CN106749192B - A kind of nicotinoyl pyrazoline class compound and its medicinal usage - Google Patents

A kind of nicotinoyl pyrazoline class compound and its medicinal usage Download PDF

Info

Publication number
CN106749192B
CN106749192B CN201710028733.XA CN201710028733A CN106749192B CN 106749192 B CN106749192 B CN 106749192B CN 201710028733 A CN201710028733 A CN 201710028733A CN 106749192 B CN106749192 B CN 106749192B
Authority
CN
China
Prior art keywords
base
och
zyl
compound
dmso
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201710028733.XA
Other languages
Chinese (zh)
Other versions
CN106749192A (en
Inventor
邹美娟
吴晶晶
陈徐冠
张雅亮
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Medical University
Original Assignee
Nanjing Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing Medical University filed Critical Nanjing Medical University
Priority to CN201710028733.XA priority Critical patent/CN106749192B/en
Publication of CN106749192A publication Critical patent/CN106749192A/en
Application granted granted Critical
Publication of CN106749192B publication Critical patent/CN106749192B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

The invention discloses a kind of nicotinoyl pyrazoline class compound and pharmaceutically can at salt, have the following structure formula:Wherein, R1For H, Br or OCH3；R2For H, F, Cl, Br or OCH3；R3For H, Cl, OCH3、CH3.Compound of the present invention has good antitumor action, low to the toxicity of normal cell, is candidate anti-tumor drug safely, effectively, less toxic.

Description

A kind of nicotinoyl pyrazoline class compound and its medicinal usage
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of nicotinoyl pyrazoline class compound and its medicinal usage.
Background technique
Tumour is body under the action of various tumorigenesis factors, the cell paraplasm of local organization and the new life that is formed Object often shows as local lump.Tumour cell have the function of abnormal form, metabolism and.It grows vigorous and is often in duration Growth.In recent years, tumour especially malignant tumour, which has become, seriously threatens one of disease of human health.In the whole world more than 50 Malignant tumour person is died of in hundred million populations every year on average up to 6,900,000 people, new cases are 8,700,000, and number is in continuous increase. The methods of chemotherapy, radiotherapy, operation, biological therapy and western medicines in treatment have become the most efficient method for the treatment of tumour.With The development of the drug of tumour, novel anti-tumor drug are being continuously updated the replacement, in the cure rate for improving tumor patient, extend The survival of patients time delays disease etc. and has played huge effect.For many years, people constantly develop new antineoplastic Object, and pass through structure of modification, it is intended to develop anti-tumor drug derivative new in a series.
The chemical structure transformation of drug is based on the original basic chemical structure of drug, to some of them functional group It learns transformation or by two or more there is identical or different active chemical structure to be combined, obtain this kind of drug New derivative.Original physicochemical property and pharmacological activity may be changed by structure, had in clinical application extremely heavy The effect wanted.
Qin Ya-Juan etc. devise it is a kind of have inhibit the active pyrazoline compounds of microtubule polymerization (Design, synthesis and biological evaluation of novel pyrazoline-containing derivatives as potential tubulin assembling inhibitors.European Journal of Medicinal Chemistry 94 (2015) 447-457), there is certain inhibition tumour cell to increase for external activity experiment display Grow activity.
Summary of the invention
The present invention has carried out structure of modification in prior art basis, to pyrazoline compounds, has obtained a new class of Nicotinoyl pyrazoline class compound with good anti-tumor activity and pharmaceutically can at salt, have the following structure formula:
Wherein, R1For H, Br or OCH3；R2For H, F, Cl, Br or OCH3；R3For H, Cl, OCH3、CH3。
Above compound and pharmaceutically can at salt, preferably R2For H, 4-F, 4-Cl, 4-Br, 3-OCH3Or 4-OCH3、3,4- OCH3Or 3,4,5-OCH3, R3For H, 2-Cl, 6-Cl, 6-CH3、6-OCH3。
Preferred compounds of the invention is as follows:
R1For H, R2For H, 3,4,5-OCH3, R3For H, 2-Cl, 6-Cl, 6-CH3、6-OCH3；
Alternatively, R1For Br, R2For H, 4-F, 4-Cl, 4-Br, 4-OCH3、3,4-OCH3Or 3,4,5-OCH3, R3For H, 6- OCH3；Alternatively, R1For OCH3, R2For H, 4-F, 4-Cl, 4-Br, 3-OCH3、4-OCH3、3,4-OCH3Or 3,4,5-OCH3, R3For H, 6-CH3Or 6-OCH3。
More preferable compound is as follows:
Compound R1 R2 R3
ZYL-1 (formula I) H H H
ZYL-2 (formula I) H H 6-Cl
ZYL-3 (formula II) H H H
ZYL-4 (formula I) H H 6-CH3
ZYL-5 (formula I) H H 2-Cl
ZYL-6 (formula I) H H 6-OCH3
ZYL-7 (formula I) H 3,4,5-OCH3 6-CH3
ZYL-8 (formula I) Br 4-Cl H
ZYL-9 (formula I) Br 3,4,5-OCH3 H
ZYL-10 (formula II) Br 3,4-OCH3 H
ZYL-11 (formula I) Br 4-F H
ZYL-12 (formula I) Br 4-Br H
ZYL-13 (formula I) Br 3,4-OCH3 H
ZYL-14 (formula I) Br 4-OCH3 H
ZYL-15 (formula I) Br H 6-OCH3
ZYL-16 (formula I) OCH3 H H
ZYL-17 (formula I) OCH3 H 6-OCH3
ZYL-18 (formula I) OCH3 4-F 6-OCH3
ZYL-19 (formula I) OCH3 4-Cl 6-OCH3
ZYL-20 (formula I) OCH3 4-Br 6-OCH3
ZYL-21 (formula I) OCH3 4-OCH3 6-OCH3
ZYL-22 (formula I) OCH3 3,4,5-OCH3 6-OCH3
ZYL-23 (formula I) OCH3 3-OCH3 H
ZYL-24 (formula I) OCH3 3-OCH3 6-CH3
ZYL-25 (formula I) OCH3 3-OCH3 6-OCH3
Compound of the present invention and pharmaceutically can at salt can be administered in the form of single medicine or can be with it Its administered in combination.
The officinal salt of the compound of the present invention includes various inorganic or acylate such as hydrochloride, hydrobromate, phosphoric acid Salt, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalates；It is various Inorganic or organic alkali salt such as sodium hydroxide, trishydroxymethylaminomethane and N- methyl-glucamine.
It is of the invention additionally provide nicotinoyl pyrazoline class compound of the present invention and pharmaceutically can at salt preparing Application in anti-tumor drug.The preferred breast cancer of the tumour, lung cancer, liver cancer etc..
The present invention also provides a kind of antineoplastic pharmaceutical compositions, including nicotinoyl pyrazoline class compound of the present invention And pharmaceutically can at salt and pharmaceutical carrier.The antineoplastic pharmaceutical compositions include the change of the invention as active constituent Close object or its officinal salt and pharmaceutical acceptable carrier.Preferably, pharmaceutical composition of the invention has 0.1-99.9% weight percent As the compound of the present invention of active constituent or its officinal salt.
" pharmaceutical acceptable carrier " includes but is not limited to: ion exchange material, aluminium oxide, aluminum stearate, lecithin, self-emulsifying medicine Object transmission system (SEDDS) such as d- TPGS 1000, tween or other similar polymerisation medium drug The surfactant of preparation, haemocyanin such as human serum albumins, buffer substance such as phosphate, amion acetic acid, sorbic acid, mountain Potassium sorbate, the mixing of saturated vegetable fatty acid partial glyceride, water, salt, electrolyte such as sulfate protamine, disodium hydrogen phosphate, phosphorus Potassium hydrogen phthalate, sodium chloride, zinc salt, silica gel, magnesium silicate etc..Polyvinyl pyrrolidone, cellulosic material, polyvinyl alcohol, carboxymethyl cellulose Plain sodium, polyacrylate, ethylene-polyoxyethylene-block polymer and lanolin, cyclodextrin such as α-, β-, gamma-cyclodextrin or its The hydroxyalkyl cyclodextrins such as the derivative through chemical modification such as 2- and 3- hydroxypropyl-β-cyclodextrin or other soluble derivatives etc. are equal It can be used for promoting the drug delivery of the compound of the present invention, its pharmaceutical salts or prodrug.
Other pharmaceutically acceptable auxiliaries such as filler (such as Lactis Anhydrous, starch, lactose bead and glucose), adhesive are (such as micro- Crystalline cellulose), disintegrating agent (such as crosslinked carboxymethyl fecula sodium, croscarmellose sodium, low-substituted hydroxypropyl cellulose and friendship Join PVP), lubricant (such as magnesium stearate), sorbefacient, flavouring agent, sweetener, diluent, excipient, wetting agent, solvent, Solubilizer and colorant etc. can also be added in pharmaceutical composition of the invention.
The compound or pharmaceutically acceptable salt thereof and pharmaceutical composition of aforementioned present invention can pass through enteron aisle or parenteral route Administration.Non-intestinal drug delivery agent includes injection, creme, ointment, patch, spray etc..Administration route includes subcutaneous, skin In interior, intra-arterial, intravenous, intramuscular, intra-articular, synovia, breastbone is interior, intrathecal, intralesional, intracranial injection or infusion, alternatively, mouth Clothes, part, rectum, intranasal, buccal, vagina, sublingual, intradermal, mucous membrane, tracheae, urethral administration, or pass through sucking aerosol or plant Enter accumulation or needle thorn mode is administered.
The compound or pharmaceutically acceptable salt thereof of aforementioned present invention and the therapeutically effective amount of pharmaceutical composition are 0.001- Between 100mg/kg/d, it can be used for single drug or the drug combination treatment of related disease, can be managed for those skilled in the art The range of solution.
The present invention has investigated nicotinoyl pyrazoline class Compound ira vitro of the present invention to human liver cancer cell (HepG2), people The inhibiting effect of breast cancer cell (MCF-7) and human lung adenocarcinoma cell (A549) and to the thin of people's renal epithelial cell (293T) Nicotinoyl pyrazoline class compound of the present invention has good antitumor action to cellular toxicity as the result is shown, to normal cell Toxicity is low, is candidate anti-tumor drug safely, effectively, less toxic.
Specific embodiment
Illustrate specific steps of the invention by the following examples, but is not limited by the example.
Term as used in the present invention generally there are those of ordinary skill in the art usually to manage unless otherwise indicated The meaning of solution.
The present invention is described in further detail combined with specific embodiments below and referring to data.It should be understood that these embodiments are only It is in order to demonstrate the invention, rather than to limit the scope of the invention in any way.
In the examples below, the various processes and method being not described in detail are conventional methods as known in the art.
The preparation of the nicotinoyl pyrazoline class compound of the present invention of embodiment 1
Nicotinoyl pyrazoline class compound of the present invention and pharmaceutically can at salt can be prepared as follows.
Specifically the preparation method comprises the following steps: sequentially adding POCl into reaction vessel under condition of ice bath3(20mL) and DMF (40mL), compound 1 (35mmol) react 2h, pour into ice water and adjust PH to 9.0 with NaOH, drying is extracted with ethyl acetate Obtain compound 2.Under ice bath, compound 2 (25mmol) is added into reaction vessel, THF (15mL), NaH (62.5mmol) are stirred 15min is mixed, CH is added3I (33mmol) is reacted at room temperature for 24 hours.TLC tracking is sufficiently extracted with ethyl acetate after reaction dry Compound 3.Compound 3 (2mmol) and acetophenone (2mmol), dehydrated alcohol (20mL) and KOH are added into reaction vessel (6mmol), for 24 hours, ethyl alcohol and recrystallize with dichloromethane obtain compound 4 after filtering for room temperature reaction.Successively it is added into reaction vessel Ethanol solution (5mL), compound 4 (1mmol), hydrazine hydrate (2mmol), flow back 2h, cooling to be transferred to -20 DEG C overnight, Gu Body filtering cleans to obtain compound 5 with petroleum ether.Into reaction vessel be added replace niacin (2mmol), EDCHCl (3mmol), Compound 5 (1mmol) is added under inert gas protection in HOBt (1.2mmol) and methylene chloride (5mL), after reaction for 24 hours, Filter and use ethyl alcohol and water to clean, crude product is recrystallized to give a series of nicotinoyl of the present invention two in ethyl alcohol and methylene chloride Hydrogen pyrazole compound (compound 6), compound is as shown in table 1.
Table 1
Above compound Structural Identification data are as follows:
(5- (1- Methyl-1H-indole -3- base) -3- phenyl -4,5- dihydro-1 h-pyrazole -1- base) (pyridin-3-yl) ketone (ZYL-1) red crystals, yield: 29.8%, 165~166 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:9.00(s,1H), 8.69 (dd, J=4.7,1.3Hz, 1H), 8.20 (d, J=7.8Hz, 1H), 7.78 (dd, J=6.5,2.9Hz, 2H), 7.59- 7.34 (m, 7H), 7.15 (t, J=7.6Hz, 1H), 7.01 (t, J=7.5Hz, 1H), 6.07 (dd, J=11.7,4.7Hz, 1H), 3.94 (dd, J=18.0,11.8Hz, 1H), 3.75 (s, 3H), 3.35 (dd, J=18.0,4.8Hz, 1H) .MS (ESI) m/z: 318.16(C24H20N4O,[M+H]+).Anal.Calcd for C24H20N4O:C,75.77；H,5.30；N,14.73.Found:C, 75.87；H,5.31；N,14.76.
(6- chloropyridine -3- base) (5- (1- Methyl-1H-indole -3- base) -3- phenyl -4,5- dihydro-1 h-pyrazole -1- base) Ketone (ZYL-2) faint yellow solid, yield: 22.1%, 129~130 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.85 (s, 1H), 8.27 (d, J=6.3Hz, 1H), 7.87-7.72 (m, 2H), 7.65 (d, J=8.3Hz, 1H), 7.59-7.36 (m, 6H), 7.15 (t, J=7.6Hz, 1H), 7.01 (t, J=7.6Hz, 1H), 6.06 (dd, J=11.7,4.7Hz, 1H), 3.95 (dd, J=18.1,11.7Hz, 1H), 3.75 (s, 3H), 3.36 (dd, J=18.0,4.8Hz, 1H) .MS (ESI) m/z:415.12 (C24H19ClN4O,[M+H]+).Anal.Calcd for C24H19ClN4O:C,69.48；H,4.62；N,13.50.Found:C, 69.44；H,4.62；N,13.52.
(5- (1- Methyl-1H-indole -3- base) -3- phenyl -4,5- dihydro-1 h-pyrazole -1- base) (pyridin-4-yl) ketone (ZYL-3) lavender powder, yield: 23.0%, 175~176 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.72(d,J =5.6Hz, 2H), 7.86-7.76 (m, 2H), 7.70 (d, J=5.6Hz, 2H), 7.59-7.36 (m, 6H), 7.15 (t, J= 7.5Hz, 1H), 7.01 (t, J=7.5Hz, 1H), 6.05 (dd, J=11.7,4.6Hz, 1H), 3.95 (dd, J=18.1, 11.8Hz,1H),3.76(s,3H),3.44–3.31(m,1H).MS(ESI)m/z:381.16(C24H20N4O,[M+H]+) .Anal.Calcd for C24H20N4O:C,75.77；H,5.30；N,14.73.Found:C,75.85；H,5.28；N,14.74.
(5- (1- Methyl-1H-indole -3- base) -3- phenyl -4,5- dihydro-1 h-pyrazole -1- base) (6- picoline -3- Base) ketone) (ZYL-4) faint yellow solid, yield: 21.2%, 158~160 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ: 8.90 (s, 1H), 8.10 (d, J=6.6Hz, 1H), 7.79 (dd, J=6.6,2.9Hz, 2H), 7.58-7.33 (m, 7H), 7.15 (t, J=7.9Hz, 1H), 7.01 (t, J=7.7Hz, 1H), 6.06 (dd, J=11.7,4.8Hz, 1H), 3.95 (dd, J= 18.0,11.8Hz, 1H), 3.76 (s, 3H), 3.35 (dd, J=17.9,4.9Hz, 1H), 2.54 (s, 3H) .MS (ESI) m/z: 395.18(C25H22N4O,[M+H]+).Anal.Calcd for C25H22N4O:C,76.12；H,5.62；N,14.20.Found:C, 75.89；H,5.60；N,14.21.
(2- chloropyridine -3- base) (5- (1- Methyl-1H-indole -3- base) -3- phenyl -4,5- dihydro-1 h-pyrazole -1- base) Ketone (ZYL-5) faint yellow solid, yield: 48.2%, 191~193 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.51 (dd, J=4.8,1.9Hz, 1H), 7.89 (dd, J=7.5,1.9Hz, 1H), 7.65 (d, J=6.3Hz, 2H), 7.54 (dd, J= 7.5,4.8Hz, 1H), 7.51-7.37 (m, 6H), 7.18 (t, J=7.3Hz, 1H), 7.02 (t, J=7.3Hz, 1H), 6.04 (dd, J=11.7,4.7Hz, 1H), 4.00 (dd, J=18.2,11.7Hz, 1H), 3.79 (s, 3H), 3.38 (dd, J=18.2, 4.7Hz,1H).MS(ESI)m/z:415.12(C24H19ClN4O,[M+H]+).Anal.Calcd for C24H19ClN4O:C, 69.48；H,4.62；N,13.50.Found:C,69.67；H,4.63；N,13.49.
(6- methoxypyridine -3- base) (5- (1- Methyl-1H-indole -3- base) -3- phenyl -4,5- dihydro-1 h-pyrazole - 1- yl) ketone (ZYL-6)
Orange solids, yield: 36.4%, 174~176 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.75(s, 1H), 8.18 (dd, J=8.7,2.2Hz, 1H), 7.81 (dd, J=6.5,3.0Hz, 2H), 7.58-7.46 (m, 3H), 7.42 (d, J=8.5Hz, 2H), 7.37 (s, 1H), 7.14 (t, J=7.8Hz, 1H), 6.99 (t, J=7.4Hz, 1H), 6.91 (d, J= 8.7Hz, 1H), 6.04 (dd, J=11.8,4.8Hz, 1H), 4.07-3.84 (m, 4H), 3.75 (s, 3H), 3.33-3.30 (m, 1H).MS(ESI)m/z:411.17(C25H22N4O2,[M+H]+).Anal.Calcd for C25H22N4O2:C,73.15；H, 5.40；N,13.65.Found:C,73.34；H,5.39；N,13.64.
(5- (1- Methyl-1H-indole -3- base) -3- (3,4,5- 2,4,5-trimethoxyphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (6- picoline -3- base) ketone (ZYL-7)
Brown crystal, yield: 52.1%, 217~219 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.91(s, 1H), 8.16 (d, J=7.6Hz, 1H), 7.53-7.30 (m, 4H), 7.15 (t, J=7.6Hz, 1H), 7.06 (s, 2H), 7.02 (t, J=7.5Hz, 1H), 6.06 (dd, J=11.7,4.6Hz, 1H), 3.90 (dd, J=18.1,11.7Hz, 1H), 3.81 (s, 6H), 3.75 (s, 3H), 3.71 (s, 3H), 3.40 (dd, J=18.1,4.7Hz, 1H), 2.53 (s, 3H) .MS (ESI) m/z: 485.21(C28H28N4O4,[M+H]+).Anal.Calcd for C28H28N4O4:C,69.41；H,5.82；N,11.56.Found: C,69.19；H,5.83；N,11.53.
(5- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- (4- chlorphenyl) -4,5- dihydro-1 h-pyrazole -1- base) (pyrrole Pyridine -3- base) ketone (ZYL-8)
White solid, yield: 21.4%, 202~203 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:9.00(s, 1H), 8.70 (d, J=3.5Hz, 1H), 8.19 (d, J=7.8Hz, 1H), 7.78 (d, J=8.5Hz, 2H), 7.71 (s, 1H), 7.55 (d, J=8.6Hz, 3H), 7.46 (s, 1H), 7.42 (d, J=8.7Hz, 1H), 7.28 (dd, J=8.7,1.7Hz, 1H), 6.08 (dd, J=11.6,4.6Hz, 1H), 3.94 (dd, J=18.1,11.7Hz, 1H), 3.74 (s, 3H), 3.35 (dd, J= 18.1,4.7Hz,1H).MS(ESI)m/z:493.04(C24H18BrClN4O,[M+H]+).Anal.Calcd for C24H18BrClN4O:C,58.38；H,3.67；N,11.35.Found:C,58.46；H,3.66；N,11.37.
(5- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- (3,4,5- 2,4,5-trimethoxyphenyl) -4,5- dihydro-1 h-pyrazole - 1- yl) (pyridin-3-yl) ketone (ZYL-9)
White powder, yield: 19.2%, 194~195 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:9.03(s, 1H), 8.70 (dd, J=4.7,1.3Hz, 1H), 8.24 (d, J=7.6Hz, 1H), 7.75 (s, 1H), 7.53 (dd, J=7.7, 5.0Hz, 1H), 7.45-7.38 (m, 2H), 7.29 (dd, J=8.7,1.8Hz, 1H), 7.05 (s, 2H), 6.09 (dd, J= 11.4,4.2Hz, 1H), 3.92 (dd, J=18.0,11.5Hz, 1H), 3.81 (s, 6H), 3.73 (d, J=12.5Hz, 6H), 3.41 (dd, J=18.0,4.4Hz, 1H) .MS (ESI) m/z:549.11 (C27H25BrN4O4,[M+H]+).Anal.Calcd for C27H25BrN4O4:C,59.02；H,4.59；N,10.20.Found:C,59.19；H,4.58；N,10.21.
(5- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- (3,4- dimethoxy phenyl) -4,5- dihydro-1 h-pyrazole -1- Base) (pyridin-4-yl) ketone (ZYL-10)
Grey powder, yield: 18.9%, 168~169 DEG C of fusing point.1H NMR(DMSO-d6, 400MHz) and δ: 8.74 (d, J= 5.7Hz, 2H), 7.75 (d, J=5.8Hz, 2H), 7.71 (s, 1H), 7.42 (d, J=7.3Hz, 2H), 7.40-7.23 (m, 3H), 7.04 (d, J=8.5Hz, 1H), 6.05 (dd, J=11.4,4.2Hz, 1H), 3.90 (dd, J=18.0,11.5Hz, 1H), 3.81 (s,3H),3.78(s,3H),3.75(s,3H),3.40–3.32(m,1H).MS(ESI)m/z:519.10(C26H23BrN4O3,[M+ H]+).Anal.Calcd for C26H23BrN4O3:C,60.12；H,4.46；N,10.79.Found:C,60.02；H,4.47；N, 10.81。
(5- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- (4- fluorophenyl) -4,5- dihydro-1 h-pyrazole -1- base) (pyrrole Pyridine -3- base) ketone (ZYL-11)
Pale yellow powder, yield: 19.9%, 166~168 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.99(s, 1H), 8.69 (dd, J=4.8,1.6Hz, 1H), 8.20 (d, J=7.9Hz, 1H), 7.83 (dd, J=8.8,5.5Hz, 2H), 7.71 (s, 1H), 7.53 (dd, J=7.8,4.9Hz, 1H), 7.49-7.39 (m, 2H), 7.39-7.24 (m, 3H), 6.07 (dd, J =11.6,4.6Hz, 1H), 3.94 (dd, J=18.1,11.6Hz, 1H), 3.75 (s, 3H), 3.44-3.31 (m, 1H)13C NMR (DMSO-d6,101MHz)δ:165.12,163.91,162.65,156.24,151.67,150.39,137.42,136.04, 131.10,129.67,129.27,128.02,127.32,124.24,123.55,121.38,116.57,116.35,114.46, 112.67,112.27,54.27,41.10,33.02.MS(ESI)m/z:477.06(C24H18BrFN4O,[M+H]+) .Anal.Calcd for C24H18BrFN4O:C,60.39；H,3.80；N,11.74.Found:C,60.50；H,3.79；N, 11.74。
(5- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- (4- bromophenyl) -4,5- dihydro-1 h-pyrazole -1- base) (pyrrole Pyridine -3- base) ketone (ZYL-12)
White powder, yield: 26.5%, 213~214 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.99(s, 1H), 8.70 (dd, J=4.7,1.2Hz, 1H), 8.19 (d, J=7.8Hz, 1H), 7.89-7.64 (m, 5H), 7.61-7.52 (m, 1H), 7.45 (dd, J=26.9,16.2Hz, 2H), 7.28 (dd, J=8.7,1.8Hz, 1H), 6.08 (dd, J=11.6, 4.6Hz, 1H), 3.94 (dd, J=18.1,11.7Hz, 1H), 3.74 (s, 3H), 3.36-3.28 (m, 1H) .MS (ESI) m/z: 536.98(C24H18Br2N4O,[M+H]+).Anal.Calcd for C24H18Br2N4O:C,53.56；H,3.37；N, 10.41.Found:C,53.44；H,3.38；N,10.43.
(5- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- (3,4- dimethoxy phenyl) -4,5- dihydro-1 h-pyrazole -1- Base) (pyridin-3-yl) ketone (ZYL-13)
Pink powder, yield: 32.3%, 112~114 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:9.02(s, 1H), 8.69 (d, J=4.1Hz, 1H), 8.22 (d, J=7.6Hz, 1H), 7.72 (s, 1H), 7.53 (dd, J=7.7,5.0Hz, 1H), 7.42 (d, J=8.4Hz, 2H), 7.39-7.24 (m, 3H), 7.05 (d, J=8.4Hz, 1H), 6.05 (dd, J=11.4, 4.2Hz, 1H), 3.91 (dd, J=18.0,11.5Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H), 3.39- 3.31(m,1H).MS(ESI)m/z:519.10(C26H23BrN4O3,[M+H]+).Anal.Calcd for C26H23BrN4O3:C, 60.12；H,4.46；N,10.79.Found:C,59.99；H,4.47；N,10.78.
(5- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- (4- anisyl) -4,5- dihydro-1 h-pyrazole -1- base) (pyridin-3-yl) ketone (ZYL-14)
White crystal, yield: 25.4%, 180~181 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:9.00(s, 1H), 8.69 (dd, J=4.8,1.5Hz, 1H), 8.20 (d, J=7.9Hz, 1H), 7.79-7.64 (m, 3H), 7.53 (dd, J= 7.8,4.9Hz, 1H), 7.48-7.38 (m, 2H), 7.27 (dd, J=8.7,1.8Hz, 1H), 7.03 (d, J=8.9Hz, 2H), 6.04 (dd, J=11.5,4.4Hz, 1H), 3.91 (dd, J=18.0,11.6Hz, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.34–3.29(m,1H).MS(ESI)m/z:489.08(C25H21BrN4O2,[M+H]+).Anal.Calcd for C25H21BrN4O2:C,61.36；H,4.33；N,11.45.Found:C,61.49；H,4.32；N,11.43.
(5- (the bromo- 1- Methyl-1H-indole -3- base of 5-) -3- phenyl -4,5- dihydro-1 h-pyrazole -1- base) (pyridine -3- Base) ketone (ZYL-15)
Orange crystal, yield: 40.1%, 185~186 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:9.00(s, 1H), 8.70 (dd, J=4.8,1.5Hz, 1H), 8.20 (d, J=7.8Hz, 1H), 7.87-7.73 (m, 2H), 7.71 (s, 1H), 7.64-7.38 (m, 6H), 7.28 (dd, J=8.7,1.8Hz, 1H), 6.07 (dd, J=11.6,4.6Hz, 1H), 3.95 (dd, J =18.0,11.6Hz, 1H), 3.75 (s, 3H), 3.40-3.30 (m, 1H) .MS (ESI) m/z:459.07 (C24H19BrN4O,[M+ H]+).Anal.Calcd for C24H19BrN4O:C,62.76；H,4.17；N,12.20.Found:C,62.88；H,4.18；N, 12.21。
(5- (5- methoxyl group -1- Methyl-1H-indole -3- base) -3- phenyl -4,5- dihydro-1 h-pyrazole -1- base) (pyridine - 3- yl) ketone (ZYL-16)
Pink powder, yield: 24.3%, 134~136 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.99(s, 1H), 8.68 (dd, J=4.8,1.6Hz, 1H), 8.19 (d, J=7.8Hz, 1H), 7.80 (dd, J=6.5,3.0Hz, 2H), 7.63-7.44 (m, 4H), 7.44-7.29 (m, 2H), 6.88 (d, J=1.9Hz, 1H), 6.80 (dd, J=8.9,2.4Hz, 1H), 6.05 (dd, J=11.6,4.1Hz, 1H), 3.94 (dd, J=18.0,11.7Hz, 1H), 3.71 (s, 3H), 3.56 (s, 3H), 3.35–3.31(m,1H).MS(ESI)m/z:411.17(C25H22N4O2,[M+H]+).Anal.Calcd for C25H22N4O2:C, 75.77；H,5.30；N,14.73.Found:C,75.89；H,5.30；N,14.68.
(5- (5- methoxyl group -1- Methyl-1H-indole -3- base) -3- phenyl -4,5- dihydro-1 h-pyrazole -1- base) (6- first Oxygroup pyridin-3-yl) ketone (ZYL-17)
White solid, yield: 17.3%, 148~150 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.76(s, 1H), 8.19 (dd, J=8.7,2.2Hz, 1H), 7.92-7.77 (m, 2H), 7.59-7.42 (m, 3H), 7.31 (d, J=8.6Hz, 2H), 6.92 (d, J=8.7Hz, 1H), 6.86 (d, J=2.3Hz, 1H), 6.78 (dd, J=8.8,2.4Hz, 1H), 6.02 (dd, J=11.7,4.3Hz, 1H), 4.04-3.82 (m, 4H), 3.71 (s, 3H), 3.55 (s, 3H), 3.32 (dd, J=18.0, 4.3Hz,1H).MS(ESI)m/z:441.18(C26H24N4O3,[M+H]+).Anal.Calcd for C26H24N4O3:C,70.89； H,5.49；N,12.72.Found:C,70.91；H,5.48；N,12.74.
(3- (4- fluorophenyl) -5- (5- methoxyl group -1- Methyl-1H-indole -3- base) -4,5- dihydro-1 h-pyrazole -1- base) (6- methoxypyridine -3- base) ketone (ZYL-18)
Brown solid, yield: 14.7%, 123~126 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.76(s, 1H), 8.19 (d, J=8.7Hz, 1H), 7.89 (dd, J=8.7,5.5Hz, 2H), 7.40-7.28 (m, 4H), 6.92 (d, J= 8.7Hz, 1H), 6.87 (d, J=2.1Hz, 1H), 6.79 (dd, J=8.8,2.3Hz, 1H), 6.03 (dd, J=11.7,4.3Hz, 1H), 3.97-3.85 (m, 4H), 3.71 (s, 3H), 3.58 (s, 3H), 3.33 (dd, J=18.0,4.3Hz, 1H) .MS (ESI) m/ z:459.18(C26H23FN4O3,[M+H]+).Anal.Calcd for C26H23FN4O3:C,68.11；H,5.06；N, 12.22.Found:C,68.29；H,5.07；N,12.26.
(3- (4- chlorphenyl) -5- (5- methoxyl group -1- Methyl-1H-indole -3- base) -4,5- dihydro-1 h-pyrazole -1- base) (6- methoxypyridine -3- base) ketone (ZYL-19)
Yellow solid, yield: 18.6%, 157~159 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.75(s, 1H), 8.17 (dd, J=8.6,2.1Hz, 1H), 7.84 (d, J=8.6Hz, 2H), 7.57 (d, J=8.6Hz, 2H), 7.38- 7.29 (m, 2H), 6.92 (d, J=8.7Hz, 1H), 6.86 (d, J=2.1Hz, 1H), 6.80 (dd, J=8.9,2.3Hz, 1H), 6.03 (dd, J=11.7,4.4Hz, 1H), 4.00-3.84 (m, 4H), 3.71 (s, 3H), 3.59 (s, 3H), 3.32 (dd, J= 18.1,4.4Hz,1H).MS(ESI)m/z:475.15(C26H23ClN4O3,[M+H]+).Anal.Calcd for C26H23ClN4O3:C,65.75；H,4.88；N,11.80.Found:C,65.81；H,4.88；N,11.78.
(3- (4- bromophenyl) -5- (5- methoxyl group -1- Methyl-1H-indole -3- base) -4,5- dihydro-1 h-pyrazole -1- base) (6- methoxypyridine -3- base) ketone (ZYL-20)
Orange solids, yield: 21.7,163~164 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.75(s,1H), 8.17 (dd, J=8.7,2.0Hz, 1H), 7.74 (dd, J=23.5,8.6Hz, 4H), 7.37-7.29 (m, 2H), 6.92 (d, J= 8.7Hz, 1H), 6.86 (d, J=2.1Hz, 1H), 6.80 (dd, J=8.8,2.3Hz, 1H), 6.03 (dd, J=11.7,4.4Hz, 1H), 3.96-3.81 (m, 4H), 3.71 (s, 3H), 3.59 (s, 3H), 3.31 (dd, J=18.1,4.5Hz, 1H)13C NMR (DMSO-d6,101MHz)δ:165.12,163.37,155.70,153.79,149.49,140.93,132.75,132.40, 130.84,129.09,128.68,125.56,124.48,124.34,114.08,111.48,111.34,110.12,101.01, 55.52,54.91,54.12,32.91.MS(ESI)m/z:519.10(C26H23BrN4O3,[M+H]+).Anal.Calcd for C26H23BrN4O3:C,60.12；H,4.46；N,10.79.Found:C,60.19；H,4.47；N,10.78.
(5- (5- methoxyl group -1- Methyl-1H-indole -3- base) -3- (4- anisyl) -4,5- dihydro-1 h-pyrazole -1- Base) (6- methoxypyridine -3- base) ketone (ZYL-21)
Faint yellow solid, yield: 17.8%, 90~93 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.76(s, 1H), 8.23-8.17 (m, 1H), 7.80-7.73 (m, 4H), 7.32 (d, J=8.6Hz, 2H), 6.92 (d, J=8.7Hz, 1H), 6.87 (d, J=2.1Hz, 1H), 6.79 (dd, J=8.9,2.3Hz, 1H), 6.00 (dd, J=11.5,4.2Hz, 1H), 3.92- 3.79 (m, 7H), 3.71 (s, 3H), 3.57 (s, 3H), 3.29 (dd, J=18.1,4.2Hz, 1H) .MS (ESI) m/z:471.20 (C27H26N4O4,[M+H]+).Anal.Calcd for C27H26N4O4:C,68.92；H,5.57；N,11.91.Found:C, 69.04；H,5.56；N,11.94.
(5- (5- methoxyl group -1- Methyl-1H-indole -3- base) -3- (3,4,5- 2,4,5-trimethoxyphenyl) -4,5- dihydro -1H- pyrrole Azoles -1- base) (6- methoxypyridine -3- base) ketone (ZYL-22)
Yellow solid, yield: 18.9%, 175~177 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.71(s, 1H), 8.23 (d, J=8.2Hz, 1H), 7.37-7.23 (m, 2H), 7.09 (s, 2H), 6.93 (d, J=9.1Hz, 2H), 6.80 (dd, J=8.9,2.3Hz, 1H), 6.03 (dd, J=11.6,4.0Hz, 1H), 3.92 (s, 3H), 3.90-3.76 (m, 7H), 3.72 (d, J=2.2Hz, 6H), 3.61 (s, 3H), 3.43-3.38 (m, 1H) .MS (ESI) m/z:531.22 (C29H30N4O6,[M+ H]+).Anal.Calcd for C29H30N4O6:C,65.65；H,5.70；N,10.56.Found:C,65.75；H,5.71；N, 10.58。
(5- (5- methoxyl group -1- Methyl-1H-indole -3- base) -3- (5- methoxyl group -1- Methyl-1H-indole -3- base) -4, 5- dihydro-1 h-pyrazole -1- base) (pyridin-3-yl) ketone (ZYL-23)
Orange solids, yield: 21.2%, 145~148 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.99(s, 1H), 8.69 (dd, J=4.8,1.4Hz, 1H), 8.20 (d, J=7.8Hz, 1H), 7.54 (dd, J=7.7,4.9Hz, 1H), 7.48-7.26 (m, 5H), 7.22-7.02 (m, 1H), 6.89 (d, J=1.5Hz, 1H), 6.81 (dd, J=8.9,2.3Hz, 1H), 6.05 (dd, J=11.6,4.1Hz, 1H), 3.93 (dd, J=18.0,11.7Hz, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 3.59(s,3H),3.47–3.27(m,1H).13C NMR(DMSO-d6,101MHz)δ:163.73,159.94,157.01, 153.82,151.63,150.41,137.46,132.82,132.79,131.19,130.56,128.70,125.55,123.51, 119.54,116.54,113.95,112.64,111.53,111.36,101.03,55.68,55.50,54.72,32.92.MS (ESI)m/z:441.18(C26H24N4O3,[M+H]+).Anal.Calcd for C26H24N4O3:C,70.89；H,5.49；N, 12.72.Found:C,70.86；H,5.51；N,12.75.
(5- (5- methoxyl group -1- Methyl-1H-indole -3- base) -3- (3- anisyl) -4,5- dihydro-1 h-pyrazole -1- Base) (6- picoline -3- base) ketone (ZYL-24)
Yellow solid, yield: 36.4%, 138~139 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.89(s, 1H), 8.10 (d, J=7.4Hz, 1H), 7.42-7.27 (m, 6H), 7.08 (s, 1H), 6.88 (d, J=1.8Hz, 1H), 6.79 (dd, J=8.9,2.3Hz, 1H), 6.02 (dd, J=11.6,4.1Hz, 1H), 3.90 (dd, J=18.0,11.8Hz, 1H), 3.79(s,3H),3.71(s,3H),3.58(s,3H),3.32–3.28(m,1H),2.53(s,3H).MS(ESI)m/z:455.20 (C27H26N4O3,[M+H]+).Anal.Calcd for C27H26N4O3:C,71.35；H,5.77；N,12.33.Found:C, 71.44；H,5.78；N,12.33.
(5- (5- methoxyl group -1- Methyl-1H-indole -3- base) -3- (3- anisyl) -4,5- dihydro-1 h-pyrazole -1- Base) (6- methoxypyridine -3- base) ketone (ZYL-25)
Gray solid, yield: 25.5%, 133~135 DEG C of fusing point.1H NMR(DMSO-d6,400MHz)δ:8.75(s, 1H), 8.20 (d, J=8.4Hz, 1H), 7.43 (d, J=5.3Hz, 2H), 7.39-7.29 (m, 3H), 7.23-6.97 (m, 1H), 6.93 (d, J=8.7Hz, 1H), 6.87 (d, J=2.1Hz, 1H), 6.80 (dd, J=8.8,2.3Hz, 1H), 6.02 (dd, J= 11.7,4.2Hz,1H),3.96–3.82(m,4H),3.81(s,3H),3.71(s,3H),3.58(s,3H),3.33–3.28(m, 1H).MS(ESI)m/z:471.20(C27H26N4O4,[M+H]+).Anal.Calcd for C27H26N4O4:C,68.92；H, 5.57；N,11.91.Found:C,69.04；H,5.56；N,11.93.
2 in vitro antitumor activity assay of embodiment
IC50: half inhibiting rate kills cancer cell ability for compound.
Human liver cancer cell (HepG2), human breast cancer cell (MCF-7), human lung adenocarcinoma cell (A549).
CC50: half toxic concentration, toxicity of the compound to normal cell.
People's renal epithelial cell (293T).
Embodiment 1 is measured using MTT [3- (4,5)-bis- methyl -2- thiazole-(2,5)-phenyl bromination tetrazole is blue] method The compound being prepared is to human liver cancer cell (HepG2), human breast cancer cell (MCF-7) and human lung adenocarcinoma cell (A549) Drug concentration (half maximal inhibitory concentration, IC of the inhibiting rate when reaching 50%50).And To the cytotoxicity of people's renal epithelial cell (293T), the toxicity of each compound is with when inhibiting 293T cell survival rate to 50% Concentration C C50To indicate.
(1) preparation of culture solution: DMEM (basal medium) 89%, fetal calf serum 10%, Penicillin Streptomycin Solution (10000IU/mL, 10000 μ g/mL) 1%.
The culture of (2) four kinds of adherent cancer cells: using above-mentioned culture solution, (nutrient solution volume is about the 1/ of culture bottle capacity 10), at 37 DEG C, 5%CO2It is cultivated in incubator, judges the generation time according to the growth conditions of cancer cell.
(3) preparation of various concentration drug: stock solution is prepared using DMEM (a small amount of DMSO hydrotropy), every hole after dosing is thin The final concentration of DMSO is usually no more than 0.05%-0.1% in born of the same parents' suspension；Stock solution is diluted to six concentration gradients with DMEM (100 μM, 50 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM)；It is stored in spare in -20 DEG C of refrigerators.
(4) cell incubation: logarithmic growth phase tumour cell, tune concentration of cell suspension are 1-1.5 × 105/ mL, after mixing (100 hole μ L/) is added in 96 well culture plates, at 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator.
(5) dosing: the drug of the various concentration gradient diluted is added separately in 96 well culture plates, each concentration ladder Degree sets 3 multiple holes, continues to cultivate 48h.Experiment is divided into experimental group (culture solution, cell, drug), control group (culture solution and cell) With blank group (only culture solution).
(6) survivaling cell detects: in having cultivated 96 orifice plates after 48h, adding 10 hole μ L/ MTT (5mg/mL)；It is put at 37 DEG C After setting 4h, supernatant is removed, adds 150 hole μ L/ DMSO, oscillation to first a ceremonial jade-ladle, used in libation crystallizes all dissolutions；Existed using automatic microplate reader The optical density (OD value) in each hole is detected at 570nm wavelength.
The calculating of inhibiting rate:
Growth inhibition ratio=(1- survival rate) × 100%=[1- (OD experiment-OD blank)/(OD control-OD is empty It is white)] × 100% (average optical density of OD experiment expression experimental group, the average optical density of OD control expression control group, OD blank Indicate the average optical density of blank group).
According to drug concentration-inhibitory rate of cell growth standard curve, its IC is sought50, unit μM.
The results are shown in Table 2.
Table 2
The above result shows that nicotinoyl pyrazoline class compound of the present invention has good antitumor action, to just The toxicity of normal cell is low.

Claims (3)

1. a kind of pyrazoline class compound and pharmaceutically can at salt, have the following structure formula:
Wherein, R1For H or OCH3；R2For H；R3For H.
2. pyrazoline class compound described in claim 1 and pharmaceutically can at salt application in preparation of anti-tumor drugs.
3. a kind of antineoplastic pharmaceutical compositions, it is characterised in that including pyrazoline class compound and pharmacy described in claim 1 On can at salt and pharmaceutically acceptable carrier.
CN201710028733.XA 2017-01-16 2017-01-16 A kind of nicotinoyl pyrazoline class compound and its medicinal usage Active CN106749192B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710028733.XA CN106749192B (en) 2017-01-16 2017-01-16 A kind of nicotinoyl pyrazoline class compound and its medicinal usage

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710028733.XA CN106749192B (en) 2017-01-16 2017-01-16 A kind of nicotinoyl pyrazoline class compound and its medicinal usage

Publications (2)

Publication Number Publication Date
CN106749192A CN106749192A (en) 2017-05-31
CN106749192B true CN106749192B (en) 2019-05-17

Family

ID=58945536

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710028733.XA Active CN106749192B (en) 2017-01-16 2017-01-16 A kind of nicotinoyl pyrazoline class compound and its medicinal usage

Country Status (1)

Country Link
CN (1) CN106749192B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109535126B (en) * 2018-11-27 2021-03-12 西安交通大学医学院第二附属医院 COX/LOX inhibitor for anti-inflammation and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101243048A (en) * 2005-08-16 2008-08-13 默克专利有限公司 1-acyldihydropyrazol derivatives
CN105541805A (en) * 2016-03-04 2016-05-04 南京大学 Preparation method and application of indole acetyl pyrazole derivatives
CN105541804A (en) * 2016-03-04 2016-05-04 南京大学 Preparation method and application of indole formylamino-pyrazole derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009086303A2 (en) * 2007-12-21 2009-07-09 University Of Rochester Method for altering the lifespan of eukaryotic organisms

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101243048A (en) * 2005-08-16 2008-08-13 默克专利有限公司 1-acyldihydropyrazol derivatives
CN105541805A (en) * 2016-03-04 2016-05-04 南京大学 Preparation method and application of indole acetyl pyrazole derivatives
CN105541804A (en) * 2016-03-04 2016-05-04 南京大学 Preparation method and application of indole formylamino-pyrazole derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Synthesis and biological evaluation of some new pyrazole, chromene incorporated indole derivatives;Saundane, Anand R等;《Journal of Applicable Chemistry》;20141231;第3卷(第1期);117-128
一类二氢吡唑BRAF激酶抑制剂的合成及抗黑色素瘤活性研究;李翠云;《南京大学硕士学位论文》;20130501;正文第3页，第11-12页1.3，图1.4

Also Published As

Publication number Publication date
CN106749192A (en) 2017-05-31

Similar Documents

Publication Publication Date Title
CN105037355B (en) The indazole inhibitors and its therapeutical uses of Wnt signal transduction paths
KR101544624B1 (en) Pyrimidinyl pyridazinone derivatives
CN102741256A (en) Bicyclic heteroaryl derivatives having inhibitory activity for protein kinase
EP2581371B1 (en) Pyrrolyl substituted dihydroindol-2-one derivatives, preparation methods and uses thereof
CN102015694A (en) Pyridazinone derivatives
CN107383016A (en) The preparation and application of the Pyrrolopyrimidine compounds of the structure containing heteroaryl amide
JP2019524790A (en) Thienopyrimidine compound, method for producing the same, pharmaceutical composition and application thereof
JP4805166B2 (en) Aroylfuran and aroylthiophene
CN101417995B (en) Phenoxy pyrimidine derivates and preparation method and use thereof
CN114920704B (en) Phenyl piperazine quinazoline compound or pharmaceutically acceptable salt thereof, preparation method and application
CN106749192B (en) A kind of nicotinoyl pyrazoline class compound and its medicinal usage
CN103360317A (en) Dicyclo-substituted pyrazolone azo derivatives, as well as preparation method and use thereof
CN107253964A (en) The preparation and application of the thienopyrimidines of the structure containing heteroaryl amide
CN105669823A (en) Piperazine-framework-containing glycyrrhetinic acid derivatives, and preparation method and application thereof
CN107445979B (en) 6- methYl-thiazol and triazole -5- carboxamides derivatives and application
CN114181212B (en) Pyridazinone AhR inhibitors
CN106831724B (en) A kind of 1- Methyl-1H-indole-pyrazoline thiourea and its medicinal usage
CN102731488A (en) Benzimidazole derivatives, preparation method thereof, pharmaceutical composition thereof and application thereof
CN105541805A (en) Preparation method and application of indole acetyl pyrazole derivatives
CN110407839B (en) Preparation and application of triazole heterocyclic compound containing heteroaryl amide structure
CN101935318A (en) 2,3-dihydro-4(1H)- quinazolone derivative and application thereof
CN102827160B (en) PI3K or PI3K/m-TOR pathway inhibitor and the purposes in pharmacy thereof
CN107235994B (en) Simultaneously [3,2-a] pyrimidine -3- acetamide derivative and the application of 5,7- diphenyl -5H- thiazole
CN104829534A (en) Preparation method of dihydro-pyrazole morpholine derivatives containing naphthalene nucleus frameworks and application of dihydro-pyrazole morpholine derivatives to preparation of antitumor drugs
CN104529905B (en) Benzimidazole acyl diamine analog derivatives of N 3 and preparation method and application

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant