CN102875549A - 7-arylamine/methylamino-5-amino-6-azaindole derivative, preparation method and application - Google Patents
7-arylamine/methylamino-5-amino-6-azaindole derivative, preparation method and application Download PDFInfo
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Abstract
The invention provides a 7-arylamine/methylamino-5-amino-6-azaindole derivative, and medicinal salt thereof. The derivative is prepared by reacting aminomethyl aromatic heterocyclic with 2,6-dichloro-3-nitropyridine, and reacting a reaction product with di-tert-butyl dicarbonate in a tetrahydrofuran solution under the protection of Boc at room temperature for 9 hours by taking dimethylamino pyridine as a catalyst. Raw materials required during synthesis are readily available, the derivative and the medicinal salt thereof are convenient to prepare and suitable for industrial production. Pharmacological experiments prove that the derivative and the medicinal salt thereof have relatively good in-vitro inhibitory and proliferous effects on a plurality of tumor cell strains such as human colon cancer cells, human leukemia cells, human lung cancer cells and human ovarian cells, the relatively good in-vitro cytostatic action and preliminary enzyme inhibitory activity are generally shown, and the derivative can be applied to preparation of antitumor medicines. The derivative is shown in the following general structural formula.
Description
Technical field
The invention belongs to the organic compound preparation, relate generally to 7-virtue (first) amido-5-amido-6-7-azaindole derivatives and preparation method thereof and the application in antitumor drug.
Background technology
The operation of the health of cell cycle depends on the precision monitoring that perfect cell cycle is finished in turn to numerous cell cycle events, thus advance the cell cycle each the time phase stable running and in order conversion.Wherein, core regulation and control person as cell cycle, cyclin-dependent kinase (cyclin dependent kinases, CDKs) is shown one's talent in the protein kinase of numerous participation cell cycle regulatings, is subject to antitumor drug research staff's close attention; Simultaneously Mammals experiment shows, interkinesis CDKs(CDK2, CDK4 and CDK6) between exist the complementary phenomenon of compensatory, and wherein only having CDK1 in Cycle Regulation, to show to a certain degree functional uniqueness and irreplaceability, it is mainly by forming mixture and then regulate G in the cell cycle with Cyclin B protein binding
2The carrying out of phase and to the transition of M phase (m period).In addition, recent research proves, the kinase whose inhibition of CDK1 with effective inducing apoptosis of tumour cell, is only caused Normocellular in short-term reversibility cycle arrest simultaneously.Above-mentioned multinomial result of study has confirmed that all effectively the CDK1 kinases will show significant advantage at aspects such as improving drug selectivity, reduction toxic side effect as the oncotherapy target spot.CDK1 kinases to overexpression in the tumour cell suppresses, thereby contains that effectively tumor cell proliferation will become an ideas of cancer therapy that has potentiality.
Up to now, the CDK1 micromolecular inhibitor of having reported in the research both at home and abroad is all the ATP competitive inhibitor, and as one of CDK1 inhibitor that occurs the earliest, the purines derivative is the study hotspot of design novel potent CDK micromolecular inhibitor always, in entering at present the CDK micromolecular inhibitor structure type of II/III clinical trial phase and preclinical test, occupy larger proportion, being subject to research staff's extensive concern, is one of CDK1 inhibitor structure type of great exploitation potential for its.
As having entered at present purines CDK micromolecular inhibitor R-roscovitine(Seliciclib or the CYC202 that the clinical II phase tests, CDK1/cyclin B IC
50=0.45 μ M, CDK2/cyclin E IC
50=0.7 μ M) and at present just entered the purines CDK micromolecular inhibitor SCH 727965(Figure 1-1 that the clinical II phase studies, CDK1/cyclin B IC
50=3 nM, CDK2/cyclin E IC
50=1 nM) etc., stronger inhibition tumor cell proliferation activity and significant CDK1 kinase inhibiting activity have all been shown, for the follow-up study of purine analogue in this field provides solid foundation and a new direction.
Summary of the invention
First purpose of the present invention provides 7-virtue (first) amido that has no bibliographical information of a class formation novelty-5-amido-6-7-azaindole derivatives and pharmaceutical salts thereof.Described derivative has following general structure:
Ⅳ
Wherein:
Ar be without replace, mono-substituted phenyl ring or fragrant heterocycle, wherein the substituting group on the single-substituted ring is fluorine, chlorine, bromine, nitro, contains alkoxyl group and 2-pyridine, 3-pyridine and the 4-pyridine ring of the straight or branched of 1 to 3 carbon atom; The virtue heterocycle is selected pyridine, pyrimidine, thiophene, furans or pyrroles;
N is 0 or 1;
R
1With R
2Identical or different, select hydrogen, contain alkyl and the hydroxyalkyl of the straight or branched of 1 to 3 carbon atom; Perhaps NR
1R
2Be the six-ring that replaces, its six-ring can be piperidines, morpholine or piperazine.
Second purpose of the present invention provides the preparation method of 7-virtue (first) amido-5-amido-6-7-azaindole derivatives and pharmaceutical salts thereof, realizes by following steps:
The synthetic route of the present invention's preparation:
Can make the target product IV according to above-mentioned reaction.Wherein chemical compounds I can be according to literature method (Schmid; S. et al; Org Biomol Chem. 2005; 3; 3408.), by corresponding aminomethyl virtue heterocycle (amino fragrant heterocycle) and 2, the reaction of 6-dichloro-3-nitropyridine; and via Boc protection (in tetrahydrofuran solution take Dimethylamino pyridine as catalyzer, under the room temperature with tert-Butyl dicarbonate reaction 9 hours) after make.Its reaction is as described below:
(1) in polar solvent, under alkaline condition and 50-80 ℃ of temperature of reaction, chemical compounds I generates compound ii with corresponding aminated compounds generation alkylated reaction, and products therefrom can get sterling through column chromatography.Polar solvent is DMF, methyl alcohol, ethanol, Virahol and methyl-sulphoxide etc., and alkaline matter can be selected a kind of in salt of wormwood, yellow soda ash or the sodium bicarbonate.
(2) in the anhydrous tetrahydrofuran solution of compound ii; under nitrogen protection ,-78 ℃ of temperature of reaction, drip the tetrahydrofuran solution of vinyl bromination magnesium; and reaction generated the compound III in 16-24 hour under-20 ℃ of conditions; the ammonium chloride solution that reaction finishes rear adding 20% in solution carries out cancellation, and products therefrom can get sterling through column chromatography.
(3) the compound III removes the Boc protecting group in the saturated ethyl acetate solution of hydrochloric acid, and reaction times 12-24 hour, generate the dihydrochloride of compounds Ⅳ, can obtain the target compound sterling through suction filtration.
The 3rd purpose of the present invention provides 7-virtue (first) amido-5-amido-6-7-azaindole derivatives and the application of pharmaceutical salts in the preparation antitumor drug thereof.Preliminary pharmacological evaluation finds that they are to various tumor cell strains, comprise human colon cancer cell (HCT116), human leukemia cell (HL60), human lung carcinoma cell (A549), Proliferation of Human Ovarian Cell (A2780) etc. all has preferably vitro inhibition proliferation function, wherein part of compounds has the inhibition proliferation function of highly significant, IC
50Reach 10
-2-10
-4The μ M order of magnitude; In addition, tentatively externally press down the enzyme experiment and show that under 10 μ M concentration, the overwhelming majority has the restraining effect of highly significant to CDK1/Cyclin B in this compounds, wherein part of compounds (IV
a, IV
c, IV
d, IV
e, IV
i, IV
j) inhibiting rate of CDK1 has been reached 100%(10 μ M).
Characteristics of the present invention are: made up 7-virtue (first) amido that has no bibliographical information of a class formation novelty-5-amido-6-7-azaindole derivatives and pharmaceutical salts thereof, synthetic desired raw material is easy to get, and it is convenient to prepare, and is suitable for suitability for industrialized production.Simultaneously, preliminary pharmacological activity screening experiment shows, compares with positive control, and this compounds has generally shown better vitro inhibition proliferation function and preliminary Inhibiting enzyme activity.
Embodiment
The present invention is further described in conjunction with the embodiments.Following embodiment is that explanation is of the present invention, rather than limits by any way the present invention.
Embodiment 1, tertiary butyl benzyl (6-piperidines-3-nitropyridine-2-yl) carbamate (II
a)
With 4g(11.0mmol) tertiary butyl benzyl (6-chloro-3-nitropyridine-2-yl) carbamate is dissolved in the anhydrous DMF of 10ml, adds 1.1g(1.3ml, 13.2mmol in solution) piperidines and 1.8g (13.2mmol) K
2CO
3, in 50 ℃ of left and right sides reacting by heating 7h(TLC monitorings).After reaction finished, with ethyl acetate extraction, organic layer was through the saturated common salt water washing, and anhydrous sodium sulfate drying reclaims solvent.And by silica gel column chromatography (eluent: petrol ether/ethyl acetate 7:1), get the semi-solid 4.3g of aureus, yield 95%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.29?(s,?9?H,?CH
3×3),?1.48?(m,?4?H,?Piperidine-H),?1.61?(m,?2?H,?Piperidine-H),?3.58?(m,?4?H,?Pip-H),?5.12?(s,?2?H,?CH
2),?6.70?(d,?1?H,?
J?=?9.0?Hz,?Ar-H),?7.23?(m,?1?H,?Ar-H),?7.31?(t,?2?H,?
J?=?7.0?Hz,?Ar-H),?7.37?(m,?2?H,?Ar-H),?8.13?(d,?1?H,?
J?=?9.0?Hz,?Ar-H)。
Embodiment 2, tertiary butyl benzyl (6-morpholine-3-nitropyridine-2-yl) carbamate (II
b)
Operating process is identical with embodiment 1, just substitutes piperidines with morpholine, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 7:1), get the aureus solid, yield 95%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.29?(s,?9?H,?CH
3×3),?3.56?(s,?4?H,?Morpholine-H),?3.62?(s,?4?H,?Morpholine-H),?5.12?(s,?2?H,?CH
2),?6.72?(d,?1?H,?
J?=?9.0?Hz,?Ar-H),?7.23?(m,?1?H,?Ar-H),?7.31?(t,?2?H,?
J?=?7.0?Hz,?Ar-H),?7.37?(d,?2?H,?
J?=?7.0?Hz,?Ar-H),?8.19?(d,?1?H,?
J?=?9.5?Hz,?Ar-H)。
Embodiment 3, tertiary butyl benzyl (6-diethylin-3-nitropyridine-2-yl) carbamate (II
c)
Operating process is identical with embodiment 1, just substitutes piperidines with diethylamine, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 9:1), get the aureus semisolid, yield 90%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ0.88?(m,?6?H,?CH
3×2),?1.29?(s,?9?H,?CH
3×3),?3.38?(m,?4?H,?CH
2×2),?5.14?(m,?2?H,?CH
2),?6.55?(d,?1?H,?
J?=?9.5?Hz,?Ar-H),?7.23?(m,?1?H,?Ar-H),?7.32?(t,?2?H,?
J?=?7.0?Hz,?Ar-H),?7.37?(m,?2?H,?Ar-H),?8.14?(d,?1?H,?
J?=?9.0?Hz,?Ar-H)。
Embodiment 4, tertiary butyl benzyl (6-(2-(2-tertbutyloxycarbonyl oxygen ethyl) piperidin-1-yl)-3-nitropyridine-2-yl) carbamate (II
d)
Operating process is identical with embodiment 1; just substitute piperidines with 2-piperidines ethanol; get aureus semi-solid intermediate; via Boc protection (in tetrahydrofuran solution take Dimethylamino pyridine as catalyzer; in reacting 9 hours with tert-Butyl dicarbonate under the room temperature) after; by silica gel column chromatography (eluent: petrol ether/ethyl acetate 9:1), get the aureus semisolid, yield 93%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.29?(s,?9?H,?OtBu),?1.36?(s,?9?H,?CH
3×3),?2.05?(m,?8?H,?Piperidine-H,?CH
2),?3.41?(m,?3?H,?Piperidine-H),?3.89?(m,?2?H,?CH
2),?5.11?(s,?2?H,?CH
2),?6.66?(d,?1?H,?
J?=?9.5?Hz,?Ar-H),?7.22?(t,?1?H,?
J?=?7.5?Hz,?Ar-H),?7.30?(t,?2?H,?
J?=?7.5?Hz,?Ar-H),?7.36?(d,?2?H,?
J?=?7.0?Hz,?Ar-H),?8.12?(d,?1?H,?
J?=?9.0?Hz,?Ar-H)。
Embodiment 5, tertiary butyl benzyl (6-(4-(2-tertbutyloxycarbonyl oxygen ethyl) piperidin-1-yl)-3-nitropyridine-2-yl) carbamate (II
e)
Operating process is identical with embodiment 4, just substitutes 2-piperidines ethanol with 4-piperidines ethanol, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 8:1), get the aureus semisolid, yield 91%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.17?(m,?2?H,?Piperidine-H),?1.38?(s,?9?H,?CH
3×3),?1.52?(s,?9?H,?CH
3×3),?1.64?(q,?3?H,?
J?=?6.5?Hz,?Piperidine-H),?1.79?(d,?2?H,?
J?=?13.5?Hz,?CH
2),?2.90?(m,?2?H,?Piperidine-H),?4.15?(m,?2?H,?Piperidine-H),?4.30?(d,?2?H,?
J?=?13.0?Hz,?CH
2),?5.10?(s,?2?H,?CH
2),?6.35?(d,?1?H,?
J?=?9.0?Hz,?Ar-H),?7.22?(t,?1?H,?
J?=?7.5?Hz,?Ar-H),?7.30?(t,?2?H,?
J?=?7.5?Hz,?Ar-H),?7.43?(d,?2?H,?
J?=?7.5?Hz,?Ar-H),?8.14?(d,?1?H,?
J?=?9.0?Hz,?Ar-H)。
Embodiment 6, tertiary butyl benzyl (6-(2-(2-tertiary butyloxycarbonyl yloxymethyl) piperidin-1-yl)-3-nitropyridine-2-yl) carbamate (II
f)
Operating process is identical with embodiment 4, just substitutes 2-piperidines ethanol with the 2-piperidine carbinols, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 8:1), get the aureus semisolid, yield 93%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.28?(s,?9?H,?CH
3×3),?1.38?(s,?9?H,?CH
3×3),?1.55?(m,?4?H,?Piperidine-H),?1.67?(m,?2?H,?Piperidine-H),?3.04?(m,?1?H,?Piperidine-H),?4.04?(m,?3?H,?Piperidine-H,?CH),?4.43?(m,?1?H,?CH),?5.10?(s,?2?H,?CH
2),?6.68?(d,?1?H,?
J?=?9.0?Hz,?Ar-H),?7.22?(t,?1?H,?
J?=?7.5?Hz,?Ar-H),?7.35?(m,?4?H,?Ar-H),?8.13?(d,?1?H,?
J?=?9.0?Hz,?Ar-H)。
Embodiment 7, tertiary butyl benzyl (6-(4-(2-tertiary butyloxycarbonyl yloxymethyl) piperidin-1-yl)-3-nitropyridine-2-yl) carbamate (II
g)
Operating process is identical with embodiment 4, just substitutes 2-piperidines ethanol with the 4-piperidine carbinols, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 7:1), get the aureus semisolid, yield 91%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.27?(m,?2?H,?Piperidine-H),?1.38?(s,?9?H,?CH
3×3),?1.49?(s,?9?H,?CH
3×3),?1.82?(d,?2?H,?
J?=?12.5?Hz,?Piperidine-H),?1.98?(m,?1?H,?Piperidine-H),?2.91?(t,?2?H,?
J?=?12.0?Hz,?Piperidine-H),?3.95?(d,?2?H,?
J?=?6.5?Hz,?Piperidine-H),?4.32?(d,?2?H,?
J?=?12.5?Hz,?CH
2),?5.10?(s,?2?H,?CH
2),?6.53?(d,?1?H,?
J?=?9.0?Hz,?Ar-H),?7.22?(t,?1?H,?
J?=?7.5?Hz,?Ar-H),?7.30?(t,?2?H,?
J?=?8.0?Hz,?Ar-H),?7.42?(d,?2?H,?
J?=?7.5?Hz,?Ar-H),?8.15?(d,?1?H,?
J?=?9.5?Hz,?Ar-H)。
Embodiment 8, butyl benzyl (6-((2-tertbutyloxycarbonyl oxygen base) ethyl-(N-tertbutyloxycarbonyl) amido)-3-nitropyridine-2-yl) carbamate (II
h)
Operating process is identical with embodiment 4, just substitutes 2-piperidines ethanol with thanomin, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 9:1), get aureus liquid, yield 90%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.29?(s,?9?H,?CH
3×3),?1.32?(s,?9?H,?CH
3×3),?1.49?(s,?9?H,?CH
3×3),?4.04?(m,?4?H,?CH
2),?5.09?(s,?2?H,?CH
2),?7.25?(m,?1?H,?Ar-H),?7.35?(m,?4?H,?Ar-H),?7.75?(d,?1?H,?
J?=?9.0?Hz,?Ar-H),?8.41?(d,?1?H,?
J?=?9.0?Hz,?Ar-H)。
Embodiment 9, butyl benzyl (6-((2-tertbutyloxycarbonyl oxygen base) ethyl-(N-tertbutyloxycarbonyl) amido)-3-nitropyridine-2-yl) carbamate (II
i)
Operating process is identical with embodiment 4, just substitutes 2-piperidines ethanol with the 2-amino butanol, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 9:1), get aureus liquid, yield 89%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ0.62?(m,?3?H,?CH
3),?1.38?(m,?2?H,?CH
2),?1.29?(s,?9?H,?CH
3×3),?1.32?(s,?9?H,?CH
3×3),?1.45?(s,?9?H,?CH
3×3),?4.07?(m,?1?H,?CH),?4.31?(m,?1?H,?CH),?4.56?(m,?1?H,?CH),?5.09?(s,?2?H,?CH
2),?7.23?(m,?1?H,?Ar-H),?7.32?(m,?4?H,?Ar-H),?7.44?(d,?1?H,?
J?=?9.0?Hz,?Ar-H),?8.40?(d,?1?H,?
J?=?9.0?Hz,?Ar-H)。
Embodiment 10, butyl benzyl (6-two (2-tertbutyloxycarbonyl oxygen ethylamine)-3-nitropyridine-2-yl) carbamate (II
j)
Operating process is identical with embodiment 4, just substitutes 2-piperidines ethanol with diethanolamine, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 9:1), get the aureus semisolid, yield 93%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.37?(s,?9?H,?CH
3×3),?1.45?(s,?9?H,?CH
3×3),?1.47?(s,?9?H,?CH
3×3),?3.69?(m,?4?H,?CH
2×2),?4.14?(m,?4?H,?CH
2×2),?5.19?(s,?2?H,?CH
2),?6.43?(d,?1?H,?
J?=?9.0?Hz,?Ar-H),?7.21?(t,?1?H,?
J?=?7.5?Hz,?Ar-H),?7.30?(t,?2?H,?
J?=?7.5?Hz,?Ar-H),?7.37?(d,?2?H,?
J?=?7.5?Hz,?Ar-H),?8.17?(d,?1?H,?
J?=?9.5?Hz,?Ar-H)。
Embodiment 11, tertiary butyl benzyl 6-(4-(2-tertbutyloxycarbonyl oxygen ethyl) piperidin-1-yl)-3-nitropyridine-2-base (pyridine-2-methyl) carbamate (II
k)
Operating process is identical with embodiment 4, just substitute tertiary butyl benzyl (6-chloro-3-nitropyridine-2-yl) carbamate with tertiary butyl 6-chloro-3-nitropyridine-2-base (pyridine-2-methyl) carbamate, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 2:1), it is semi-solid to get brown color, two step yields 75%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.12?(m,?2?H,?Piperidine-H),?1.38?(s,?9?H,?CH
3×3),?1.49?(d,?9?H,?
J?=?10.0?Hz,?CH
3×3),?1.61?(q,?2?H,?
J?=?6.5?Hz,?Piperidine-H),?1.72?(m,?3?H,?Piperidine-H,?CH
2),?2.82?(t,?2?H,?
J?=?12.5?Hz,?Piperidine-H),?4.11?(m,?2?H,?CH
2),?4.18?(d,?2?H,?
J?=?13.0?Hz,?Piperidine-H),?5.21?(s,?2?H,?CH
2),?6.34?(d,?1?H,?
J?=?9.0?Hz,?Ar-H),?7.13?(t,?1?H,?
J?=?5.5?Hz,?Ar-H),?7.56?(d,?1?H,?
J?=?8.0?H,?Ar-H?z),?7.63?(t,?1?H,?
J?=?7.5?Hz,?Ar-H),?8.15?(d,?1?H,?
J?=?9.5?Hz,?Ar-H),?8.50?(d,?1?H,?
J?=?4.5?Hz,?Ar-H)。
Embodiment 12, tertiary butyl benzyl 6-(4-(2-tertbutyloxycarbonyl oxygen ethyl) piperidin-1-yl)-3-nitropyridine-2-base (pyridine-3-methyl) carbamate (II
l)
Operating process is identical with embodiment 4, just substitute tertiary butyl benzyl (6-chloro-3-nitropyridine-2-yl) carbamate with tertiary butyl 6-chloro-3-nitropyridine-2-base (pyridine-3-methyl) carbamate, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 1:2), it is semi-solid to get brown color, two step yields 60%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.18?(m,?2?H,?Piperidine-H),?1.37?(s,?9?H,?CH
3×3),?1.49?(s,?9?H,?CH
3×3),?1.64?(q,?2?H,?
J?=?8.0?Hz,?Piperidine-H),?1.76?(m,?1?H,?Piperidine-H),?1.81?(d,?2?H,?
J?=?16.0?Hz,?Piperidine-H),?2.93?(t,?2?H,?
J?=?15.5?Hz,?CH
2),?4.14?(t,?2?H,?
J?=?8.0?Hz,?CH
2),?4.30?(d,?2?H,?
J?=?10.0?Hz,?Piperidine-H),?5.10?(s,?2?H,?CH
2),?6.36?(d,?1?H,?
J?=?11.5?Hz,?Ar-H),?7.24?(m,?1?H,?Ar-H),?7.89?(d,?1?H,?
J?=?8.5?Hz,?Ar-H),?8.12?(d,?1?H,?
J?=?11.5?Hz,?Ar-H),?8.47?(d,?1?H,?
J?=?5.0?Hz,?Ar-H),?8.57?(s,?1?H,?Ar-H)。
Embodiment 13, tertiary butyl benzyl 6-(4-(2-tertbutyloxycarbonyl oxygen ethyl) piperidin-1-yl)-3-nitropyridine-2-base (pyridine-4-methyl) carbamate (II
m)
Operating process is identical with embodiment 4, just substitute tertiary butyl benzyl (6-chloro-3-nitropyridine-2-yl) carbamate with tertiary butyl 6-chloro-3-nitropyridine-2-base (pyridine-4-methyl) carbamate, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 1:3), it is semi-solid to get brown color, two step yields 40%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.14?(m,?2?H,?Piperidine-H),?1.37?(s,?9?H,?CH
3×3),?1.49?(s,?9?H,?CH
3×3),?1.62?(q,?2?H,?
J?=?8.5?Hz,?Piperidine-H),?1.70?(m,?1?H,?Piperidine-H),?1.77?(d,?2?H,?
J?=?16.5?Hz,?Piperidine-H),?2.88?(t,?2?H,?
J?=?16.0?Hz,?CH
2),?4.13?(t,?2?H,?
J?=?8.5?Hz,?CH
2),?4.21?(d,?2?H,?
J?=?16.5?Hz,?Piperidine-H),?5.15?(s,?2?H,?CH
2),?6.36?(d,?1?H,?
J?=?11.5?Hz,?Ar-H),?7.36?(d,?2?H,?
J?=?7.5?Hz,?Ar-H),?8.15?(d,?1?H,?
J?=?11.5?Hz,?Ar-H),?8.52?(d,?2?H,?
J?=?7.0?Hz,?Ar-H)。
Embodiment 14, butyl benzyl (5-(piperidin-1-yl)-1H-pyrrolo-[2,3-c] pyridin-7-yl) carbamate (III
a)
With compound 2g(4.8mmol) II
aBe dissolved among the anhydrous tetrahydro furan 25ml N
2Protection is cooled to solution-78 ℃.Under this temperature, drip 14.6ml(1 Mol/L, 14.6mmol) tetrahydrofuran solution of vinyl bromination magnesium, dropwise rear continuation-78 ℃ of lower stirrings 1 hour.Then slowly be warming up to-20 ℃, reaction is 16 hours under this temperature.A large amount of solvents were reclaimed in the ammonium chloride solution 25ml cancellation of adding 20% in solution after reaction finished.Then with ethyl acetate extraction, organic layer is through the saturated common salt water washing, and anhydrous sodium sulfate drying reclaims solvent.And through silica gel column chromatography (eluent: petrol ether/ethyl acetate 6:1), get light yellow semi-solid 190mg, yield 10%.
H?NMR?(500?MHz,?DMSO-
d 6):
δ1.33?(s,?9?H,?CH
3×3),?1.51?(m,?6?H,?Piperidine-H),?4.23?(m,?4?H,?Piperidine-H),?4.79?(s,?2?H,?CH
2),?6.58?(d,?1?H,?
J?=?8.5?Hz,?Ar-H),?7.07?(s,?1?H,?Ar-H),?7.20?(m,?1?H,?Ar-H),?7.27?(t,?3?H,?
J?=?7.5?Hz,?Ar-H),?7.39?(m,?3?H,?Ar-H)。
Embodiment 15, butyl benzyl (5-morpholine-1H-pyrrolo-[2,3-c] pyridin-7-yl) carbamate (III
b)
Operating process is identical with embodiment 14, just with compound ii
bThe alternative compounds II
a, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 6:1), get light yellow semisolid, yield 13%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.39?(s,?9?H,?CH
3×3),?3.30?(t,?4?H,?
J?=?4.5?Hz,?Morpholine-H),?3.80?(t,?4?H,?
J?=?4.5?Hz,?Morpholine-H),?4.94?(s,?2H,?CH
2),?7.04?(d,?1?H,?
J?=?8.5?Hz,?Ar-H),?7.23?(t,?1?H,?
J?=?7.5?Hz,?Ar-H),?7.30?(m,?3?H,?Ar-H),?7.38?(m,?3?H,?Ar-H)。
Embodiment 16, butyl benzyl (5-diethylamide-1H-pyrrolo-[2,3-c] pyridin-7-yl) carbamate (III
c)
Operating process is identical with embodiment 14, just with compound ii
cThe alternative compounds II
a, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 7:1), get light yellow semisolid, yield 10%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ0.81?(m,?6?H,?CH
3×2),?1.30?(s,?9?H,?CH
3×3),?3.22?(m,?4?H,?CH
2×2),?4.79?(s,?2?H,?CH
2),?6.34?(d,?1?H,?
J?=?8.5?Hz,?Ar-H),?7.06?(d,?1?H,?
J?=?7.5?Hz,?Ar-H),?7.20?(m,?1?H,?Ar-H),?7.28?(t,?3?H,?
J?=?7.5?Hz,?Ar-H),?7.41?(d,?2?H,?
J?=?7.5?Hz,?Ar-H)。
Embodiment 17, butyl benzyl (5-(2-(2-tertbutyloxycarbonyl oxygen ethyl) piperidin-1-yl)-1H-pyrrolo-[2,3-c] pyridin-7-yl) carbamate (III
d)
Operating process is identical with embodiment 14, just with compound ii
dThe alternative compounds II
a, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 6:1), get light yellow semisolid, yield 15%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.33?(s,?9?H,?CH
3×3),?1.38?(s,?9?H,?CH
3×3),?1.55?(m,?6?H,?Piperidine-H,?CH
2),?1.80?(m,?2?H,?Piperidine-H),?2.80?(m,?1?H,?Piperidine-H),?3.95?(m,?2?H,?CH
2,?Piperidine-H),?4.09?(m,?2?H,?CH
2),?4.81?(s,?2?H,?CH
2),?6.51?(d,?1?H,?
J?=?8.5?Hz,?Ar-H),?7.05?(s,?1?H,?Ar-H),?7.19?(m,?1?H,?Ar-H),?7.27?(t,?3?H,?
J?=?7.0?Hz,?Ar-H),?7.37?(m,?3?H,?Ar-H)。
Embodiment 18, butyl benzyl (5-(4-(2-tertbutyloxycarbonyl oxygen ethyl) piperidin-1-yl)-1H-pyrrolo-[2,3-c] pyridin-7-yl) carbamate (III
e)
Operating process is identical with embodiment 14, just with compound ii
eThe alternative compounds II
a, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 7:1), get light yellow semisolid, yield 13%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.14?(m,?2?H,?Piperidine-H),1.33?(s,?9?H,?CH
3×3),?1.41?(s,?9?H,?CH
3×3),?1.52?(m,?3?H,?Piperidine-H),?1.67?(d,?2?H,?
J?=?12.0?Hz,?Piperidine-H),?3.94?(d,?2?H,?
J?=?12.0?Hz,?Piperidine-H),?4.07?(t,?2?H,?
J?=?6.5?Hz,?CH
2),?4.14?(m,?2?H,?CH
2),?4.79?(s,?2?H,?CH
2),?6.59?(d,?1?H,?
J?=?8.5?Hz,?Ar-H),?7.07?(d,?1?H,?
J?=?8.0?Hz,?Ar-H),?7.19?(m,?1?H,?Ar-H),?7.27?(t,?3?H,?
J?=?7.5?Hz,?Ar-H),?7.39?(d,?3?H,?
J?=?8.0?Hz,?Ar-H)。
Embodiment 19, butyl benzyl (5-(2-(2-tertiary butyloxycarbonyl yloxymethyl) piperidin-1-yl)-1H-pyrrolo-[2,3-c] pyridin-7-yl) carbamate (III
f)
Operating process is identical with embodiment 14, just with compound ii
fThe alternative compounds II
a, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 6:1), get light yellow semisolid, yield 9%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.32?(s,?9?H,?CH
3×3),?1.36?(s,?9?H,?CH
3×3),?1.54?(m,?4?H,?Piperidine-H),?1.68?(m,?2?H,?Piperidine-H),?3.72?(m,?1?H,?Piperidine-H),?4.13?(m,?3?H,?Piperidine-H,?CH),?4.46?(m,?1?H,?CH),?4.78?(s,?2?H,?CH
2),?6.55?(d,?1?H,?
J?=?8.5?Hz,?Ar-H),?7.07?(m,?1?H,?Ar-H),?7.19?(m,?1?H,?Ar-H),?7.26?(t,?3?H,?
J?=?7.5?Hz,?Ar-H),?7.38?(m,?3?H,?Ar-H)。
Embodiment 20, butyl benzyl (5-(4-(2-tertiary butyloxycarbonyl yloxymethyl) piperidin-1-yl)-1H-pyrrolo-[2,3-c] pyridin-7-yl) carbamate (III
g)
Operating process is identical with embodiment 14, just with compound ii
gThe alternative compounds II
a, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 6:1), get light yellow semisolid, yield 11%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.28?(m,?2?H,?Piperidine-H),?1.40?(s,?9?H,?CH
3×3),?1.47?(s,?9?H,?CH
3×3),?1.73?(d,?2?H,?
J?=?12.0?Hz,?Piperidine-H),?1.83?(m,?1?H,?Piperidine-H),?2.71?(t,?2?H,?
J?=?12.0?Hz,?Piperidine-H),?3.93?(d,?2?H,?
J?=?6.5?Hz,?Piperidine-H),?4.04?(d,?2?H,?
J?=?12.0?Hz,?CH
2),?4.61?(s,?2?H,?CH
2),?6.66?(d,?1?H,?
J?=?8.5?Hz,?Ar-H),?7.23?(m,?1?H,?Ar-H),?7.29?(t,?3?H,?
J?=?7.0?Hz,?Ar-H),?7.38?(m,?3?H,?Ar-H)。
Embodiment 21, butyl benzyl (5-((N-tertbutyloxycarbonyl)-2-tertbutyloxycarbonyl oxygen ethylamine)-1H-pyrrolo-[2,3-c] pyridin-7-yl) carbamate (III
h)
Operating process is identical with embodiment 14, just with compound ii
hThe alternative compounds II
a, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 7:1), get light yellow semisolid, yield 13%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.31?(s,?9?H,?CH
3×3),?1.34?(s,?9?H,?CH
3×3),?1.39?(s,?9?H,?CH
3×3),?3.88?(t,?2?H,?
J?=?6.0?Hz,?CH
2),?4.06?(t,?2?H,?
J?=?6.0?Hz,?CH
2),?5.00?(s,?2?H,?CH
2),?6.48?(m,?1?H,?Ar-H),?7.18?(m,?1?H,?Ar-H),?7.25?(t,?2?H,?
J?=?7.5?Hz,?Ar-H),?7.34?(m,?3?H,?Ar-H),?7.36?(s,?1?H,?Ar-H),?7.56?(m,?1?H,?Ar-H)。
Embodiment 22, butyl benzyl (5-(1-tertbutyloxycarbonyl oxygen butane-2-(N-tertbutyloxycarbonyl) amino)-1H-pyrrolo-[2,3-c] pyridin-7-yl) carbamate (III
i)
Operating process is identical with embodiment 14, just with compound ii
iThe alternative compounds II
a, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 7:1), get light yellow semisolid, yield 10%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ0.77?(m,?2?H,?CH
2),?0.89?(t,?3?H,?
J?=?7.5?Hz,?CH
3),?1.35?(s,?9?H,?CH
3×3),?1.38?(s,?9?H,?CH
3×3),?1.40?(s,?9?H,?CH
3×3),?3.99?(m,?1?H,?CH),?4.28?(m,?1?H,?CH),?4.47?(d,?1?H,?
J?=?5.5?Hz,?CH),?4.99?(s,?2?H,?CH
2),?6.58?(m,?1?H,?Ar-H),?7.18?(m,?1?H,?Ar-H),?7.23?(m,?2?H,?Ar-H),?7.33?(m,?4?H,?Ar-H),?7.57?(m,?1?H,?Ar-H)。
Embodiment 23, butyl benzyl (5-two (2-tertbutyloxycarbonyl oxygen ethylamine)-1H-pyrrolo-[2,3-c] pyridin-7-yl) carbamate (III
j)
Operating process is identical with embodiment 14, just with compound ii
jThe alternative compounds II
a, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 7:1), get light yellow semisolid, yield 10%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ?1.32?(s,?9?H,?CH
3×3),?1.38?(s,?18?H,?CH
3×6),?3.55?(m,?4?H,?CH
2×2),?4.06?(t,?4?H,?
J?=?5.5?Hz,?CH
2×2),?4.81?(s,?2?H,?CH
2),?6.49?(d,?1?H,?
J?=?8.5?Hz,?Ar-H),?7.09?(m,?1?H,?Ar-H),?7.19?(m,?1?H,?Ar-H),?7.30?(t,?3?H,?
J?=?7.5?Hz,?Ar-H),?7.36?(d,?2?H,?
J?=?7.5?Hz,?Ar-H)。
Embodiment 24, N-benzyl-5-(piperidin-1-yl)-1H-pyrrolo-[2,3-c] pyridine-7-amine hydrochlorate (IV
a)
With 60mg(0.15 mmol) the compound III
aBe dissolved in the ethyl acetate, under condition of ice bath, drip the saturated ethyl acetate solution of hydrochloric acid, rise to room temperature, stir 12h, suction filtration, a small amount of ethyl acetate washing gets reddish-brown solid product 30mg, yield 65%.
1H?NMR?(500?MHz,?DMSO-
d 6):?
δ1.52?(m,?2?H,?Piperidine-H),?1.61?(m,?4?H,?Piperidine-H),?2.90?(t,?4?H,?
J?=?5?Hz,?Piperidine-H),?4.33?(d,?2?H,?
J?=?6.5?Hz,?CH
2),?6.00?(m,?2?H,?Ar-H),?6.80?(d,?1?H,?
J?=?8.0?Hz,?Ar-H),?7.19?(t,?1?H,?
J?=?7.5?Hz,?Ar-H),?7.29?(m,?2?H,?Ar-H),?7.33?(d,?2?H,?
J?=?7.0?Hz,?Ar-H)。
Embodiment 25, N-benzyl-5-morpholine-1H-pyrrolo-[2,3-c] pyridine-7-amine hydrochlorate (IV
b)
Operating process is identical with embodiment 24, just with the compound III
bThe alternative compounds III
a, get the reddish-brown semisolid, yield 61%.
1H?NMR?(500?MHz,?DMSO-
d 6):?
δ3.40?(t,?4?H,?
J?=?4.5?Hz,?Morpholine-H),?3.73?(t,?4?H,?
J?=?4.5?Hz,?Morpholine-H),?4.66?(s,?2?H,?CH
2),?7.25?(t,?1?H,?
J?=?7.5?Hz,?Ar-H),?7.33?(t,?2?H,?
J?=?7.5?Hz,?Ar-H),?7.39?(d,?1?H,?
J?=?4.0?Hz,?Ar-H),?7.04?(m,?4?H,?Ar-H)。
Embodiment 26, N
7-benzyl-N
5, N
5-diethyl-1H-pyrrolo-[2,3-c] pyridine-5,7-diamine hydrochloride (IV
c)
Operating process is identical with embodiment 24, just with the compound III
cThe alternative compounds III
a, get the reddish-brown semisolid, yield 69%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ0.80?(m,?6?H,?CH
3×2),?3.32?(m,?4?H,?CH
2×2),?4.60?(s,?2?H,?CH
2),?6.87?(s,?1?H,?Ar-H),?7.21?(m,?1?H,?Ar-H),?7.30?(t,?3?H,?
J?=?7.5?Hz,?Ar-H),?7.34?(m,?3?H,?Ar-H)。
Embodiment 27,2-(1-(7-benzyl ammonia-1H-pyrrolo-[2,3-c] pyridine-5-yl) piperidin-2-yl) ethylate hydrochlorate (IV
d)
Operating process is identical with embodiment 24, just with the compound III
dThe alternative compounds III
a, get the reddish-brown semisolid, yield 63%.
1H?NMR?(500?MHz,?DMSO-
d 6):?
δ1.98?(m,?8?H,?Piperidine-H,?CH
2),?3.37?(m,?2?H,?Piperidine-H),?3.80?(m,?3?H,?Piperidine-H,?CH
2),?4.65?(d,?2?H,?
J?=?7.0?Hz,?CH
2),?7.05?(m,?1?H,?Ar-H),?7.25?(m,?1?H,?Ar-H),?7.36?(m,?4?H,?Ar-H),?7.41?(m,?4?H,?Ar-H)。
Embodiment 28,2-(1-(7-benzyl ammonia-1H-pyrrolo-[2,3-c] pyridine-5-yl) piperidin-4-yl) ethylate hydrochlorate (IV
e)
Operating process is identical with embodiment 24, just with the compound III
eThe alternative compounds III
a, get the reddish-brown semisolid, yield 61%.
1H?NMR?(500?MHz,?DMSO-
d 6):?
δ1.61?(m,?3?H,?Piperidine-H),1.67?(q,?2?H,?
J?=?6.5?Hz,?CH
2),?1.98?(m,?2?H,?Piperidine-H),?3.34?(m,?1?H,?Piperidine-H),?3.57?(m,?2?H,?Piperidine-H),?3.65?(m,?1?H,?Piperidine-H),?4.16?(t,?2?H,?
J?=?6.5?Hz,?CH
2),?4.66?(s,?2?H,?CH
2),?7.24?(m,?1?H,?Ar-H),?7.33?(t,?3?H,?
J?=?7.5?Hz,?Ar-H),?7.40?(d,?3?H,?
J?=?9.5?Hz,?Ar-H),?7.49?(s,?1?H,?Ar-H)。
Embodiment 29, (1-(7-benzyl ammonia-1H-pyrrolo-[2,3-c] pyridine-5-yl) piperidin-2-yl) methylate hydrochlorate (IV
f)
Operating process is identical with embodiment 24, just with the compound III
fThe alternative compounds III
a, get the reddish-brown semisolid, yield 57%.
1H?NMR?(500?MHz,?DMSO-
d 6):?
δ2.02?(m,?6?H,?Piperidine-H),?3.01?(d,?1?H,?
J?=?12.0?Hz,?Piperidine-H),?3.21?(d,?1?H,?
J?=?12.0?Hz,?Piperidine-H),?3.39?(m,?3?H,?Piperidine-H,?CH
2),?4.66?(d,?2?H,?
J?=?8.0?Hz,?CH
2),?7.24?(t,?1?H,?
J?=?7.5?Hz,?Ar-H),?7.33?(t,?3?H,?
J?=?7.5?Hz,?Ar-H),?7.40?(d,?3?H,?
J?=?7.5?Hz,?Ar-H),?7.46?(s,?1?H,?Ar-H)。
Embodiment 30, (1-(7-benzyl ammonia-1H-pyrrolo-[2,3-c] pyridine-5-yl) piperidin-4-yl) methylate hydrochlorate (IV
g)
Operating process is identical with embodiment 24, just with the compound III
gThe alternative compounds III
a, get the reddish-brown semisolid, yield 65%.
1H?NMR?(500?MHz,?DMSO-
d 6):?
δ2.08?(m,?5?H,?Piperidine-H),?3.21?(m,?2?H,?Piperidine-H),?3.77?(m,?2?H,?Piperidine-H),?4.01?(d,?2?H,?
J?=?6.0?Hz,?CH
2),?4.67?(s,?2?H,?CH
2),?7.21?(m,?1?H,?Ar-H),?7.35?(m,?3?H,?Ar-H),?7.43?(m,?4?H,?Ar-H)。
Embodiment 31,2-(7-benzyl ammonia-1H-pyrrolo-[2,3-c] pyridine-5-base amine) ethylate hydrochlorate (IV
h)
Operating process is identical with embodiment 24, just with the compound III
hThe alternative compounds III
a, get the reddish-brown semisolid, yield 60%.
1H?NMR?(500?MHz,?DMSO-
d 6):?
δ3.25?(t,?1?H,?
J?=?5.0?Hz,?CH),?3.32?(m,?1?H,?CH),?3.70?(m,?1?H,?CH),?3.76?(t,?1?H,?
J?=?5.0?Hz,?CH),?4.69?(s,?2?H,?CH
2),?7.23?(m,?1?H,?Ar-H),?7.34?(m,?2?H,?Ar-H),?7.40?(t,?3?H,?
J?=?7.5?Hz,?Ar-H),?7.44?(d,?2?H,?
J?=?7.5?Hz,?Ar-H),?7.48?(s,?1?H,?Ar-H)。
Embodiment 32,2-(7-benzyl ammonia-1H-pyrrolo-[2,3-c] pyridine-5-base amine) Kauri-butanol hydrochloric salt (IV
i)
Operating process is identical with embodiment 24, just with the compound III
iThe alternative compounds III
a, get the reddish-brown semisolid, yield 64%.
1H?NMR?(500?MHz,?DMSO-
d 6):?
δ1.04?(m,?3?H,?CH
3),?2.05?(m,?2?H,?CH
2),?3.61?(m,?1?H,?CH),?3.86?(m,?1?H,?CH),?4.19?(m,?1?H,?CH),?4.77?(s,?2?H,?CH
2),?7.38?(m,?2?H,?Ar-H),?7.44?(m,?3?H,?Ar-H),?7.50?(m,?3?H,?Ar-H)。
Embodiment 33,2,2 '-(7-benzyl ammonia-1H-pyrrolo-[2,3-c] pyridine-5-base amine) diethylate hydrochlorate (IV
j)
Operating process is identical with embodiment 24, just with the compound III
jThe alternative compounds III
a, get the reddish-brown semisolid, yield 66%.
1H?NMR?(500?MHz,?DMSO-
d 6):?
δ3.49?(t,?4?H,?
J?=?5.0?Hz,?CH
2×2),?3.75?(t,?4?H,?
J?=?5.0?Hz,?CH
2×2),?4.65?(s,?2?H),?7.30?(m,?2?H,?Ar-H),?7.36?(t,?3?H,?
J?=?7.5?Hz,?Ar-H),?7.42?(d,?2?H,?
J?=?7.0?Hz,?Ar-H),?7.62?(s,?1?H,?Ar-H)。
Embodiment 34,2-(1-(7-(pyridine-2-ylmethyl ammonia)-1H-pyrrolo-[2,3-c] pyridine-5-yl) piperidin-4-yl) ethylate hydrochlorate (IV
k)
Operating process is identical with embodiment 14, just with compound ii
kThe alternative compounds II
a, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 2:1), obtain light yellow semi-solid intermediate; Directly drop into next step, specific operation process is identical with embodiment 24, just with this intermediate alternative compounds III
a, two step yields 11%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.25?(m,?2?H,?Piperidine-H),?2.03?(m,?5?H,?Piperidine-H,?CH
2),?3.68?(m,?2?H,?Piperidine-H),?4.19?(m,?4?H,?Piperidine-H,?CH
2),?5.18?(s,?2?H,?CH
2),?7.40?(d,?1?H,?
J?=?10.5?Hz,?Ar-H),?7.82?(d,?1?H,?
J?=?10.0?Hz,?Ar-H),?8.04?(m,?1?H,?Ar-H),?8.14?(m,?1?H,?Ar-H),?8.22?(d,?1?H,?
J?=?7.5?Hz,?Ar-H),?8.64?(m,?2?H,?Ar-H),?8.84?(d,?1?H,?
J?=?6.0?Hz,?Ar-H)。
Embodiment 35,2-(1-(7-(pyridin-3-yl methyl ammonia)-1H-pyrrolo-[2,3-c] pyridine-5-yl) piperidin-4-yl) ethylate hydrochlorate (IV
l)
Operating process is identical with embodiment 14, just with compound ii
lThe alternative compounds II
a, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 1:1), obtain light yellow semi-solid intermediate; Directly drop into next step, specific operation process is identical with embodiment 24, just with this intermediate alternative compounds III
a, two step yields 10%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.70?(m,?4?H,?Piperidine-H),?2.05?(d,?3?H,?
J?=?13.5?Hz,?Piperidine-H,?CH
2),?3.60?(m,?4?H,?Piperidine-H?),?4.10?(m,?2?H,?CH
2),?4.45?(s,?2?H,?CH
2),?5.26?(m,?2?H,?Ar-H),?5.84?(s,?1?H,?Ar-H),?8.21?(d,?1?H,?
J?=?9.0?Hz,?Ar-H),?8.77?(d,?1?H,?
J?=?10.5?Hz,?Ar-H),?8.97?(d,?1?H,?
J?=?7.0?Hz,?Ar-H),?9.06?(s,?1?H,?Ar-H)。
Embodiment 36,2-(1-(7-(pyridin-4-yl methyl ammonia)-1H-pyrrolo-[2,3-c] pyridine-5-yl) piperidin-4-yl) ethylate hydrochlorate (IV
m)
Operating process is identical with embodiment 14, just with compound ii
mThe alternative compounds II
a, through silica gel column chromatography (eluent: petrol ether/ethyl acetate 1:2), obtain the semi-solid intermediate of light brown; Directly drop into next step, specific operation process is identical with embodiment 24, just with this intermediate alternative compounds III
a, two step yields 8%.
1H?NMR?(500?MHz,?DMSO-
d 6):
δ1.32?(m,?2?H,?Piperidine-H),?2.04?(m,?5?H,?Piperidine-H,?CH
2),?4.16?(m,?6?H,?,?Piperidine-H,?CH
2),?4.55?(s,?2?H,?CH
2),?8.11?(m,?2?H?Ar-H),?8.18?(d,?2?H,?
J?=?6.0?Hz?Ar-H),?8.78?(d,?1?H,?
J?=?6.5?Hz?Ar-H),?8.99?(d,?2?H,?
J?=?6.5?Hz?Ar-H)。
Embodiment 37, anti-tumor biological testing method:
The tumour cell isolated culture: choose tumour cell HL60, A549, HCT116, A2780 is in 37 ℃, 5% CO
2Hatch in the cell culture incubator, until cell density is long goes down to posterity during to 70-90% (attached cell Puck ' s EDTA digestion then go down to posterity), be used for later test required.
Mtt assay is measured 7-virtue (first) amido-5-amido-6-7-azaindole derivatives dihydrochloride to the In-vitro Inhibitory Effect of different knurl strains:
Compound is dissolved dilution with DMSO; To be in the above-mentioned tumour cell of logarithmic phase, with 2 * 10
4Individual/mL is inoculated in 96 well culture plates, and every hole adds compound 2 μ l, and final concentration is 12.0 μ M, 6.0 μ M, and 3.0 μ M, 1.5 μ M are jointly in 37 ℃, 5% CO
2Hatched in the cell culture incubator 48 hours, take DMSO(1%) be blank.It is the MTT solution 20 μ L of 2.5mg/mL that every hole adds concentration, continues to cultivate 4h, sucks supernatant liquor, and every hole adds the DMSO of 100 μ L, shakes up, and uses microplate reader to measure the absorbancy (OD value) in each hole under the 570nM wavelength, and the data obtained is used for calculating IC
50Acquired results is referring to table 1, and table 1 is that part 7-virtue (first) amido-5-amido-6-7-azaindole derivatives dihydrochloride is active to the vitro inhibition of different tumor cell lines.
" nd " expression undetermined IC
50Value.
Can find out from the external activity test result of table 1:
(1) to comprising the HL60(human leukemia cell), the A549(human lung carcinoma cell), the HCT116(human colon cancer cell) and the A2780(Proliferation of Human Ovarian Cell) etc. the various human tumor cell line, 7-virtue (first) amido that is synthesized-5-amido-6-7-azaindole derivatives dihydrochloride generally shows and is better than positive control (CYC202, IC
50=2.85 ~ 6.65 μ M) remarkable inhibiting activity (IC
50=0.00024 ~ 3.95 μ M), wherein particularly evident to the restraining effect of HCT116.
(2) compounds Ⅳ wherein
d, IV
e, IV
f, IV
g, IV
hAnd IV
jExtracorporeal anti-tumor particularly outstanding, it is to the IC of above-mentioned cell
50Value is respectively between 0.0038-0.16 μ M, 0.0064-0.67 μ M, 0.00076-0.24 μ M, 0.00024-0.043 μ M, 0.0054-0.17 μ M and 0.00077-0.023 μ M.
The measuring method of embodiment 38, CDK1/Cyclin B kinase inhibiting activity:
Experiment material: CDK1 kinase activity detection kit (MBL, code 5235), demecolcine solution (sigma), Hela cell (Shanghai cell bank)
Experimental technique:
(1) the CDK1 kinases extracts: when treating that cell density reaches 80% degree of converging, add demecolcine solution 20ng/ml(final concentration), collect with cell scraper after 14 hours, add protein lysate, liquid nitrogen multigelation 6 times is stored under subzero 80 centigradetemperature conditions, or is directly used in experiment.
(2) experiment arranges CDK1 kinases control group; The blank group; Administration group (at first with DMSO storing solution is diluted to 500 μ M, then is diluted to 100 μ M with DDW).After such as table 2 each sample being ready to, hatch 20min for 37 ℃.
Annotate: the kinase reaction damping fluid forms (1mM ATP, 10 * cdc2 reaction solution).
(3) add each 5ul of kinase substrate Biotinylatel MV peptide in every pipe, suspendible is gently hatched 30min under 37 ℃.
(4) every pipe adds phosphorylation reaction stop buffer 200ul.
(5) centrifugal 15s, 8 * 103rpm.
(6) get supernatant mixture 100ul adding and be coated with in the microwell plate of monoclonal antibody 4A4 incubated at room 60min.
(7) discard supernatant in the pipe, add dcq buffer liquid, behind the chucked, remove liquid, such as method washing 5 times.
(8) the POD liquid of adding 100uL in every hole, incubated at room 30min.
(9) operation of repeating step 7.
(10) every hole adds the test kit substrate reagent, hatches 3-5min under room temperature and lucifuge condition.
(11) in every hole, add reaction terminating liquid 100ul.
(12) measure absorption value in wavelength 492nm place with spectrophotometer, the data obtained is used for calculating the inhibiting rate value.
Acquired results is referring to table 3, and table 3 is external Inhibiting enzyme activities of CDK1/Cyclin B (10 μ M) of part 7-virtue (first) amido-5-amido-6-7-azaindole derivatives dihydrochloride.
Pressing down the enzyme test result and can find out that under 10 μ M concentration, fragrant (first) amidos of the 7-that the overwhelming majority synthesize-5-amido-6-7-azaindole derivatives dihydrochloride shows and is better than positive control from table 3
CYC202Significant CDK1 suppress active (inhibiting rate: 95.8% ~ 100%); Part of compounds (IV wherein
a, IV
c, IV
d, IV
e, IV
i, IV
j) inhibiting rate of CDK1 has been reached 100%(10 μ M).
In sum, this compounds has preferably antitumor application prospect, thereby has further developing drugs value.
Claims (5)
1. a 7-virtue (first) amido-5-amido-6-7-azaindole derivatives is characterized in that general structure is:
Ar be without replace, mono-substituted phenyl ring or fragrant heterocycle, wherein the substituting group on the single-substituted ring is fluorine, chlorine, bromine, nitro, contains alkoxyl group and 2-pyridine, 3-pyridine and the 4-pyridine ring of the straight or branched of 1 to 3 carbon atom; The virtue heterocycle is pyridine, pyrimidine, thiophene, furans or pyrroles;
N is 0 or 1;
R
1With R
2Identical or different, select hydrogen, contain alkyl and the hydroxyalkyl of the straight or branched of 1 to 3 carbon atom; Perhaps NR
1R
2Be the six-ring that replaces, this six-ring is selected piperidines, morpholine or piperazine.
2. the preparation method of a 7-virtue (first) amido-5-amido-6-7-azaindole derivatives and pharmaceutical salts thereof is characterized in that, realizes by following steps:
(1) in polar solvent, under alkaline condition and 50-80 ℃ of temperature of reaction, chemical compounds I generates compound ii with corresponding aminated compounds generation alkylated reaction, products therefrom can get sterling through column chromatography, polar solvent is N, dinethylformamide, methyl alcohol, ethanol, Virahol and methyl-sulphoxide etc., alkaline matter can be selected a kind of in salt of wormwood, yellow soda ash or the sodium bicarbonate;
(2) in the anhydrous tetrahydrofuran solution of compound ii, under nitrogen protection ,-78 ℃ of temperature of reaction, drip the tetrahydrofuran solution of vinyl bromination magnesium, and reaction generated the compound III in 16-24 hour under-20 ℃ of conditions, the ammonium chloride solution that reaction finishes rear adding 20% in solution carries out cancellation, and products therefrom can get sterling through column chromatography;
(3) the compound III removes the Boc protecting group in the saturated ethyl acetate solution of hydrochloric acid, and reaction times 12-24 hour, generate the dihydrochloride of compounds Ⅳ, can obtain the target compound sterling through suction filtration;
Synthetic route:
Wherein Ar, n, R
1And R
2Definition with claim 1.
3. a kind of 7-virtue (first) amido according to claim 1-application of 5-amido-6-7-azaindole derivatives in the preparation antitumor drug.
4. according to claim 2 a kind of 7-virtue (first) amido of described method preparation-5-amido-6-7-azaindole derivatives and the application of pharmaceutical salts in the preparation antitumor drug thereof.
5. according to claim 4 described application is characterized in that, described pharmaceutical salts is selected hydrochloride, vitriol, phosphoric acid salt, tartrate, mesylate, benzene sulfonate, tosilate, Citrate trianion, maleate, fumarate and oxalate.
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