma etc.
The pharmacologically active test:
One, BRaf kinase activity test material and method
1, material
Braf(Invitrogen，USA)
5X?Kinase?Buffer?A
Kinase?Tracer178
LanthaScreen
TM?Eu-anti-GST?Antibody
384 hole black microwell plates (Corning, USA)
Rifle head (Axygen, USA)
2, experimental procedure
1) determine the Kd of tracer agent
I) tracer agent of preparation different concns, every hole adds 5tl.
Ii) mixing solutions (3 times of final concentrations) of preparation kinases and antibody, every hole adds 5 μ l.
Iii) positive drug (dasatinib) of preparation different concns is established the DMSO contrast that does not add positive drug simultaneously, and every hole adds 5 μ l.
Iv) after room temperature reaction 1h, detect.
2) determine the IC of positive drug
50, tracer concentration and Kd approach
I) positive drug (BAY 43-9006) of preparation different concns, every hole adds 5 μ l.
Ii) mixing solutions (3 times of final concentrations) of preparation kinases and antibody, every hole adds 5 μ l.
Iii) preparation tracer concentration close to Kd, every hole adds 5 μ l.
Iv) after room temperature reaction 1h, detect.
3, testing sample is processed
Testing sample configures mother liquor with DMSO, with reaction buffer, is diluted to working concentration.
Two, the materials and methods of cytoactive test
1, material and instrument
HepG2 cell strain, A431 cell strain, HUVEC cell strain (preservation of China Medicine University's drug screening center)
96 porocyte culture plates (Coming, USA)
T25 Tissue Culture Flask (Corning, USA)
T75 Tissue Culture Flask (Corning, USA)
Centrifuge tube (Corning, USA)
Transfer pipet (Corning, USA)
dyestuff (Invitrogen, USA)
3%SDS phosphate buffered saline buffer (Invitrogen, USA)
Wall culture plate (Coming, USA) is deceived in 384 holes
Rifle head (Axygen, USA)
Multidrop sample injector (Thermo, USA)
Janus liquid processing system (Perkinelmer, USA)
The long microwell plate plate reading of Safire2 all-wave (Tecan, Switzerland)
2, experimental procedure
Cell strain is that preserve in this ventricular cell storehouse, after recovery, according to following condition, cultivates observation, and rear use goes down to posterity
Before detecting, cell is processed 24-72 hour with testing compound,
according to ten times of Dilution ratios, add in cell culture medium, 37 ℃, lucifuge is hatched 1-4 hour.Use 50 μ l3%SDS to add 100 μ l to contain
cell system in termination reaction.Adopt the long microwell plate plate reading of all-wave (Safire2, Switzerland) to detect fluorescent value, instrument arranges Em:540nm, Em:585nm.
3, testing sample is processed
Testing sample and positive drug are provided by Lu Tao teach problem group, and DMSO configures mother liquor, and reaction buffer is diluted to working concentration 50 μ mol/L.
4, pharmacology test result
athe concentration of pharmacology test is 50 μ mol/L.
b1R:inhibiton Ratio (inhibiting rate).
Embodiment:
Embodiment 1
1-(4-nitrophenyl) piperazine 2a
By starting raw material p-fluoronitrobenzene (4.20g, 30mmol), piperazine (8.61g, 10mmol), salt of wormwood (4.15g, 30mmol) and anhydrous acetonitrile 100ml add at the bottom of the garden of 250ml in bottle, react 5h under 90 ℃, cooling after, concentrating under reduced pressure is removed acetonitrile, the water that adds about 200ml, transfer in separating funnel, with ethyl acetate extraction, 100ml * 2, with the washing organic phase, after collecting the organic phase drying, suction filtration concentrates away during ethyl acetate falls back, and obtains light yellow solid 2a (4.00g, 19.3lmmol), yield 64.4%.mp：128～131℃；MS[M+H]
+208.0。
Embodiment 2
1-(2-methyl 4-nitrophenyl) piperazine 2b
The fluoro-2-methyl of the 1-of take 4-oil of mirbane is starting raw material, and the synthetic method of similar compound 2a, obtain light yellow solid 2b, yield 50.3%.MS[M+H]222.1。
Embodiment 3
1-(2-chlorine 4-nitrophenyl) piperazine 2c
The fluoro-2-chlorine of the 1-of take 4-oil of mirbane is starting raw material, and the synthetic method of similar compound 2a, obtain light yellow solid 2c, yield 61.67%.MS[M+H]242.1。
Embodiment 4
(1H-benzimidazolyl-2 radicals-yl) [4-(4-nitrophenyl) piperazine-1 base] ketone 3a
Under ice bath, by 1H-benzimidazolyl-2 radicals-formic acid (486mg, 3mmol), EDCI (603mg, 3.15mmol) and HOBt (426mg, 3.15mmol) add and fill anhydrous CH
2cl
2in the 50ml eggplant-shape bottle of 30ml, after continuing under ice bath to react 30min, 1-(4-nitrophenyl) piperazine 2a (414.2mg, 2mmol) is added in reaction system, under room temperature, react and spend the night.Concentrating under reduced pressure is gone out to desolventizing, add after suitable quantity of water with saturated NaHCO
3the 8-9 of solution adjust pH, add ethyl acetate extraction 50ml * 2, washing organic phase 50ml * 2, after anhydrous magnesium sulfate drying, suction filtration, concentrated, column chromatography for separation obtains light yellow solid 3a (649mg, 1.85mmol), yield 92.4%.mp：MS[M-H]
-350.2；
Embodiment 5
(1H-benzimidazolyl-2 radicals-yl) [4-(2-methyl-4-nitrophenyl) piperazine-1 base] ketone 3b
With 1H-benzimidazolyl-2 radicals-formic acid (486mg, 3mmol), EDCI (603mg, 3.15mmol) and HOBt (426mg, 3.15mmol) and 1-(2-methyl-4-nitrophenyl) piperazine 2b (442mg, 2mmol) be starting raw material, the synthetic method of similar compound 3a, obtain light yellow solid 3b (657mg, 1.80mmol), yield 89.9%.MS[M-H]
-364.1。
Embodiment 6
(1H-benzimidazolyl-2 radicals-yl) [4-(2-chloro-4 nitrophenyl) piperazine-1 base] ketone 3c
With 1H-benzimidazolyl-2 radicals-formic acid (486mg, 3mmol), EDCI (603mg, 3.15mmol) and HOBt (426mg, 3.15mmol) and 1-(2-chloro-4 nitrophenyl) piperazine 2c (482mg, 2mmol) be starting raw material, the synthetic method of similar compound 3a, obtain light yellow solid 3c (660mg, 1.71mmol), yield 85.7%.MS[M-H]
-384.1。
Embodiment 7
(1H-indoles-2-yl) [4-(4-nitrophenyl) piperazine-1 base] ketone 3d
Draw diindyl-2-formic acid (483mg with 1H-, 3mmol), EDCI (603mg, 3.15mmol) and HOBt (426mg, 3.15mmol) and 1-(4-nitrophenyl) piperazine 2a (414.2mg, 2mmol) be starting raw material, the synthetic method of similar compound 3a, obtain light yellow solid 3d (632mg, 1.81mmol), yield 90.3%.MS[M-H]
-349.2。
Embodiment 8
(1H-draws diindyl-2-yl) [4-(2-methyl-4-nitrophenyl) piperazine-1 base] ketone 3e
Draw diindyl-2-formic acid (483mg with 1H-, 3mmol), EDCI (603mg, 3.15mmol) and HOBt (426mg, 3.15mmol) and 1-(2-methyl-4-nitrophenyl) piperazine 2b (442mg, 2mmol) be starting raw material, the synthetic method of similar compound 3a, obtain light yellow solid 3e (664mg, 1.82mmol), yield 91.2%.MS[M-H]
-363.1。
Embodiment 9
[2-(t-butoxycarbonyl amino) phenyl] [4-(4-nitrophenyl) piperazine-1 base] ketone 3f
With 2-(t-butoxycarbonyl amino) phenylformic acid (711mg, 3mmol), EDCI (603mg, 3.15mmol) and HOBt (426mg, 3.15mmol) and 1-(4-nitrophenyl) piperazine 2a (414.2mg, 2mmol) be starting raw material, the synthetic method of similar compound 3a, obtain light yellow solid 3f (820mg, 1.92mmol), yield 96.2%.MS[M+H]
+427.2。
Embodiment 10
[2-(t-butoxycarbonyl amino) phenyl] [4-(2-chlorine 4-nitrophenyl) piperazine-1 base] ketone 3g
With 2-(t-butoxycarbonyl amino) phenylformic acid (711mg, 3mmol), EDCI (603mg, 3.15mmol) and HOBt (426mg, 3.15mmol) and 1-(2-chloro-4 nitrophenyl) piperazine 2c (482mg, 2mmol) be starting raw material, the synthetic method of similar compound 3a, obtain light yellow solid 3g (862mg, 1.87mmol), yield 93.7%.MS[M-H]
-459.1。
Embodiment 11
(2-hydroxy phenyl) [4-(4-nitrophenyl) piperazine-1 base] ketone 3h
With 2 hydroxybenzoic acid (414mg, 3mmol), EDCI (603mg, 3.15mmol) and HOBt (426mg, 3.15mmol) and 1-(4-nitrophenyl) piperazine 2a (414.2mg, 2mmol) be starting raw material, the synthetic method of similar compound 3a, obtain light yellow solid 3h (582mg, 1.78mmol), yield 88.9%.MS[M-H]
-325.2。
Embodiment 12
(1H-pyrroles-2-yl) [4-(4-nitrophenyl) piperazine-1 base] ketone 3i
With 1H-pyrroles-2-formic acid (333mg, 3mmol), EDCI (603mg, 3.15mmol) and HOBt (426mg, 3.15mmol) and 1-(4-nitrophenyl) piperazine 2a (414.2mg, 2mmol) be starting raw material, the synthetic method of similar compound 3a, obtain light yellow solid 3i (527mg, 1.76mmol), yield 87.8%.MS[M+H]
+301.2。
Embodiment 13
(1H-pyrroles-2-yl) [4-(2-chloro-4 nitrophenyl) piperazine-1 base] ketone 3j
With 1H-pyrroles-2-formic acid (333mg, 3mmol), EDCI (603mg, 3.15mmol) and HOBt (426mg, 3.15mmol) and 1-(2-chloro-4 nitrophenyl) piperazine 2c (482mg, 2mmol) be starting raw material, the synthetic method of similar compound 3a, obtain light yellow solid 3j (560mg, 1.76mmol), yield 83.9%.MS[M+H]
+335.1。
Embodiment 14
(1H-pyrazole-3-yl) [4-(4-nitrophenyl) piperazine-1 base] ketone 3k
With 1H-pyrazoles-3-formic acid (336mg, 3mmol), EDCI (603mg, 3.15mmol) and HOBt (426mg, 3.15mmol) and 1-(4-nitrophenyl) piperazine 2a (414.2mg, 2mmol) be starting raw material, the synthetic method of similar compound 3a, obtain light yellow solid 3k (497mg, 1.65mmol), yield 82.5%.MS[M-H]
-300.1。
Embodiment 15
(1H-pyrazole-3-yl) [4-(2-methyl 4-nitrophenyl) piperazine-1 base] ketone 31
With 1H-pyrazoles-3-formic acid (336mg, 3mmol), EDCI (603mg, 3.15mmol) and HOBt (426mg, 3.15mmol) and 1-(2-methyl-4-nitrophenyl) piperazine 2a (442mg mg, 2mmol) be starting raw material, the synthetic method of similar compound 3a, obtain light yellow solid 31 (529mg, 1.68mmol), yield 83.9%.MS[M-H]
-314.l。
Embodiment 16
(1H-benzimidazolyl-2 radicals-yl) [4-(4-aminophenyl) piperazine-1-yl] ketone 4a
By (1H-benzimidazolyl-2 radicals-yl) [4-(4-nitrophenyl) piperazine-1 base] ketone 3a (526mg, 1.50mmol), 10mg5%Pd/C, methyl alcohol 5ml adds in the two neck bottles of 10ml, passes into hydrogen, react 1h under room temperature, suction filtration is gone out solid, the white solid 4a (482mg, 1.50mmol) that filtrate is concentrated, yield 100.0%, mp:203 ℃.[M+H]
+322.2；
1HNMR(DMSO，300MHz)δ：13.11(s，1H)，7.75(dd，2H，J＝4.8)，7.54(dd，2H，J＝4.8)，7.32(t，2H，J＝4.5)，7.26(t，2H，J＝4.5)，6.75(dd，2H，J＝5.1)，6.52(dd，2H，J＝5.1)，4.60(br，2H)，4.58(t，2H)，3.85(t，2H)，3.02(t，4H)。
Embodiment 17
(1H-benzimidazolyl-2 radicals-yl) [4-(2-methyl-4-aminophenyl) piperazine-1-yl] ketone 4b
By (1H-benzimidazolyl-2 radicals-yl) [4-(2-methyl-4-nitrophenyl) piperazine-1 base] ketone 3b (548mg, 1.50mmol), 10mg5%Pd/C, methyl alcohol 5ml adds in the two neck bottles of 10ml, passes into hydrogen, under room temperature, reacts 1h, suction filtration is gone out solid, the white solid 4b (516mg, 1.54mmol) that filtrate is concentrated, yield 102.7%.MS[M+H]
+336.2。
Embodiment 18
(1H-benzimidazolyl-2 radicals-yl) [4-(the chloro-4-aminophenyl of 2-) piperazine-1-yl] ketone 4c
By (1H-benzimidazolyl-2 radicals-yl) [4-(2-chloro-4 nitrophenyl) piperazine-1 base] ketone 3c (578mg, 1.50mmol), 10mg5%Pd/C, methyl alcohol 5ml adds in the two neck bottles of 10ml, passes into hydrogen, under room temperature, reacts 1h, suction filtration is gone out solid, the white solid 4c (529mg, 1.48mmol) that filtrate is concentrated, yield 99.0%.MS[M+H]
+356.2。
Embodiment 19
(1H-indoles-2-yl) [4-(4-aminophenyl) piperazine-1 base] ketone 4d
By (1H-indoles-2-yl) [4-(4-nitrophenyl) piperazine-1 base] ketone 3d (525mg, 1.50mmol), 10mg5%Pd/C, methyl alcohol 5ml adds in the two neck bottles of 10ml, passes into hydrogen, under room temperature, reacts 1h, suction filtration is gone out solid, the white solid 4d (474mg, 1.48mmol) that filtrate is concentrated, yield 98.7%.MS[M+H]
+577.2
Embodiment 20
(1H-indoles-2-yl) [4-(2-methyl-4-aminophenyl) piperazine-1 base] ketone 4e
By (1H-indoles-2-yl) [4-(2-methyl-4-nitrophenyl) piperazine-1-yl] ketone 3e (546mg, 1.50mmol), 10mg5%Pd/C, methyl alcohol 5ml adds in the two neck bottles of 10ml, passes into hydrogen, under room temperature, reacts 1h, suction filtration is gone out solid, the white solid 4e (341mg, 1.53mmol) that filtrate is concentrated, yield 102.0%.MS[M+H]
+335.1。
Embodiment 21
[2-(t-butoxycarbonyl amino) phenyl] [4-(4-aminophenyl) piperazine-1 base] ketone 4f
By [2-(t-butoxycarbonyl amino) phenyl] [4-(4-nitrophenyl) piperazine-1-yl] ketone 3f (639mg, 1.50mmol), 10mg5%Pd/C, methyl alcohol 5ml adds in the two neck bottles of 10ml, passes into hydrogen, under room temperature, reacts 1h, suction filtration is gone out solid, the white solid 4f (598mg, 1.51mmol) that filtrate is concentrated, yield 100.7%.MS[M+H]
+397.2。
Embodiment 22
[2-(t-butoxycarbonyl amino) phenyl] [4-(2-methyl-4-aminophenyl) piperazine-1 base] ketone 4g
By [2-(t-butoxycarbonyl amino) phenyl] [4-(2-methyl-4-nitrophenyl) piperazine-1-yl] ketone 3g (639mg, 1.50mmol), 10mg5%Pd/C, methyl alcohol 5ml adds in the two neck bottles of 10ml, passes into hydrogen, under room temperature, reacts 1h, suction filtration is gone out solid, the white solid 4g (399mg, 1.51mmol) that filtrate is concentrated, yield 100.7%.MS[M+H]
+431.2。
Embodiment 23
(2-hydroxy phenyl) [4-(4-aminophenyl) piperazine-1 base] ketone 4h
By (2-hydroxy phenyl) [4-(2-methyl-4-nitrophenyl) piperazine-1-yl] ketone 3h (491mg, 1.50mmol), 10mg5%Pd/C, methyl alcohol 5ml adds in the two neck bottles of 10ml, passes into hydrogen, under room temperature, reacts 1h, suction filtration is gone out solid, the white solid 4h (452mg, 1.52mmol) that filtrate is concentrated, yield 101.4%.MS[M+H]
+298.2。
Embodiment 24
(1H-pyrroles-2-yl) [4-(4-aminophenyl) piperazine-1 base] ketone 4i
By (1H-pyrroles-2-yl) [4-(4-nitrophenyl) piperazine-1 base] ketone 4i (450mg, 1.50mmol), 10mg5%Pd/C, methyl alcohol 5ml adds in the two neck bottles of 10ml, passes into hydrogen, under room temperature, reacts 1h, suction filtration is gone out solid, the white solid 4i (396mg, 1.47mmol) that filtrate is concentrated, yield 97.8%.MS[M+H]
+271.2。
Embodiment 25
(1H-pyrroles-2-yl) [4-(the chloro-4-aminophenyl of 2-) piperazine-1 base] ketone 4j
By (1H-pyrroles-2-yl) [4-(4-nitrophenyl) piperazine-1 base] ketone 3j (501mg, 1.50mmol), 10mg5%Pd/C, methyl alcohol 5ml adds in the two neck bottles of 10ml, passes into hydrogen, under room temperature, reacts 1h, suction filtration is gone out solid, the white solid 4j (435mg, 1.43mmol) that filtrate is concentrated, yield 95.3%.MS[M+H]
+305.1。
Embodiment 26
(1H-pyrazole-3-yl) [4-(4-aminophenyl) piperazine-1 base] ketone 4k
By (1H-pyrazole-3-yl) [4-(4-nitrophenyl) piperazine-1 base] ketone 3k (452mg, 1.50mmol), 10mg5%Pd/C, methyl alcohol 5ml adds in the two neck bottles of 10ml, passes into hydrogen, under room temperature, reacts 1h, suction filtration is gone out solid, the white solid 4k (381mg, 1.40mmol) that filtrate is concentrated, yield 93.6%.MS[M+H]
+272.1。
Embodiment 27
(1H-pyrazole-3-yl) [4-(2-methyl-4-aminophenyl) piperazine-1 base] ketone 41
By (1H-pyrazole-3-yl) [4-(2-methyl-4-nitrophenyl) piperazine-1 base] ketone 31 (473mg, 1.50mmol), 10mg5%Pd/C, methyl alcohol 5ml adds in the two neck bottles of 10ml, passes into hydrogen, under room temperature, reacts 1h, suction filtration is gone out solid, the white solid 41 (394mg, 1.38mmol) that filtrate is concentrated, yield 92.1%.MS[M+H]
+286.1。
Embodiment 28
N-[4-[4-(1H-benzimidazolyl-2 radicals-carbonyl) piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea 5a
By (1H-benzimidazolyl-2 radicals-yl) [4-(4-aminophenyl) piperazine-1-yl] ketone 4a (321mg, 1mmol), 4-chloro-3-trifluoromethyl phenylisocyanate (221mg, 1mmol) will enter to fill the CH of 5ml drying
2cl
2the 10ml eggplant-shape bottle in, react 1h under room temperature, the adularescent solid is separated out, suction filtration, with dry CH
2cl
2washing leaching cake, obtain white powder solid 5a (414mg, 0.763mmol), productive rate 76.3%.mp：234℃；MS[M+H]
+543.2；
1HNMR(DMSO，300MHZ)δ：13.17(br，1H)，9.16(s，1H)，8.67(s，1H)，7.77(d，1H)，7.56(m，3H)，7.31(m，4H)，6.97(s，1H)，4.63(s，2H)，3.87(t，2H)，3.20(t，4H)。
Embodiment 29
N-[4-[4-(1H-benzimidazolyl-2 radicals-carbonyl) piperazine-1-yl]-the 2-aminomethyl phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea 5b
Think (1H-benzimidazolyl-2 radicals-yl) [4-(2-methyl-4-aminophenyl) piperazine-1-yl] ketone 4b (335mg, 1mmol) starting raw material, the synthetic method of similar compound 5a, obtain white solid 5b (413mg, 0.742mmol), productive rate 74.2%.mp：217℃。MS[M+H]
+557.2；
1HNMR(DMSO，300MHZ)δ：9.08(s，1H)，8.63(s，1H)，8.10(s，1H)，7.61(m，4H)，7.24(m，4H)，4.62(s，2H)，3.88(s，2H)，2.92(s，4H)，2.31(s，3H)。
Embodiment 30
N-[4-[4-(1H-benzimidazolyl-2 radicals-carbonyl) piperazine-1-yl]-the 2-chloro-phenyl-]-N '-(the chloro-3-trifluoromethyl of 4-) urea 5c
With (1H-benzimidazolyl-2 radicals-yl) [4-(the chloro-4-aminophenyl of 2-) piperazine-1-yl] ketone 4c (355mg, 1mmol) be starting raw material, the synthetic method of similar compound 5a, obtain white solid 5c (412mg, 0.715mmol), productive rate 71.5%.mp.221℃。MS[M+H]
+577.2；
1HNMR(DMSO，300MHZ)δ：13.17(s，1H)，9.19(s，1H)，8.91(s，1H)，8.09(s，1H)，7.76(d，1H)，7.70(d，1H)，7.61(d，2H)，7.55(d，1H)，7.39(m，3H)，7.17(d，1H)，4.64(s，2H)，3.88(s，2H)，3.04(s，4H)。
Embodiment 31
N-[4-[4-(1H-indole-2-carbonyl) piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea 5d
[4-(4-aminophenyl) piperazine-1 base] the ketone 4d (320mg, 1mmol) of take in (1H-indoles-2-yl) is starting raw material, and the synthetic method of similar compound 5a, obtain white solid 5d (440mg, 0.813mmol), productive rate 81.3%.mp：211℃。MS[M+H]
+542.2，[M+Na]
+564.1；
1HNMR(DMSO，300MHZ)δ：11.62(s，1H)，9.08(s，1H)，8.62(s，1H)，8.10(s，1H)，7.62(m，3H)，7.43(d，1H)，7.34(d，2H)，7.19(t，1H)，7.07(t，1H)，6.95(d，2H)，6.85(s，1H)，3.91(t，4H)，3.16(t，4H)。
Embodiment 32
N-[4-[4-(1H-indole-2-carbonyl) piperazine-1-yl]-the 2-aminomethyl phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea 5e
[4-(4-aminophenyl) piperazine-1 base] the ketone 4e (334mg, 1mmol) of take in (1H-indoles-2-yl) is starting raw material, and the synthetic method of similar compound 5a, obtain white solid 5e (470mg, 0.847mmol), productive rate 84.7%.mp：218℃。MS[M+H]
+556.2，[M-H]554.3；
1HNMR(DMSO，300MHZ)δ：11.64(s，1H)，9.13(s，1H)，8.69(s，1H)，8.12(s，1H)，7.61(s，2H)，7.42(s，1H)，7.27(m，4H)，7.04(m，2H)，6.84(s，1H)，3.92(s，4H)，2.87(s，4H)，2.30(s，3H)。
Embodiment 33
The N-[4-[4-[(2-amino benzoyl) piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea 5f
With [2-(t-butoxycarbonyl amino) phenyl] [4-(4-aminophenyl) piperazine-1 base] ketone 4f (430mg, 1mmol) be starting raw material, the synthetic method of similar compound 5a, obtain white solid, then white solid is dissolved in and fills in 10mlMeOH, add excessive concentrated hydrochloric acid, after under 40 ℃, reacting 4h, concentrating under reduced pressure goes out desolventizing, adds suitable quantity of water, with saturated NaCO
3solution adjust pH to 8～9, the adularescent solid is separated out, the white solid 5f (358mg, 0.692mmol) of suction filtration, productive rate 69.2%.mp：228℃。MS[M+H]
+518.2；
1HNMR(DMSO，300MHZ)δ：9.05(s，1H)，8.58(s，1H)，8.09(s，1H)，7.60(s，2H)，7.32(d，2H)，7.06(m，4H)，6.72(d，1H)，5.56(t，1H)，5.19(br，1H)，3.59(s，4H)，3.09(s，4H)。
Embodiment 34
The N-[4-[4-[(2-amino benzoyl)] piperazine-1-yl]-the 2-chloro-phenyl-]-N '-(the chloro-3-trifluoromethyl of 4-) urea 5g
With [2-(t-butoxycarbonyl amino) phenyl] [4-(the chloro-4-aminophenyl of 2-) piperazine-1 base] ketone 4g (430mg, 1mmol) be starting raw material, the synthetic method of similar compound 5f, obtain white solid 5g (372mg, 0.676mmol), productive rate 67.6%.mp：224℃。MS[M+H]
+552.2，；
1HNMR(DMSO，300MHZ)δ：9.17(s，1H)，8.89(s，1H)，8.09(d，1H)，7.67(d，1H)，7.62(m，2H)，7.30(m，1H)，7.12(d，2H)，7.04(m，1H)，7.02(d，1H)，6.57(t，1H)，5.19(s，2H)，3.62(s，4H)，2.93s，4H)。
Embodiment 35
The N-[4-[4-[(2-hydroxy benzoyl)] piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea 5h
[4-(4-aminophenyl) piperazine-1 base] the ketone 4h (297mg, 1mmol) of take (2-hydroxy phenyl) is starting raw material, and the synthetic method of similar compound 5a, obtain white solid 5h (365mg, 0.704mmol), productive rate 70.4%.mp：224℃。MS[M+H]
+519.2，[M+Na]
+541.2；
1HNMR(DMSO，300MHZ)δ：9.79(s，1H)，9.05(s，1H)，8.58(s，1H)，8.09(d，1H)，7.61(m，2H)，7.23(m，4H)，6.88(m，3H)，3.73(t，4H)，3.07(t，4H)。
Embodiment 36
N-[4-[4-(1H-pyrroles-2-carbonyl) piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea 5i
[4-(4-aminophenyl) piperazine-1 base] the ketone 4i (270mg, 1mmol) of take in (1H-pyrroles-2-yl) is starting raw material, and the synthetic method of similar compound 5a, obtain white solid 5i (370mg, 0.754mmol), productive rate 75.4%.mp：219℃。MS[M+H]
+492.2；
1HNMR(DMSO，300MHZ)δ：11.46(s，1H)，9.05(s，1H)，8.58(s，1H)，8.10(d，1H)，7.61(t，1H)，7.33(t，2H)，6.90(m，3H)，6.53(m，1H)，6.13(m，1H)，3.84(t，4H)，3.12(t，4H)。
Embodiment 37
N-[4-[4-(1H-pyrroles-2-carbonyl) piperazine-1-yl]-the 2-chloro-phenyl-]-N '-(the chloro-3-trifluoromethyl of 4-) urea 5j
With (1H-pyrroles-2-yl) [4-(the chloro-4-aminophenyl of 2-) piperazine-1 base] ketone 4j (304mg, 1mmol) be starting raw material, the synthetic method of similar compound 5a, obtain white solid 5j (406mg, 0.773mmol), productive rate 77.3%.mp：221℃。MS[M+H]
+526.1；
1HNMR(DMSO，300MHZ)δ：11.47(s，1H)，9.20(s，1H)，8.92(s，1H)，8.09(s，1H)，7.64(d，2H)，7.31(d，1H)，7.14(d，1H)，6.90(d，1H)，6.54(d，1H)，6.13(d，1H)，5.76(s，1H)，3.85(t，4H)，2.95(t，4H)。
Embodiment 37
N-[4-[4-(1H-pyrazoles-3-carbonyl) piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea 5k
[4-(4-aminophenyl) piperazine-1 base] the ketone 4k (271mg, 1mmol) of take (1H-pyrazole-3-yl) is starting raw material, and the synthetic method of similar compound 5a, obtain white solid 5k (355mg, 0.721mmol), productive rate 72.1%.mp：223℃。MS[M+H]
+493.2；
1HNMR(DMSO，300MHZ)δ：13.20(s，1H)，9.06(s，1H)，8.59(s，1H)，8.08(t，1H)，7.82(s，1H)，7.60(t，2H)，7.32(d，2H)，6.93(d，2H)，6.60(s，1H)，4.10(s，2H)，3.77(s，2H)，3.32(s，4H)。
Embodiment 38
N-[4-[4-(1H-pyrazoles-3-carbonyl) piperazine-1-yl]-the 2-aminomethyl phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea 51
With (1H-pyrazole-3-yl) [4-(2-methyl-4-aminophenyl) piperazine-1 base] ketone 41 (285mg, 1mmol) be starting raw material, the synthetic method of similar compound 5a, obtain white solid 51 (355mg, 0.682mmol), productive rate 68.2%.mp：227℃。MS[M+H]
+507.2；
1HNMR(DMSO，300MHZ)δ：13.18(s，1H)，9.08(s，1H)，8.62(s，1H)，8.10(s，1H)，7.82(s，1H)，7.60(s，2H)，7.29(s，1H)，7.22(d，1H)，6.98(d，1H)，6.60(d，1H)，4.07(s，2H)，3.77(s，2H)，2.82(s，4H)，2.50(s，3H)。
Claims (12)
1. the compound of general formula (A) or its pharmacy acceptable salt:
R wherein
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12or R
13independently mean separately hydrogen, hydroxyl, nitro, amino, methyl, ethyl, methoxyl group, trifluoromethyl, halogen, cyano group;
Ar means five yuan of aromatic heterocyclics, hexa-atomic aromatic heterocyclic, phenyl or substituted-phenyl, indyl, benzimidazolyl-;
Mean-NHCONH-of X ,-NHCO-or-CONH-.
2. according to general formula (A) compound or its pharmacy acceptable salt, the wherein R of claim 1
1, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11or R
13mean hydrogen.
3. according to general formula (A) compound or its pharmacy acceptable salt of claim 1, R
2mean hydrogen, trifluoromethyl.
4. according to general formula (A) compound or its pharmacy acceptable salt of claim 1, R
3mean hydrogen, halogen.
5. according to general formula (A) compound or its pharmacy acceptable salt of claim 1, R
12mean hydrogen, methyl, halogen.
6. according to general formula (A) compound or its pharmacy acceptable salt of claim 1, Ar means 2-pyrryl, 2-pyrazolyl, 2-aminophenyl, 2-hydroxy phenyl, 2-indyl, 2-benzimidazolyl-.
7. according to general formula (A) compound or its pharmacy acceptable salt of claim 1, mean-NHC of X (O) NH-.
8. according to general formula (A) compound or its pharmacy acceptable salt of claim 1, be wherein following arbitrary compound or its pharmacy acceptable salt:
N-[4-[4-(1H-benzimidazolyl-2 radicals-Ji formyl radical) piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5a),
N-[4-[4-(1H-benzimidazolyl-2 radicals-carbonyl) piperazine-1-yl]-the 2-aminomethyl phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5b),
N-[4-[4-(1H-benzimidazolyl-2 radicals-carbonyl) piperazine-1-yl]-the 2-chloro-phenyl-]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5c),
N-[4-[4-(1H-indole-2-carbonyl) piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5d),
N-[4-[4-(1H-indole-2-carbonyl) piperazine-1-yl]-the 2-aminomethyl phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5e),
The N-[4-[4-[(2-amino benzoyl) piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5f),
The N-[4-[4-[(2-amino benzoyl)] piperazine-1-yl]-the 2-chloro-phenyl-]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5g),
The N-[4-[4-[(2-hydroxy benzoyl)] piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5h),
N-[4-[4-(1H-pyrroles-2-carbonyl) piperazine-1-yl] phenyl]-3-(the chloro-3-trifluoromethyl of 4-) urea (5i),
N-[4-[4-(1H-pyrroles-2-carbonyl) piperazine-1-yl]-the 2-chloro-phenyl-]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5j),
N-[4-[4-(1H-pyrazoles-3-carbonyl) piperazine-1-yl] phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (5k),
N-[4-[4-(1H-pyrazoles-3-carbonyl) piperazine-1-yl]-the 2-aminomethyl phenyl]-N '-(the chloro-3-trifluoromethyl of 4-) urea (51).
9. according to general formula (A) compound or its pharmacy acceptable salt of claim 1, wherein pharmacy acceptable salt comprises the acid salt that general formula (A) compound and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetic acid, toxilic acid, fumaric acid, Phenylsulfonic acid, tosic acid, methylsulfonic acid.
10. a pharmaceutical composition, wherein containing general formula (A) compound and pharmaceutically-acceptable salts and the pharmaceutically acceptable carrier of with good grounds claim 1.
11. the purposes according to the compound of the general formula (A) of claim 1 or its pharmacy acceptable salt in the medicine for the preparation of prevention or the treatment clinical disease relevant with the Raf kinase inhibitor.
12., according to the purposes of claim 11, wherein the relevant clinical disease of Raf kinase inhibitor is melanoma, liver cancer, kidney, acute leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, cancer of the stomach or mesothelioma.
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