CN105985319A - Arylphthalazine compound and its preparation method and use - Google Patents
Arylphthalazine compound and its preparation method and use Download PDFInfo
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Abstract
The invention belongs to the field of drug synthesis, relates to an arylphthalazine compound with a structure shown in a general formula (I) and its pharmaceutically acceptable salt and especially relates to an arylphthalazine compound containing piperazine, pyrrolidine or azetidine and its preparation method and use in medical science. An in-vitro Hedgehog signal path target gene Gli inhibition activity test proves that the compound has good Hedgehog signal path inhibition activity. The compound can be used for preparation of a novel anti-tumor drug.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, relate to new aryl phthalazine compound, preparation method and application.Specifically
Relate to a kind of aryl phthalazine compound containing piperazine or pyrrolidine or azetidine, and preparation method thereof and doctor
Application on.
Background technology
Research report, malignant tumor has become the commonly encountered diseases that serious harm people's life is healthy.According to incompletely statistics,
The whole world there are about the new cases of 20,000,000 every year；The annual new cases of China are about 160-200 ten thousand, extremely
Die 1,300,000.There is in early days the ability of transfer, the patient of about 50% in clinical diagnosis primary tumo(u)r due to tumor
Having produced amphi position transfer, tumor cell length soon, easily make a variation, thus produces multidrug resistance, causes chemotherapy failure,
According to the relevent statistics, wherein more than 90% is relevant to the multidrug resistance of tumor cell, and that applies the most clinically is anti-
Tumour medicine is far from the requirement of satisfied treatment.
The research of molecular targeted antitumor drug become current antineoplastic medicine research field main trend and
Trend.In recent years, the antitumor drug of targeting Hedgehog (Hh) signal path becomes the research heat in this field
Point.Research display, Hedgehog (Hh) signal path plays an important role in tumor develops,
Close contacting is had with the tumor of the mankind about 1/3.Abnormal activation Hh signal conducts, and will cause pith mother cells
The generation of the kinds of tumors such as tumor, breast carcinoma, carcinoma of prostate, pulmonary carcinoma, colon cancer, bladder cancer, ovarian cancer.
Hedgehog is a kind of merism gene found in the growth course of research fruit bat, and Hh signal is the most logical
Cross transmembrane protein Ptch and Smo mediation to transmit to intracellular.During signal without Hh, Ptch with Smo is combined, and presses down
The effect of Smo processed, causes the suppression of transcription factor Gli transcriptional activity downstream.When there being Hh signal, Hh
Being combined with Ptch, release the Ptch inhibitory action to Smo, the Smo of activity recovery is passed on by level time signal,
Activate Gli transcriptional activity, start the transcript and expression of Hh target gene.
During antitumor drug at targeting Hh signal path is studied at present, existing multiple medicines listing or entrance are faced
Bed research, such as the Vismodegid (GDC-0449) of Genentech company of the U.S. in 2012 by FDA
Approval listing, for the treatment of skin carcinoma.It addition, Erismodegid (LDE225, Norvatis company of Switzerland),
LEQ-506 (Norvatis company of Switzerland) and LY-2940680 (Lilly company of the U.S.) etc. are carrying out clinical II
Phase and III phase, clinical studies show is evident in efficacy to skin carcinoma, the brain cancer, medulloblastoma and other solid tumors.
Studies have reported that Hedgehog signal pathway inhibitor in treatment to her horse of tyrosine kinase inhibitor
Produce for Buddhist nun in nonsmall-cell lung cancer (CML) patient procedure of drug resistance, the number of CML cell can not only be reduced
Amount, moreover it is possible to reduce the growth of the CML of resistance to imatinib cell；But have antitumor drug drug resistance at present
Problem is still the important problem that clinical therapy of tumor faces.In consideration of it, present inventor intends providing new target
To the antitumor drug of Hh signal path, it, by improving the financial burden of China's tumor patient, improves tumor
Clinical therapeutic efficacy, has great importance.
Summary of the invention:
It is an object of the invention to provide the new aryl phthalein with good Hedgehog signal path inhibitory action
Piperazine compound, is specifically related to a kind of aryl phthalazine compound containing piperazine or pyrrolidine or azetidine and can
Pharmaceutical salts.
It is a further object of the present invention to provide the preparation method of above-mentioned aryl phthalazine compound, particularly relate to preparation and contain
The method of the aryl phthalazine compound of piperazine or pyrrolidine or azetidine.
The aryl phthalazine compound of the present invention has structure and an officinal salt thereof of following logical formula I:
Wherein:
R1=H or methyl
R2=H or methyl or methoxy or chlorine or methylol or methylol ester or nitro or cyanogen
Base or acetyl group
In the present invention, preferred compound have following compound 1,2,3,4,5,6,7,8,9,10,
11,12,13,14,15,16,17,18,19,20,21,22,23,24,25 structure and
Officinal salt:
In the present invention, as a example by compound 6, its preparation process is as follows:
Compound of the present invention has carried out external Hedgehog signal path inhibitory activity testing experiment, result
Display, described compound has good Hedgehog signal path inhibitory activity, can prepare new further
The Hedgehog signal pathway inhibitor of type, and preparation is relevant with Hedgehog path with treatment for diagnosis
Pathological changes, include but not limited to tumor formation, cancer, neoplasia and the medicine of non-malignant excess proliferative disease.
The present invention is by external Hedgehog signal path inhibitory activity testing experiment, and result shows, the present invention
Compound demonstrate preferable Hedgehog signal path inhibitory activity, wherein compound 6,7,8,12,
14,15,16,18,19,20,23 and 25 for target gene Gli inhibitory activity IC in Hh signal path50
Value is less than 15nM for target gene Gli inhibitory activity IC in Hh signal path50Value is less than 10nM.Described change
Compound can prepare Hedgehog signal pathway inhibitor, and preparation for diagnosis and is treated and Hedgehog
The pathological changes that path is relevant, includes but not limited to tumor formation, cancer, neoplasia and non-malignant excess proliferative disease
Sick medicine.
The compound of the present invention is additionally operable to prepare the described compound comprising therapeutically effective amount and pharmaceutical salts thereof
Pharmaceutical composition.
In the present invention, the pharmacodynamics test method used, is method well-known to those skilled in the art；
In the present invention, the NIH3T3 cell used and Dual-Luciferase report detection kit are this areas
Technical staff can be obtained by commercial approach.
The aryl phthalazine compound containing piperazine or pyrrolidine or azetidine of the present invention and officinal salt thereof are outstanding
It can prepare Hedgehog signal pathway inhibitor and for diagnosis with treatment relevant with Hedgehog path
Pathological changes, includes but not limited to tumor formation, cancer, neoplasia and non-malignant excess proliferative disease.In view of different
Often activate the conduction of Hh signal, will cause medulloblastoma, breast carcinoma, carcinoma of prostate, pulmonary carcinoma, colon cancer,
The generation of the kinds of tumors such as bladder cancer, ovarian cancer；Therefore, malignant tumor of the present invention includes Hedgehog
Related neoplasms caused by signal path abnormal activation, including medulloblastoma, breast carcinoma, carcinoma of prostate, pulmonary carcinoma,
Colon cancer, bladder cancer, ovarian cancer, skin carcinoma.
Detailed description of the invention:
Embodiment 1: prepare compound 1, N-(1-(4-(1-methyl pyrazole-5-base)-phthalazines-1-base) piperidines-3-base)-4-fluorine
-2-trifluoromethyl benzamide
1) synthesis N-(1-Bezyl-piperidin-3-base)-4-fluoro-2-trifluoromethyl benzamide
In the eggplant-shape bottle of 50mL, it is sequentially added into 2-trifluoromethyl-4-fluobenzoic acid (546mg, 2.63mmol),
Super dry THF (10mL), EDC.HCl (1.0g, 5.26mmol), stirs 0.5h, adds DMAP (65 under room temperature
Mg, 0.53mmol), the air of argon displacement reaction system, drip compound N-benzyl-3-anilinic piperidines (500
Mg, 2.63mmol) super dry THF (5mL) solution.Drip complete, stirring at normal temperature 16h under ar gas environment,
TLC (PE:EA=1:1) detection reaction completely, adds saturated sodium bicarbonate solution (150mL), DCM (50mL × 3)
Extraction, merges organic layer, and saturated aqueous common salt (50mL × 1) washs, and anhydrous sodium sulfate is dried, and decompression boils off molten
Agent, obtains crude product 9.8g, silica gel column chromatography purification, PE:EA=2:1 eluting, obtains the product of purification: 4.3g (white
Color solid) productivity: 56.0%.1H NMR(400MHz,CDCl3)δ(ppm):1H NMR(400MHz,
CDCl3) δ 7.52 (dd, J=8.3,5.5Hz, 1H), 7.41 (dd, J=8.9,2.5Hz, 1H), 7.32 7.20 (m,
6H),6.50(br,1H),4.29(s,1H),3.55–3.38(m,2H),2.64(s,2H),2.45(s,1H),2.15(s,
1H),1.80(s,1H),1.79-1.59(m,4H).HPLC-MS(ESI+):[M+H]+:381.2.
2) synthesis N-(piperidines-3-base)-4-fluoro-2-trifluoromethyl benzamide
In the eggplant-shape bottle of 50mL, it is sequentially added into N-(1-Bezyl-piperidin-3-base)-4-fluoro-2-trifluoromethylbenzoyl
Amine (360mg, 0.95mmol), EtOH (20mL), displacement argon three times, add Pd/C (100mg), put
Changing hydrogen three times, stirring at normal temperature 18h, TLC (PE:EA=1:1) detection reaction completely, filters Pd/C, directly
Decompression boils off solvent, obtains product 0.24g (white solid), productivity: 87%.Without purification, it is directly used in down
Single step reaction.
3) synthesis N-(1-(4-chloro-phthalazines-1-base) piperidines-3-base)-4-fluoro-2-trifluoromethyl benzamide
In the eggplant-shape bottle of 50mL, it is sequentially added into N-(piperidines-3-base)-4-fluoro-2-trifluoromethyl benzamide (0.24
G, 0.83mmol), DMF (10mL), K2CO3(573mg, 4.15mmol), Isosorbide-5-Nitrae-dichloro phthalazines (200mg,
0.99mmol), the air in argon displacement system, lower 80 DEG C of stirrings 12h, TLC (PE:EA=1:1) of ar gas environment
Detection reaction completely, boils off DMF under vacuum, add EA and each 25mL of water, water layer EA (20mL × 3)
Extraction, merges organic layer, and saturated aqueous common salt (50mL × 1) washs, and anhydrous sodium sulfate is dried, and decompression boils off molten
Agent, obtains crude product 680mg, silica gel column chromatography purification, PE:EA=2:1～1:1 eluting, obtains the product 270 of purification
Mg (white solid) productivity: 72.0%.1H NMR(400MHz,CDCl3) δ (ppm): 8.21 (dd, J=6.3,
3.1Hz, 1H), 8.09 (dd, J=6.4,3.1Hz, 1H), 7.96 7.88 (m, 2H), 7.59 (dd, J=8.4,5.4
Hz, 1H), 7.38 (dd, J=8.9,2.5Hz, 1H), 7.29 (dd, J=8.0,2.4Hz, 1H), 4.45 (s, 1H),
3.83 (dd, J=13.0,2.8Hz, 1H), 3.66 3.50 (m, 3H), 2.10 1.94 (m, 4H) .HPLC-MS
(ESI+):[M+H]+:453.1.
4) synthesis N-(1-(4-(1-methyl pyrazole-5-base)-phthalazines-1-base) piperidines-3-base)-4-fluoro-2-trifluoromethylbenzoyl
Amine
By N-(1-(4-chloro-phthalazines-1-base) piperidines-3-base)-4-fluoro-2-trifluoromethyl benzamide (100mg, 0.22
Mmol) it is dissolved in meta-xylene (3mL) with 1-methyl pyrazole-5-pinacol borate (92mg, 0.44mmol),
Add potassium phosphate trihydrate (117mg, 0.44mmol), potassium fluoride (26mg, 0.44mmol), use argon
Air in displacement reaction bottle, adds four triphenyl phosphorus palladiums (25mg, 0.022mmol) of catalytic amount, microwave
Reaction (biotage microwave reacter, 120 DEG C, High absorption) radiation 3h, TLC (EA) detection is instead
Should, display reaction is complete, and solvent xylene is spin-dried for by post processing, adds 20mL water, by ethyl acetate (3 × 20
ML) extraction, merges organic layer, and saturated sodium-chloride (2 × 10mL) washs, and anhydrous sodium sulfate is dried.Filter,
Crude product 260mg, prepares thin layer purification, and EA launches to obtain the product 32mg (faint yellow solid) of purification, productivity
16%.1H NMR(400MHz,CDCl3) δ (ppm): 8.14 (d, J=8.1Hz, 1H), 8.03 (d, J=8.0
Hz, 1H), 7.89 (t, J=7.1Hz, 1H), 7.82 (t, J=7.1Hz, 1H), 7.68 7.56 (m, 2H), 7.37
(dd, J=8.9,2.4Hz, 1H), 7.30 7.26 (m, 1H), 6.56 (d, J=1.9Hz, 1H), 4.80 (br, 2H),
4.48(s,1H),3.96(s,3H),3.75–3.56(m,3H),2.11–2.00(m,2H),1.91–1.78(m,
2H).HPLC-MS(ESI+):[M+H]+:499.3.。
Embodiment 2: prepare compound 2, N-methyl-N-(1-(4-(1-methyl pyrazole-5-base)-phthalazines-1-base) piperidines-3-
Base)-4-fluoro-2-trifluoromethyl benzamide
1) synthesis N-methyl-N-(1-t-butoxycarbonyl-piperidin-3-base)-4-fluoro-2-trifluoromethyl benzamide
In the eggplant-shape bottle of 50mL, it is sequentially added into 2-trifluoromethyl-4-fluobenzoic acid (1.5g, 7.1mmol), super
Dry THF (25mL), EDC.HCl (1.8g, 9.3mmol), stirs 0.5h, adds DMAP (120 under room temperature
Mg, 0.93mmol), the air of argon displacement reaction system, drip compound N-tertbutyloxycarbonyl-3-amine methyl
Super dry THF (5mL) solution of piperidines (1.0g, 4.7mmol).Drip complete, stirring at normal temperature under ar gas environment
16h, TLC (PE:EA=1:1) detection reaction completely, adds saturated sodium bicarbonate solution (50mL), DCM (50
ML × 3) extraction, merge organic layer, saturated aqueous common salt (50mL × 1) washs, and anhydrous sodium sulfate is dried, decompression
Boil off solvent, obtain crude product 4.3g, silica gel column chromatography purification, PE:EA=2:1 eluting, obtain the product 2.6 of purification
G (white solid) productivity: 84.2%.HPLC-MS(ESI+):[M+H]+:405.3.
2) synthesis N-methyl-N-(piperidines-3-base)-4-fluoro-2-trifluoromethyl benzamide fluoroform sulphonate
In the eggplant-shape bottle of 50mL, it is sequentially added into N-methyl-N-(1-t-butoxycarbonyl-piperidin-3-base) the fluoro-2-of-4-
Trifluoromethyl benzamide (1.0g, 2.5mmol), DCM (10mL), trifluoracetic acid (1.5g, 12.5mmol),
Stirring at normal temperature 5h, TLC (PE:EA=1:1) detection reaction is complete, and direct solvent evaporated obtains product 1.1g (white
Color solid) productivity: 99%.Without purification, it is directly used in next step reaction.
3) synthesis N-methyl-N-(1-(4-chloro-phthalazines-1-base) piperidines-3-base)-4-fluoro-2-trifluoromethyl benzamide
In the eggplant-shape bottle of 50mL, it is sequentially added into N-methyl-N-(piperidines-3-base)-4-fluoro-2-trifluoromethylbenzoyl
Amine fluoroform sulphonate (1.1g, 2.5mmol), DMF (25mL), K2CO3(1.8g, 12.5mmol), Isosorbide-5-Nitrae-
Dichloro phthalazines (600mg, 3.0mmol), the air in argon displacement system, the lower 80 DEG C of stirring 12h of ar gas environment,
TLC (PE:EA=1:1) detection reaction completely, boils off DMF, adds EA and each 50mL of water, water under vacuum
Layer EA (50mL × 3) extraction, merges organic layer, and saturated aqueous common salt (50mL × 1) washs, and anhydrous sodium sulfate is dried,
Decompression boils off solvent, obtains crude product 1.6g, silica gel column chromatography purification, PE:EA=4:1～2:1 eluting, obtains purification
Product 0.4g (white solid) productivity: 34.0%.1H NMR(400MHz,CDCl3)δ(ppm):8.21(dd,
J=6.3,3.1Hz, 1H), 8.09 (dd, J=6.4,3.1Hz, 1H), 7.96 7.88 (m, 2H), 7.59 (dd, J=
8.4,5.4Hz, 1H), 7.38 (dd, J=8.9,2.5Hz, 1H), 7.29 (dd, J=8.0,2.4Hz, 1H), 5.03 (s,
1H), 3.96-3.89 (m, 2H), 3.38 3.17 (m, 1H), 3.09 (d, J=14.4Hz, 2H), 2.76 (s, 3H),
2.12-1.90(m,4H).HPLC-MS(ESI+):[M+H]+:467.1.
4) synthesis N-methyl-N-(1-(4-(1-methyl pyrazole-5-base)-phthalazines-1-base) piperidines-3-base)-4-fluoro-2-fluoroform
Yl-benzamide
By N-methyl-N-(1-(4-chloro-phthalazines-1-base) piperidines-3-base)-4-fluoro-2-trifluoromethyl benzamide (300
Mg, 0.64mmol) and 1-methyl pyrazole-5-pinacol borate (270mg, 1.3mmol) be dissolved in meta-xylene
(8mL), in, potassium phosphate trihydrate (350mg, 1.3mmol) is added, potassium fluoride (76mg, 1.3mmol),
With the air in argon displacement reaction bottle, add four triphenyl phosphorus palladiums (74mg, 0.064mmol) of catalytic amount,
Microwave reaction (biotage microwave reacter, 120 DEG C, High absorption) radiation 3h, TLC (EA) inspection
Measured reaction, display reaction is complete, and solvent xylene is spin-dried for by post processing, adds 20mL water, uses acetic acid
Ethyl ester (3 × 20mL) extracts, and merges organic layer, and saturated sodium-chloride (2 × 10mL) washs, and anhydrous sodium sulfate is dried.
Filtering, obtain crude product 460mg, prepare thin layer purification, EA launches to obtain the product of purification: 123mg is (faint yellow
Solid), productivity 37.5%.1H NMR(400MHz,CDCl3) δ (ppm): 8.05 (t, J=7.5Hz, 1H),
7.92 (t, J=7.6Hz, 1H), 7.82 (dd, J=7.8,4.8Hz, 2H), 7.65 (d, J=1.6Hz, 1H),
7.41-7.30 (m, 3H), 6.59 (dd, J=7.7,1.7Hz, 1H), 5.08 (s, 1H), 4.13 3.77 (m, 5H),
3.44 3.24 (m, 1H), 3.11 (d, J=11.8Hz, 1H), 2.78 (s, 2H), 2.15-2.03 (m, 2H),
1.93-1.70(m,2H).HPLC-MS(ESI+):[M+H]+:513.3.。
Embodiment 3: preparing compound 3, (2-trifluoromethyl-4-is fluoro-for-6-for 2-(4-(1-methylpyrazole-5-base) phthalazines-1-base)
Benzoyl)-2,6-diaza spiro [3,3] heptane
1) synthesis 2-tertbutyloxycarbonyl-6-(the fluoro-benzoyl of 2-trifluoromethyl-4-)-2,6-diaza spiro [3,3] heptane
In the eggplant-shape bottle of 50mL, it is sequentially added into 2-trifluoromethyl-4-fluobenzoic acid (1.5g, 7.1mmol), super
Dry THF (25mL), EDC.HCl (1.8g, 9.3mmol), stirs 0.5h, adds DMAP (120 under room temperature
Mg, 0.93mmol), the air of argon displacement reaction system, surpassing of dropping compound 11 (1.0g, 7.4mmol)
Dry THF (5mL) solution.Dripping complete, stirring at normal temperature 16h under ar gas environment, TLC (PE:EA=1:3) examines
Measured reaction is complete, adds saturated sodium bicarbonate solution (50mL), and DCM (50mL × 3) extracts, and merges organic layer,
Saturated aqueous common salt (50mL × 1) washs, and anhydrous sodium sulfate is dried, and decompression boils off solvent, obtains crude product 2.3g, silicon
Gel column chromatography eluting, PE:EA=1:1～1:3 eluting, obtain the product of purification: 1.4g (white solid) productivity:
50.8%.HPLC-MS(ESI+):[M+H]+:389.2.
2) synthesis 2-(the fluoro-benzoyl of 2-trifluoromethyl-4-)-2,6-diaza spiro [3,3] heptane fluoroform sulphonate
In the eggplant-shape bottle of 50mL, it is sequentially added into 2-tertbutyloxycarbonyl-6-(the fluoro-benzoyl of 2-trifluoromethyl-4-
Base)-2,6-diaza spiro [3,3] heptane (1.0g, 2.6mmol), DCM (10mL), trifluoracetic acid (1.5g, 12.5
Mmol), stirring at normal temperature 5h, TLC (PE:EA=1:1) detection reaction is complete, and direct solvent evaporated obtains product
1.1g (white solid) productivity: 99%.Without purification, it is directly used in next step reaction.
3) synthesis 2-(4-chlorine phthalazines-1-base)-6-(the fluoro-benzoyl of 2-trifluoromethyl-4-)-2,6-diaza spiro [3,3] heptane
In the eggplant-shape bottle of 50mL, it is sequentially added into 2-(the fluoro-benzoyl of 2-trifluoromethyl-4-)-2,6-diaza spiro
[3,3] heptane fluoroform sulphonate (1.1g, 2.6mmol), DMF (25mL), K2CO3(1.8g,12.5
Mmol), Isosorbide-5-Nitrae-dichloro phthalazines (600mg, 3.0mmol), the air in argon displacement system, under ar gas environment
80 DEG C of stirring 12h, TLC (PE:EA=1:1) detection reactions completely, boil off DMF under vacuum, add EA and
The each 50mL of water, water layer EA (50mL × 3) extract, and merge organic layer, and saturated aqueous common salt (50mL × 1) washs,
Anhydrous sodium sulfate is dried, and decompression boils off solvent, obtains crude product 1.6g, silica gel column chromatography purification, PE:EA=1:1～1:3
Eluting, obtains product 0.28g (white solid) productivity of purification: 23.8%.HPLC-MS(ESI+):[M+H]+:
451.1.
4) synthesis 2-(4-(1-methylpyrazole-5-base) phthalazines-1-base)-6-(the fluoro-benzoyl of 2-trifluoromethyl-4-)-2,6-phenodiazine
Miscellaneous spiral shell [3,3] heptane
By 2-(4-chlorine phthalazines-1-base)-6-(the fluoro-benzoyl of 2-trifluoromethyl-4-)-2,6-diaza spiro [3,3] heptane
(200mg, 0.44mmol) and 1-methyl pyrazole-5-pinacol borate (270mg, 1.3mmol) be dissolved between two
In toluene (8mL), add potassium phosphate trihydrate (350mg, 1.3mmol), and potassium fluoride (76mg, 1.3
Mmol), with the air in argon displacement reaction bottle, add catalytic amount four triphenyl phosphorus palladiums (74mg, 0.064
Mmol), microwave reaction (biotage microwave reacter, 120 DEG C, High absorption) radiation 3h,
TLC (EA) detects reaction, and display reaction is complete, and solvent xylene is spin-dried for by post processing, adds 20mL water,
Extracting by ethyl acetate (3 × 20mL), merge organic layer, saturated sodium-chloride (2 × 10mL) washs, anhydrous slufuric acid
Sodium is dried.Filtering, obtain crude product 460mg, prepare thin layer purification, DCM:MeOH=15:1 launches to obtain purification
Product 23mg (faint yellow solid), productivity 3.5%.1H NMR(400MHz,CDCl3)δ(ppm):7.99
(d, J=8.1Hz, 1H), 7.90 (d, J=8.0Hz, 1H), 7.81 (t, J=7.1Hz, 1H), 7.62 (t, J=7.1
Hz, 1H), 7.46 7.40 (m, 2H), 7.36 (dd, J=8.9,2.4Hz, 1H), 7.32 7.28 (m, 1H),
6.52 (d, J=1.9Hz, 1H), 4.75 (s, 2H), 4.68 (s, 2H), 4.46 (s, 2H), 4.13 (s, 2H), 3.98 (s,
3H).HPLC-MS(ESI+):[M+H]+:497.3.。
Embodiment 4: prepare compound 4, N-(1-(4-(1-methyl pyrazole-5-base) phthalazines-1-base) azetidine-3-
Base)-4-fluoro-2-trifluoromethyl benzamide
1) synthesis N-(1-tertbutyloxycarbonyl-azetidine-3-base)-4-fluoro-2-trifluoromethyl benzamide
In the eggplant-shape bottle of 50mL, it is sequentially added into 2-trifluoromethyl-4-fluobenzoic acid (900mg, 4.4mmol),
Super dry THF (10mL), EDC.HCl (1.1g, 5.8mmol), stirs 0.5h, adds DMAP (71 under room temperature
Mg, 0.58mmol), the air of argon displacement reaction system, drip compound 1-tertbutyloxycarbonyl-azetidin
Super dry THF (5mL) solution of-3-amine (500mg, 2.9mmol).Dripping complete, under ar gas environment, room temperature stirs
Mix 16h, TLC (PE:EA=1:1) detection reaction completely, add saturated sodium bicarbonate solution (50mL),
DCM (50mL × 3) extracts, and merges organic layer, and saturated aqueous common salt (50mL × 1) washs, and anhydrous sodium sulfate is dried,
Decompression boils off solvent, obtains crude product 9.8g, silica gel column chromatography purification, PE:EA=1:1 eluting, obtains the product of purification
Thing 1.1g (white solid) productivity: 69.0%.HPLC-MS(ESI+):[M+H]+:363.2.
2) synthesis N-(azetidine-3-base)-4-fluoro-2-trifluoromethyl benzamide trifluoroacetate
In the eggplant-shape bottle of 50mL, it is sequentially added into N-(1-tertbutyloxycarbonyl-azetidine-3-base) the fluoro-2-of-4-tri-
Methyl fluoride Benzoylamide (1.0g, 2.76mmol), DCM (20mL), trifluoracetic acid (1.6g, 18.8mmol),
Stirring at normal temperature 5h, completely, directly decompression boils off solvent, obtains product 1.1g in TLC (PE:EA=1:1) detection reaction
(white solid) productivity: 99%.Without purification, it is directly used in next step reaction.
3) synthesis N-(1-(4-chlorine phthalazines-1-base) azetidine-3-base)-4-fluoro-2-trifluoromethyl benzamide
In the eggplant-shape bottle of 50mL, it is sequentially added into N-(azetidine-3-base)-4-fluoro-2-trifluoromethylbenzoyl
Amine trifluoroacetate (0.76g, 1.1mmol), DMF (20mL), K2CO3(760mg, 5.5mmol), Isosorbide-5-Nitrae-
Dichloro phthalazines (440mg, 2.2mmol), the air in argon displacement system, the lower 80 DEG C of stirring 12h of ar gas environment,
TLC (PE:EA=2:1) detection reaction completely, boils off DMF, adds EA and each 50mL of water, water under vacuum
Layer EA (20mL × 3) extraction, merges organic layer, and saturated aqueous common salt (50mL × 1) washs, and anhydrous sodium sulfate is dried,
Decompression boils off solvent, obtains crude product 1.4g, silica gel column chromatography purification, PE:EA=2:1～1:2 eluting, obtains purification
Product: 0.27g (white solid) productivity: 57.8%.[M+H]+:425.1.
4) synthesis N-(1-(4-(1-methyl pyrazole-5-base) phthalazines-1-base) azetidine-3-base)-4-fluoro-2-trifluoromethyl
Benzoylamide
By N-(1-(4-chlorine phthalazines-1-base) azetidine-3-base)-4-fluoro-2-trifluoromethyl benzamide (100
Mg, 0.24mmol) and 1-methyl pyrazole-5-pinacol borate (92mg, 0.44mmol) be dissolved in meta-xylene
(3mL), in, potassium phosphate trihydrate (117mg, 0.44mmol) is added, and potassium fluoride (26mg, 0.44
Mmol), with the air in argon displacement reaction bottle, add catalytic amount four triphenyl phosphorus palladiums (25mg, 0.022
Mmol), microwave reaction (biotage microwave reacter, 120 DEG C, High absorption) radiation 3h,
TLC (EA) detects reaction, and display reaction is complete, and solvent xylene is spin-dried for by post processing, adds 20mL water,
Extracting by ethyl acetate (3 × 20mL), merge organic layer, saturated sodium-chloride (2 × 10mL) washs, anhydrous slufuric acid
Sodium is dried.Filtering, obtain crude product 160mg, prepare thin layer purification, EA launches three times to obtain the product of purification: 22
Mg (faint yellow solid), productivity 10.6%.1H NMR(400MHz,CDCl3) δ (ppm): 7.94 (dt, J=
8.9,5.9Hz, 2H), 7.84 7.65 (m, 2H), 7.62 (t, J=2.1Hz, 1H), 7.48 7.39 (m, 1H),
7.38–7.22(m,2H),6.51(s,1H),6.00-5.71(m,1H),5.34–5.31(m,1H),3.94(s,
3H),3.84-3.79(m,2H),3.21-3.17(m,2H)HPLC-MS(ESI+):[M+H]+:471.3.。
Embodiment 5: prepare compound 5, N-methyl-N-(1-(4-(1-methyl pyrazole-5-base) phthalazines-1-base) azetidin
Alkane-3-base)-4-fluoro-2-trifluoromethyl benzamide
1) synthesis N-methyl-N-(1-tertbutyloxycarbonyl-azetidine-3-base)-4-fluoro-2-trifluoromethyl benzamide
In the eggplant-shape bottle of 50mL, it is sequentially added into 2-trifluoromethyl-4-fluobenzoic acid (1.7g, 8.1mmol), super
Dry THF (20mL), EDC.HCl (2.1g, 10.8mmol), stirs 0.5h, adds DMAP (132 under room temperature
Mg, 1.08mmol), the air of argon displacement reaction system, drip compound (1-tertbutyloxycarbonyl-azetidin
Alkane-3-base) super dry THF (5mL) solution of-methylamine (1.0g, 5.4mmol).Drip complete, under ar gas environment often
Temperature stirring 16h, TLC (PE:EA=1:1) detection reaction completely, adds saturated sodium bicarbonate solution (50mL),
DCM (50mL × 3) extracts, and merges organic layer, and saturated aqueous common salt (50mL × 1) washs, and anhydrous sodium sulfate is dried,
Decompression boils off solvent, obtains crude product 2.4g, silica gel column chromatography purification, PE:EA=1:1 eluting, obtains the product of purification
Thing: 1.1g (white solid) productivity: 36.1%.HPLC-MS(ESI+):[M+H]+:377.3.
2) synthesis N-methyl-N-(azetidine-3-base)-4-fluoro-2-trifluoromethyl benzamide trifluoroacetate
In the eggplant-shape bottle of 50mL, it is sequentially added into N-methyl-N-(1-tertbutyloxycarbonyl-azetidine-3-base)-4-
Fluoro-2-trifluoromethyl benzamide (1.0g, 2.66mmol), DCM (20mL), trifluoracetic acid (1.6g, 18.8
Mmol), stirring at normal temperature 5h, completely, directly decompression boils off solvent in TLC (PE:EA=1:1) detection reaction,
Product 1.1g (white solid) productivity: 99%.Without purification, it is directly used in next step reaction.
3) synthesis N-methyl-N-(1-(4-chlorine phthalazines-1-base) azetidine-3-base)-4-fluoro-2-trifluoromethyl benzamide
In the eggplant-shape bottle of 50mL, it is sequentially added into N-methyl-N-(azetidine-3-base)-4-fluoro-2-trifluoromethyl
Benzoylamide trifluoroacetate (1.7g, 4.7mmol), DMF (20mL), K2CO3(3.3g, 23.5mmol),
Isosorbide-5-Nitrae-dichloro phthalazines (1.2g, 5.6mmol), the air in argon displacement system, the lower 80 DEG C of stirrings 12 of ar gas environment
H, TLC (PE:EA=1:1) detection reaction completely, boils off DMF, adds EA and each 50mL of water under vacuum,
Water layer EA (20mL × 3) extracts, and merges organic layer, and saturated aqueous common salt (50mL × 1) washs, and anhydrous sodium sulfate is done
Dry, decompression boils off solvent, obtains crude product 1.4g, silica gel column chromatography purification, PE:EA=2:1～1:2 eluting, obtains pure
Product 0.27g (white solid) productivity changed: 13.1%.HPLC-MS(ESI+):[M+H]+:439.1.
4) synthesis N-methyl-N-(1-(4-(1-methyl pyrazole-5-base) phthalazines-1-base) azetidine-3-base) the fluoro-2-of-4-
Trifluoromethyl benzamide
By N-methyl-N-(1-(4-chlorine phthalazines-1-base) azetidine-3-base)-4-fluoro-2-trifluoromethyl benzamide
(160mg, 0.36mmol) and 1-methyl pyrazole-5-pinacol borate (114mg, 0.55mmol) be dissolved between two
In toluene (3mL), add potassium phosphate trihydrate (200mg, 0.73mmol), and potassium fluoride (48mg, 0.73
Mmol), with the air in argon displacement reaction bottle, add catalytic amount four triphenyl phosphorus palladiums (46mg, 0.04
Mmol), microwave reaction (biotage microwave reacter, 120 DEG C, High absorption) radiation 3h,
TLC (EA) detects reaction, and display reaction is complete, and solvent xylene is spin-dried for by post processing, adds 20mL water,
Extracting by ethyl acetate (3 × 20mL), merge organic layer, saturated sodium-chloride (2 × 10mL) washs, anhydrous slufuric acid
Sodium is dried.Filtering, obtain crude product 160mg, prepare thin layer purification, DCM:MeOH launches to obtain the product of purification:
16mg (faint yellow solid), productivity 6.0%.1H NMR(400MHz,CDCl3) δ (ppm): 7.96 (dt, J=
8.9,5.9Hz, 2H), 7.74 7.55 (m, 2H), 7.52 (t, J=2.1Hz, 1H), 7.37 7.28 (m, 1H),
7.26–7.12(m,2H),6.44(s,1H),6.00-5.71(m,1H),5.34–5.31(m,1H),3.94(s,
3H),3.84-3.79(m,2H),3.21-3.17(m,2H),2.83(s,3H).HPLC-MS(ESI+):
[M+H]+:485.3.。
Embodiment 6: prepare compound 6, N-(1-(4-(1-methyl pyrazole-5-base)-phthalazines-1-base) pyrroles's-3-base)-4-
Fluoro-2-trifluoromethyl benzamide
1) synthesis N-(1-tertbutyloxycarbonyl-pyrroles's-3-base)-4-fluoro-2-trifluoromethyl benzamide
In the eggplant-shape bottle of 50mL, it is sequentially added into 2-trifluoromethyl-4-fluobenzoic acid (2.0g, 9.6mmol), super
Dry THF (50mL), EDC.HCl (4.4g, 19.2mmol), stirs 0.5h, adds DMAP (235 under room temperature
Mg, 1.92mmol), the air of argon displacement reaction system, drip compound 1-tertbutyloxycarbonyl-3-amido pyrrole
Cough up super dry THF (5mL) solution of (1.79g, 9.6mmol).Drip complete, stirring at normal temperature 16 under ar gas environment
H, TLC (PE:EA=1:1) detection reaction completely, adds saturated sodium bicarbonate solution (150mL), DCM (100
ML × 3) extraction, merge organic layer, saturated aqueous common salt (100mL × 1) washs, and anhydrous sodium sulfate is dried, decompression
Boil off solvent, obtain crude product 3.3g, silica gel column chromatography purification, PE:EA=2:1 eluting, obtain the product 2.3 of purification
G (white solid) productivity: 63.6%.HPLC-MS(ESI+):[M+H]+:377.2.
2) synthesis N-(pyrroles's-3-base)-4-fluoro-2-trifluoromethyl benzamide fluoroform sulphonate
In the eggplant-shape bottle of 50mL, it is sequentially added into N-(1-tertbutyloxycarbonyl-pyrroles's-3-base)-4-fluoro-2-trifluoromethyl
Benzoylamide (2.2g, 5.84mmol), DCM (50mL), trifluoracetic acid (1.6g, 18.8mmol), room temperature stirs
Mixing 5h, TLC (PE:EA=1:1) detection reaction completely, directly decompression boils off solvent, obtains product 2.2g (white
Solid) productivity: 99%.Without purification, it is directly used in next step reaction.
3) synthesis N-(1-(4-chloro-phthalazines-1-base) pyrroles's-3-base)-4-fluoro-2-trifluoromethyl benzamide
In the eggplant-shape bottle of 50mL, it is sequentially added into N-(pyrroles's-3-base)-4-fluoro-2-trifluoromethyl benzamide trifluoro
Mesylate (2.2g, 5.9mmol), DMF (20mL), K2CO3(4.0g, 29mmol), Isosorbide-5-Nitrae-dichloro phthalazines
(1.4g, 7.08mmol), the air in argon displacement system, ar gas environment lower 80 DEG C of stirrings 12h, TLC
(PE:EA=1:1) detection reaction is completely, boils off DMF under vacuum, adds EA and each 50mL of water, water layer
EA (50mL × 3) extracts, and merges organic layer, and saturated aqueous common salt (50mL × 1) washs, and anhydrous sodium sulfate is dried,
Decompression boils off solvent, obtains crude product 3.6g, silica gel column chromatography purification, PE:EA=4:1～1:1～1:2 eluting, obtains pure
Product 2.3g (white solid) productivity changed: 88.9%.HPLC-MS(ESI+):[M+H]+:439.9.
4) synthesis N-(1-(4-(1-methyl pyrazole-5-base)-phthalazines-1-base) pyrroles's-3-base)-4-fluoro-2-trifluoromethylbenzoyl
Amine
By N-(1-(4-chloro-phthalazines-1-base) pyrroles's-3-base)-4-fluoro-2-trifluoromethyl benzamide (200mg, 0.46
And 1-methyl pyrazole-5-pinacol borate (189mg, 0.92mmol) is dissolved in meta-xylene (3mL) mmol)
In, add potassium phosphate trihydrate (245mg, 0.92mmol), potassium fluoride (54mg, 0.92mmol), use
Air in argon displacement reaction bottle, adds four triphenyl phosphorus palladiums (58mg, 0.05mmol) of catalytic amount, micro-
Ripple reaction (biotage microwave reacter, 120 DEG C, High absorption) radiation 3h, TLC (EA) detection
Reaction, solvent xylene completely, is spin-dried for, adds 20mL water, with ethyl acetate (3 × 20mL) by display reaction
Extraction, merges organic layer, and saturated sodium-chloride (2 × 10mL) washs, and anhydrous sodium sulfate is dried.Filter, obtain slightly
Product 260mg, prepares thin layer purification, and EA launches three times to obtain the product 35mg (faint yellow solid) of purification, produces
Rate 13.8%.1H NMR(400MHz,CDCl3)δ(ppm):8.24–8.02(m,1H),8.01–7.92
(m,1H),7.86–7.64(m,2H),7.55–7.46(m,2H),7.41-7.29(m,5H),5.47(br,1H),
4.20-3.74(m,5H),2.45(s,3H),2.26–1.91(m,2H).HPLC-MS(ESI+):[M+H]+:
485.3.。
Embodiment 7: prepare compound 7, Isosorbide-5-Nitrae-dichloro phthalazines N-methyl-N-(1-(4-(4-methylphenyl)-phthalazines-1-base)
Pyrroles's-3-base)-4-fluoro-2-trifluoromethyl benzamide
1) synthesis N-methyl-N-(1-tertbutyloxycarbonyl-pyrroles's-3-base)-4-fluoro-2-trifluoromethyl benzamide
In the eggplant-shape bottle of 50mL, it is sequentially added into 2-trifluoromethyl-4-fluobenzoic acid (1.2g, 5.8mmol), super
Dry THF (50mL), EDC.HCl (1.9g, 9.6mmol), stirs 0.5h, adds DMAP (140 under room temperature
Mg, 0.96mmol), the air of argon displacement reaction system, drip compound 1-tertbutyloxycarbonyl-3-amine methyl
Super dry THF (5mL) solution of pyrroles (1.0g, 4.8mmol).Drip complete, stirring at normal temperature under ar gas environment
16h, TLC (PE:EA=1:1) detection reaction completely, adds saturated sodium bicarbonate solution (50mL), DCM (50
ML × 3) extraction, merge organic layer, saturated aqueous common salt (50mL × 1) washs, and anhydrous sodium sulfate is dried, decompression
Boil off solvent, obtain crude product 2.1g, silica gel column chromatography purification, PE:EA=2:1 eluting, obtain the product 1.0 of purification
G (white solid) productivity: 44.2%.HPLC-MS(ESI+):[M+H]+:391.2.
2) synthesis N-methyl-N-(pyrroles's-3-base)-4-fluoro-2-trifluoromethyl benzamide fluoroform sulphonate
In the eggplant-shape bottle of 50mL, it is sequentially added into N-methyl-N-(1-tertbutyloxycarbonyl-pyrroles's-3-base) the fluoro-2-of-4-
Trifluoromethyl benzamide (0.9g, 2.3mmol), DCM (10mL), trifluoracetic acid (0.9g, 9.4mmol),
Stirring at normal temperature 5h, completely, directly decompression boils off solvent, obtains product: 1.0 in TLC (PE:EA=1:1) detection reaction
G (white solid) productivity: 99%.Without purification, it is directly used in next step reaction.
3) synthesis N-methyl-N-(1-(4-chloro-phthalazines-1-base) pyrroles's-3-base)-4-fluoro-2-trifluoromethyl benzamide
In the eggplant-shape bottle of 50mL, it is sequentially added into N-methyl-N-(pyrroles's-3-base)-4-fluoro-2-trifluoromethylbenzoyl
Amine fluoroform sulphonate (1.0g, 2.2mmol), DMF (20mL), K2CO3(1.8g, 12.8mmol), Isosorbide-5-Nitrae-
Dichloro phthalazines (0.61g, 3.1mmol), the air in argon displacement system, the lower 80 DEG C of stirring 12h of ar gas environment,
TLC (PE:EA=1:1) detection reaction completely, boils off DMF, adds EA and each 50mL of water, water under vacuum
Layer EA (50mL × 3) extraction, merges organic layer, and saturated aqueous common salt (50mL × 1) washs, and anhydrous sodium sulfate is dried,
Decompression boils off solvent, obtains crude product 1.3g, silica gel column chromatography purification, PE:EA=1:1～1:2 eluting, obtains purification
Product 0.78g (white solid) productivity: 78.3%.1H NMR(400MHz,CDCl3)δ(ppm):8.22–
8.05(m,2H),7.91–7.78(m,2H),7.46–7.26(m,3H),5.43(br,1H),4.25–3.63(m,
5H),2.81(s,3H),2.43–2.07(m,2H).HPLC-MS(ESI+):[M+H]+:453.1.
4) synthesis N-methyl-N-(1-(4-(4-methylphenyl)-phthalazines-1-base) pyrroles's-3-base)-4-fluoro-2-trifluoromethylbenzene first
Amide
By N-methyl-N-(1-(4-chloro-phthalazines-1-base) pyrroles's-3-base)-4-fluoro-2-trifluoromethyl benzamide (200
Mg, 0.44mmol) and 4-methylphenylboronic acid pinacol ester (120mg, 0.88mmol) be dissolved in meta-xylene (3mL)
In, add potassium phosphate trihydrate (235mg, 0.88mmol), potassium fluoride (52mg, 0.88mmol), use
Air in argon displacement reaction bottle, adds four triphenyl phosphorus palladiums (51mg, 0.044mmol) of catalytic amount,
Microwave reaction (biotage microwave reacter, 120 DEG C, High absorption) radiation 3h, TLC (EA) inspection
Measured reaction, display reaction is complete, and solvent xylene is spin-dried for by post processing, adds 20mL water, uses acetic acid
Ethyl ester (3 × 20mL) extracts, and merges organic layer, and saturated sodium-chloride (2 × 10mL) washs, and anhydrous sodium sulfate is dried.
Filtering, obtain crude product 250mg, prepare thin layer purification, the product 33mg that EA launches three times to obtain purification is (yellowish
Color solid), productivity 14.7%.1H NMR(400MHz,CDCl3)δ(ppm):8.28–8.06(m,1H),
8.05–7.94(m,1H),7.85–7.68(m,2H),7.65–7.49(m,2H),7.43-7.33(m,5H),
5.47(br,1H),4.20-3.74(m,5H),2.83(s,3H),2.45(s,3H),2.26–1.91(m,
2H).HPLC-MS(ESI+):[M+H]+:509.3.。
Embodiment 8: prepare compound 8, Isosorbide-5-Nitrae-dichloro phthalazines N-methyl-N-(1-(4-(4-methylol-phenyl)-phthalazines-1-
Base) pyrroles's-3-base)-4-fluoro-2-trifluoromethyl benzamide
By N-methyl-N-(1-(4-chloro-phthalazines-1-base) pyrroles's-3-base)-4-fluoro-2-trifluoromethyl benzamide (200
Mg, 0.44mmol) and 4-methylol phenylboric acid pinacol ester (208mg, 1.37mmol) be dissolved in a dioxane
(3mL), in, add cesium carbonate (446mg, 1.37mmol), potassium fluoride (80mg, 1.37mmol), use argon
Air in gas displacement reaction bottle, adds four triphenyl phosphorus palladiums (51mg, 0.044mmol) of catalytic amount, micro-
Ripple reaction (biotage microwave reacter, 120 DEG C, High absorption) radiation 3h, TLC (EA) detection
Reaction, display reaction is complete, and solvent dioxane is spin-dried for by post processing, adds 20mL water, uses acetic acid
Ethyl ester (3 × 20mL) extracts, and merges organic layer, and saturated sodium-chloride (2 × 10mL) washs, and anhydrous sodium sulfate is dried.
Filtering, obtain crude product 320mg, prepare thin layer purification, EA launches three times to obtain the product of purification: 27mg is (yellowish
Color solid), productivity 11.7%.1H NMR(400MHz,CDCl3)δ(ppm):8.28–8.08(m,1H),
7.96 (d, J=7.8Hz, 1H), 7.84 7.69 (m, 2H), 7.69 7.57 (m, 2H), 7.52 7.28 (m,
5H),5.45(br,1H),4.77(s,2H),4.30–3.68(m,5H),2.83(s,2H),2.21–1.87(m,
2H).HPLC-MS(ESI+):[M+H]+:525.3.。
Embodiment 9: prepare compound 9,3-(N-(4-(1-methyl pyrazole-5-base)-phthalazines-1-base)) amino-1-(the fluoro-2-of 4-
Trifluoromethvl-benzovl)-pyrroles
1) synthesis 3-(N-(4-chloro-phthalazines-1-base)) amino-1-tertbutyloxycarbonyl-pyrroles
In 10mL microwave tube, by Isosorbide-5-Nitrae-dichloro phthalazines (800mg, 4.5mmol) and 1-tertbutyloxycarbonyl-3-ammonia
Base pyrroles (800mg, 4.0mmol) is dissolved in a N-methyl ketopyrrolidine (5mL), add triethylamine (1.8mL,
12.9mmol), with the air in argon displacement reaction bottle, microwave reaction (biotage microwave reacter,
180 DEG C, High absorption) radiation 2h, TLC (PE:EA=1:1) detection reaction, display is reacted completely, after
Processing, reactant liquor joins 50mL water, extracts by ethyl acetate (3 × 50mL), merges organic layer, saturated
Sodium chloride (3 × 30mL) washs, and anhydrous sodium sulfate is dried.Filter, obtain crude product 1.9g, silica gel column chromatography purification,
PE:EA=2:1～1:1 eluting, obtains the product 27mg (faint yellow solid) of purification, productivity 11.7%.1H NMR
(400MHz,CDCl3) δ (ppm): 8.16 (d, J=7.5Hz, 1H), 7.93 (d, J=7.5Hz, 1H), 7.90
7.81(m,2H),5.59(s,1H),4.90-4.86(m,1H),3.83(br,1H),3.55–3.38(m,3H),2.33
(br,1H),2.09(br,1H),1.43(s,9H).HPLC-MS(ESI+):[M+H]+:525.1.
2) synthesis 3-(N-(4-(1-methyl pyrazole-5-base)-phthalazines-1-base)) amino-1-tertbutyloxycarbonyl-pyrroles
By 3-(N-(4-chloro-phthalazines-1-base)) amino-1-tertbutyloxycarbonyl-pyrroles (900mg, 2.3mmol) and 1-
Methyl pyrazole-5-pinacol borate (973mg, 4.7mmol) is dissolved in dimethylbenzene (3mL), adds phosphoric acid
Potassium trihydrate (1.25g, 4.7mmol), potassium fluoride (273mg, 4.7mmol), with in argon displacement reaction bottle
Air, add four triphenyl phosphorus palladiums (266mg, 0.23mmol) of catalytic amount, microwave reaction (biotage
Microwave reacter, 120 DEG C, High absorption) radiation 2h, TLC (EA) detection reaction, display reaction
Completely, post processing, solvent dioxane is spin-dried for, adds 50mL water, extract by ethyl acetate (2 × 50mL)
Taking, merge organic layer, saturated sodium-chloride (1 × 50mL) washs, and anhydrous sodium sulfate is dried.Filter, obtain crude product
The product 700mg that 1.7g, silica gel column chromatography purification, PE:EA=2:1～1:1～1:3 eluting obtain purification is (faint yellow
Solid), productivity 77.2%.1H NMR(400MHz,CDCl3) δ (ppm): 8.04 (s, 1H), 7.94 (d, J=
7.0Hz,1H),7.86–7.72(m,2H),7.60(s,1H),6.51(s,1H),5.94(br,1H),5.07–4.93
(m,1H),3.97(s,3H),3.93–3.74(m,1H),3.66–3.35(m,3H),2.38(br,1H),2.11(br,
1H),1.43(s,9H).HPLC-MS(ESI+):[M+H]+:395.3.
3) synthesis 3-(N-(4-(1-methyl pyrazole-5-base)-phthalazines-1-base)) amino-pyrroles's fluoroform sulphonate
In the eggplant-shape bottle of 50mL, it is sequentially added into 3-(N-(4-(1-methyl pyrazole-5-base)-phthalazines-1-base)) amino-1-
Tertbutyloxycarbonyl-pyrroles (700mg, 1.77mmol), DCM (50mL), trifluoracetic acid (1.6g, 18.8
Mmol), stirring at normal temperature 5h, completely, directly decompression boils off solvent in TLC (PE:EA=1:1) detection reaction,
Product: 800mg (white solid) productivity: 99%.Without purification, it is directly used in next step reaction.
4) synthesis 3-(N-(4-(1-methyl pyrazole-5-base)-phthalazines-1-base)) amino-pyrroles
Compound 3-(N-(4-(1-methyl pyrazole-5-base)-phthalazines-1-base)) amino-pyrroles's fluoroform sulphonate
(800mg, 1.7mmol), is dissolved in the saturated solution (100mL) of sodium carbonate, and 40% sodium hydrate aqueous solution is adjusted
PH to about 10, n-butanol extraction (4 × 50mL), the crude product 900mg being evaporated, it is directly used in next step anti-
Should.
5) synthesis 3-(N-(4-(1-methyl pyrazole-5-base)-phthalazines-1-base)) amino-1-(4-fluoro-2-Trifluoromethyl-phenacyl
Base)-pyrroles
In the eggplant-shape bottle of 50mL, it is sequentially added into 4-fluoro-2-trifluoromethylbenzene boronic acid (400mg, 1.92mmol),
Super dry THF (50mL), EDC.HCl (600mg, 3.13mmol), stirs 0.5h, adds under room temperature
DMAP (140mg, 0.33mmol), the air of argon displacement reaction system, drip compound 3-(N-(4-(1-
Methyl pyrazole-5-base)-phthalazines-1-base)) the super dry THF (5mL) of amino-pyrroles (300mg, 1.0mmol) is molten
Liquid.Dripping complete, stirring at normal temperature 16h under ar gas environment, TLC (EA) detection reaction completely, adds saturated
Sodium bicarbonate solution (50mL), DCM (50mL × 3) extracts, and merges organic layer, saturated aqueous common salt (50mL × 1)
Washing, anhydrous sodium sulfate is dried, and decompression boils off solvent, obtains crude product 560mg, prepares thin layer purification, EA exhibition
Open three times, obtain the product 27mg (faint yellow solid) of purification, productivity 5.6%.1H NMR(400MHz,
CDCl3) δ (ppm): 7.94 (dt, J=8.9,5.9Hz, 2H), 7.84 7.65 (m, 2H), 7.62 (t, J=2.1
Hz,1H),7.48–7.39(m,1H),7.38–7.22(m,2H),6.51(s,1H),6.00-5.71(m,1H),
5.19–4.96(m,1H),4.09–4.01(m,1H),3.94(s,3H),3.86–3.72(m,1H),3.40–
3.30(m,1H),2.54-2.47(m,1H),2.31–2.13(m,1H).HPLC-MS(ESI+):
[M+H]+:485.3.。
Embodiment 10: prepare compound 10, N-(1-(4-(1-methyl pyrazole-4-base) phthalazines-1-base) azetidine-3-
Base)-4-fluoro-2-trifluoromethyl benzamide
By N-(1-(4-chlorine phthalazines-1-base) azetidine-3-base)-4-fluoro-2-trifluoromethyl benzamide (200
Mg, 0.47mmol) and 1-methyl pyrazole-5-pinacol borate (148mg, 0.55mmol) be dissolved in meta-xylene
(3mL), in, potassium phosphate trihydrate (200mg, 0.73mmol) is added, and potassium fluoride (48mg, 0.73
Mmol), with the air in argon displacement reaction bottle, add catalytic amount four triphenyl phosphorus palladiums (46mg, 0.04
Mmol), microwave reaction (biotage microwave reacter, 120 DEG C, High absorption) radiation 3h,
TLC (EA) detects reaction, and display reaction is complete, and solvent xylene is spin-dried for by post processing, adds 20mL water,
Extracting by ethyl acetate (3 × 20mL), merge organic layer, saturated sodium-chloride (2 × 10mL) washs, anhydrous slufuric acid
Sodium is dried.Filtering, obtain crude product 160mg, prepare thin layer purification, DCM:MeOH=20:1 launches to obtain purification
Product: 22mg (faint yellow solid), productivity 9.95%.1H NMR(400MHz,CDCl3)δ(ppm):
7.94 (dt, J=8.9,5.9Hz, 2H), 7.84 7.65 (m, 2H), 7.62 (t, J=2.1Hz, 1H), 7.48
7.39(m,1H),7.38–7.22(m,2H),6.51(s,1H),6.00-5.71(m,1H),5.34–5.31(m,
1H),3.94(s,3H),3.84-3.79(m,2H),3.21-3.17(m,2H)HPLC-MS(ESI+):
[M+H]+:471.3.。
Embodiment 11: prepare compound 11, N-methyl-N-(1-(4-(1-methyl pyrazole-4-base) phthalazines-1-base) azacyclo-
Butane-3-base)-4-fluoro-2-trifluoromethyl benzamide
By raw material N-methyl-N-(1-(4-chlorine phthalazines-1-base) azetidine-3-base)-4-fluoro-2-trifluoromethylbenzene first
Amide (160mg, 0.36mmol) and 1-methyl pyrazole-5-pinacol borate (114mg, 0.55mmol) are molten
In meta-xylene (3mL), add potassium phosphate trihydrate (200mg, 0.73mmol), potassium fluoride (48mg,
0.73mmol), with the air in argon displacement reaction bottle, add catalytic amount four triphenyl phosphorus palladiums (46mg,
0.04mmol), microwave reaction (biotage microwave reacter, 120 DEG C, High absorption) radiation 3h,
TLC (EA) detects reaction, and display reaction is complete, and solvent xylene is spin-dried for by post processing, adds 20mL water,
Extracting by ethyl acetate (3 × 20mL), merge organic layer, saturated sodium-chloride (2 × 10mL) washs, anhydrous slufuric acid
Sodium is dried.Filtering, obtain crude product 160mg, prepare thin layer purification, DCM:MeOH=15:1 launches to obtain purification
Product 18mg (faint yellow solid), productivity 10.2%.1H NMR(400MHz,CDCl3)δ(ppm):
7.96 (dt, J=8.9,5.9Hz, 2H), 7.74 7.55 (m, 2H), 7.52 (t, J=2.1Hz, 1H), 7.37
7.28(m,1H),7.26–7.12(m,2H),6.44(s,1H),6.00-5.71(m,1H),5.34–5.31(m,
1H),3.94(s,3H),3.84-3.79(m,2H),3.21-3.17(m,2H),2.83(s,3H).HPLC-MS
(ESI+):[M+H]+:485.3.。
Embodiment 12: prepare compound 12, N-(1-(4-(the chloro-phenyl of 2-)-phthalazines-1-base) pyrroles's-3-base) the fluoro-2-of-4-tri-
Methyl fluoride Benzoylamide
By N-(1-(4-chloro-phthalazines-1-base) pyrroles's-3-base)-4-fluoro-2-trifluoromethyl benzamide (200mg, 0.46
Mmol) it is dissolved in meta-xylene (3mL) with 2-chloro-phenylboric acid pinacol ester (146mg, 0.91mmol), then adds
Enter potassium phosphate trihydrate (245mg, 0.92mmol), potassium fluoride (54mg, 0.92mmol), replace with argon
Air in reaction bulb, adds four triphenyl phosphorus palladiums (58mg, 0.05mmol) of catalytic amount, microwave reaction
(biotage microwave reacter, 120 DEG C, High absorption) radiation 3h, TLC (EA) detection reaction,
Display reaction is complete, and solvent xylene is spin-dried for by post processing, adds 20mL water, with ethyl acetate (3 × 20mL)
Extraction, merges organic layer, and saturated sodium-chloride (2 × 10mL) washs, and anhydrous sodium sulfate is dried.Filter, obtain slightly
Product 260mg, prepares thin layer purification, and EA launches three times to obtain the product of purification: 36mg (faint yellow solid),
Productivity 15.2%.1H NMR(400MHz,CDCl3) δ (ppm): 8.09 (d, J=7.9Hz, 1H), 7.92 (d,
J=6.7Hz, 1H), 7.70 7.59 (m, 2H), 7.58 7.49 (m, 1H), 7.49 7.39 (m, 2H), 7.39
7.15 (m, 3H), 7.05 (t, J=7.0Hz, 1H), 4.81 (s, 1H), 4.32 4.09 (m, 2H), 3.87-3.77 (m,
1H),2.30-2.12(m,2H).HPLC-MS(ESI+):[M+H]+:515.1.。
Embodiment 13: prepare compound 13, N-(1-(4-(1-methyl pyrazole-4-base) phthalazines-1-base) pyrrolidin-3-yl)-4-
Fluoro-2-trifluoromethyl benzamide
With the synthesis of compound 14, add 1-methyl pyrazole-4-pinacol borate (189mg, 0.92mmol).
Product: 33mg (faint yellow solid) productivity: 15.1%.1H NMR(400MHz,DMSO-d6)δ(ppm):
8.88 (d, J=6.5Hz, 1H), 8.30 8.26 (m, 1H), 8.22 (s, 1H), 8.19 8.14 (m, 1H), 7.91
7.84 (m, 3H), 7.69 (dd, J=9.2,2.1Hz, 1H), 7.63 7.55 (m, 2H), 4.55 (d, J=6.4
Hz, 1H), 4.16 (dd, J=11.0,5.9Hz, 1H), 4.05 3.92 (m, 4H), 3.85 (dd, J=13.4,9.2
Hz, 1H), 3.74 (dd, J=11.0,3.5Hz, 1H), 2.24 (dd, J=12.7,5.5Hz, 1H), 2.10-2.01 (m,
1H).HPLC-MS(ESI+):[M+H]+:485.3.。
Embodiment 14: prepare compound 14, N-(1-(4-(4-aminomethyl phenyl) phthalazines-1-base) pyrrolidin-3-yl) the fluoro-2-of-4-
Trifluoromethyl benzamide
With the synthesis of compound 12, add 4-methyl-phenylboric acid pinacol ester (200mg, 0.92mmol).
Product: 27mg (faint yellow solid) productivity: 12.1%.1H NMR(400MHz,DMSO-d6)δ(ppm):
8.89 (d, J=6.5Hz, 1H), 8.30 (d, J=8.1Hz, 1H), 7.90 7.78 (m, 3H), 7.69 (dd, J=
9.3,2.2Hz, 1H), 7.65 7.58 (m, 2H), 7.49 (d, J=8.0Hz, 2H), 7.34 (d, J=8.0Hz,
2H), 4.55 (s, 1H), 4.19 (dd, J=11.0,5.9Hz, 1H), 4.08 3.98 (m, 1H), 3.88 (dd, J=
13.3,9.4Hz, 1H), 3.78 (dd, J=11.1,3.4Hz, 1H), 2.39 (s, 3H), 2.25 (dd, J=12.7,5.6
Hz,1H),2.10-2.01(m,1H).HPLC-MS(ESI+):[M+H]+:495.3.。
Embodiment 15: prepare compound 15, N-(1-(4-(4-chlorphenyl) phthalazines-1-base) pyrrolidin-3-yl) the fluoro-2-of-4-tri-
Methyl fluoride Benzoylamide
With the synthesis of compound 12, add 4-chloro-phenylboric acid pinacol ester (220mg, 0.92mmol).
Product: 31mg (faint yellow solid) productivity: 13.4%.1H NMR(400MHz,DMSO-d6)δ(ppm):
8.89 (d, J=6.4Hz, 1H), 8.34 (d, J=7.8Hz, 1H), 7.90-7.78 (m, 3H), 7.73 7.56 (m,
7H), 4.56 (s, 1H), 4.22 (dd, J=11.0,5.9Hz, 1H), 4.08 3.98 (m, 1H), 3.91 (dd, J=
13.3,9.4Hz, 1H), 3.81 (dd, J=11.1,3.4Hz, 1H), 2.25 (dd, J=12.7,5.6Hz, 1H),
2.10-2.01(m,1H).HPLC-MS(ESI+):[M+H]+:515.1.。
Embodiment 16: prepare compound 16, N-(1-(4-(4-hydroxymethyl phenyl) phthalazines-1-base) pyrrolidin-3-yl)-4-fluorine
-2-trifluoromethyl benzamide
With the synthesis of compound 12, add 4-chloro-phenylboric acid pinacol ester (220mg, 0.92mmol).
Product: 37mg (faint yellow solid) productivity: 16.1%.1H NMR(400MHz,DMSO-d6)δ(ppm):
8.89 (d, J=6.5Hz, 1H), 8.31 (d, J=8.0Hz, 1H), 7.89-7.80 (m, 3H), 7.69 (dd, J=9.4,
2.0Hz, 1H), 7.64 7.53 (m, 4H), 7.48 (d, J=8.0Hz, 2H), 5.30 (t, J=5.7Hz, 1H),
4.62 4.53 (m, 3H), 4.19 (dd, J=11.1,5.9Hz, 1H), 4.04 (dd, J=18.1,7.5Hz, 1H),
3.89 (dd, J=13.3,9.1Hz, 1H), 3.79 (dd, J=11.1,3.4Hz, 1H), 2.25 (dd, J=12.9,5.6
Hz,1H),2.10-2.01(m,1H).HPLC-MS(ESI+):[M+H]+:511.3.。
Embodiment 17: prepare compound 17, N-(1-(4-phenyl phthalazines-1-base) pyrrolidin-3-yl)-4-fluoro--2-fluoroform
Yl-benzamide
With the synthesis of compound 12, add phenylboric acid pinacol ester (188mg, 0.92mmol).
Product: 31mg (faint yellow solid) productivity: 14.3%.1H NMR(400MHz,DMSO-d6)δ(ppm):
8.89 (d, J=6.3Hz, 1H), 8.33 (d, J=8.0Hz, 1H), 7.90-7.79 (m, 3H), 7.69 (dd, J=9.4,
2.0Hz, 1H), 7.64 7.47 (m, 7H), 4.56 (s, 1H), 4.21 (dd, J=11.0,6.0Hz, 1H), 4.05
(dd, J=18.0,7.8Hz, 1H), 3.90 (dd, J=13.3,9.1Hz, 1H), 3.80 (dd, J=11.1,3.4Hz,
1H), 2.26 (dd, J=13.4,5.6Hz, 1H), 2.10-2.01 (m, 1H) .HPLC-MS (ESI+):[M+H]+:
481.3.。
Embodiment 18: prepare compound 18, N-(1-(4-(4-nitrobenzophenone) phthalazines-1-base) pyrrolidin-3-yl) the fluoro-2-of-4-
Trifluoromethyl benzamide
With the synthesis of compound 12, add p-nitrophenyl pinacol borate (229mg, 0.92mmol).
Product: 17mg (faint yellow solid) productivity: 7.2%.1H NMR(400MHz,DMSO-d6)δ(ppm):
8.90 (d, J=6.3Hz, 1H), 8.39-8.34 (m, 2H), 7.96 7.82 (m, 4H), 7.69 (d, J=9.2Hz,
1H), 7.62-7.51 (m, 4H), 4.56 (s, 1H), 4.23 (dd, J=10.9,5.8Hz, 1H), 4.07 (dd, J=
18.0,7.8Hz, 1H), 3.93 (dd, J=13.3,9.1Hz, 1H), 3.83 (dd, J=11.1,3.4Hz, 1H),
2.25 (dd, J=13.4,5.6Hz, 1H), 2.10-2.01 (m, 1H) .HPLC-MS (ESI+):[M+H]+:
526.3.。
Embodiment 19: prepare compound 19, N-(1-(4-(4-cyano-phenyl) phthalazines-1-base) pyrrolidin-3-yl) the fluoro-2-of-4-
Trifluoromethyl benzamide
With the synthesis of compound 12, add p-nitrophenyl pinacol borate (210mg, 0.92mmol).
Product: 22mg (faint yellow solid) productivity: 9.7%.1H NMR(400MHz,DMSO-d6)δ(ppm):
8.89 (d, J=6.5Hz, 1H), 8.34 (d, J=8.6Hz, 1H), 8.01 (d, J=8.3Hz, 2H), 7.92
7.76 (m, 5H), 7.69 (dd, J=9.3,2.2Hz, 1H), 7.64 7.54 (m, 2H), 4.56 (s, 1H), 4.22
(dd, J=11.2,5.9Hz, 1H), 4.06 (dd, J=18.5,7.4Hz, 1H), 3.96 3.89 (m, 1H), 3.82
(dd, J=11.2,3.4Hz, 1H), 2.26 (dd, J=13.0,5.3Hz, 1H), 2.13 2.07 (m, 1H).
HPLC-MS(ESI+):[M+H]+:506.3.。
Embodiment 20: prepare compound 20, N-(1-(4-(pyridin-4-yl) phthalazines-1-base) pyrrolidin-3-yl) the fluoro-2-of-4-
Trifluoromethyl benzamide (24)
With the synthesis of compound 12, add pyridine-3-pinacol borate (189mg, 0.92mmol).
Product: 28mg (faint yellow solid) productivity: 12.9%.1H NMR(400MHz,DMSO-d6)δ(ppm):
8.89 (d, J=6.1Hz, 1H), 8.74 (d, J=4.6Hz, 2H), 8.34 (d, J=7.7Hz, 1H), 7.91-7.82
(m, 3H), 7.70-7.55 (m, 5H), 4.56 (s, 1H), 4.23 (dd, J=10.8,5.8Hz, 1H), 4.06 (dd, J=
18.5,7.4Hz, 1H), 3.92 (dd, J=13.3,9.1Hz, 1H), 3.82 (dd, J=11.2,3.4Hz, 1H),
2.25 (dd, J=13.0,5.3Hz, 1H), 2.13 2.07 (m, 1H) .HPLC-MS (ESI+):[M+H]+:
482.3.。
Embodiment 21: prepare compound 21, R-N-(1-(4-(4-acetoxyl group is for aminomethyl phenyl) phthalazines-1-base) pyrroles
Alkane-3-base)-4-fluoro-2-trifluoromethyl benzamide
50mL three-necked bottle adds R-N-(1-(4-(4-hydroxymethyl phenyl) phthalazines-1-base) pyrrolidin-3-yl)-4-fluorine
-2-trifluoromethyl benzamide (500mg, 0.98mmol), adds the excess of imports and does THF (10mL) dissolving, add
K2CO3(405mg, 2.93mmol), the air of argon displacement reaction system, syringe addition acetic anhydride (0.3g,
2.93mmol), completely, reduce pressure lower solvent evaporated, residue in return stirring 4h, TLC (EA) monitoring reaction
Adding ethyl acetate, each 20mL of water, separatory, water layer EA (20mL × 2) extracts, and merges organic layer, saturated
Sodium chloride (50mL × 1) washs, and anhydrous sodium sulfate is dried, and is spin-dried for solvent, obtains crude product 540mg, prepares thin layer
Chromatography purification, EA launches, obtains product 410mg (faint yellow solid) productivity of purification: 75.7%.1H NMR
(400MHz,DMSO-d6) δ (ppm): 8.90 (d, J=6.5Hz, 1H), 8.34 (d, J=7.9Hz, 1H), 7.92
7.81 (m, 3H), 7.71 (dd, J=9.4,2.3Hz, 1H), 7.65-7.62 (m, 3H), 7.56 (d, J=8.2Hz,
2H),5.20(s,2H),4.58(br,1H),4.27-4.20(m,1H),4.11–4.03(m,1H),3.93-3.89(m,
1H),3.83-3.80(m,1H),2.29-2.26(m,1H),2.13(s,3H),2.10-2.07(m,
1H).HPLC-MS(ESI+):[M+H]+:552.8.。
Embodiment 22: prepare compound 22, S-N-(1-(4-(4-hydroxymethyl phenyl) phthalazines-1-base) pyrrolidin-3-yl)-4-
Fluoro-2-trifluoromethyl benzamide
Compound 16 chirality HPLC splits the compound 22 obtaining S configuration, [а]D=55.7 (25 DEG C,
C=1g/100mL), ee=95%.
1H NMR(400MHz,DMSO-d6)δ(ppm):9.56(s,1H),7.99-7.93(m,2H),7.84(s,1H),
7.77-7.51(m,6H),7.44–7.24(m,2H),4.63(s,1H),4.31(s,1H),4.17–3.85(m,
3H),3.61-3.44(m,2H),2.41(s,2H),2.30(br,1H),2.16(br,1H).HPLC-MS(ESI+):
[M+H]+:511.3.。
Embodiment 23: prepare compound 23, R-N-(1-(4-(4-hydroxymethyl phenyl) phthalazines-1-base) pyrrolidin-3-yl)-4-
Fluoro-2-trifluoromethyl benzamide
Compound 16 chirality HPLC splits the compound 23 obtaining R configuration, [а]D=-54.8 (25 DEG C,
C=1g/100mL), ee=94%.
1H NMR(400MHz,DMSO-d6)δ(ppm):9.57(s,1H),7.84(s,1H),7.81–7.71(m,
1H), 7.59 (s, 3H), 7.34 7.24 (m, 1H), 7.13 6.92 (m, 3H), 6.58 (d, J=7.3Hz, 2H),
4.76 (s, 1H), 4.48 4.29 (m, 1H), 4.08 (dd, J=10.7,5.3Hz, 1H), 3.76 3.64 (m, 1H),
3.59-3.57(m,1H),2.40(s,4H),2.30-2.22(m,2H).HPLC-MS(ESI+):[M+H]+:
511.3.。
Embodiment 24: prepare compound 24, S-N-(1-(4-(4-aminomethyl phenyl) phthalazines-1-base) pyrrolidin-3-yl)-4-
Fluoro-2-trifluoromethyl benzamide
Compound 14 chiral column splits the compound 24 obtaining S configuration, [а]D=57.6 (25 DEG C, C=1g/100
ML), ee=95%.
1H NMR(400MHz,DMSO-d6)δ(ppm):9.28(s,1H),7.86(s,1H),7.74–7.53
(m, 4H), 7.27 (d, J=7.1Hz, 3H), 6.98 (t, J=7.3Hz, 1H), 6.77 (d, J=7.2Hz, 2H),
4.69 (d, J=11.6Hz, 3H), 4.34 (d, J=7.1Hz, 1H), 4.07 (d, J=5.3Hz, 1H), 3.76
3.49(m,2H),2.81–2.64(m,1H),2.31-2.25(m,2H).HPLC-MS(ESI+):[M+H]+:
495.3.。
Embodiment 25: prepare compound 25, R-N-(1-(4-(4-aminomethyl phenyl) phthalazines-1-base) pyrrolidin-3-yl)-4-
Fluoro-2-trifluoromethyl benzamide
Compound 14 chiral column splits the compound 25 obtaining R configuration, [а]D=-58.4 (25 DEG C, C=1g/100
ML), ee=95%.
1H NMR(400MHz,DMSO-d6)δ(ppm):9.27(s,1H),7.85(s,1H),7.76–7.66
(m, 1H), 7.59 (s, 3H), 7.27 (d, J=6.8Hz, 3H), 6.99 (t, J=7.4Hz, 1H), 6.76 (d, J=
7.3Hz, 2H), 4.70 (s, 3H), 4.42 4.29 (m, 1H), 4.09-4.05 (m, 1H), 3.68 (d, J=10.0
Hz, 1H), 3.59 (d, J=10.8Hz, 1H), 2.56-2.50 (m, 1H), 2.38 2.23 (m, 2H) .HPLC-MS
(ESI+):[M+H]+:495.3.。
Embodiment 26: external Hedgehog signal path inhibitory activity testing experiment
The luciferase reporter gene experiment of transcription factor Gli: NIH3T3 cell is seeded to 48 orifice plates, 24h
After with lipo2000 transfection reagent transfect Gli-firefly luciferase reporter and TK-Renilla luciferase
Reporter carrier is to NIH3T3 cell.After transfection 36h, SHH and the medicine to be measured recombinated in Mus source add to
(often group sets 3 multiple holes to 48 orifice plates；N=3).After cellar culture 36h, cell PBS washes 1 time, with double glimmering
Light element enzyme report detection kit (Promega company) measures Gli-luciferase activity, as judging Hh
Pathway activity index.
Result shows (as shown in table 1), and described compound demonstrates preferable Hedgehog signal path
Inhibitory activity, wherein compound 6,7,8,12,14,15,16,18,19,20,23 and 25 for
Target gene Gli inhibitory activity IC in Hh signal path50Value is less than 15nM.Described compound can enter one
Step develops Hedgehog signal pathway inhibitor, as new type antineoplastic medicine.
Table 1 is the vitro inhibition Activity Results of the Hedgehog signal path of the compounds of this invention.
Table 1
Claims (30)
1. aryl phthalazine compound, it is characterised in that described compound is containing piperazine or pyrrolidine or azetidin
The aryl phthalazine compound of alkane, has structure and the officinal salt thereof of logical formula (I),
Wherein:
R1=H or methyl
Pyridine
R2=H or methyl or methoxy or chlorine or methylol or methylol ester or nitro or cyanogen
Base or acetyl group.
Aryl phthalazine compound the most according to claim 1, is characterized in that, under described compound is for having
State the compound 1 of structure,
Aryl phthalazine compound the most according to claim 1, is characterized in that, under described compound is for having
State the compound 2 of structure,
Aryl phthalazine compound the most according to claim 1, is characterized in that, under described compound is for having
State the compound 3 of structure,
Aryl phthalazine compound the most according to claim 1, is characterized in that, under described compound is for having
State the compound 4 of structure,
Aryl phthalazine compound the most according to claim 1, is characterized in that, under described compound is for having
State the compound 5 of structure,
Aryl phthalazine compound the most according to claim 1, is characterized in that, under described compound is for having
State the compound 6 of structure,
Aryl phthalazine compound the most according to claim 1, is characterized in that, under described compound is for having
State the compound 7 of structure,
Aryl phthalazine compound the most according to claim 1, is characterized in that, under described compound is for having
State the compound 8 of structure,
Aryl phthalazine compound the most according to claim 1, is characterized in that, under described compound is for having
State the compound 9 of structure,
11. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 10 of structure,
12. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 11 of structure,
13. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 12 of structure,
14. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 13 of structure,
15. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 14 of structure,
16. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 15 of structure,
17. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 16 of structure,
18. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 17 of structure,
19. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 18 of structure,
20. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 19 of structure,
21. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 20 of structure,
22. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 21 of structure,
23. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 22 of structure,
24. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 23 of structure,
25. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 24 of structure,
26. aryl phthalazine compounds according to claim 1, is characterized in that, under described compound is for having
State the compound 25 of structure,
The aryl phthalazine compound of 27. claim 1 and officinal salt thereof are at preparation Hedgehog signal pathway inhibitor
In purposes.
The aryl phthalazine compound of 28. claim 1 purposes in preparation treatment malignant tumor medicine.
29. purposes according to claim 28, it is characterised in that described malignant tumor is that Hedgehog signal leads to
Related neoplasms caused by the abnormal activation of road, including medulloblastoma, breast carcinoma, carcinoma of prostate, pulmonary carcinoma, colon
Cancer, bladder cancer, ovarian cancer, skin carcinoma.
Compound described in 30. claim 1 comprising therapeutically effective amount and the pharmaceutical composition of pharmaceutical salts thereof.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101657430A (en) * | 2007-03-15 | 2010-02-24 | 诺瓦提斯公司 | organic compounds and their uses |
| CN102066353A (en) * | 2008-04-29 | 2011-05-18 | 伊莱利利公司 | Disubstituted phthalazine Hedgehog pathway antagonists |
| CN102202737A (en) * | 2008-11-03 | 2011-09-28 | 伊莱利利公司 | Disubstituted phthalazine hedgehog pathway antagonists |
| CN102459233A (en) * | 2009-06-19 | 2012-05-16 | 伊莱利利公司 | Disubstituted phthalazine hedgehog pathway antagonists |
| WO2014191736A1 (en) * | 2013-05-28 | 2014-12-04 | Redx Pharma Limited | Heterocyclic compounds as hedgehog signaling pathway inhibitors |
-
2015
- 2015-02-11 CN CN201510070469.7A patent/CN105985319B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101657430A (en) * | 2007-03-15 | 2010-02-24 | 诺瓦提斯公司 | organic compounds and their uses |
| CN102066353A (en) * | 2008-04-29 | 2011-05-18 | 伊莱利利公司 | Disubstituted phthalazine Hedgehog pathway antagonists |
| CN102202737A (en) * | 2008-11-03 | 2011-09-28 | 伊莱利利公司 | Disubstituted phthalazine hedgehog pathway antagonists |
| CN102459233A (en) * | 2009-06-19 | 2012-05-16 | 伊莱利利公司 | Disubstituted phthalazine hedgehog pathway antagonists |
| WO2014191736A1 (en) * | 2013-05-28 | 2014-12-04 | Redx Pharma Limited | Heterocyclic compounds as hedgehog signaling pathway inhibitors |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107163028A (en) * | 2017-05-24 | 2017-09-15 | 东南大学 | A kind of benzamides Hedgehog inhibitor and its preparation method and application |
| CN107163028B (en) * | 2017-05-24 | 2019-07-12 | 东南大学 | A kind of benzamides Hedgehog inhibitor and its preparation method and application |
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| CN105985319B (en) | 2019-02-26 |
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