CN101481353B - Tetrahydro indazolone or tetrahydro indolone substituted indazole derivative and salt thereof - Google Patents
Tetrahydro indazolone or tetrahydro indolone substituted indazole derivative and salt thereof Download PDFInfo
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- CN101481353B CN101481353B CN2008100557382A CN200810055738A CN101481353B CN 101481353 B CN101481353 B CN 101481353B CN 2008100557382 A CN2008100557382 A CN 2008100557382A CN 200810055738 A CN200810055738 A CN 200810055738A CN 101481353 B CN101481353 B CN 101481353B
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- 0 CC(C)(Cc1c2c(C)c[n]1-c1cc(NCCN3CCCCC3)c3C(N)=N*c3c1)CC2=O Chemical compound CC(C)(Cc1c2c(C)c[n]1-c1cc(NCCN3CCCCC3)c3C(N)=N*c3c1)CC2=O 0.000 description 3
- UWJCUIZXBWAHDS-UHFFFAOYSA-N CC(C)(Cc1c2c(C)c[n]1-c1cc([nH]nc3N)c3c(NCCN3CCOCC3)c1)CC2=O Chemical compound CC(C)(Cc1c2c(C)c[n]1-c1cc([nH]nc3N)c3c(NCCN3CCOCC3)c1)CC2=O UWJCUIZXBWAHDS-UHFFFAOYSA-N 0.000 description 1
- PJFASODYXSUIQP-UHFFFAOYSA-N CC(C)(Cc1c2c(C)n[n]1-c(cc(c1c3)[n](CC=C)nc1N)c3Cl)CC2=O Chemical compound CC(C)(Cc1c2c(C)n[n]1-c(cc(c1c3)[n](CC=C)nc1N)c3Cl)CC2=O PJFASODYXSUIQP-UHFFFAOYSA-N 0.000 description 1
- BBZDEOJFPOEZIP-UHFFFAOYSA-N CC(C)(Cc1c2c(C)n[n]1-c1cc(NC3CCCC3)c3c(N)n[nH]c3c1)CC2=O Chemical compound CC(C)(Cc1c2c(C)n[n]1-c1cc(NC3CCCC3)c3c(N)n[nH]c3c1)CC2=O BBZDEOJFPOEZIP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to tetrahydroindazolone or tetrahydroindazolone-substituted indazole derivatives with the following general formula (I) or (II) and pharmaceutically acceptable salt thereof. The compounds and the pharmaceutically acceptable salt thereof are characterized by inhibiting growth of tumor cells and malignant cells. The tumor cells comprise cancer cells such as breast cancer, lung cancer,cervical carcinoma, rectum cancer, prostatic cancer, liver cancer, blood cancer and the like, thus the tetrahydroindazolone or tetrahydroindazolone-substituted indazole derivatives and the salt thereof can be used for preparing drugs for preventing and treating the breast cancer, the lung cancer, the cervical carcinoma, the rectum cancer, the prostatic cancer, the liver cancer and the blood cancer.
Description
Technical field
The present invention relates to indazole derivatives and salt thereof that tetrahydro-indazolone or tetrahydro-indolone replace, and their preparation method and the application in the treatment anti-tumor drug.
Background technology
Last decade comes, and oncotherapy has obtained remarkable progress, and annual all have new antitumor drug to come into the market, and improved the survival and the quality of life of tumour patient.But cancer is still the No.1 killer of harm health of people.There are defectives such as toxicity is big, resistance difference in the cancer therapy drug that uses clinically at present.Wherein a lot of medicines are to synthesize by inhibition DNA to stop growth of cancer cells.Yet these medicines not only have lethality to cancer cells, and normal cell is also had same lethal effect.These medicines often also cause irreversible toxicity and side effect to patient as a result.People urgently wish to obtain the novel and effective antitumor drug.
Summary of the invention
The indazole derivatives that the object of the present invention is to provide tetrahydro-indolone with anti-tumor activity and tetrahydro-indazolone to replace, and their preparation method and the application in the treatment anti-tumor drug.
The invention provides the indazole-derived compounds that a kind of tetrahydro-indolone replaces, have following general formula (I):
Wherein, R
11Expression H, halogen, the amino of replacement, the piperazine of replacement, the pyrrolidyl of replacement or the piperidines of replacement;
Preferably, the amino of described replacement is hexamethylene amino, ethylamino, 4-hydroxyl hexamethylene amino, the own amino of 4-glycyl oxygen basic ring, 2-diethylin ethylamino, 2-(4-morpholine) ethylamino, 2-(1,2,3) triazole ethylamino, 2-(1-(3, the 5-lupetidine)) ethylamino, 2-(1-piperidines) ethylamino, 2-(1-pyrrolidyl) ethylamino or (2-tetrahydrofuran (THF)) methylamino-;
Preferably, the piperazine of described replacement is 4-methylpiperazine, 4-(2-(4-morpholine) ethyl) piperazine, (4-pentamethylene base) piperazine, 4-(2-hydroxyethyl) piperazine or 4-(2-pyridine) piperazine;
Preferably, the pyrrolidyl of described replacement is a 3-hydroxyl pyrrolidine base;
Preferably, the piperidines of described replacement is 4-oxygen-piperidines, 4-hydroxy piperidine, 3-hydroxy piperidine, 4-glycyl oxygen phenylpiperidines, 4-(4-morpholine) piperidines, 4-(1-pyrrolidyl) piperidines or 4-(2-(1-piperidines) oxyethyl group) piperidines;
R
21Represent the aromatic base of alkyl, aromatic base or the replacement of H, alkyl, replacement;
R
31Represent H or halogen (F, Cl, Br, I).
The invention provides the indazole-derived compounds that a kind of tetrahydro-indazolone replaces, have following general formula (II):
Wherein, R
12Expression H, halogen, the amino of replacement, the piperazine of replacement, the pyrrolidyl of replacement or the piperidines of replacement;
Preferably, the amino of described replacement is hexamethylene amino, ethylamino, 4-hydroxyl hexamethylene amino, the own amino of 4-glycyl oxygen basic ring, 2-diethylin ethylamino, 2-(4-morpholine) ethylamino, 2-(1,2,3) triazole ethylamino, 2-(1-(3, the 5-lupetidine)) ethylamino, 2-(1-piperidines) ethylamino, 2-(1-pyrrolidyl) ethylamino or (2-tetrahydrofuran (THF)) methylamino-;
Preferably, the piperazine of described replacement is 4-methylpiperazine, 4-(2-(4-morpholine) ethyl) piperazine, (4-pentamethylene base) piperazine, 4-(2-hydroxyethyl) piperazine or 4-(2-pyridine) piperazine;
Preferably, the pyrrolidyl of described replacement is a 3-hydroxyl pyrrolidine base;
Preferably, the piperidines of described replacement is 4-oxygen-piperidines, 4-hydroxy piperidine, 3-hydroxy piperidine, 4-glycyl oxygen phenylpiperidines, 4-(4-morpholine) piperidines, 4-(1-pyrrolidyl) piperidines or 4-(2-(1-piperidines) oxyethyl group) piperidines;
R
22Represent the aromatic base of alkyl, aromatic base or the replacement of H, alkyl, replacement;
R
42Represent alkyl, alkyloyl or the aromaticacyl radical of H, alkyl, replacement;
R
32Represent H or halogen (F, Cl, Br, I).
Determination of activity is the result show, above-claimed cpd provided by the invention, and all have characteristics that suppress tumour cell and malignant cell growth at pharmacy acceptable salt, described tumour cell comprises cancer cells such as mammary cancer, lung cancer, cervical cancer, the rectum cancer, prostate cancer, liver cancer, leukemia, thereby can be used for preparing the medicine of preventing and treating mammary cancer, lung cancer, cervical cancer, the rectum cancer, prostate cancer, liver cancer, leukemia.
Described above-claimed cpd comprises the vitriol (sulfuric) of these compounds at pharmacy acceptable salt, hydrochloride (hydrochloric), phosphoric acid salt (phosphoric), hydrobromate (hydrobromic), Citrate trianion (citric), maleate (maleic), mandelate (mandelic), succinate (succinic), fumarate (fumaric), acetate (acetic), lactic acid salt (lactic), nitrate (nitric), sulfonate (sulfonic), tosilate (p-toluenesulfonic), mesylate (methane sulfonic), benzoate (benzoic), tartrate (tartaric) or carbonate (carbonic acid)
Embodiment
One, intermediate (A1-A14) is synthetic
1.1-the preparation of trimethyl carbinol oxygen formyl radical-3-trimethyl carbinol oxygen formamido group-6-fluorine indazole (A1)
Add 2,4 difluorobenzene cyanogen (15 grams, 0.11 mole) in reaction flask, ethanol (50 milliliters) stirs adding 85% hydrazine hydrate (4.5 grams, 0.12 mole) down.The reaction mixture reflux stirred 3 hours, cooling back dichloromethane extraction, saturated NaCl solution washing, anhydrous magnesium sulfate drying.Filter, remove solvent, the product silica gel column chromatography separating purification with methylene chloride (90: 10) washing, obtains 5.3 grams, productive rate 32%; Mp (℃) 163-165;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.5 (s, 1H), 7.65 (d, 1H), 6.97 (d, 1H), 6.72 (b, 1H), 5.40 (s, 2H); MS 152.2 (M+H).
The said products (5.0 grams, 33 mmoles) is dissolved in exsiccant methylene dichloride (40 milliliters), adds DMAP (4-N, N-Dimethylamino pyridine, 1.2 grams, 10 mmoles), add uncle's fourth oxygen carbonic anhydride (16 grams, 73 mmoles) again, reaction is at room temperature stirred and is spent the night.Use ethyl acetate extraction, saturated NaCl solution washing, anhydrous magnesium sulfate drying.Filter, remove solvent, the product silica gel column chromatography separating purification with ethyl acetate/hexanaphthene (70: 30) wash-out, obtains 9.4 grams, productive rate 81%; Mp (℃) 121-123;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.95 (b, 1H), 7.70 (d, 1H), 7.00 (d, 1H), 6.75 (d, H), 1.35-1.50 (b, 18H); MS 352.2 (M+H).
2.1H-3-the preparation of trimethyl carbinol oxygen formamido group-6-fluorine indazole (A2)
The same A1 of synthetic method, the consumption of uncle's fourth oxygen carbonic anhydride reduces to (1: 1.10), productive rate 96%; Mp (℃) 186-188;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 10.95 (s, 1H), 7.82 (b, 1H), 7.58 (d, 1H), 7.15 (d, 1H), 6.63 (d, H), 1.40-1.50 (s, 9H); MS 252.2 (M+H).
3.1-the preparation of methyl-3-trimethyl carbinol oxygen formamido group-6-fluorine indazole (A3)
With 1H-3-trimethyl carbinol oxygen formamido group-6-fluorine indazole (A2) (2.5 grams, 0.01 mole) be dissolved among the exsiccant DMF (25 milliliters), add sodium hydride (0.26 gram, 0.011 mole), stir after 3 minutes, drip the dichloromethane solution (10 milliliters) of methyl iodide (1.41 grams, 0.01 mole), add the back and stirred 1 hour.Use ethyl acetate extraction, saturated NaCl solution washing, anhydrous magnesium sulfate drying.Filter, remove solvent, the product silica gel column chromatography separating purification with ethyl acetate/hexanaphthene (70: 30) wash-out, obtains 2.2 grams, productive rate 83%; Mp (℃) 161-163;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.88 (b, 1H), 7.63 (d, 1H), 6.94 (d, 1H), 6.72 (d, H), 3.65 (s, 3H), 1.35-1.45 (s, 9H); MS 266.1 (M+H).
4.1-the preparation of propenyl-3-trimethyl carbinol oxygen formamido group-6-fluorine indazole (A4)
(A4)
The same A3 of synthetic method, productive rate 76%; Mp (℃) 175-177;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.94 (b, 1H), 7.72 (d, 1H), 7.12 (d, 1H), 6.86 (d, H), 5.52 (b, 1H), 4.90-4.98 (b, 2H), 3.95 (b, 2H), 1.35-1.45 (s, 9H); MS 292.1 (M+H).
5.1-trimethyl carbinol oxygen formyl radical-3-trimethyl carbinol oxygen formamido group-4, the preparation of 6-difluoro indazole (A5)
The same A1 of synthetic method, productive rate 45% (two steps); Mp (℃) 155-157;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.90 (b, 1H), 6.74 (d, 1H), 6.47 (d, 1H), 1.30-1.50 (b, 18H); MS 370.2 (M+H).
6.1H-3-trimethyl carbinol oxygen formamido group-4, the preparation of 6-difluoro indazole (A6)
The same A2 of synthetic method, productive rate 87%; Mp (℃) 165-678;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.88 (s, 1H), 7.84 (b, 1H), 6.93 (d, 1H), 6.56 (d, H), 1.35-1.50 (s, 9H); MS 270.2 (M+H).
7.1-methyl-3-trimethyl carbinol oxygen formamido group-4, the preparation of 6-difluoro indazole (A7)
The same A3 of synthetic method is a starting raw material with A6, productive rate 54%; Mp (℃) 173-175;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.87 (b, 1H), 6.88 (d, 1H), 6.47 (d, H), 3.72 (s, 3H), 1.35-1.45 (s, 9H); MS 284.1 (M+H).
8.1-propenyl-3-trimethyl carbinol oxygen formamido group-4, the preparation of 6-difluoro indazole (A8)
The same A4 of synthetic method, productive rate 56%; Mp (℃) 181-183;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.84 (b, 1H), 6.92 (d, 1H), 6.45 (d, 1H), 5.61 (b, 1H), 4.85-4.93 (b, 2H), 4.12 (b, 2H), 1.35-1.50 (s, 9H); MS 310.2 (M+H).
9.1-trimethyl carbinol oxygen formyl radical-3-trimethyl carbinol oxygen formamido group-5, the preparation of 6-difluoro indazole (A9)
The same A5 of synthetic method, productive rate 41% (two steps); Mp (℃) 177-179;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.86 (b, 1H), 6.91 (d, 1H), 6.72 (d, 1H), 1.30-1.50 (b, 18H); MS 370.2 (M+H).
10.1-methyl-3-trimethyl carbinol oxygen formamido group-5, the preparation of 6-difluoro indazole (A10)
(A10)
The same A3 of synthetic method, productive rate 67%; Mp (℃) 166-168;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.92 (b, 1H), 6.95 (d, 1H), 6.80 (d, H), 3.68 (s, 3H), 1.35-1.45 (s, 9H); MS 284.1 (M+H).
11.1-propenyl-3-trimethyl carbinol oxygen formamido group-5, the preparation of 6-difluoro indazole (A11)
The same A4 of synthetic method, productive rate 52%; Mp (℃) 157-159;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.89 (b, 1H), 7.02 (d, 1H), 6.85 (d, 1H), 5.64 (b, 1H), 4.88-4.95 (b, 2H), 4.16 (b, 2H), 1.35-1.50 (s, 9H); MS 310.2 (M+H).
12.1-the preparation of trimethyl carbinol oxygen formyl radical-3-trimethyl carbinol oxygen formamido group-5-chloro-6-fluorine indazole (A12)
The same A5 of synthetic method, productive rate 52% (two steps): mp (℃) 181-183;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.91 (b, 1H), 6.86 (d, 1H), 6.65 (d, 1H), 1.30-1.50 (b, 18H); MS 386.2 (M+H).
13.1-the preparation of methyl-3-trimethyl carbinol oxygen formamido group-5-chloro-6-fluorine indazole (A13)
(A13)
The same A3 of synthetic method, productive rate 55%; Mp (℃) 172-174;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.89 (b, 1H), 6.91 (d, 1H), 6.72 (d, H), 3.65 (s, 3H), 1.35-1.45 (s, 9H); MS 300.2 (M+H).
14.1-the preparation of propenyl-3-trimethyl carbinol oxygen formamido group-5-chloro-6-fluorine indazole (A14)
The same A4 of synthetic method, productive rate 60%; Mp (℃) 166-168;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.92 (b, 1H), 6.98 (d, 1H), 6.79 (d, 1H), 5.59 (b, 1H), 4.89-4.94 (b, 2H), 4.05 (b, 2H), 1.35-1.50 (s, 9H); MS 326.1 (M+H).
This patent synthesizes used other intermediate, as 3,6,6-trimethylammonium 1,5,6,7-tetrahydrochysene indazole-4-ketone and 3,6,6-trimethylammonium 1,5,6, the synthetic method of 7-tetrahydro indole-4-ketone etc. as, Zhang Tongxiang quick, Wang Yifei and Xing Guowen in the summer at " derivative of tetrahydro-indolone and the derivative of tetrahydro-indazolone and their application " (Chinese invention patent, application number: 200610087495.1; PCT patent of invention, application number: PCT/CN2006/001281) " in disclosed.
Two, the preparation of The compounds of this invention
Embodiment 1.1-(6-(3-amino-1-methyl) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
In reaction flask, add 3,6,6-trimethylammonium 1,5,6,7-tetrahydrochysene indazole-4-ketone (0.20 gram, 1.1 mmoles), exsiccant DMF (15 milliliters), (33 milligrams of sodium hydrides, 1.3 mmole), stir adding A3 (0.3 gram, 1.1 mmoles) down, reactant is heated to 150 ℃ and stirred 2 hours.After the cooling, use ethyl acetate extraction, saturated NaCl solution washing, anhydrous magnesium sulfate drying.Filter, remove solvent, the product silica gel column chromatography separating purification with ethyl acetate/hexanaphthene (60: 40) wash-out, obtains 0.34 gram intermediate, it is dissolved in (15 milliliters) in the trifluoroacetic acid, stirring at room 2 hours, the solvent decompression is removed, and uses ethyl acetate extraction, saturated NaCl solution washing, anhydrous magnesium sulfate drying.Filter, remove solvent, the product silica gel column chromatography separating purification with methylene chloride (90: 10) wash-out, obtains 0.22 gram, productive rate 84%; Mp (℃) 195-197;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.67-7.69 (d, 1H), 7.38-7.40 (b, 1H), 7.13-7.15 (d, 1H), 3.76 (b, 2H), 3.62 (s, 3H), 2.66 (s, 3H), 2.41 (s, 2H), 2.38 (s, 2H), 1.09-1.11 (s, 6H); MS 324.2 (M
++ 1).
Embodiment 2.1-(6-(3-amino-1-propenyl) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
With intermediate A 4 is starting raw material, with the synthetic 1-(6-(3-amino-1-propenyl) indazole)-3,6 of the method among the embodiment 1, and 6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone, productive rate 54% (two steps); Mp (℃) 173-175;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.71-7.73 (d, 1H), 7.39-7.41 (b, 1H), 7.11-7.13 (d, 1H), 5.75 (m, 1H), 4.95-4.98 (m, 2H), 3.97 (m, 2H), 3.72 (s, 2H), 2.64 (s, 3H), 2.42 (s, 2H), 2.37 (s, 2H), 1.07-1.10 (s, 6H); MS 350.2 (M
++ 1).
Embodiment 3.1-(6-(3-amino-1-(3-(1-methyl cyclohexane-4-amino)-4-carboxamide phenyl)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
According to the method for embodiment 1, by 3,6,6-trimethylammonium 1,5,6, synthetic corresponding 1-(6-(uncle's 1-fourth oxygen formyl radical-uncle's 3-fourth oxygen formamido group) indazole)-3,6, the 6-trimethylammonium-1 of obtaining of 7-tetrahydrochysene indazole-4-ketone and A1,5,6,7-tetrahydrochysene indazole-4-ketone, productive rate 78%; Mp (℃) 157-159;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.92-7.94 (b, 1H), 7.69-7.71 (d, 1H), 7.51-7.53 (d, 1H), 6.78-6.80 (m, 1H), 2.66 (s, 3H), 2.44 (s, 2H), 2.35 (s, 2H), 1.08-1.11 (s, 6H); MS 510.3 (M
++ 1).
The said products (0.25 gram, 0.4 mmole) is dissolved in trifluoroacetic acid (15 milliliters) and sloughs uncle's fourth oxygen formyl radical and obtain corresponding 1-(6-(1H-3-amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone 0.1 gram, productive rate 80%.With 1-(6-(1H-3-amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone (0.1 gram, 0.3 mmole) is dissolved in exsiccant DMF (15 milliliters), adds (10 milligrams of sodium hydrides, 0.4 mmole), stir adding 4-fluoro-2-(1-methyl piperidine-4-amino) benzene cyanogen (70 milligrams, 0.3 mmole) down, reaction is heated to 150 ℃ and stirred 2 hours.Cooling back ethyl acetate extraction, saturated NaCl solution washing, anhydrous magnesium sulfate drying.Filter, remove solvent, the product silica gel column chromatography separating purification with ethyl acetate/hexanaphthene (80: 20) wash-out, obtains 97 milligrams of products.It is dissolved in methyl alcohol (20 milliliters), adds DMSO (5 milliliters), 2N NaOH (1 milliliter) and 30% hydrogen peroxide (1 milliliter), reactant at room temperature stirred 3 hours, used ethyl acetate extraction, saturated NaCl solution washing, anhydrous magnesium sulfate drying.Filter, remove solvent, the product silica gel column chromatography separating purification with methylene chloride (95: 5) wash-out, obtains 52 milligrams, productive rate 33%; Mp (℃) 218-220;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.72-7.74 (d, 1H), 7.67-7.69 (d, 1H), 7.63-7.65 (d, 1H), and 7.33-7.35 (d, 1H), 6.77-6.79 (d, 1H), 6.45-6.47 (s, 1H), 5.68 (b, 2H), 3.67 (b, 2H), 3.32 (s, 3H), 2.69 (s, 3H), 2.42 (s, 2H), 2.15-2.25 (m, 6H), 1.10-1.12 (s, 6H); MS 541.3 (M
++ 1).
Embodiment 4.1-(6-(3-amino-1-(3-(4-hydroxyl hexamethylene amino)-4-carboxamide phenyl)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
According to the method among the embodiment 3, synthesize 1-(6-(3-amino-1-(3-(4-hydroxyl hexamethylene amino)-4-carboxamide phenyl)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone, productive rate 28%; Mp (℃) 203-205;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.64-7.66 (d, 1H), 7.58-7.70 (d, 1H), 7.53-7.56 (d, 1H), and 7.24-7.26 (d, 1H), 6.63-6.65 (d, 1H), 6.41-6.43 (s, 1H), 5.66 (b, 2H), 3.65 (b, 2H), 2.67 (s, 3H), 2.41 (s, 2H), 2.32 (s, 2H), 1.55-1.65 (m, 8H), 1.07-1.10 (s, 6H); MS 542.3 (M
++ 1).
Embodiment 5.1-(6-(3-amino-1H-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-amino-1H-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone are by 3,6, and it is synthetic that 6-trimethylammonium 1,5,6,7-tetrahydrochysene indazole-4-ketone and A5 are pressed embodiment 1 method, productive rate 57%; Mp (℃) 171-173;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.35 (s, 1H), 7.18-7.20 (d, 1H), 6.83-6.85 (d, 1H), 3.66 (b, 2H), 2.66 (s, 3H), 2.43 (s, 2H), 2.35 (s, 2H), 1.08-1.10 (s, 6H); MS 328.1 (M
++ 1).
Embodiment 6.1-(6-(3-amino-1H-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-amino-1H-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone are by 3,6, and it is synthetic that 6-trimethylammonium 1,5,6,7-tetrahydrochysene indazole-4-ketone and A9 are pressed embodiment 1 method, productive rate 44%; Mp (℃) 182-183;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.43 (s, 1H), 7.48-7.50 (d, 1H), 7.26-6.28 (d, 1H), 3.68 (b, 2H), 2.65 (s, 3H), 2.42 (s, 2H), 2.36 (s, 2H), 1.07-1.09 (s, 6H); MS 328.1 (M
++ 1).
Embodiment 7.1-(6-(3-amino-1H-5-chlorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-amino-1H-5-chlorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone are by 3,6, and it is synthetic that 6-trimethylammonium 1,5,6,7-tetrahydrochysene indazole-4-ketone and A12 are pressed embodiment 1 method, productive rate 51%; Mp (℃) 193-195;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.51 (s, 1H), 7.61-7.63 (d, 1H), 7.42-7.45 (d, 1H), 3.66 (b, 2H), 2.64 (s, 3H), 2.43 (s, 2H), 2.37 (s, 2H), 1.09-1.11 (s, 6H); MS 344.1 (M
++ 1).
Embodiment 8.1-(6-(3-amino-1-propenyl-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-amino-1-propenyl-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone are by 3,6, and it is synthetic that 6-trimethylammonium 1,5,6,7-tetrahydrochysene indazole-4-ketone and A8 are pressed embodiment 1 method, productive rate 36%; Mp (℃) 157-159;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.32-7.34 (d, 1H), 6.67-6.69 (d, 1H), 5.68 (m, 1H), 4.91-4.93 (m, 2H), 4.03 (m, 2H), 3.69 (b, 2H), 2.65 (s, 3H), 2.44 (s, 2H), 2.36 (s, 2H), 1.07-1.10 (s, 6H); MS 368.2 (M
++ 1).
Embodiment 9.1-(6-(3-amino-1-propenyl-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-amino-1-propenyl-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone are by 3,6, and it is synthetic that 6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone and A11 are pressed embodiment 1 method, productive rate 42%; Mp (℃) 164-166;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.27-7.29 (d, 1H), 6.97-6.99 (d, 1H), 5.72 (m, 1H), 4.96-4.98 (m, 2H), 3.97 (m, 2H), 3.68 (b, 2H), 2.67 (s, 3H), 2.46 (s, 2H), 2.34 (s, 2H), 1.07-1.09 (s, 6H); MS 368.2 (M
++ 1).
Embodiment 10.1-(6-(3-amino-1-propenyl-5-chlorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-amino-1-propenyl-5-chlorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone are by 3,6, and it is synthetic that 6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone and A14 are pressed embodiment 1 method, productive rate 48%; Mp (℃) 177-179;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.68-7.70 (d, 1H), 7.62-7.64 (d, 1H), 5.69 (m, 1H), 4.95-4.98 (m, 2H), 4.07 (m, 2H), 3.71 (b, 2H), 2.69 (s, 3H), 2.476 (s, 2H), 2.36 (s, 2H), 1.08-1.10 (s, 6H); MS 384.1 (M
++ 1).
Embodiment 11.1-(6-(3-amino-1-methyl-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-amino-1-methyl-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone are by 3,6, and it is synthetic that 6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone and A7 are pressed embodiment 1 method, productive rate 65%; Mp (℃) 176-178;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.23-7.25 (d, 1H), 6.78-6.80 (d, 1H), 3.70 (b, 2H), 3.63 (s, 3H), 2.68 (s, 3H), 2.40 (s, 2H), 2.37 (s, 2H), 1.10-1.12 (s, 6H); MS 342.2 (M
++ 1).
Embodiment 12.1-(6-(3-amino-1-methyl-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-amino-1-methyl-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone are by 3,6, and it is synthetic that 6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone and A10 are pressed embodiment 1 method, productive rate 57%; Mp (℃) 182-184;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.44-7.47 (d, 1H), 7.28-7.30 (d, 1H), 3.74 (b, 2H), 3.65 (s, 3H), 2.69 (s, 3H), 2.43 (s, 2H), 2.39 (s, 2H), 1.07-1.09 (s, 6H); MS 342.2 (M
++ 1).
Embodiment 13.1-(6-(3-amino-1-methyl-5-chloro) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-amino-1-methyl-5-chloro) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone are by 3,6, and it is synthetic that 6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone and A13 are pressed embodiment 1 method, productive rate 53%; Mp (℃) 174-176;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.51-7.53 (d, 1H), 7.33-7.35 (d, 1H), 3.70 (b, 2H), 3.62 (s, 3H), 2.67 (s, 3H), 2.44 (s, 2H), 2.37 (s, 2H), 1.09-1.11 (s, 6H); MS 358.1 (M
++ 1).
Embodiment 14.1-(6-(3-acetylaminohydroxyphenylarsonic acid 1-methyl) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-amino-1-methyl) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone (embodiment 1) (100 milligrams, 0.3 mmole) is dissolved in exsiccant DMF (15 milliliters), adds
N, N-diisopropylethylamine (0.5 milliliter) stirs adding diacetyl oxide (36 milligrams, 0.3 mmole) down.Ethyl acetate extraction, saturated NaCl solution washing, anhydrous magnesium sulfate drying were at room temperature stirred in reaction 2 hours.Filter, remove solvent, the product silica gel column chromatography separating purification with methylene chloride (95: 5) wash-out, obtains 76 milligrams, productive rate 69%; Mp (℃) 187-189;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.67-7.70 (d, 1H), 7.55-7.57 (d, 1H), 7.42-7.44 (d, 1H), 6.91-6.93 (d, 1H), 3.72 (s, 3H), 2.68 (s, 3H), 2.43 (s, 2H), 2.35 (s, 2H), 2.14 (s, 3H), 1.08-1.11 (s, 6H); MS 366.2 (M
++ 1).
Embodiment 15.1-(6-(3-acetylaminohydroxyphenylarsonic acid 1-propenyl) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-acetylaminohydroxyphenylarsonic acid 1-propenyl) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone is by 1-(6-(3-amino-1-propenyl) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone (embodiment 2) and diacetyl oxide are pressed the method for embodiment 14 and are synthesized productive rate 55%; Mp (℃) 193-195;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.72-7.74 (b, 1H), 7.63-7.65 (d, 1H), 7.47-7.49 (d, 1H), 6.92-6.94 (d, 1H), 5.71 (m, 1H), 4.97-4.99 (m, 2H), 3.95 (m, 2H), 2.70 (s, 3H), 2.45 (s, 2H), 2.37 (s, 2H), 2.20 (s, 3H), 1.10-1.12 (s, 6H); MS 392.2 (M
++ 1).
Embodiment 16.1-(6-(3-acetylaminohydroxyphenylarsonic acid 1-propenyl-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-acetylaminohydroxyphenylarsonic acid 1-propenyl-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone is by 1-(6-(3-amino-1-propenyl-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone (embodiment 8) and diacetyl oxide are pressed the method for embodiment 14 and are synthesized productive rate 76%; Mp (℃) 201-203;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.67-7.69 (b, 1H), 7.37-7.39 (d, 1H), 6.77-6.79 (d, 1H), 5.68 (m, 1H), 4.93-4.95 (m, 2H), 3.91 (m, 2H), 2.68 (s, 3H), 2.42 (s, 2H), 2.35 (s, 2H), 2.17 (s, 3H), 1.07-1.10 (s, 6H); MS 410.2 (M
++ 1).
Embodiment 17.1-(6-(3-acetylaminohydroxyphenylarsonic acid 1-propenyl-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-acetylaminohydroxyphenylarsonic acid 1-propenyl-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone is by 1-(6-(3-amino-1-propenyl-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone (embodiment 9) and diacetyl oxide are pressed the method for embodiment 14 and are synthesized productive rate 62%; Mp (℃) 214-216;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.69-7.71 (b, 1H), 7.25-7.27 (d, 1H), 6.94-6.96 (d, 1H), 5.66 (m, 1H), 4.91-4.93 (m, 2H), 3.96 (m, 2H), 2.64 (s, 3H), 2.44 (s, 2H), 2.37 (s, 2H), 2.12 (s, 3H), 1.08-1.11 (s, 6H); MS 410.2 (M
++ 1).
Embodiment 18.1-(6-(3-acetylaminohydroxyphenylarsonic acid 1-propenyl-5-chlorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(3-acetylaminohydroxyphenylarsonic acid 1-propenyl-5-chlorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone is by 1-(6-(3-amino-1-propenyl-5-chlorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone (embodiment 10) and diacetyl oxide are pressed the method for embodiment 14 and are synthesized productive rate 71%; Mp (℃) 189-191;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.73-7.75 (b, 1H), 7.58-7.60 (d, 1H), 7.26-7.28 (d, 1H), 5.69 (m, 1H), 4.97-4.99 (m, 2H), 3.97 (m, 2H), 2.67 (s, 3H), 2.43 (s, 2H), 2.35 (s, 2H), 2.15 (s, 3H), 1.07-1.10 (s, 6H); MS 426.2 (M
++ 1).
The common intermediate (B1) of embodiment 19 to embodiment 35---1-(6-(uncle's 1-fourth oxygen formyl radical-uncle's 3-fourth oxygen formamido group-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone synthetic
1-(6-(uncle's 1-fourth oxygen formyl radical-uncle's 3-fourth oxygen formamido group-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone (B1) is by 3,6,6-trimethylammonium 1,5,6,7-tetrahydrochysene indazole-4-ketone and A5 are by the method synthetic (removing uncle's fourth oxygen formyl radical protecting group without trifluoroacetic acid) of embodiment 1, productive rate 63%; Mp (℃) 232-234;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.67-7.69 (s, 1H), 6.75-6.77 (d, 1H), 6.56-6.58 (d, 1H), 2.68 (s, 3H), 2.44 (s, 2H), 2.37 (s, 2H), 1.35-1.50 (b, 18H), 1.09-1.11 (s, 6H); MS 528.2 (M
++ 1).
Embodiment 19.1-(6-(3-amino-1H-4-hexamethylene amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
1-(6-(uncle's 1-fourth oxygen formyl radical-uncle's 3-fourth oxygen formamido group-4-fluorine) indazole)-3,6,6-trimethylammonium-1; 5,6,7-tetrahydrochysene indazole-4-ketone (B1) (0.2 gram; 0.3 mmole), DMF (15 milliliters), N; N-diisopropylethylamine (0.2 milliliter), hexahydroaniline (0.2 milliliter), reactant are heated to 100 ℃ and stirred 3 hours; cooling; ethyl acetate extraction, saturated NaCl solution washing, anhydrous magnesium sulfate drying.Filter, remove solvent, the product silica gel column chromatography separating purification with ethyl acetate/hexanaphthene (85: 15) wash-out, obtains a yolk yellow powdery solid, is dissolved in trifluoroacetic acid (15 milliliters) and also at room temperature stirs 2 hours.The product dichloromethane extraction, saturated NaCl solution washing, anhydrous magnesium sulfate drying.Filter, remove solvent, the product silica gel column chromatography separating purification with methylene chloride (90: 10) wash-out, obtains 55 milligrams of products, productive rate 44%; Mp (℃) 197-199;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.43 (b, 1H), 6.56-6.59 (d, 1H), 6.32-6.34 (d, 1H), 3.82 (m, 3H), 2.68 (s, 3H), 2.42 (s, 2H), 2.36 (s, 2H), 1.45-1.70 (m, 11H), 1.09-1.11 (s, 6H); MS 407.3 (M
++ 1).
Embodiment 20.1-(6-(3-amino-1H-4-encircles penta amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 51%; Mp (℃) 175-177;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.52 (b, 1H), 6.61-6.63 (d, 1H), 6.35-6.37 (d, 1H), 3.86 (m, 3H), 2.69 (s, 3H), 2.43 (s, 2H), 2.37 (s, 2H), 1.50-1.72 (m, 9H), 1.10-1.12 (s, 6H); MS 393.2 (M
++ 1).
Embodiment 21.1-(6-(3-amino-1H-4-ring fourth amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 43%; Mp (℃) 154-156;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.56 (b, 1H), 6.65-6.67 (d, 1H), 6.02-6.04 (d, 1H), 3.72-3.75 (m, 3H), 2.67 (s, 3H), 2.42 (s, 2H), 2.35 (s, 2H), 1.73-2.11 (m, 7H), 1.08-1.10 (s, 6H); MS 379.2 (M
++ 1).
Embodiment 22.1-(6-(3-amino-1H-4-cyclopropylamino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 36%; Mp (℃) 167-169;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.63 (b, 1H), 6.57-6.59 (d, 1H), 6.11-6.13 (d, 1H), 3.80-3.82 (m, 3H), 2.69 (s, 3H), 2.43 (s, 2H), 2.36 (s, 2H), 1.26 (b, 1H), 1.10-1.11 (s, 6H), 0.5-0.7 (m, 4H); MS 365.2 (M
++ 1).
Embodiment 23.1-(6-(3-amino-1H-4-acrylic-amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 62%; Mp (℃) 173-175;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.54 (b, 1H), 6.64-6.66 (d, 1H), 6.25-6.27 (d, 1H), 5.65 (m, 1H), 4.96-4.98 (m, 2H), 3.76-3.78 (m, 3H), 3.63 (m, 2H), 2.68 (s, 3H), 2.42 (s, 2H), 2.34 (s, 2H), 1.07-1.09 (s, 6H), MS 365.2 (M
++ 1).
Embodiment 24.1-(6-(3-amino-1H-4-(4-hydroxyl hexamethylene amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 62%; Mp (℃) 173-175;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.63 (b, 1H), 6.67-6.69 (d, 1H), 6.19-6.21 (d, 1H), 3.68-3.74 (m, 3H), 2.67 (s, 3H), 2.43 (s, 2H), 2.35 (s, 2H), 1.46-1.58 (m, 4H), 1.10-1.12 (s, 6H), MS 423.2 (M
++ 1).
Embodiment 25.1-(6-(3-amino-1H-4-(3-hydroxyl hexamethylene amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 28%; Mp (℃) 142-146;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.57 (b, 1H), 6.62-6.64 (d, 1H), 6.23-6.25 (d, 1H), 3.72-3.76 (m, 3H), 2.68 (s, 3H), 2.42 (s, 2H), 2.34 (s, 2H), 1.43-1.59 (m, 8H), 1.10-1.13 (s, 6H), MS 423.2 (M
++ 1).
Embodiment 26.1-(6-(3-amino-1H-4-(2-hydroxyl hexamethylene amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 23%; Mp (℃) 157-159;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.54 (b, 1H), 6.65-6.67 (d, 1H), 6.32-6.34 (d, 1H), 3.71-3.75 (m, 3H), 2.67 (s, 3H), 2.43 (s, 2H), 2.35 (s, 2H), 1.38-1.55 (m, 8H), 1.09-1.11 (s, 6H), MS 423.2 (M
++ 1).
Embodiment 27.1-(6-(3-amino-1H-4-(3-hydroxycyclopent amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 31%; Mp (℃) 172-174;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.57 (b, 1H), 6.62-6.64 (d, 1H), 6.26-6.28 (d, 1H), 3.69-3.74 (m, 3H), 2.68 (s, 3H), 2.45 (s, 2H), 2.37 (s, 2H), 1.58-1.75 (m, 6H), 1.07-1.10 (s, 6H), MS 410.2 (M
++ 1).
Embodiment 28.1-(6-(3-amino-1H-4-(2-(4-morpholine) ethylamino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 36%; Mp (℃) 187-189;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.53 (b, 1H), 6.67-6.69 (d, 1H), 6.33-6.35 (d, 1H), and 3.73-3.77 (m, 3H), 3.69-3.72 (t, 4H), 2.98-3.01 (b, 2H), 2.55-2.58 (b, 6H), 2.57 (s, 3H), 2.54 (b, 4H), 2.67 (s, 3H), 2.42 (s, 2H), 2.34 (s, 2H), and 1.06-1.09 (s, 6H), MS 438.3 (M
++ 1).
Embodiment 29.1-(6-(3-amino-1H-4-(2-[1,2,3] the triazole ethylamino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 40%; Mp (℃) 173-175;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.57 (b, 1H), 7.47-7.50 (m, 2H), 6.66-6.68 (d, 1H), 6.29-6.31 (d, 1H), 3.68-3.76 (b, 5H), 3.31-3.33 (b, 2H), 2.58 (s, 3H), 2.45 (s, 2H), 2.34 (s, 2H), 1.07-1.09 (s, 6H), MS 420.2 (M
++ 1).
Embodiment 30.1-(6-(3-amino-1H-4-(2-(1-pyrroles)) ethylamino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 53%; Mp (℃) 184-186;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.54 (b, 1H), 6.69-6.71 (d, 1H), 6.33-6.35 (d, 1H), 3.68-3.72 (m, 3H), 3.03-3.05 (b, 2H), 2.59 (s, 3H), 2.42-2.47 (b, 4H), 2.33 (s, 2H), 1.94-1.96 (m, 4H), 1.52-1.54 (m, 4H), 1.07-1.09 (s, 6H), MS422.3 (M
++ 1).
Embodiment 31.1-(6-(3-amino-1H-4-(2-(1-piperidines)) ethylamino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 37%; Mp (℃) 168-170;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.57 (b, 1H), 6.73-6.75 (d, 1H), 6.28-6.30 (d, 1H), 3.71-3.76 (m, 3H), 2.97-2.99 (b, 2H), 2.59 (s, 3H), 2.17-2.51 (b, 8H), and 1.46-1.51 (m, 6H), 1.08-1.10 (s, 6H), MS 436.3 (M
++ 1).
Embodiment 32.1-(6-(3-amino-1H-4-(4-(1-methyl-4-pyridine) amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 24%; Mp (℃) 157-159;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.63 (b, 1H), 6.67-6.69 (d, 1H), 6.34-6.36 (d, 1H), 3.69-3.74 (m, 3H), 2.57 (s, 3H), 2.39-2.44 (b, 5H), 2.34 (s, 2H), 2.06-2.09 (m, 4H), 1.57-1.62 (m, 4H), 1.08-1.10 (s, 6H), MS 422.3 (M
++ 1).
Embodiment 33.1-(6-(3-amino-1H-4-(4-(1-propenyl-4-pyridine) amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 36%; Mp (℃) 184-186;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.58 (b, 1H), 6.71-6.73 (d, 1H), 6.37-6.39 (d, 1H), 5.59 (m, 1H), 4.92-4.94 (m, 2H), 3.71-3.76 (m, 3H), 2.89-2.91 (m, 1H), 2.58 (s, 3H), 2.45 (b, 2H), 2.34 (s, 2H), and 2.15-2.18 (m, 4H), 1.54-1.58 (m, 4H), and 1.07-1.09 (s, 6H), MS 448.3 (M
++ 1).
Embodiment 34.1-(6-(3-amino-1H-4-(1-pyridine)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 18%; Mp (℃) 199-201;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.55 (b, 1H), 6.62-6.64 (d, 1H), 6.23-6.25 (d, 1H), 3.66-3.71 (b, 2H), 3.21-3.23 (b, 4H), 2.59 (s, 3H), 2.42 (s, 2H), 1.91-1.93 (b, 4H), 1.50-1.52 (b, 2H), 1.08-1.09 (s, 6H); MS 393.2 (M
++ 1).
Embodiment 35.1-(6-(3-amino-1H-4-(4-hydroxyl-1-pyridine)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone
Synthetic method is with embodiment 19, productive rate 22%; Mp (℃) 173-175;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.58 (b, 1H), 6.67-6.69 (d, 1H), 6.26-6.28 (d, 1H), 5.00-5.02 (m, 1H), 3.69-3.74 (b, 2H), 3.50-3.53 (m, 2H), 3.21-3.24 (m, 2H), 2.84 (s, 2H), 2.57 (s, 3H), 2.43 (s, 2H), 1.95-1.97 (m, 2H), 1.09-1.11 (s, 6H); MS 409.2 (M
++ 1).
Compound in embodiment 36 to embodiment 55 all contains one 3,6,6-trimethylammonium-1,5,6, the substituting group of 7-tetrahydro indole-4-ketone.Wherein, a lot of compounds are synthetic by intermediate B 2.
1-(6-(uncle's 1-fourth oxygen formyl radical-uncle's 3-fourth oxygen formamido group-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone (B2) is by 3,6,6-trimethylammonium 1,5,6,7-tetrahydro indole-4-ketone and A5 are by embodiment 1 method synthetic (removing uncle's fourth oxygen formyl radical protecting group without trifluoroacetic acid), productive rate 75%; Mp (℃) 194-196;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.83-7.85 (b, 1H), 6.78-6.80 (d, 1H), 6.63-6.65 (d, 1H), 6.42-6.44 (b, 1H), 2.66-2.68 (s, 2H), 2.34-2.36 (s, 2H), 2.11-2.13 (s, 3H), 1.33-1.47 (b, 18H), 1.08-1.10 (s, 6H); MS527.3 (M
++ 1).
Embodiment 36.1-(6-(3-amino-1H-4-(4-hydroxyl-1-pyridine)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1H-4-(4-hydroxyl-1-pyridine)) indazole)-3,6,6-trimethylammonium-1,5,6, the method that 7-tetrahydro indole-4-ketone is pressed embodiment 19 by intermediate B 2 and 4-hydroxy piperidine is synthetic, productive rate 29%; Mp (℃) 147-149;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.63 (b, 1H), 6.72-6.74 (d, 1H), 6.38-6.41 (d, 1H), 6.21-6.23 (m, 1H), 3.73-3.77 (b, 2H), 3.42-3.44 (m, 2H), 3.17-3.19 (m, 2H), 2.43 (s, 2H), 2.34-2.36 (s, 2H), 2.13 (s, 3H), 1.38-1.47 (m, 4H), 1.07-1.10 (s, 6H); MS 408.2 (M
++ 1).
Embodiment 37.1-(6-(3-amino-1H-4-(4-(1-propenyl-4-pyridine) amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
Synthetic method is with embodiment 36, productive rate 37%; Mp (℃) 184-186;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.67 (b, 1H), 6.63-6.65 (d, 1H), 6.42-6.44 (d, 1H), 6.18-6.20 (m, 1H), 5.57 (m, 1H), 4.97-4.99 (m, 2H), 3.69-3.74 (b, 2H), 3.12-3.14 (m, 2H), 2.42 (s, 2H), 2.32-2.34 (s, 2H), 2.11 (s, 3H), 1.48-1.51 (m, 4H), 1.07-1.10 (s, 6H); MS 447.3 (M
++ 1).
Embodiment 38.1-(6-(3-amino-1-propenyl) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1-propenyl) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone be by A4 and 3,6,6-trimethylammonium-1,5,6, and 7-tetrahydro indole-4-ketone obtains productive rate 39% by the method for embodiment 2 is synthetic; Mp (℃) 186-188;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 7.69-7.71 (d, 1H), 7.43-7.45 (b, 1H), 6.96-6.98 (d, 1H), 6.37-6.39 (s, 1H), 5.75-5.77 (m, 1H), 4.91-4.94 (m, 2H), 3.99-4.01 (m, 2H), 3.69-3.72 (b, 2H), 2.43 (s, 2H), 2.36 (s, 2H), 2.00 (s, 3H), 1.07-1.09 (s, 6H); MS 349.2 (M
++ 1).
Embodiment 39.1-(6-(3-amino-1H-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1H-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone press the method for embodiment 36 (B2) and synthesize, and the process trifluoroacetic acid is handled and obtained again.Productive rate 54%; Mp (℃) 169-171;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.71 (b, 1H), 6.83-6.85 (d, 1H), 6.47-6.49 (d, 1H), 6.23-6.25 (m, 1H), 3.72-3.75 (b, 2H), 2.43 (s, 2H), 2.31-2.33 (s, 2H), 2.14 (s, 3H), 1.07-1.09 (s, 6H); MS 327.1 (M
++ 1).
Embodiment 40.1-(6-(3-amino-1H-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1H-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5; 6,7-tetrahydro indole-4-ketone synthetic, 6-trimethylammonium 1 by A9 and 3,6; 5,6, it is synthetic that 7-tetrahydro indole-4-ketone is pressed the method for embodiment 1, removes the BOC blocking group and obtain through trifluoroacetic acid.Productive rate 47%; Mp (℃) 183-185;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.69 (b, 1H), 6.81-6.83 (d, 1H), 6.65-6.67 (d, 1H), 6.17-6.19 (m, 1H), 3.68-3.72 (b, 2H), 2.45 (s, 2H), 2.33-2.35 (s, 2H), 2.17 (s, 3H), 1.08-1.10 (s, 6H); MS 327.1 (M
++ 1).
Embodiment 41.1-(6-(3-amino-1H-5-chlorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1H-5-chlorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone be by A12 and 3,6, and it is synthetic that 6-trimethylammonium 1,5,6,7-tetrahydro indole-4-ketone are pressed the method for embodiment 1, removes the BOC blocking group and obtain through trifluoroacetic acid.Productive rate 62%; Mp (℃) 171-172;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.66 (b, 1H), 7.24-7.26 (d, 1H), 6.78-6.80 (d, 1H), 6.21-6.23 (m, 1H), 3.70-3.74 (b, 2H), 2.43 (s, 3H), 2.31-2.33 (s, 2H), 2.14 (s, 3H), 1.06-1.09 (s, 6H); MS 343.1 (M
++ 1).
Embodiment 42.1-(6-(3-amino-1-allyl group-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1-allyl group-4-fluorine) indazole)-3,6,6-trimethylammonium-1,5; 6,7-tetrahydro indole-4-ketone is by A8 and 3,6,6-trimethylammonium 1; 5,6, it is synthetic that 7-tetrahydro indole-4-ketone is pressed the method for embodiment 1, removes the BOC blocking group and obtain through trifluoroacetic acid.Productive rate 48%; Mp (℃) 188-190;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 6.76-6.78 (d, 1H), 6.38-6.40 (d, 1H), 6.23-6.24 (s, 1H), 5.73 (m, 1H), 4.91-4.93 (m, 2H), 3.94-3.96 (m, 2H), 3.68-3.72 (b, 2H), 2.43 (s, 2H), 2.32 (s, 2H), 2.16 (s, 3H), 1.08-1.10 (s, 6H); MS367.2 (M
++ 1).
Embodiment 43.1-(6-(3-amino-1-propenyl-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1-propenyl-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5; 6,7-tetrahydro indole-4-ketone is by A11 and 3,6,6-trimethylammonium 1; 5,6, it is synthetic that 7-tetrahydro indole-4-ketone is pressed the method for embodiment 1, removes the BOC blocking group and obtain through trifluoroacetic acid.Productive rate 62%; Mp (℃) 174-176;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 6.89-6.91 (d, 1H), 6.57-6.59 (d, 1H), 6.17-6.19 (s, 1H), 5.74-5.76 (m, 1H), 4.93-4.95 (m, 2H), 3.96-3.98 (m, 2H), 3.69-3.75 (b, 2H), 2.45 (s, 2H), 2.34 (s, 2H), 2.17 (s, 3H), and 1.07-1.10 (s, 6H); MS367.2 (M
++ 1).
Embodiment 44.1-(6-(3-amino-1-propenyl-5-chlorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1-propenyl-5-chlorine) indazole)-3,6,6-trimethylammonium-1,5; 6,7-tetrahydro indole-4-ketone is by A14 and 3,6,6-trimethylammonium 1; 5,6, it is synthetic that 7-tetrahydro indole-4-ketone is pressed the method for embodiment 1, removes the BOC blocking group and obtain through trifluoroacetic acid.Productive rate 54%; Mp (℃) 191-193;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 6.97-6.99 (d, 1H), 6.65-6.67 (d, 1H), 6.25-6.27 (s, 1H), 5.67-5.69 (m, 1H), 4.84-4.86 (m, 2H), 3.91-3.93 (m, 2H), 3.67-3.71 (b, 2H), 2.43 (s, 2H), 2.35 (s, 2H), 2.15 (s, 3H), and 1.07-1.10 (s, 6H); MS383.1 (M
++ 1).
Embodiment 45.1-(6-(3-amino-1-methyl-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1-methyl-5-fluorine) indazole)-3,6,6-trimethylammonium-1,5; 6,7-tetrahydro indole-4-ketone is by A10 and 3,6,6-trimethylammonium 1; 5,6, it is synthetic that 7-tetrahydro indole-4-ketone is pressed the method for embodiment 1, removes the BOC blocking group and obtain through trifluoroacetic acid.Productive rate 68%; Mp (℃) 164-166;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 6.87-6.89 (d, 1H), 6.53-6.55 (d, 1H), 3.68-3.72 (b, 2H), 3.63 (s, 3H), 2.44 (s, 2H), 2.37 (s, 2H), 2.21 (s, 3H), 1.07-1.09 (s, 6H); MS 341.2 (M
++ 1).
Embodiment 46.1-(6-(3-amino-1-methyl-5-chloro) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1-methyl-5-chloro) indazole)-3,6,6-trimethylammonium-1,5; 6,7-tetrahydro indole-4-ketone is by A13 and 3,6,6-trimethylammonium 1; 5,6, it is synthetic that 7-tetrahydro indole-4-ketone is pressed the method for embodiment 1, removes the BOC blocking group and obtain through trifluoroacetic acid.Productive rate 42%; Mp (℃) 175-177;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 6.73-6.75 (d, 1H), 6.57-6.59 (d, 1H), 3.69-3.72 (b, 2H), 3.67 (s, 3H), 2.43 (s, 2H), 2.35 (s, 2H), 2.18 (s, 3H), 1.08-1.10 (s, 6H); MS 357.1 (M
++ 1).
Embodiment 47.1-(6-(3-amino-1H-4-hexamethylene amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1H-4-hexamethylene amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone is obtained by the method for embodiment 36 is synthetic by B2 and hexahydroaniline.Productive rate 33%; Mp (℃) 155-157;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.72 (b, 1H), 6.49-6.51 (d, 1H), 6.24-6.26 (s, 1H), 6.08-6.10 (d, 1H), 3.69-3.74 (m, 3H), 2.43 (s, 2H), 2.35 (s, 2H), 2.18 (s, 3H), 1.57-1.62 (m, 4H), 1.35-1.45 (m, 6H), and 1.07-1.10 (s, 6H); MS 406.2 (M
++ 1).
Embodiment 48.1-(6-(3-amino-1H-4-encircles penta amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1H-4-encircles penta amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone is obtained by the method for embodiment 36 is synthetic by B2 and cyclopentamine.Productive rate 26%; Mp (℃) 161-162;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.65 (b, 1H), 6.53-6.55 (d, 1H), 6.27-6.29 (s, 1H), 6.12-6.14 (d, 1H), 3.69-3.72 (m, 3H), 2.44 (s, 2H), 2.34 (s, 2H), 2.15 (s, 3H), 1.62-1.65 (m, 4H), 1.41-1.44 (m, 4H), and 1.07-1.10 (s, 6H); MS 392.2 (M
++ 1).
Embodiment 49.1-(6-(3-amino-1H-4-ring fourth amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1H-4-ring fourth amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone is obtained by the method for embodiment 36 is synthetic by B2 and ring butylamine.Productive rate 40%; Mp (℃) 156-157;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.62 (b, 1H), 6.61-6.63 (d, 1H), 6.22-6.24 (s, 1H), 6.15-6.17 (d, 1H), 3.67-3.71 (m, 3H), 2.45 (s, 2H), 2.34 (s, 2H), 2.17 (s, 3H), 1.91-1.93 (m, 4H), 1.74-1.76 (m, 2H), and 1.08-1.10 (s, 6H); MS 378.2 (M
++ 1).
Embodiment 50.1-(6-(3-amino-1H-4-acrylic-amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1H-4-acrylic-amino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone is obtained by the method for embodiment 36 is synthetic by B2 and allylamine.Productive rate 36%; Mp (℃) 152-154;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.73 (b, 1H), 6.67-6.69 (d, 1H), 6.23-6.25 (d, 1H), and 6.16-6.18 (s, 1H), 5.61-5.63 (m, 1H), and 4.92-4.94 (m, 2H), 3.72-3.76 (m, 3H), and 3.66-3.68 (m, 2H), 2.43 (s, 2H), 2.35 (s, 2H), 2.17 (s, 3H), and 1.07-1.09 (s, 6H), MS 364.2 (M
++ 1).
Embodiment 51.1-(6-(3-amino-1H-4-(4-hydroxyl hexamethylene amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1H-4-(4-hydroxyl hexamethylene amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone is obtained by the method for embodiment 36 is synthetic by B2 and 4-hydroxyl hexahydroaniline.Productive rate 45%; Mp (℃) 163-165;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.67 (b, 1H), 6.62-6.64 (d, 1H), 6.22-6.24 (d, 1H), 6.11-6.13 (s, 1H), 3.67-3.72 (m, 3H), 2.45 (s, 2H), 2.34 (s, 2H), 2.17 (s, 3H), 1.45-1.56 (m, 8H), 1.07-1.10 (s, 6H), MS 422.2 (M
++ 1).
Embodiment 52.1-(6-(3-amino-1H-4-(3-hydroxyl hexamethylene amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1H-4-(3-hydroxyl hexamethylene amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone is obtained by the method for embodiment 36 is synthetic by B2 and 3-hydroxyl hexahydroaniline.Productive rate 36%; Mp (℃) 172-174;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.59 (b, 1H), 6.57-6.59 (d, 1H), 6.25-6.27 (d, 1H), 6.09-6.11 (s, 1H), 3.71-3.75 (m, 3H), 2.46 (s, 2H), 2.35 (s, 2H), 2.15 (s, 3H), 1.37-1.49 (m, 8H), 1.08-1.10 (s, 6H), MS 422.2 (M
++ 1).
Embodiment 53.1-(6-(3-amino-1H-4-(3-hydroxycyclopent amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1H-4-(3-hydroxycyclopent amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone is obtained by the method for embodiment 36 is synthetic by B2 and 3-hydroxycyclopent amine.Productive rate 51%; Mp (℃) 174-176;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.63 (b, 1H), 6.63-6.65 (d, 1H), 6.21-6.23 (d, 1H), 6.13-6.15 (s, 1H), 3.69-3.73 (m, 3H), 2.43 (s, 2H), 2.34 (s, 2H), 2.16 (s, 3H), 1.62-1.75 (m, 6H), 1.07-1.09 (s, 6H), MS 408.2 (M
++ 1).
Embodiment 54.1-(6-(3-amino-1H-4-(2-(4-morpholine) ethylamino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1H-4-(2-(4-morpholine) ethylamino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone is obtained by the method for embodiment 36 is synthetic by B2 and 2-(4-morpholine) ethamine.Productive rate 42%; Mp (℃) 158-160;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.57 (b, 1H), 6.65-6.67 (d, 1H), 6.25-6.27 (s, 1H), and 6.14-6.16 (s, 1H), 3.71-3.74 (m, 3H), and 3.65-3.67 (t, 4H), 2.95-2.97 (b, 2H), and 2.46-2.58 (b, 8H), 2.42 (s, 2H), 2.35 (s, 2H), 2.16 (s, 3H), and 1.07-1.09 (s, 6H), MS 437.3 (M
++ 1).
Embodiment 55.1-(6-(3-amino-1H-4-(2-(1-piperidines)) ethylamino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone
1-(6-(3-amino-1H-4-(2-(1-piperidines)) ethylamino) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone by B2 and and 2-(1-piperidines) ethamine obtain by the method for embodiment 36 is synthetic.Productive rate 57%; Mp (℃) 174-176;
1HNMR (500MHz, DMSO-D
6) δ (ppm): 11.61 (b, 1H), 6.68-6.70 (d, 1H), 6.27-6.29 (d, 1H), 6.13-6.15 (s, 1H), 3.68-3.73 (m, 3H), 2.93-2.96 (b, 2H), 2.19-2.43 (b, 8H), 2.14 (s, 3H), and 1.40-1.45 (m, 6H), 1.08-1.10 (s, 6H), MS 435.3 (M
++ 1).
The compound 1-(6-(3-amino-1H-4-(4-hydroxyl hexamethylene amino)) indazole)-3,6 of embodiment 56. preparation embodiment 24,6-trimethylammonium-1,5,6, the hydrochloride of 7-tetrahydrochysene indazole-4-ketone
Get 1-(6-(3-amino-1H-4-(4-hydroxyl hexamethylene amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone 0.50 gram is dissolved in 70 milliliters of ethyl acetate, ice bath feeds down the exsiccant hydrogen chloride gas, stirs after 5-20 minute except that desolvate white solid product.
In this way, the hydrochloride of the compound of preparation embodiment 1 to embodiment 23, embodiment 25 to embodiment 55 gained.
Embodiment 57. preparation 1-(6-(3-amino-1H-4-(4-hydroxyl hexamethylene amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone tosilate.
Get 1-(6-(3-amino-1H-4-(4-hydroxyl hexamethylene amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone 0.50 gram is dissolved in 75 milliliters of ethyl acetate, ice bath adds down the doubly normal tosic acid of 1-5, stirs after 5-20 minute except that desolvate white solid product.
In this way, the tosilate of the compound of preparation embodiment 1 to embodiment 23, embodiment 25 to embodiment 55 gained.
Embodiment 58. preparation 1-(6-(3-amino-1H-4-(4-hydroxyl hexamethylene amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone tartrate.
Get 1-(6-(3-amino-1H-4-(4-hydroxyl hexamethylene amino)) indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone 0.55 gram is dissolved in 90 milliliters of ethyl acetate, ice bath adds down the doubly normal tartrate of 1-5, stirs after 5-20 minute except that desolvate white solid product.
In this way, the tartrate of the compound of preparation embodiment 1 to embodiment 23, embodiment 25 to embodiment 55 gained.
Embodiment 59. anti-tumor biologicals
With the metamorphosis of microscopically observation of cell in conjunction with mtt assay tested embodiment of the invention 1-55 preparation 55 compounds (hydrochloride of Compound I-01 to Compound I-55 used in the anti-tumor biological test) and the positive drug vincristine(VCR) to A549 (lung cancer), MCF-7 (mammary cancer), K562 (chronic leukemia), HL60 (acute leukemia), HT-29 (rectum cancer), HeLa (cervical cancer), HepG2 (liver cancer), the isocellular toxicity of PC3 (prostate cancer).
1. test objective
Measure Compound I-01 to Compound I-55 altogether 55 samples to A549, MCF-7, K562, HL60, HT-29, Hela, HepG2, the toxicity of PC3 cell.
2. the dissolving of sample
Compound I-01 to Compound I-55 takes by weighing above-claimed cpd 4-5mg sample respectively, and with a spot of DMSO dissolving, adding PBS again, to make its concentration be 4-5mg/mL.
The positive control drug vincristine(VCR): take by weighing the 5.0mg vincristine(VCR), being dissolved in 1mL PBS final concentration is 5mg/mL.
3. test materials
Cell: A549 (lung cancer), MCF-7 (mammary cancer), K562 (chronic leukemia), HL60 (acute leukemia), HT-29 (rectum cancer), Hela (cervical cancer), HepG2 (liver cancer), PC3 (prostate cancer).
Cell growth medium: the RPMI1640 nutrient solution that contains 10%FBS.
Cell maintenance medium: the RPMI1640 nutrient solution that contains 1%FBS.
Positive drug: vincristine(VCR)
4. test method
Adopt 96 orifice plates trace cell culture method.
4.1 monolayer cell preparation (pre-plate): well-grown cell in the culturing bottle with the conventional digestion of Digestive system, is made 1.58 * 10 with the RPMI1640 growth media
5The cell suspension of cell/mL adds in 96 orifice plates, and every hole 100 μ L put 37 ℃, 5%CO
2Hatch 24h in the incubator, grow into the monolayer cell of uniformity.
4.2 drug dilution: the mother liquor of each sample is done 10 times, 100 times, 500 times, 1000 times, 5000 times, 10000 times, 100000 times dilutions with cell maintenance medium respectively, get 7 working concentration gradients.
4.3 application of sample: abandon growth media in the micropore, add the above-mentioned good sample solution that diluted, every hole 100 μ L, each concentration is established 3 multiple holes, establishes H behavior normal cell contrast (adding no medicine cell maintenance medium 100 μ L/ holes) group simultaneously, puts 37 ℃, 5%CO
2Continue in the incubator to cultivate.
4.4 the result observes: every day the observation of cell growing state, observe 48h continuously.
4.5 mtt assay: after 48 hours, add 5% MTT, every hole 10 μ L, in 37 ℃, 5%CO
2Continue in the incubator to cultivate, behind the 4h, abandon supernatant, add 10% SDS, every hole 100 μ L spend the night, elisa reading instrument colorimetric (λ=570nm), survey the absorbance A value and calculate medicine to screened cell inhibiting rate.Screened cell survival rate (%)=(medicine group A value/cell control group A value) * 100%, inhibiting rate (%)=1-survival rate.Press the half-inhibition concentration (IC that the Reed-Muench method is calculated cell
50).
5. experimental result
The result who measures by test method 4 shows that The compounds of this invention I-01 to I-55 and positive control drug vincristine(VCR) have significant inhibition growth activity to screened tumour cell; But relatively there were significant differences P＜0.05 of effect between the two, illustrate Compound I-01 to the antitumor cell toxicity of I-55 apparently higher than vincristine(VCR).The results are shown in Table 1, table 1 is The compounds of this invention (I-01 to I-55) suppresses growth activity to screened tumour cell a experimental data.
Table 1. embodiment compound is to the inhibition activity of 8 kinds of tumour cells
In the experiment, what all compounds adopted all is the form of its hydrochloride.
Claims (11)
1. the indazole-derived compounds that replaces of a tetrahydro-indolone, for:
2. the described compound of claim 1 is at pharmacy acceptable salt.
3. the described compound of claim 1 is at pharmacy acceptable salt.
4. compound according to claim 2 is at pharmacy acceptable salt, and wherein said salt is hydrochloride, tosilate or tartrate.
5. described compound of claim 1 or claim 2 or 3 described compounds are in the application of pharmacy acceptable salt in preparation medicine for treating tumor thing.
6. application according to claim 4, wherein tumour is mammary cancer, lung cancer, cervical cancer, the rectum cancer, prostate cancer, liver cancer or leukemia.
7. the indazole-derived compounds that replaces of a tetrahydro-indazolone, for:
8. the described compound of claim 6 is at pharmacy acceptable salt.
9. compound according to claim 7 is at pharmacy acceptable salt, and wherein said salt is hydrochloride, tosilate or tartrate.
10. described compound of claim 6 or claim 7 or 8 described compounds are in the application of pharmacy acceptable salt in preparation medicine for treating tumor thing.
11. application according to claim 9, wherein tumour is mammary cancer, lung cancer, cervical cancer, the rectum cancer, prostate cancer, liver cancer or leukemia.
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| CN101273991A (en) * | 2007-03-28 | 2008-10-01 | 北京国药龙立生物医药新技术有限公司 | Applications of tetrahydroindolone/tetrahydroindazolone/tetrahydrocarbazole derivatives and salts thereof in preparation of antiviral medicine |
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| CN101273991A (en) * | 2007-03-28 | 2008-10-01 | 北京国药龙立生物医药新技术有限公司 | Applications of tetrahydroindolone/tetrahydroindazolone/tetrahydrocarbazole derivatives and salts thereof in preparation of antiviral medicine |
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