CN110343109A - A kind of dihydro pteridinone-sulfonic acid amide derivatives and its pharmaceutically acceptable salt, preparation method and its application - Google Patents
A kind of dihydro pteridinone-sulfonic acid amide derivatives and its pharmaceutically acceptable salt, preparation method and its application Download PDFInfo
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Abstract
In view of the problems of the existing technology the present invention, provides a kind of dihydro pteridinone-sulfonic acid amide derivatives and its preparation method and application, provide new selection for the anti-tumor drug research and development in terms of inhibiting brominated domain protein BRD4.Confirm that the new compound of the present invention with dihydro pteridinone structure has good BRD4 albumen inhibitory effect by activity experiment, it can inhibit tumor cell proliferation, in particular for stomach cancer cell, the inhibitory activity of part of compounds reaches or better than positive reference compound JQ1.The present invention will provide new medicament selection for the treatment of the diseases such as BRD4 inhibitor, tumour.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to dihydro pteridinone-sulfonic acid amide derivatives and its pharmaceutically may be used
Salt, preparation method and its application of receiving.
Background technique
Malignant tumour is to threaten the No.1 major disease of our people's health of the masses.National Cancer Center data show, mesh
Preceding China just has 7.5 people to be diagnosed to suffer from cancer per minute.Therefore, the research of anti-tumor drug and its related target inhibitor has weight
The clinical meaning and social value wanted.
BRD (Bromodomain), also known as bromine domain protein, be one kind can specific recognition acetylated lysine it is residual
The conserved protein domain of base plays crucial regulating and controlling effect to chromatin assembling and genetic transcription.Multinomial research has shown that BRD
It is the drug target that height can be adapted to, the micromolecular inhibitor for acting on BRD holds out broad prospects in oncotherapy.
BRD4 is a member in bromine domain protein family, and biological function research is the most extensive.BRD4 is not only
It can identify promoter region, can also identify between gene and intragenic region, it is related with gene expression.BRD4 albumen is in life
Transcripting regulating function is executed under reason state, adjusts normal cellular processes；And under abnormality, they raise various protein
To chromatin and transcription site, the transcription with the closely related gene of gene expression such as c-Myc and BCL-2 is adjusted.Existed with BRD4
Interphase cell with positive transcriptional elongation factors (positive transcription elongation factor, P-TEFb) according to
Rely property mode to raise protein, and adjust transcription by being coupled with RNA polymerase II, to promote the relevant base of disease
Because of unconventionality expression.
A large number of studies show that the occurrence and development of BRD4 albumen and tumour have substantial connection, such as the Bromodomain of BRD4
Code area and NUT (nucleoprotein in testis) gene chromatin dystopy, which form BRD-NUT pattern of fusion proto-oncogene, can lead to middle line
Cancer；Inhibit the BRD4 expression in melanoma that can obviously slow down the growth of melanoma cells；Inhibit pernicious peripheral nerve sheath
BRD4 expression in oncocyte, can lead to the death of the tumour cell；BRD4 is inhibited to can inhibit the proliferation of liver cancer cells；By dry
The combination for disturbing BRD4 and oncogene MYC, in a variety of hematopoietic system cancers, as AML, Burkitt lymthoma, Huppert's disease and
In the model of B cell acute lymphatic leukemia, the silencing of oncogene MYC can be directly resulted in.The controllable inflammation of bromine domain protein
The acetylation of histone of disease gene expression relies on the assembling of sex chromatin compound and adjusts the transcription of inflammation gene expression.Research shows that
BRD4 can serve as the transcription co-activation factor of NF-Kb and promote the generation of inflammation.In cardiovascular disease field, BRD4 is also sent out
The crucial coactivator for playing the role of pathological gene trans-activation during existing cardiac myocyte hypertrophy, plays in heart failure
Important role；BRD4 micromolecular inhibitor JQ1 is likely to become the drug of potential treatment heart failure, improves cardiac function.
Bromine domain protein family causes the major drugmaker in the whole world and height in anti-inflammatory, anti-tumor aspect potential value
The highest attention in school, scientific research institution, BRD4 also become the important target in related fields.Using BRD4 as target, it is living to find its height
Property, highly selective micromolecular inhibitor become the disease researches heat such as Current therapeutic tumour, inflammation, cardiovascular disease, AIDS
Point has wide development and application prospect.
Currently, be reported by a variety of BRD4 micromolecular inhibitors of representative of JQ1, related compound OTX-015, I-
BET762, TEN-010, CPI-0610, RVX-208 etc. have entered clinical stage research, dislike for acute leukemia, other blood
It is property tumour, advanced solid tumor, glioblastoma, lymthoma, myeloma, center line cancer, breast cancer, coronary heart disease, artery sclerosis, non-
The treatment of Small Cell Lung Cancer etc. tumour and malignant disease.However, at present into the BRD4 little molecules in inhibiting of clinical stage research
Agent is simultaneously few, there is an urgent need to find more novel, efficient BRD4 inhibitor, provides new choosing for the treatment of the diseases such as tumour
It selects.
Applicant once reported a kind of novel dihydropteridine ketone BRD4 in Chinese invention patent CN109503586A
Protein inhibitor, the structure feature with hydrazone bond, to BRD4 protein inhibiting activity up to IC500.24μM.To further increase
The activity of BRD4 inhibitor, provides the new selection of anti-tumor drug, and applicant has done further research to such compound.
Summary of the invention
In view of the problems of the existing technology the present invention, provides a kind of dihydro pteridinone-sulfonic acid amide derivatives and its system
Preparation Method and application provide new selection for the anti-tumor drug research and development in terms of inhibiting brominated domain protein BRD4.
The technical solution adopted by the invention is as follows:
A kind of dihydro pteridinone-sulfonic acid amide derivatives, structure is as shown in logical formula (I):
Wherein, R1For saturated hydrocarbyl, aryl or heterocycle；
The saturated hydrocarbyl is the cyclic saturated hydrocarbon of the linear chain or branched chain saturated hydrocarbyl of 1-6 carbon atom, 3-6 carbon atom
Base, be connected with 1-6 carbon atom linear chain or branched chain saturated hydrocarbyl 3-6 carbon atom cyclic saturated hydrocarbon base；
The aryl is any in phenyl that is pure and being replaced by 1,2 or 3 the first substituent group, benzyl, naphthalene
It is a kind of；
The heterocycle be piperidyl that is pure and being replaced by 1,2 or 3 the first substituent group, pyrrole radicals, pyrazolyl,
Imidazole radicals, furyl, indyl, it is morpholinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl group, phonetic
Piperidinyl, piperazinyl, substituted piperazinyl, pyrazinyl, any one in pyridazinyl；
R2For hydrogen, alkoxy, aryloxy group or heterocycle；
Alkyl in the alkoxy is the ring-type of the linear chain or branched chain saturated hydrocarbyl of 1-6 carbon atom, 3-6 carbon atom
Saturated hydrocarbyl or be connected with 1-6 carbon atom linear chain or branched chain saturated hydrocarbyl 3-6 carbon atom cyclic saturated hydrocarbon base,
And wherein each carbon atom is optionally substituted with an oxygen；
Aryl in the aryloxy group is phenyl, benzyl, naphthalene that be pure and being replaced by 1,2 or 3 the first substituent group
Any one in base；
The heterocycle be piperidyl that is pure and being replaced by 1,2 or 3 the first substituent group, pyrrole radicals, pyrazolyl,
Imidazole radicals, furyl, indyl, it is morpholinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl group, phonetic
Piperidinyl, piperazinyl, substituted piperazinyl, pyrazinyl, any one in pyridazinyl；
First substituent group is independently selected from halogen, halogenated alkyl, alkyl, cyano, hydroxyl, nitro, sulfydryl, alcoxyl
Base, alkylthio group, aralkyl, alkyl diaryl；
R3For miscellaneous alkyl, aryl, heterocycle；
The miscellaneous alkyl is the linear chain or branched chain for the 1-8 carbon atom that each carbon atom is optionally replaced by oxygen atom or nitrogen-atoms
Saturated hydrocarbyl, the cyclic saturated hydrocarbon base of 3-8 carbon atom, or be connected with the linear chain or branched chain saturated hydrocarbyl of 1-8 carbon atom
3-8 carbon atom cyclic saturated hydrocarbon base；
The aryl is any one in phenyl that is pure or being replaced by 1,2 or 3 the second substituent group, benzyl, naphthalene
Kind；
The heterocycle is piperidyl, pyrrole radicals, pyrazolyl, miaow that be pure or being replaced by 1,2 or 3 the second substituent group
Oxazolyl, furyl, morpholinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl group, pyrimidine radicals, piperazine
Base, substituted piperazinyl, pyrazinyl, pyridazinyl, quinolyl, quinoxalinyl, indyl, benzimidazolyl, benzoxazolyl, benzo
Isoxazolyl, benzothienyl, benzisoxa thienyl, benzofuranyl, benzodioxane base, in benzdioxolanyl
Any one；
Second substituent group independently selected from halogen, halogenated alkyl, alkyl, cyano, hydroxyl, sulfydryl, amino, nitro,
Alkoxy, alkylthio group, aralkyl, alkyl diaryl, nafoxidine base, morpholinyl, alcoxyl morpholinyl, piperazinyl, piperidyl, alkane
Amino piperidine base.
Preferably, the R1For methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopenta, hexamethylene
Base, phenyl, benzyl, naphthalene, thienyl, furyl, cinnamyl group, indyl, any one in pyrrole radicals, pyridyl group；
The R2For hydrogen, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, cyclobutoxy group, cyclopentyloxy, ring
Hexyloxy, phenoxy group, benzyloxy, methylamino, ethylamino-, Propylamino, isopropylamine base, cyclopropyl amino, substituted cyclopropane amido, piperidines
Base, pyrrole radicals, pyrazolyl, imidazole radicals, indyl, it is morpholinyl, piperazinyl, substituted piperazinyl, pyrazinyl, any in pyridazinyl
It is a kind of；
The R3For methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl,
Benzyl, naphthalene, indyl, pyridyl group contain heteroatomic alkyl, methyl and/or halogen is monosubstituted, disubstituted cyclopropyl, first
The mono-substituted phenyl of base, the mono-substituted phenyl of tert-butyl, the mono-substituted phenyl of halogen, hydroxyl and the disubstituted phenyl of methoxyl group,
The disubstituted phenyl of halogen, the phenyl that dimethoxy replaces, hydroxyl and the disubstituted phenyl of halogen, halogen and nitro are disubstituted
Phenyl, ethyoxyl and the disubstituted phenyl of hydroxyl, lignocaine and the disubstituted phenyl of hydroxyl, the mono-substituted phenyl of acetonitrile, naphthalene
Base, indyl, the mono-substituted naphthalene of hydroxyl, pyridyl group, the mono-substituted pyridyl group of methyl, the mono-substituted pyridyl group of methoxyl group, ammonia
The mono-substituted pyridyl group of base, the mono-substituted pyridyl group of halogen, halogen Disubstituted pyridine base, the mono-substituted pyridyl group of nitro, halogen
The trisubstituted pyridyl group of element.
It is further preferred that the R1For cyclopenta, benzyl；
The R2For hydrogen, ethyoxyl, morpholinyl, phenoxy group, hetero atom substituent phenoxy；
The R3It is the phenyl that replaces for hydrogen atom, benzyl, methoxy-substituted benzyl, halogen, phenyl, methoxy-substituted
Phenyl, the phenyl of halogen substitution, the methylene of thiophene substitution, cyclopenta, cyclohexyl, cyclopropyl, methyl, ethyl, propyl, isopropyl
Base, dimethyl, butyl, diethyl, amyl, hydroxypropyl, hydroxyethyl, oxo butyl, hexyl, methyl piperazine base,
Its specific structure is as shown in formula 1 to 35:
Dihydro pteridinone-sulfonic acid amide derivatives pharmaceutically acceptable salt is the sour addition that it is formed with following acid
Salt: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, borate, methanesulfonic acid, p-methyl benzenesulfonic acid, naphthalene sulfonic acids, benzene sulfonic acid, citric acid, lactic acid,
Pyruvic acid, tartaric acid, acetic acid, maleic acid, succinic acid, tussol, fumaric acid, salicylic acid or phenylacetic acid；It is heretofore described
Dihydro pteridinone-sulfonic acid amide derivatives are as alkali compounds, it is convenient to which in solvent, (common organic solvents contain water-soluble
Agent) in by be added above compound react to obtain with aforementioned acid corresponding to salt, be acid common and conventional in the art
Alkali reaction, specific method repeat no more.
The present invention provides dihydro pteridinone-sulfonic acid amide derivatives preparation methods, include the following steps:
A. it is raw material with adjacent nitro fluorobenzene 36, is stirred to react 5-12 hours at 80-120 DEG C with chlorosulfonic acid, the adjacent nitro
The molar ratio of fluorobenzene 36 and chlorosulfonic acid is 1:1-40；System is slowly added dropwise after the reaction was completed, extra chlorine sulphur is quenched into ice water
Acid three times with extractant extraction reaction system is washed after merging with saturated sodium bicarbonate solution, liquid separation, organic phase is dry, rotation
It does to get intermediate 37.The extractant can be ethyl acetate, methylene chloride, chloroform or dichloroethanes.Yield
80%.
B. in the presence of an organic base, at 0-10 DEG C, intermediate 37 and corresponding aminated compounds are stirred with molar ratio 1:1-2
Reaction is mixed, TLC is detected after the reaction was completed, chromatographed to obtain intermediate 38 by column.The organic base can be triethylamine, pyridine,
Triethylene diamine, N-methylmorpholine, potassium tert-butoxide, sodium tert-butoxide or butyl lithium.Corresponding aminated compounds is described takes
For base R3Corresponding aminated compounds.Yield 60%.
C. intermediate 38 is dissolved in organic solvent, corresponding reagent is added, stirred at 10-100 DEG C, the intermediate
38 with the molar ratio of corresponding reagent be 1:1-5；After the reaction was completed, weak acid is washed, and ethyl acetate aqueous phase extracted three times, merges
Organic phase, it is dry, intermediate 39 is obtained after being spin-dried for.The organic solvent can be dimethyl sulfoxide or N, N- dimethyl formyl
Amine.Corresponding reagent is the substituent R2Corresponding compound.Yield 50-80%.
D. intermediate 39 is dissolved in solvent, is added the palladium-carbon catalyst of catalytic amount, under hydrogen atmosphere, be heated to 20-80
DEG C, it stirs 4 to 8 hours, TLC detection filters out palladium carbon afterwards after the reaction was completed, and filtrate is spin-dried for obtaining intermediate 40.The organic solvent
It can be tetrahydrofuran, ether, methanol, ethyl alcohol or acetic acid.Yield 50-90%.
E. compound 41 is dissolved in methanol, thionyl chloride, back flow reaction, the compound 41 and dichloro is added dropwise under ice bath
The molar ratio of sulfoxide is 1:1-10；After reaction, reaction system is concentrated under reduced pressure, product is precipitated, up to product 42 after filtering,
Crude product carries out the next step without further purification.Yield about 90%.
F. intermediate 42 is dissolved in chloroform, methylene chloride or dichloroethanes, is added corresponding carbonyls, under ice bath
Suitable alkali compounds and reducing agent is added, stirring to raw material disappears at 0-30 DEG C.Quenching reaction after reaction, through extracting
It takes, organic phase is dried after merging, filtered, being concentrated up to intermediate 43, can directly carry out the next step without further purification.Yield
70%.Corresponding carbonyls is substituent R1Corresponding compound；The alkali compounds can be Na2CO3、
K2CO3、CsCO3, NaOAc or KOAc；The reducing agent can be NaBH4、KBH4、NaBH(OAc)3Or NaBH3CN；The centre
The molar ratio of body 42 and corresponding carbonyls is 1:1-2, the intermediate 42 and the alkali compounds molar ratio
For 1:1 to 1:3, the molar ratio of the intermediate 42 and the reducing agent is 1:0.25-10；
G. intermediate 43 is dissolved in chloroform, methylene chloride or dichloroethanes, it is phonetic that the chloro- 5- nitro of 2,4- bis- is added under ice bath
Pyridine and the alkali compounds, stirring to raw material disappears at 0-30 DEG C.It is concentrated under reduced pressure after reaction and removes solvent, diluted,
Washing, after organic layer is dry, silica gel column chromatography separates to obtain intermediate 44.Yield 85%.The alkali compounds can be
Na2CO3、K2CO3、CsCO3,NaOAc,KOAc；
The molar ratio of the intermediate 43, the chloro- 5- nitro-pyrimidine of 2,4- bis- and the alkali compounds is 1:1-3:1-3；
H. intermediate 44 is dissolved in acetic acid and is heated to 50-70 DEG C, addition reduced iron powder is stirred to react, is warming up to 100
DEG C -110 DEG C the reaction was continued.After reaction, it filters, washs residue, column chromatography for separation obtains intermediate 45 after filtrate concentration.Yield
About 60%；
The molar ratio of the intermediate 44 and reduced iron powder is 1:2-20；
I. intermediate 45 is added into anhydrous DMF, iodomethane (being 1.3 equivalents relative to intermediate 45) is added under ice bath
And NaH (being 1.3 equivalents relative to intermediate 45), it is stirred to react at 0-30 DEG C, after reaction quenching reaction system, through extracting
It takes, organic phase washing, is concentrated to give intermediate 46 at drying, can be directly used for the next step without purification.Yield 90%；
J. it is compound shown in 1:0.5-1 formula 40 and formula 46 as raw material using molar ratio, is dissolved in organic solvent, phase is added
The hydrochloric acid that mass fraction for the 2-10 times of equivalent (with HCl content meter) of compound 40 is 20-38%, is heated in 60-120 DEG C
Reaction 24-72 hours；After the reaction was completed, it is spin-dried for solvent, is washed with saturated sodium bicarbonate solution, ethyl acetate extraction merges second
Acetoacetic ester phase, concentration, column chromatograph to obtain final product 1-35.Yield 53-78%；
The organic solvent can be methanol, ethyl alcohol, isopropanol, tetrahydrofuran, 1,4- dioxane single solvent or
Mixed solvent.
Above-mentioned dihydro pteridinone-sulfonic acid amide derivatives answering in the preparation of antitumor drugs as BRD4 protein inhibitor
With for preventing or treating various parenchymatous organ's tumours of BRD4 mediation, including but not limited to gastric cancer, the cancer of the esophagus, liver cancer, kidney
Cancer, lung cancer, prostate cancer, leukemia, lymthoma etc..
The total recovery of target compound of the invention is demonstrate,proved up to 15% -22% (with the calculating of raw material 41) by activity experiment
The real new compound of the present invention with dihydro pteridinone structure has good BRD4 albumen inhibitory effect, can inhibit
Tumor cell proliferation, in particular for stomach cancer cell, the inhibitory activity of part of compounds reaches or better than positive reference compound
JQ1.The present invention will provide new medicament selection for the treatment of the diseases such as BRD4 inhibitor, tumour.
Specific embodiment
The present invention is further described with reference to embodiments, these embodiments are merely to illustrate the present invention and not limit this hair
Bright range.
In following embodiment, the determination to the structure of compound is by nuclear magnetic resonance (NMR) and high resolution mass spec
(HRMS) it determines.Nuclear Magnetic Resonance used is Sweden Bruker DPX-400 type NMR spectrometer with superconducting magnet, tetramethylsilane
It (TMS) is internal standard；High resolution mass spectrum used is Waters-Micromass company Q-Tof mass spectrograph.
For the preparation process for synthesizing required intermediate 40a and 46a by compound 29 below, to illustrate 40 He of intermediate
46 synthesis process.
The synthesis of intermediate 37
Chlorosulfonic acid (2.48g, 21.26mmol) and 2- fluoronitrobenzene (1.00g, 7.09mmol) are added in round-bottomed flask,
100 DEG C are warming up to, 12h is stirred, TLC is detected after the reaction was completed, reaction system is down to room temperature, system solution is slowly added dropwise to
Extra chlorosulfonic acid is quenched in ice water, three times with ethyl acetate (30mL × 3) extraction reaction system, merges organic phase, organic phase
It is washed with saturated sodium bicarbonate solution (30mL), after liquid separation, is spin-dried for after organic phase water removal as product.Yield 80%, it is light yellow
Oily liquids.1H NMR(400MHz,CDCl3) δ 8.93-8.67 (m, 1H), 8.44-8.24 (m, 1H), 7.62 (t, J=9.3Hz,
1H).13C NMR(100MHz,CDCl3)δ160.34,157.59,140.66,140.61,133.98,133.88,126.17,
126.16,120.85,120.62.
The synthesis of intermediate 38a
Intermediate 37 (100mg, 0.417mmol) is added in round-bottomed flask, the anhydrous THF of 10mL is added and dissolves, under ice bath
Cool down 10min, adds cyclopropylamine (23.83mg, 0.417mmol) and triethylamine (105.49mg, 1.04mmol), stirs under ice bath
20min is mixed, TLC detection is spin-dried for solvent, ethyl acetate (20mL) and saturated salt solution (20mL) diluted system after the reaction was completed, adjusts
PH to 7 or so, liquid separation, water phase discards, and is spin-dried for organic phase, pure using silica gel column chromatography (petroleum ether PE/ ethyl acetate EA=4:1)
Change obtains product, yield 60%.Light yellow solid, fusing point: 143-144 DEG C of1H NMR(400MHz,CDCl3) δ 8.84 (d, J=
2.2Hz, 1H), 8.59 (s, 1H), 8.02-7.89 (m, 1H), 7.50 (d, J=9.2Hz, 1H), 2.75-2.66 (m, 1H),
1.11–1.01(m,2H),0.79–0.72(m,2H).13C NMR(100MHz,CDCl3)δ149.93,133.80,129.29,
116.58,24.91,8.05.HR-MS(ESI):Calcd.C9H9FN2O4S,[M+H]+m/z:409.2352,found:
409.2351.
The synthesis of intermediate 39a
Intermediate 38a (50mg, 0.19mmol) and phenol (21.70mg, 0.228mmol) are added in round-bottomed flask, added
Enter 8mL dimethyl sulfoxide and make solvent, be warming up to 100 DEG C, stir 4-5h, TLC is detected after the reaction was completed, and ethyl acetate is added
(15mL) diluting reaction system is washed, liquid separation using saturated salt solution (10mL × 3), abandons water phase, takes organic phase, organic relevant
It is spin-dried for after dry as product.Yield 78%.White solid, fusing point: 153-154 DEG C of1H NMR(400MHz,DMSO-d6)δ8.55
(s, 1H), 8.30 (d, J=2.3Hz, 1H), 7.99-7.84 (m, 1H), 7.55 (d, J=9.2Hz, 1H), 7.46-7.38 (m,
2H), 7.34 (t, J=7.3Hz, 1H), 7.15-7.06 (m, 2H), 2.83-2.65 (m, 1H), 0.99-0.88 (m, 2H), 0.76-
0.67(m,2H).13C NMR(100MHz,DMSO-d6)δ148.96,148.88,133.72,130.45,130.09,127.74,
127.55,122.18,119.67,117.16,25.07,7.50.HR-MS(ESI):Calcd.C15H14N2O5S,[M+H]+m/z:
335.0696,found:335.0695.
The synthesis of intermediate 40a
It takes intermediate 39a (50mg, 0.15mmol, 1eq.) to be added in round-bottomed flask, 10mL tetrahydrofuran is added and makees solvent,
The palladium carbon of catalytic amount is added, under hydrogen atmosphere, is heated to 50 DEG C, stirs 6-8h, TLC detection filters out palladium carbon afterwards after the reaction was completed,
Filtrate is spin-dried for obtaining intermediate 40a.Yield 80%, light yellow solid, fusing point: 156-157 DEG C of1H NMR(400MHz,CDCl3)δ
7.32-7.24 (m, 3H), 7.24-7.19 (m, 1H), 7.12 (d, J=2.1Hz, 1H), 7.05-6.93 (m, 3H), 4.52 (s,
1H),3.27(s,2H),2.52–2.43(m,1H),0.85–0.78(m,2H),0.60–0.53(m,2H).13C NMR(100MHz,
CDCl3)δ149.94,144.19,132.54,129.44,126.76,123.11,122.61,122.56,116.11,110.64,
24.92,7.38.HR-MS(ESI):Calcd.C15H16N2O3S,[M+H]+m/z:305.0955,found:305.0956.
The synthesis of intermediate 42
2-amino-butyric acid (1.00g, 1.0eq.) is added in 50mL eggplant-shape bottle, anhydrous methanol 15mL is added, at 0 DEG C slowly
SOCl is added2(2.31g, 2.0eq.), after being heated to reflux 1.5 hours, TLC display reaction is completed.It is obtained after will volatilize object evaporation
White solid uses Et2O grinds solid, and the crude product that intermediate 42 is obtained after suction filtration can directly carry out the next step without further purification,
Yield 90%.White solid, fusing point: 120-122 DEG C of1H NMR(400MHz,D2O) δ 4.04 (t, J=6.2Hz, 1H), 3.76
(s,3H),1.99–1.82(m,2H),0.97–0.87(m,3H).13C NMR(101MHz,D2O)δ170.79,53.99,53.46,
23.21,8.42.HR-MS(ESI):Calcd.C5H12ClNO2,[M+H]+m/z:118.0863,found:118.0867.
The synthesis of intermediate 43a
NaOAc is added in intermediate 42 (1.00g, 1.0eq.) and cyclopentanone (548mg, 1.0eq.) ice bath 10 minutes
(547mg, 1.0eq.) and NaBH (OAc)3(2.07g, 1.5eq.).Reaction mixture is stirred at room temperature overnight.TLC is shown
After reaction, the NaHCO of saturation is added into reaction system3Solution quenching reaction, then uses CH2Cl2(20mL × 2) extraction
Water layer merges organic layer, through anhydrous Na2SO4It is dried, filtered and concentrated, obtains intermediate 43a, yield 65%.Colorless oil
Liquid1H NMR(400MHz,DMSO-d6) δ 3.63 (s, 3H), 3.10 (t, J=6.6Hz, 1H), 2.98-2.84 (m, 1H),
1.80(s,1H),1.67–1.54(m,4H),1.54–1.48(m,2H),1.47–1.39(m,2H),1.32–1.21(m,2H),
0.84 (t, J=7.4Hz, 3H)13C NMR(101MHz,DMSO-d6)δ175.71,60.88,57.32,51.19,33.17,
32.10,26.25,23.38,23.33,10.21.HR-MS(ESI):Calcd.C10H19NO2,[M+H]+m/z:186.1494,
found:186.1495.
The synthesis of intermediate 44a
Acetone 15mL is added in intermediate 43a (1.00g, 1.0eq.), the chloro- 5- nitro of 2,4- bis- is added in ice bath after ten minutes
Pyrimidine (1.05g, 1.0eq.), adds K2CO3(750mg, 1.0eq.), is stirred overnight at room temperature.It removes after the reaction was completed molten
Agent is dissolved residue with ethyl acetate, and is washed with water, collected organic layer, after anhydrous sodium sulfate drying, with the quick column of silica gel
Chromatography (PE/EA=10:1) purifying obtains intermediate 44a, yield 89%.Yellow solid, fusing point: 110-111 DEG C of1H NMR
(400MHz,DMSO-d6)δ8.84(s,1H),4.29–4.14(m,1H),3.64(s,3H),3.52–3.48(m,1H),2.28–
2.15(m,1H),2.04–1.90(m,2H),1.85–1.77(m,2H),1.72–1.61(m,3H),1.51–1.35(m,2H),
0.94 (t, J=7.8Hz, 3H)13C NMR(101MHz,DMSO-d6)δ164.21,151.73,151.14,137.83,
119.27,61.06,59.38,28.30,28.28,26.36,23.88,23.86,8.33.HR-MS(ESI):
Calcd.C14H19ClN4O4,[M+Na]+m/z:365.0993,found:365.0992.
The synthesis of intermediate 45a
Glacial acetic acid 20mL is added in intermediate 44a (1.00g, 1.0eq.), 70 DEG C is heated to, is added portionwise in 5 minutes
Iron powder (325mg, 2.0eq.).Reactant is stirred 1 hour at 70 DEG C, then heats to 100 DEG C of reactions 4-5 hours, is reacted
After the completion, mixture is filtered with diatomite, rinses washing filter residue with appropriate methanol, after volatile matter is evaporated off, uses flash column chromatography
(PE/EA=1.5:1) purifying obtains intermediate 45a, yield 50%.Yellow solid, fusing point: 180-182 DEG C of1H NMR
(400MHz,DMSO-d6)δ10.85(s,1H),7.57(s,1H),4.30–4.20(m,1H),4.18–4.04(m,1H),2.00–
1.76(m,7H),1.76–1.65(m,1H),1.62–1.42(m,2H),0.92–0.68(m,3H).13C NMR(101MHz,
DMSO-d6)δ164.21,151.73,151.14,137.83,119.27,61.06,59.38,28.30,28.28,26.36,
23.88,23.86,8.33.HR-MS(ESI):Calcd.C13H17ClN4O,[M+Na]+m/z:303.0989,found:
303.0975.
The synthesis of intermediate 46a
By intermediate 45a (1.00g, 1.0eq.) be added anhydrous DMF, ice bath after ten minutes, be added iodomethane (657mg,
It 1.3eq.) stirs 3 hours with mass percentage for 60% NaH (185mg, 1.3eq.), after the reaction was completed, uses at room temperature
Ice water quenching reaction system extracts product with EtOAc, and organic layer is washed twice with water, and is spin-dried for after being dried with anhydrous sodium sulfate
It is directly thrown in next step to intermediate 46a without purifying, yield 90%.Yellow solid, fusing point: 182-183 DEG C of1H NMR
(400MHz,DMSO-d6) δ 7.87 (s, 1H), 4.39-4.31 (m, 1H), 4.17 (p, J=8.3Hz, 1H), 3.24 (s, 3H),
1.97-1.77 (m, 7H), 1.74-1.65 (m, 1H), 1.61-1.48 (m, 2H), 0.74 (t, J=7.5Hz, 3H)13C NMR
(101MHz,DMSO)δ163.16,152.13,151.53,138.49,121.24,60.76,59.32,28.38,28.33,
27.91,26.61,23.85,23.81,8.48.HR-MS(ESI):Calcd.C14H19ClN4O,[M+H]+m/z:295.1325,
found:295.1322.
Intermediate 40a corresponding to the synthesis process and above compound 29 of the corresponding intermediate 40 and 46 of remaining compound
Substituent R is that with the essential difference of 46a synthesis process1、R2、R3The difference of corresponding raw material, other than raw material replacement,
Those skilled in the art, which carry out general adjustment referring to above scheme, can be obtained the corresponding intermediate 40 and 46 of remaining compound
Synthesis process, details are not described herein for specific synthesis process, and raw material is listed below table one below:
Substituent R in one compound 1 to 35 of table1、R2、R3Corresponding raw material
Embodiment 29: the synthesis of compound 29
The preparation method of compound 1-35 is identical, by taking the preparation method of compound 29 as an example.
Make solvent with dehydrated alcohol and Isosorbide-5-Nitrae-dioxane, by the above-mentioned 40a being prepared and 46a according to molar ratio 1:1
It is dissolved in solvent, and the concentrated hydrochloric acid of 2.5 equivalents (relative to 40a) is added, be heated to reflux 48h, after the reaction was completed, be spin-dried for molten
Agent is washed with saturated sodium bicarbonate solution, ethyl acetate extraction, combined ethyl acetate phase, concentration, and column chromatographs to obtain final product
29.Yield 76%, light yellow solid, fusing point: 146-147 DEG C.1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),8.44
(s, 1H), 7.87 (s, 1H), 7.83 (d, J=8.0Hz, 1H), 7.77 (d, J=1.8Hz, 1H), 7.44-7.31 (m, 5H),
7.27 (d, J=7.2Hz, 2H), 5.48 (d, J=15.3Hz, 1H), 4.36 (d, J=15.3Hz, 1H), 4.09 (t, J=
4.8Hz, 1H), 3.28 (s, 3H), 2.07 (s, 1H), 1.86-1.74 (m, 2H), 0.75 (t, J=7.3Hz, 3H), 0.46-0.39
(m,2H),0.37(s,2H).13C NMR(100MHz,DMSO-d6)δ162.53,155.03,151.23,141.69,140.49,
138.56,136.87,129.06,128.55,127.80,127.36,121.28,118.12,116.02,114.95,60.33,
46.94,27.75,24.24,24.09,8.62,5.14,5.10.HR-MS(ESI):Calcd.C25H28N6O3S,[M+H]+m/z:
493.2017,found:493.2016.
Embodiment 1: the synthesis of compound 1
Method is the same as embodiment 29.Yield 63%, light yellow solid, fusing point: 179-180 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.41 (s, 1H), 8.45 (s, 1H), 8.04 (t, J=6.3Hz, 1H), 7.87-7.80 (m, 2H), 7.43 (t, J=
8.0Hz, 1H), 7.32-7.21 (m, 6H), 4.62-4.51 (m, 1H), 4.23-4.17 (m, 1H), 3.99 (d, J=6.3Hz,
2H), 3.25 (s, 3H), 2.03 (d, J=6.2Hz, 1H), 1.93 (d, J=6.4Hz, 1H), 1.71 (d, J=10.8Hz, 5H),
1.64-1.55 (m, 3H), 0.78 (t, J=7.5Hz, 3H)13C NMR(100MHz,DMSO-d6)δ162.83,154.92,
151.58,141.88,140.90,138.53,137.81,129.11,128.17,127.50,127.07,121.30,117.82,
115.73,115.60,58.84,57.42,46.15,28.94,28.74,27.78,26.46,23.06,22.66,9.05.HR-
MS(ESI):Calcd.C27H32N6O3S,[M+H]+m/z:521.2335,found:521.2334.
Embodiment 2: the synthesis of compound 2
Method is the same as embodiment 29.Yield 63%, light yellow solid, fusing point: 155-156 DEG C.1H NMR(400MHz,DMSO-
d6) δ 10.22 (s, 1H), 9.40 (s, 1H), 8.44 (s, 1H), 7.82 (s, 1H), 7.78 (d, J=9.5Hz, 1H), 7.37 (t, J
=8.0Hz, 1H), 7.25-7.18 (m, 3H), 7.10 (d, J=7.6Hz, 2H), 7.00 (t, J=7.3Hz, 1H), 4.60-4.48
(m, 1H), 4.24-4.18 (m, 1H), 3.25 (s, 3H), 2.03 (d, J=5.9Hz, 1H), 1.91 (d, J=9.3Hz, 1H),
1.78-1.65 (m, 5H), 1.65-1.55 (m, 3H), 0.78 (t, J=7.5Hz, 3H)13C NMR(100MHz,DMSO-d6)δ
162.84,154.80,151.57,141.86,139.93,138.42,137.88,129.11,129.02,123.77,121.66,
119.80,117.86,115.79,58.83,57.40,28.93,28.71,27.78,26.46,23.05,22.64,9.04.HR-
MS(ESI):Calcd.C26H30N6O3S,[M+H]+m/z:507.2178,found:507.2179.
Embodiment 3: the synthesis of compound 3
Method is the same as embodiment 29.Yield 65%, light yellow solid, fusing point: 145-146 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.81 (s, 1H), 9.35 (s, 1H), 8.32 (t, J=1.9Hz, 1H), 7.80 (s, 1H), 7.78-7.74 (m, 1H), 7.35
(t, J=8.0Hz, 1H), 7.17 (d, J=7.7Hz, 1H), 7.01-6.95 (m, 2H), 6.81-6.75 (m, 2H), 4.56-4.45
(m, 1H), 4.23-4.12 (m, 1H), 3.64 (d, J=7.4Hz, 3H), 3.22 (d, J=9.3Hz, 3H), 2.06-1.96 (m,
1H), 1.94-1.87 (m, 1H), 1.79-1.65 (m, 5H), 1.64-1.52 (m, 3H), 0.76 (t, J=7.5Hz, 3H)13C
NMR(100MHz,DMSO-d6)δ162.84,156.36,154.81,151.56,141.76,139.89,138.40,130.30,
128.95,123.32,121.51,117.98,115.84,115.76,114.16,58.87,57.41,55.07,28.92,
28.72,27.76,26.45,23.06,22.66,9.03.HR-MS(ESI):Calcd.C27H32N6O4S,[M+H]+m/z:
537.2284,found:537.2285.
Embodiment 4: the synthesis of compound 4
Method is the same as embodiment 29.Yield 61%, light yellow solid, fusing point: 147-148 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.39 (s, 1H), 8.44 (s, 1H), 8.03 (t, J=6.3Hz, 1H), 7.84 (d, J=8.5Hz, 2H), 7.43 (t, J=
8.0Hz, 1H), 7.32-7.21 (m, 6H), 4.61-4.52 (m, 1H), 4.22-4.16 (m, 1H), 3.99 (d, J=6.3Hz,
2H), 3.25 (s, 3H), 2.03 (d, J=6.2Hz, 1H), 1.98-1.90 (m, 1H), 1.71 (d, J=10.9Hz, 5H), 1.66-
1.56 (m, 3H), 0.78 (t, J=7.5Hz, 3H)13C NMR(100MHz,DMSO-d6)δ162.84,154.93,151.59,
141.88,140.91,138.52,137.80,129.10,128.16,127.49,127.07,121.31,117.83,115.74,
115.62,58.87,57.44,46.16,28.95,28.75,27.78,26.46,23.07,22.67,9.04.HR-MS(ESI):
Calcd.C27H31BrN6O3S,[M+H]+m/z:599.1440,found:599.1440.
Embodiment 5: the synthesis of compound 5
Method is the same as embodiment 29.Yield 68%, light yellow solid, fusing point: 157-158 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.41 (s, 1H), 8.43 (s, 1H), 8.07 (t, J=6.3Hz, 1H), 7.88-7.79 (m, 2H), 7.42 (t, J=
8.0Hz, 1H), 7.32-7.24 (m, 3H), 4.57 (d, J=7.4Hz, 1H), 4.23-4.16 (m, 1H), 3.98 (d, J=
6.2Hz,2H),3.25(s,3H),2.06–1.99(m,1H),1.92(s,1H),1.72(s,5H),1.65–1.54(m,3H),
0.78 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6)δ162.83,154.90,151.57,141.87,
140.86,138.53,134.04,129.52,129.43,129.11,128.11,125.03,121.29,117.79,115.72,
115.56,114.99,114.78,58.83,57.40,54.88,45.38,28.93,28.72,27.78,26.45,23.05,
22.64.HR-MS(ESI):Calcd.C27H31FN6O3S,[M+H]+m/z:539.2240,found:539.2239.
Embodiment 6: the synthesis of compound 6
Method is the same as embodiment 29.Yield 63%, light yellow solid, fusing point: 178-179 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.40 (s, 1H), 8.43 (s, 1H), 7.95 (t, J=6.2Hz, 1H), 7.84 (d, J=10.2Hz, 2H), 7.43 (t, J=
7.9Hz, 1H), 7.29 (d, J=7.7Hz, 1H), 7.16 (d, J=8.3Hz, 2H), 6.83 (d, J=8.4Hz, 2H), 4.66-
4.49 (m, 1H), 4.26-4.14 (m, 1H), 3.92 (d, J=6.1Hz, 2H), 3.71 (s, 3H), 3.25 (s, 3H), 2.03 (s,
1H), 1.93 (s, 1H), 1.73 (s, 5H), 1.66-1.55 (m, 3H), 0.78 (t, J=7.4Hz, 3H)13C NMR(100MHz,
DMSO-d6)δ162.82,158.39,154.92,151.57,141.85,140.94,138.54,129.59,129.07,
128.86,121.23,117.82,115.71,115.61,113.56,58.84,57.41,55.00,45.69,28.94,
28.73,27.77,26.45,23.06,22.66,9.04.HR-MS(ESI):Calcd.C28H34N6O4S,[M+H]+m/z:
551.2440,found:551.2441.
Embodiment 7: the synthesis of compound 7
Method is the same as embodiment 29.Yield 67%, light yellow solid, fusing point: 191-192 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.54 (s, 1H), 7.95-7.84 (m, 4H), 7.66 (d, J=8.9Hz, 2H), 7.19 (t, J=7.9Hz, 1H), 6.84-
6.76 (m, 3H), 4.48-4.40 (m, 1H), 4.26-4.21 (m, 1H), 3.93 (d, J=6.3Hz, 2H), 3.69 (s, 3H),
3.26 (s, 3H), 2.09-2.01 (m, 1H), 1.93 (d, J=8.7Hz, 1H), 1.85-1.72 (m, 5H), 1.67-1.57 (m,
3H), 0.78 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6)δ162.90,159.15,154.62,151.53,
144.88,139.36,138.32,131.06,129.21,127.38,119.65,117.10,116.03,112.89,112.65,
59.27,57.96,54.90,46.03,28.77,28.36,27.76,26.47,22.87,22.53,8.93.HR-MS(ESI):
Calcd.C28H34N6O4S,[M+H]+m/z:551.2440,found:551.2441.
Embodiment 8: the synthesis of compound 8
Method is the same as embodiment 29.Yield 74%, light yellow solid, fusing point: 167-168 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.41 (s, 1H), 8.44 (s, 1H), 7.93-7.78 (m, 3H), 7.43 (t, J=8.0Hz, 1H), 7.29 (t, J=
7.7Hz, 2H), 7.21 (t, J=7.7Hz, 1H), 6.95-6.81 (m, 2H), 4.64-4.49 (m, 1H), 4.23-4.17 (m,
1H), 3.95 (d, J=6.1Hz, 2H), 3.69 (s, 3H), 3.25 (s, 3H), 2.02 (s, 1H), 1.92 (s, 1H), 1.72 (s,
5H), 1.64-1.52 (m, 3H), 0.78 (t, J=7.3Hz, 3H)13C NMR(100MHz,DMSO-d6)δ162.82,156.32,
154.93,151.57,141.80,140.83,138.55,129.06,128.35,128.19,125.28,121.25,119.99,
117.85,115.70,115.64,110.29,58.82,57.40,55.13,28.93,28.73,27.77,26.46,23.05,
22.64,9.05.HR-MS(ESI):Calcd.C28H34N6O4S,[M+H]+m/z:551.244,found:551.244.
Embodiment 9: the synthesis of compound 9
Method is the same as embodiment 29.Yield 61%, light yellow solid, fusing point: 178-179 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.41 (s, 1H), 8.45 (d, J=1.8Hz, 1H), 8.16 (t, J=6.2Hz, 1H), 7.84 (d, J=8.0Hz, 2H),
7.43 (t, J=8.0Hz, 1H), 7.41-7.38 (m, 1H), 7.29 (d, J=7.8Hz, 1H), 6.94-6.90 (m, 2H), 4.63-
4.53 (m, 1H), 4.22-4.14 (m, 3H), 3.25 (s, 3H), 2.04 (d, J=5.8Hz, 1H), 1.97-1.90 (m, 1H),
1.78-1.67 (m, 5H), 1.66-1.57 (m, 3H), 0.78 (t, J=7.5Hz, 3H)13C NMR(100MHz,DMSO-d6)δ
162.83,154.91,151.58,141.89,140.86,140.73,138.54,129.13,126.64,125.83,125.55,
121.38,117.85,115.74,115.57,58.84,57.42,41.42,28.95,28.76,27.78,26.46,23.08,
22.67,9.05.HR-MS(ESI):Calcd.C25H30N6O3S2,[M+H]+m/z:,found:527.1898.
Embodiment 10: the synthesis of compound 10
Method is the same as embodiment 29.Yield 60%, light yellow solid, fusing point: 156-157 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.46 (s, 1H), 8.34 (s, 1H), 7.96 (d, J=9.6Hz, 1H), 7.86 (s, 1H), 7.51 (t, J=8.0Hz, 1H),
7.20 (d, J=8.3Hz, 1H), 4.59-4.52 (m, 1H), 4.22-4.18 (m, 1H), 3.65-3.62 (m, 4H), 3.25 (s,
3H), 2.89-2.85 (m, 4H), 2.03 (d, J=7.9Hz, 1H), 1.92 (s, 1H), 1.73 (d, J=11.4Hz, 5H), 1.65-
1.57 (m, 3H), 0.78 (t, J=7.5Hz, 3H)13C NMR(100MHz,DMSO-d6)δ162.84,154.82,151.59,
142.17,138.50,134.53,129.29,122.22,118.92,116.19,115.88,65.25,58.82,57.42,
45.93,28.92,28.70,27.81,26.45,23.09,22.69,9.05.HR-MS(ESI):Calcd.C24H32N6O4S,[M+
H]+m/z:501.2284,found:501.2285.
Embodiment 11: the synthesis of compound 11
Method is the same as embodiment 29.Yield 68%, light yellow solid, fusing point: 156-157 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.39 (s, 1H), 8.42 (d, J=1.8Hz, 1H), 7.84 (s, 1H), 7.80 (d, J=8.2Hz, 1H), 7.53 (d, J=
7.4Hz, 1H), 7.42 (t, J=8.0Hz, 1H), 7.30 (d, J=7.7Hz, 1H), 4.57 (d, J=7.8Hz, 1H), 4.23-
4.18 (m, 1H), 3.25 (s, 3H), 2.94 (s, 1H), 2.04 (d, J=5.0Hz, 1H), 1.97-1.90 (m, 1H), 1.79-
1.69 (m, 5H), 1.65-1.55 (m, 7H), 1.44 (d, J=10.8Hz, 1H), 1.17-1.04 (m, 5H), 0.78 (t, J=
7.4Hz,3H).13C NMR(100MHz,DMSO-d6)δ162.83,154.93,151.58,142.51,141.70,138.50,
129.01,121.07,117.71,115.70,115.42,58.87,57.43,52.10,33.22,28.94,28.74,27.77,
26.45,24.84,24.45,23.08,22.68,9.03.HR-MS(ESI):Calcd.C26H36N6O3S,[M+H]+m/z:
513.2648,found:513.2649.
Embodiment 12: the synthesis of compound 12
Method is the same as embodiment 29.Yield 78%, light yellow solid, fusing point: 151-152 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.45 (s, 1H), 8.35 (s, 1H), 7.92 (d, J=8.2Hz, 1H), 7.86 (s, 1H), 7.47 (t, J=8.0Hz, 1H),
7.18 (d, J=7.6Hz, 1H), 4.65-4.51 (m, 1H), 4.23-4.16 (m, 1H), 3.25 (s, 3H), 2.94-2.83 (m,
4H), 2.03 (d, J=7.4Hz, 1H), 1.96-1.89 (m, 1H), 1.81-1.66 (m, 5H), 1.65-1.51 (m, 7H), 1.36
(s, 2H), 0.78 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6)δ162.82,154.87,151.59,
142.08,138.57,135.69,129.14,121.80,118.70,115.92,115.82,58.75,57.36,46.61,
28.94,28.75,27.80,26.46,24.67,23.08,22.85,22.67,9.06.HR-MS(ESI):
Calcd.C25H34N6O3S,[M+H]+m/z:499.2491,found:499.2492.
Embodiment 13: the synthesis of compound 13
Method is the same as embodiment 29.Yield 73%, light yellow solid, fusing point: 158-159 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.40 (s, 1H), 8.42 (s, 1H), 7.84 (s, 1H), 7.80 (d, J=8.5Hz, 1H), 7.59 (d, J=7.2Hz, 1H),
7.42 (t, J=7.9Hz, 1H), 7.29 (d, J=7.8Hz, 1H), 4.62-4.50 (m, 1H), 4.24-4.18 (m, 1H), 3.25
(s, 3H), 2.91 (d, J=6.7Hz, 1H), 2.60 (d, J=11.2Hz, 2H), 2.07 (s, 4H), 1.92 (d, J=9.7Hz,
1H), 1.83-1.68 (m, 7H), 1.65-1.51 (m, 5H), 1.37 (d, J=9.5Hz, 2H), 0.78 (t, J=7.4Hz, 3H)
.13C NMR(100MHz,DMSO-d6)δ162.83,154.92,151.59,142.26,141.75,138.50,129.08,
121.17,117.71,115.72,115.39,58.86,57.42,53.91,50.17,45.71,32.25,28.94,28.75,
27.77,26.46,23.08,22.67,9.05.HR-MS(ESI):Calcd.C26H37N7O3S,[M+H]+m/z:528.2757,
found:528.2758.
Embodiment 14: the synthesis of compound 14
Method is the same as embodiment 29.Yield 53%, light yellow solid, fusing point: 166-167 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.40 (s, 1H), 8.41 (s, 1H), 7.82 (d, J=12.7Hz, 2H), 7.53 (d, J=7.1Hz, 1H), 7.43 (t, J=
8.0Hz, 1H), 7.29 (d, J=7.8Hz, 1H), 4.63-4.50 (m, 1H), 4.26-4.13 (m, 1H), 3.45-3.39 (m,
1H), 3.25 (s, 3H), 2.03 (d, J=6.3Hz, 1H), 1.98-1.89 (m, 1H), 1.82-1.67 (m, 5H), 1.66-1.50
(m, 7H), 1.43-1.22 (m, 5H), 0.78 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6)δ162.83,
154.93,151.58,141.78,141.73,138.51,129.01,121.16,117.91,115.72,58.87,57.43,
54.47,32.40,28.93,28.72,27.77,26.45,23.07,22.79,22.67,9.04.HR-MS(ESI):
Calcd.C25H34N6O3S,[M+H]+m/z:499.2491,found:499.2493.
Embodiment 15: the synthesis of compound 15
Method is the same as embodiment 29.Yield 63%, light yellow solid, fusing point: 178-179 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.41 (s, 1H), 8.44 (s, 1H), 7.89-7.83 (m, 2H), 7.81 (d, J=2.3Hz, 1H), 7.45 (t, J=
8.0Hz, 1H), 7.30 (d, J=7.8Hz, 1H), 4.63-4.48 (m, 1H), 4.25-4.16 (m, 1H), 3.25 (s, 3H),
2.16–2.09(m,1H),2.08–2.01(m,1H),1.98–1.89(m,1H),1.81–1.68(m,5H),1.67–1.56(m,
3H), 0.78 (t, J=7.4Hz, 3H), 0.51-0.45 (m, 2H), 0.44-0.37 (m, 2H)13C NMR(100MHz,DMSO-
d6)δ162.85,154.92,151.59,141.80,140.52,138.47,128.99,121.40,118.12,115.97,
115.74,58.90,57.46,28.92,28.72,27.78,26.45,24.11,23.08,22.69,9.03,5.15.HR-MS
(ESI):Calcd.C23H30N6O3S,[M+H]+m/z:471.2178,found:471.2177.
Embodiment 16: the synthesis of compound 16
Method is the same as embodiment 29.Yield 68%, light yellow solid, fusing point: 158-159 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.50 (s, 1H), 7.96-7.80 (m, 3H), 7.64 (d, J=8.8Hz, 2H), 7.41 (d, J=7.6Hz, 1H), 4.49-
4.36 (m, 1H), 4.26-4.19 (m, 1H), 3.25 (s, 3H), 2.03 (d, J=10.9Hz, 1H), 1.92 (s, 1H), 1.75 (d,
J=15.1Hz, 5H), 1.67-1.54 (m, 3H), 0.95 (d, J=6.6Hz, 3H), 0.77 (t, J=7.5Hz, 3H), 0.37-
0.28(m,1H),0.25–0.17(m,1H),0.14–0.07(m,1H),-0.02–-0.09(m,1H).13C NMR(100MHz,
DMSO-d6)δ162.90,154.62,151.52,144.58,138.33,132.64,127.23,117.01,115.98,
59.34,58.02,53.02,28.74,28.35,27.76,26.45,22.86,22.54,20.98,17.47,8.91,3.23,
2.70.HR-MS(ESI):Calcd.C25H34N6O3S,[M+H]+m/z:499.2486,found:499.2487.
Embodiment 17: the synthesis of compound 17
Method is the same as embodiment 29.Yield 67%, light yellow solid, fusing point: 167-168 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.39 (s, 1H), 8.42 (s, 1H), 7.84 (s, 1H), 7.80 (d, J=8.2Hz, 1H), 7.41 (t, J=7.9Hz, 1H),
7.33 (d, J=7.8Hz, 1H), 7.24 (s, 2H), 4.62-4.49 (m, 1H), 4.23-4.15 (m, 1H), 3.25 (s, 3H),
2.04 (d, J=9.6Hz, 1H), 1.97-1.88 (m, 1H), 1.81-1.55 (m, 8H), 0.78 (t, J=7.4Hz, 3H)13C
NMR(100MHz,DMSO-d6)δ162.83,154.97,151.57,144.37,141.62,138.51,128.80,120.82,
117.32,115.66,114.74,58.87,57.42,28.93,28.70,27.77,26.46,23.02,22.62,9.05.HR-
MS(ESI):Calcd.C20H26N6O3S,[M+H]+m/z:431.1865,found:431.1865.
Embodiment 18: the synthesis of compound 18
Method is the same as embodiment 29.Yield 63%, light yellow solid, fusing point: 156-1597 DEG C.1H NMR(400MHz,
DMSO-d6) δ 9.42 (s, 1H), 8.41 (s, 1H), 7.84 (d, J=6.8Hz, 2H), 7.44 (t, J=7.9Hz, 1H), 7.32
(d, J=5.0Hz, 1H), 7.25 (d, J=7.7Hz, 1H), 4.64-4.47 (m, 1H), 4.24-4.15 (m, 1H), 3.25 (s,
3H), 2.43 (d, J=4.9Hz, 3H), 2.03 (s, 1H), 1.92 (d, J=7.0Hz, 1H), 1.73 (s, 5H), 1.65-1.55
(m, 3H), 0.78 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6)δ162.83,154.91,151.57,
141.90,139.48,138.53,129.08,121.34,117.92,115.77,115.73,58.84,57.41,28.93,
28.73,27.78,26.46,23.07,22.67,9.04.HR-MS(ESI):Calcd.C21H28N6O3S,[M+H]+m/z:
445.2022,found:445.2021.
Embodiment 19: the synthesis of compound 19
Method is the same as embodiment 29.Yield 67%, light yellow solid, fusing point: 165-166 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.41 (s, 1H), 8.41 (t, J=1.8Hz, 1H), 7.88-7.80 (m, 2H), 7.48-7.41 (m, 2H), 7.27 (d, J=
7.7Hz,1H),4.62–4.51(m,1H),4.25–4.16(m,1H),3.25(s,3H),2.83–2.77(m,2H),2.04(d,J
=6.1Hz, 1H), 1.97-1.90 (m, 1H), 1.80-1.68 (m, 5H), 1.66-1.58 (m, 3H), 0.78 (t, J=7.4Hz,
3H).13C NMR(100MHz,DMSO-d6)δ162.82,154.92,151.57,141.84,140.77,138.52,129.07,
121.23,117.80,115.71,115.62,58.85,57.41,28.93,28.71,27.78,26.45,23.06,22.66,
14.74,9.04.HR-MS(ESI):Calcd.C22H30N6O3S,[M+H]+m/z:459.2178,found:459.2179.
Embodiment 20: the synthesis of compound 20
Method is the same as embodiment 29.Yield 65%, light yellow solid, fusing point: 166-167 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.45 (s, 1H), 8.36 (s, 1H), 7.95 (d, J=8.1Hz, 1H), 7.86 (s, 1H), 7.49 (t, J=8.0Hz, 1H),
7.21 (d, J=7.7Hz, 1H), 4.62-4.52 (m, 1H), 4.24-4.17 (m, 1H), 3.26 (s, 3H), 2.62 (s, 6H),
2.04 (d, J=7.4Hz, 1H), 1.98-1.89 (m, 1H), 1.81-1.68 (m, 5H), 1.67-1.56 (m, 3H), 0.78 (t, J
=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6)δ162.83,154.86,151.59,142.10,138.52,134.84,
129.17,121.86,118.82,116.08,115.83,58.79,57.39,37.62,28.92,28.72,27.79,26.45,
23.08,22.68,9.04.HR-MS(ESI):Calcd.C22H30N6O3S,[M+H]+m/z:459.2178,found:
459.2179.
Embodiment 21: the synthesis of compound 21
Method is the same as embodiment 29.Yield 65%, light yellow solid, fusing point: 156-156 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.54 (s, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.62 (d, J=8.9Hz, 2H), 7.18 (q, J
=5.0Hz, 1H), 4.49-4.40 (m, 1H), 4.27-4.21 (m, 1H), 3.25 (s, 3H), 2.38 (d, J=5.1Hz, 3H),
2.04 (d, J=16.9Hz, 1H), 1.92 (s, 1H), 1.86-1.71 (m, 5H), 1.67-1.57 (m, 3H), 0.77 (t, J=
7.5Hz,3H).13C NMR(100MHz,DMSO-d6)δ162.83,154.93,151.57,142.08,141.75,138.50,
129.03,121.09,117.79,115.71,115.55,58.88,57.43,45.22,28.93,28.71,27.77,26.44,
23.20,23.17,23.07,22.68,9.04.HR-MS(ESI):Calcd.C23H32N6O3S,[M+H]+m/z:473.2335,
found:473.2335.
Embodiment 22: the synthesis of compound 22
Method is the same as embodiment 29.Yield 64%, light yellow solid, fusing point: 145-146 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.41 (s, 1H), 8.40 (s, 1H), 7.89-7.77 (m, 2H), 7.50-7.40 (m, 2H), 7.27 (d, J=7.7Hz,
1H),4.67–4.46(m,1H),4.25–4.16(m,1H),3.25(s,3H),2.77–2.66(m,2H),2.09–2.01(m,
1H),1.97–1.89(m,1H),1.80–1.67(m,5H),1.66–1.55(m,3H),1.42–1.35(m,2H),0.83–0.76
(m,6H).13C NMR(100MHz,DMSO-d6)δ162.83,154.92,151.57,141.81,140.86,138.52,
129.06,121.20,117.78,115.71,115.60,58.84,57.41,44.42,28.93,28.72,27.77,26.45,
23.06,22.66,22.39,11.14,9.04.HR-MS(ESI):Calcd.C23H32N6O3S,[M+H]+m/z:473.2335,
found:473.2334.
Embodiment 23: the synthesis of compound 23
Method is the same as embodiment 29.Yield 73%, light yellow solid, fusing point: 158-159 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.41 (s, 1H), 8.41 (s, 1H), 7.89 (d, J=8.3Hz, 1H), 7.86 (s, 1H), 7.43 (t, J=8.0Hz, 1H),
7.24 (d, J=7.7Hz, 1H), 4.65-4.49 (m, 1H), 4.24-4.14 (m, 1H), 3.25 (s, 3H), 3.16 (q, J=
7.1Hz, 4H), 2.03 (d, J=6.6Hz, 1H), 1.98-1.89 (m, 1H), 1.83-1.67 (m, 5H), 1.67-1.54 (m,
3H), 1.05 (t, J=7.1Hz, 6H), 0.78 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6)δ162.83,
154.87,151.60,142.09,139.93,138.52,129.20,121.42,117.99,115.80,115.33,58.78,
57.38,41.82,28.94,28.74,27.80,26.45,23.09,22.68,14.06,9.05.HR-MS(ESI):
Calcd.C24H34N6O3S,[M+H]+m/z:487.2491,found:487.2492.
Embodiment 24: the synthesis of compound 24
Method is the same as embodiment 29.Yield 57%, light yellow solid, fusing point: 145-146 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.40 (s, 1H), 8.40 (s, 1H), 7.83 (d, J=11.7Hz, 2H), 7.48-7.38 (m, 2H), 7.27 (d, J=
7.7Hz,1H),4.64–4.47(m,1H),4.27–4.14(m,1H),3.25(s,3H),2.78–2.70(m,2H),2.08–
2.00(m,1H),1.98–1.88(m,1H),1.81–1.66(m,5H),1.66–1.54(m,3H),1.39–1.31(m,2H),
1.27–1.21(m,2H),0.83–0.75(m,6H).13C NMR(100MHz,DMSO-d6)δ162.82,154.92,151.57,
141.81,140.82,138.53,129.06,121.20,117.78,115.71,115.60,58.84,57.41,42.25,
31.05,28.93,28.73,27.77,26.45,23.07,22.66,19.21,13.44,9.04.HR-MS(ESI):
Calcd.C24H34N6O3S,[M+H]+m/z:487.2491,found:487.2489.
Embodiment 25: the synthesis of compound 25
Method is the same as embodiment 29.Yield 63%, light yellow solid, fusing point: 154-155 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.41 (s, 1H), 8.41 (s, 1H), 7.84 (d, J=7.8Hz, 2H), 7.49-7.38 (m, 2H), 7.27 (d, J=
7.8Hz, 1H), 4.63-4.50 (m, 1H), 4.42 (t, J=5.0Hz, 1H), 4.25-4.16 (m, 1H), 3.39-3.36 (m,
2H),3.26(s,3H),2.85–2.78(m,2H),2.10–2.01(m,1H),1.98–1.90(m,1H),1.79–1.67(m,
5H), 1.67-1.58 (m, 3H), 1.57-1.51 (m, 2H), 0.78 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-
d6)δ162.83,154.92,151.57,141.83,140.67,138.51,129.07,121.22,117.81,115.72,
115.65,58.85,58.12,57.41,32.34,28.94,28.71,27.77,26.45,23.07,22.66,9.04.HR-MS
(ESI):Calcd.C23H32N6O4S,[M+H]+m/z:489.2284,found:489.2284.
Embodiment 26: the synthesis of compound 26
Method is the same as embodiment 29.Yield 53%, light yellow solid, fusing point: 178-179 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.41 (s, 1H), 8.41 (t, J=1.8Hz, 1H), 7.87-7.81 (m, 2H), 7.50-7.41 (m, 2H), 7.31-7.26
(m, 1H), 4.68 (t, J=5.6Hz, 1H), 4.60-4.51 (m, 1H), 4.23-4.16 (m, 1H), 3.39 (d, J=6.4Hz,
2H),3.25(s,3H),2.84–2.78(m,2H),2.08–2.01(m,1H),1.97–1.90(m,1H),1.78–1.67(m,
5H), 1.66-1.56 (m, 3H), 0.78 (t, J=7.4Hz, 3H)13C NMR(100MHz,DMSO-d6)δ162.83,154.91,
151.57,141.83,140.76,138.53,129.08,121.25,117.82,115.71,115.58,59.89,58.84,
57.41,45.09,28.94,28.72,27.78,26.45,23.07,22.67,9.05.HR-MS(ESI):
Calcd.C22H30N6O4S,[M+H]+m/z:475.2127,found:475.2126.
Embodiment 27: the synthesis of compound 27
Method is the same as embodiment 29.Yield 60%, light yellow solid, fusing point: 176-177 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.40 (s, 1H), 8.40 (s, 1H), 7.83 (d, J=10.5Hz, 2H), 7.59 (t, J=5.7Hz, 1H), 7.43 (t, J=
7.9Hz, 1H), 7.28 (d, J=7.8Hz, 1H), 4.56 (s, 1H), 4.20 (d, J=4.3Hz, 1H), 3.25 (s, 3H), 3.17
(s, 3H), 2.91 (d, J=5.7Hz, 3H), 2.10-1.99 (m, 1H), 1.98-1.89 (m, 1H), 1.84-1.66 (m, 5H),
1.62 (d, J=6.8Hz, 3H), 0.78 (t, J=7.3Hz, 3H)13C NMR(100MHz,DMSO-d6)δ162.83,154.92,
151.57,141.82,140.83,138.54,129.07,121.27,117.80,115.72,115.55,70.50,58.85,
57.84,57.41,42.16,28.93,28.72,27.78,26.45,23.07,22.67,9.05.HR-MS(ESI):
Calcd.C23H32N6O4S,[M+H]+m/z:449.2284,found:449.2285.
Embodiment 28: the synthesis of compound 28
Method is the same as embodiment 29.Yield 70%, light yellow solid, fusing point: 156-157 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.41 (s, 1H), 8.41 (s, 1H), 7.92-7.74 (m, 2H), 7.43 (t, J=7.9Hz, 2H), 7.26 (d, J=
7.3Hz, 1H), 4.56 (s, 1H), 4.20 (d, J=4.5Hz, 1H), 3.25 (s, 3H), 2.80-2.69 (m, 2H), 2.03 (s,
1H), 1.93 (s, 1H), 1.78-1.58 (m, 7H), 1.34 (d, J=6.3Hz, 2H), 1.18 (d, J=7.6Hz, 7H), 0.87-
0.71(m,6H).13C NMR(100MHz,DMSO-d6)δ162.83,154.94,151.57,141.82,140.88,138.53,
129.03,121.19,117.78,115.70,115.59,58.84,57.41,42.56,30.72,28.94,28.89,28.74,
27.77,26.45,25.68,23.07,22.67,21.92,13.78,9.03.HR-MS(ESI):Calcd.C26H38N6O3S,[M+
H]+m/z:515.2804,found:515.2803.
Embodiment 30: the synthesis of compound 30
Method is the same as embodiment 29.Yield 73%, light yellow solid, fusing point: 156-157 DEG C.1H NMR(400MHz,DMSO-
d6)δ8.21–8.06(m,2H),7.78(s,1H),7.39–7.27(m,4H),7.05–6.99(m,3H),6.63(s,1H),
4.48–4.37(m,1H),4.18–4.11(m,1H),3.23(s,3H),2.45(s,1H),1.91–1.78(m,2H),1.71–
1.52 (m, 6H), 1.51-1.39 (m, 2H), 0.77 (q, J=7.2Hz, 5H), 0.53-0.45 (m, 2H)13C NMR(100MHz,
DMSO-d6)δ162.72,155.81,151.55,149.40,146.47,138.82,129.78,126.95,125.79,
124.72,122.08,121.82,119.25,115.48,110.25,58.99,57.42,28.86,28.70,27.77,
26.41,24.54,23.07,22.70,9.04,6.80.HR-MS(ESI):Calcd.C29H34N6O4S,[M+H]+m/z:
563.2435,found:563.2437.
Embodiment 31: the synthesis of compound 31
Method is the same as embodiment 29.Yield 63%, light yellow solid, fusing point: 178-179 DEG C.1H NMR(400MHz,DMSO-
d6) δ 8.53-8.45 (m, 1H), 8.22 (d, J=2.5Hz, 1H), 8.18-8.09 (m, 2H), 7.79 (s, 1H), 7.56-7.49
(m, 1H), 7.48-7.40 (m, 1H), 7.36-7.29 (m, 1H), 7.04 (d, J=8.7Hz, 1H), 6.72 (s, 1H), 4.48-
4.36(m,1H),4.19–4.09(m,1H),3.23(s,3H),2.47(s,1H),1.92–1.77(m,2H),1.72–1.54(m,
6H),1.50–1.39(m,2H),0.83–0.71(m,5H),0.55–0.44(m,2H).13C NMR(100MHz,DMSO-d6)δ
162.73,155.78,151.56,148.04,146.79,146.23,143.53,138.83,130.04,125.93,124.89,
124.71,121.80,118.15,115.54,110.33,58.96,57.40,28.87,28.69,27.77,26.41,24.53,
23.08,22.69,9.05,6.79.HR-MS(ESI):Calcd.C28H33N7O4S,[M+H]+m/z:564.2388,found:
564.2388.
Embodiment 32: the synthesis of compound 32
Method is the same as embodiment 29.Yield 53%.Light yellow solid, fusing point: 181-182 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.40 (s, 1H), 8.42 (d, J=1.8Hz, 1H), 7.93 (s, 1H), 7.86-7.81 (m, 2H), 7.42 (t, J=
8.0Hz, 1H), 7.27 (d, J=7.8Hz, 1H), 4.62-4.49 (m, 1H), 4.24-4.16 (m, 1H), 3.25 (s, 3H), 2.04
(d, J=6.1Hz, 1H), 1.97-1.90 (m, 1H), 1.80-1.68 (m, 5H), 1.65-1.56 (m, 3H), 1.08 (s, 3H),
0.78 (t, J=7.5Hz, 3H), 0.63 (t, J=5.1Hz, 2H), 0.36 (q, J=4.3Hz, 2H)13C NMR(101MHz,
DMSO-d6)δ162.84,154.92,143.07,141.72,138.47,128.95,121.17,118.00,115.74,
115.69,58.93,57.47,30.76,28.91,28.71,27.78,26.44,23.89,23.08,22.70,12.96,
9.04.HR-MS(ESI):Calcd.C24H32N6O3S,[M+H]+m/z:485.2330,found:485.2331
Embodiment 33: the synthesis of compound 33
Method is the same as embodiment 29.Yield 62%.Light yellow solid, fusing point: 167-168 DEG C.1H NMR(400MHz,DMSO-
d6) δ 9.62 (s, 1H), 8.44 (s, 1H), 7.89 (s, 1H), 7.84 (d, J=8.1Hz, 1H), 7.46 (t, J=8.0Hz, 1H),
7.42-7.25 (m, 5H), 7.17 (d, J=7.7Hz, 1H), 5.50 (d, J=15.3Hz, 1H), 4.39 (d, J=15.4Hz,
1H), 4.06 (t, J=4.8Hz, 1H), 3.53 (d, J=3.7Hz, 4H), 3.28 (s, 3H), 2.84-2.66 (m, 4H), 1.89-
1.74 (m, 2H), 0.74 (t, J=7.4Hz, 3H)13C NMR(101MHz,DMSO-d6)δ162.46,154.95,151.23,
142.08,138.73,136.79,134.51,129.33,128.60,127.78,127.43,122.11,118.97,115.94,
114.90,65.17,60.22,46.82,45.80,27.76,24.18,8.55.HR-MS(ESI):Calcd.C26H30N6O4S,[M
+H]+m/z:523.2122,found:523.2121.
Embodiment 34: the synthesis of compound 34
Method is the same as embodiment 29.Yield 78%.Light yellow solid, fusing point: 158-159 DEG C.1H NMR(400MHz,DMSO-
d6) δ 8.11 (s, 1H), 8.07 (d, J=2.2Hz, 1H), 7.78 (s, 1H), 7.49-7.41 (m, 1H), 7.09 (d, J=
8.7Hz, 1H), 6.50 (s, 1H), 4.42-4.33 (m, 1H), 4.18-4.13 (m, 1H), 3.98 (q, J=7.1Hz, 2H), 3.23
(s,3H),2.45(s,1H),1.91–1.85(m,1H),1.82–1.77(m,1H),1.73–1.64(m,3H),1.61–1.54
(m, 3H), 1.52-1.45 (m, 2H), 1.17 (t, J=7.1Hz, 3H), 0.82-0.71 (m, 6H), 0.56-0.44 (m, 2H)13C
NMR(101MHz,DMSO-d6)δ162.73,155.92,151.52,146.20,125.81,124.50,124.02,121.84,
120.60,115.40,110.56,66.09,59.29,57.69,28.77,28.60,27.75,26.39,24.56,23.10,
22.76,14.48,9.00,6.82.HR-MS(ESI):Calcd.C25H34N6O4S,[M+H]+m/z:515.2435,found:
515.2436.
Embodiment 35: the synthesis of compound 35
Method is the same as embodiment 29.Yield 64%.Light yellow solid, fusing point: 149-150 DEG C.1H NMR(400MHz,DMSO-
d6) δ 8.07 (s, 1H), 7.76 (d, J=2.1Hz, 1H), 7.73 (s, 1H), 7.37-7.27 (m, 1H), 7.10 (d, J=
8.6Hz,1H),6.32(s,1H),4.33–4.21(m,1H),4.18–4.09(m,1H),3.64–3.59(m,4H),3.22(s,
3H), 2.80 (d, J=4.1Hz, 4H), 2.44 (s, 1H), 1.85-1.64 (m, 5H), 1.60-1.50 (m, 3H), 1.49-1.37
(m,2H),0.80–0.72(m,5H),0.55–0.41(m,2H).13C NMR(101MHz,DMSO-d6)δ162.77,156.28,
151.55,146.59,138.74,125.60,124.73,123.56,119.63,115.28,110.39,65.27,59.74,
58.05,45.89,28.65,28.46,27.73,26.32,24.53,23.10,22.84,8.96,6.84.HR-MS(ESI):
Calcd.C27H37N7O4S,[M+H]+m/z:556.2701,found:556.2702.
The test of BRD4 protein inhibiting activity
1. experimental method
HTRF combines two kinds of technologies of fluorescence resonance energy transfer FRET and time-resolved fluorescence TRF, by the homogeneous of FRET
The low background feature of experiment method and TRF are fused together, and with easy to operate, high sensitivity, flux is big, experimental data is stable
Reliable feature.With Anti-GST-Cryptate (Eu3+Cryptate conjugated mouse monoclonal
Antibody anti-glutathione S-transferase) (Cisbio, 61GSTKLB) be used as energy donor,
Streptavidin-d2 (d2-conjugated streptavidin) (Cisbio, 610SADLB) is used as energy acceptor,
It is separately added into 384 orifice plates 1.6nM GST-BRD4 (BD1), 200nM Biotin-H4 (gill is biochemical), 0.125ng/ μ L
Anti-GST-Cryptate (Cisbio, 61GSTKLB), 2.5ng/ μ L Streptavidin-d2 (Cisbio, 610SADLB),
Assay buffer (50mM Hepes, 400mM KF, 50mM sodium chloride, BSA 0.1%, Tween20 0.1%, pH7.5), to
It surveys compound (i.e. compound 1 to 35 and JQ1), makes 20 μ L of end reaction system, 30min is reacted at room temperature, finally by hair
The intensity of two kinds of bio-molecular interactions of ratio in judgement of signal value when signal value and 620nm when the long 665nm of ejected wave, when having
After inhibitor is added, inhibitor, to inhibit the combination of BRD4 and substrate, can inhibit two in conjunction with the active site of BRD4
When a intermolecular interaction, donor and receptor are since distance is compared with far from carrying out energy transfer, therefore transmitted wave grows signal
It reduces, so as to evaluate inhibitor to the inhibition level of BRD4 and histone interaction, to test small molecule of the present invention
Inhibitory activity of the compound to BRD4 albumen, data processing SPSS or GraphPad calculating IC50.Experimental result is shown in Table two.
The BRD4 protein inhibiting activity result of compound prepared by two embodiment 1 to 35 of table
Note: JQ1 is positive control；
Mtt assay inhibiting tumour cells active testing
1. experimental method
By part of compounds of the present invention and positive reference compound JQ1 respectively with 1640 culture mediums be configured to concentration be 50,
25, the solution of 12.5,6.26,3.125,1.56,0.78,0.39,0.19 μM of concentration gradient, respectively with stomach cancer cell
SGC7901, BGC823, MGC803, MKN45, leukaemia cell THP1 are co-cultured 5 days in 96 orifice plates, the every hole paving of stomach cancer cell
1000 cells, the every hole of leukaemia cell spread 5000 cells.After compound stimulates stomach cancer cell 5 days, it is molten that MTT is added in cell
Liquid, every 20 μ l of hole continue culture 4 hours in incubator, and former culture medium is gently sucked out later, adds 150 μ L DMSO to dissolve, room temperature
It gently shakes 10 minutes, to guarantee that crystallization is completely dissolved；96 orifice plates are taken out, microplate reader 570nm measures the light absorption value in every hole.Chemical combination
After object stimulates leukaemia cell 5 days, MTT solution is added in cell, every 20 μ L of hole continues culture 4 hours, every hole in incubator
100 μ L, tri- liquid is added, reacts 24 hours, microplate reader 570nm measures the light absorption value in every hole, calculates cell survival according to light absorption value
Rate and IC50, experimental result is shown in Table three.
The part of compounds anti tumor activity in vitro of the present invention of table three
Note: JQ1 is positive control；SGC7901, BGC823, MGC803, MKN45 are stomach cancer cell, and THP1 is that leukaemia is thin
Born of the same parents
The above test result shows that compound provided by embodiment 1 to 35 has good BRD4 albumen inhibitory effect
And inhibiting tumour cells effect, part of compounds reach the inhibitory effect of BRD4 albumen or are better than having entered clinical rank well
The compound of section, such as OTX-015 (IC50 240nM)、CPI-0610(IC50 120nM)、FT-010(IC50 100nM)、RVX-
208(IC50510nM).Part of compounds reaches the inhibitory activity of stomach cancer cell or better than positive reference compound JQ1.
It should be noted last that: technical solution of the present invention that the above embodiments are only illustrative and not limiting is any right
The equivalent replacement and do not depart from the modification of spirit and scope of the invention or locally replace that the present invention carries out, should all cover in this hair
Within bright protective scope of the claims.
Claims (8)
1. a kind of dihydro pteridinone-sulfonic acid amide derivatives, it is characterised in that: its structure is as shown in logical formula (I):
Wherein, R1For saturated hydrocarbyl, aryl or heterocycle；
The saturated hydrocarbyl is unsubstituted or optionally substituted linear saturation alkyl, branched saturated hydrocarbon group or cyclic saturated hydrocarbon
Base；
The aryl is phenyl that is unsubstituted or optionally being replaced by the first substituent group, benzyl, any one in naphthalene；
The heterocycle be piperidyl that is unsubstituted or optionally being replaced by the first substituent group, pyrrole radicals, pyrazolyl, imidazole radicals,
Furyl, indyl, morpholinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl group, pyrimidine radicals, piperazine
Piperazine base, substituted piperazinyl, pyrazinyl, any one in pyridazinyl；
R2For hydrogen, alkoxy, aryloxy group or heterocycle；
Alkyl in the alkoxy is unsubstituted or optionally substituted linear saturation alkyl, branched saturated hydrocarbon group or ring-type
Saturated alkyl, and wherein each carbon atom is optionally substituted with an oxygen；
Aryl in the aryloxy group is phenyl that is unsubstituted or optionally being replaced by the first substituent group, benzyl, times in naphthalene
It anticipates one kind；
The heterocycle be piperidyl that is unsubstituted or optionally being replaced by the first substituent group, pyrrole radicals, pyrazolyl, imidazole radicals,
Furyl, indyl, morpholinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl group, pyrimidine radicals, piperazine
Piperazine base, substituted piperazinyl, pyrazinyl, any one in pyridazinyl；
First substituent group is independently selected from halogen, halogenated alkyl, alkyl, cyano, hydroxyl, nitro, sulfydryl, alkoxy, alkane
Sulfenyl, aralkyl, alkyl diaryl；
R3For miscellaneous alkyl, aryl, heterocycle；
The miscellaneous alkyl is linear saturation alkyl, branch saturated alkyl or the ring-type that each carbon atom is optionally replaced by oxygen, nitrogen-atoms
Saturated alkyl；
The aryl is phenyl that is unsubstituted or optionally being replaced by the second substituent group, benzyl, any one in naphthalene；
The heterocycle be piperidyl that is unsubstituted or optionally being replaced by the second substituent group, pyrrole radicals, pyrazolyl, imidazole radicals,
Furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl group, pyrimidine radicals, piperazinyl, takes morpholinyl
It is disliked for piperazinyl, pyrazinyl, pyridazinyl, quinolyl, quinoxalinyl, indyl, benzimidazolyl, benzoxazolyl, benzisoxa
It is oxazolyl, benzothienyl, benzisoxa thienyl, benzofuranyl, benzodioxane base, any in benzdioxolanyl
It is a kind of；
Second substituent group is independently selected from halogen, halogenated alkyl, alkyl, cyano, hydroxyl, sulfydryl, amino, nitro, alcoxyl
Base, alkylthio group, aralkyl, alkyl diaryl, nafoxidine base, morpholinyl, alcoxyl morpholinyl, piperazinyl, piperidyl, alkylamino
Piperidyl.
2. dihydro pteridinone-sulfonic acid amide derivatives according to claim 1, it is characterised in that:
The R1For methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, benzyl,
Naphthalene, thienyl, furyl, cinnamyl group, indyl, any one in pyrrole radicals, pyridyl group；
The R2For hydrogen, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, cyclobutoxy group, cyclopentyloxy, hexamethylene oxygen
Base, phenoxy group, benzyloxy, methylamino, ethylamino-, Propylamino, isopropylamine base, cyclopropyl amino, substituted cyclopropane amido, piperidyl,
Pyrrole radicals, pyrazolyl, imidazole radicals, indyl, it is morpholinyl, piperazinyl, substituted piperazinyl, pyrazinyl, any one in pyridazinyl
Kind；
The R3For methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, phenyl, benzyl,
Naphthalene, indyl, pyridyl group contain heteroatomic alkyl, methyl and/or halogen is monosubstituted, disubstituted cyclopropyl, and methyl list takes
The phenyl in generation, the mono-substituted phenyl of tert-butyl, the mono-substituted phenyl of halogen, hydroxyl and the disubstituted phenyl of methoxyl group, halogen two
Substituted phenyl, the phenyl that dimethoxy replaces, hydroxyl and the disubstituted phenyl of halogen, halogen and the disubstituted phenyl of nitro,
Ethyoxyl and the disubstituted phenyl of hydroxyl, lignocaine and the disubstituted phenyl of hydroxyl, the mono-substituted phenyl of acetonitrile, naphthalene, Yin
Diindyl base, the mono-substituted naphthalene of hydroxyl, pyridyl group, the mono-substituted pyridyl group of methyl, the mono-substituted pyridyl group of methoxyl group, amino list take
The pyridyl group in generation, the mono-substituted pyridyl group of halogen, halogen Disubstituted pyridine base, the mono-substituted pyridyl group of nitro, halogen three take
The pyridyl group in generation.
3. dihydro pteridinone-sulfonic acid amide derivatives according to claim 2, it is characterised in that: its specific structure such as formula 1
Shown in 35:
4. the pharmaceutically acceptable salt of the described in any item dihydro pteridinone-sulfonic acid amide derivatives of claims 1 to 3,
Be characterized in that: the acid-addition salts that the dihydro pteridinone-sulfonic acid amide derivatives and following acid are formed: the acid be hydrochloric acid,
Hydrobromic acid, sulfuric acid, phosphoric acid, boric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, naphthalene sulfonic acids, benzene sulfonic acid, citric acid, lactic acid, pyruvic acid, winestone
Acid, acetic acid, maleic acid, succinic acid, tussol, fumaric acid, salicylic acid or phenylacetic acid.
5. the preparation method of the described in any item dihydro pteridinone-sulfonic acid amide derivatives of claims 1 to 3, it is characterised in that:
Compound shown in formula 40 and formula 46 using molar ratio for 1:0.5-1 is dissolved in organic solvent as raw material, hydrochloric acid is added, in 60-
120 DEG C of heating are reacted 24-72 hours；
6. the preparation method of dihydro pteridinone-sulfonic acid amide derivatives according to claim 5, it is characterised in that: described
40 compound represented of formula the preparation method is as follows:
A. it is raw material with adjacent nitro fluorobenzene 36, is stirred to react 5-12 hours at 80-120 DEG C with chlorosulfonic acid, locates afterwards after the reaction was completed
It manages up to intermediate 37；The molar ratio of the adjacent nitro fluorobenzene 36 and chlorosulfonic acid is 1:1-40；
B. in the presence of an organic base, at 0-10 DEG C, intermediate 37 and corresponding aminated compounds are stirred instead with molar ratio 1:1-2
It answers, after the reaction was completed, post-processing obtains intermediate 38；The organic base is selected from triethylamine, pyridine, triethylene diamine, N- methyl
Morpholine, potassium tert-butoxide, sodium tert-butoxide or butyl lithium；Corresponding aminated compounds is substituent R3Corresponding amine chemical combination
Object；
C. intermediate 38 is dissolved in organic solvent, corresponding reagent is added, be stirred to react at 10-100 DEG C, reaction is completed
Afterwards, post-processing obtains intermediate 39；The organic solvent is dimethyl sulfoxide or N,N-dimethylformamide；Corresponding examination
Agent is substituent R2Corresponding compound；The molar ratio of the intermediate 38 and corresponding reagent is 1:1-5；
D. intermediate 39 is dissolved in solvent, is added the palladium-carbon catalyst of catalytic amount, under hydrogen atmosphere, be heated to 20-80 DEG C, stir
It mixes 4 to 8 hours, obtains intermediate 40 after the reaction was completed；
The reaction route of above step is as follows:
7. the preparation method of dihydro pteridinone-sulfonic acid amide derivatives according to claim 5, it is characterised in that: described
46 compound represented of formula the preparation method is as follows:
E. compound 41 is dissolved in organic solvent, thionyl chloride, back flow reaction is added dropwise under ice bath, reaction terminates, and post-processing is
Obtain intermediate 42；The molar ratio of the compound 41 and thionyl chloride is 1:1-10；
F. intermediate 42 is dissolved in solvent, corresponding carbonyls is added, alkali compounds and reducing agent is added under ice bath,
Stirring to raw material disappears at 0-30 DEG C, is post-processed after reaction up to intermediate 43；Corresponding carbonyls is to take
For base R1Corresponding compound；The reducing agent is selected from NaBH4、KBH4、NaBH(OAc)3Or NaBH3CN；
The intermediate 42 is 1:1-2 with the molar ratio of corresponding carbonyls, and the intermediate 42 rubs with alkali compounds
, than being 1:1-3, the molar ratio of the intermediate 42 and reducing agent is 1:0.25-10 for you；
G. intermediate 43 is dissolved in solvent, the chloro- 5- nitro-pyrimidine of 2,4- bis- and the alkali compounds, room temperature is added under ice bath
Lower stirring to raw material disappears, and is post-processed after reaction up to intermediate 44；
The molar ratio of the intermediate 43, the chloro- 5- nitro-pyrimidine of 2,4- bis- and the alkali compounds is 1:1-3；
H. intermediate 44 is dissolved in acetic acid and is heated to 50-70 DEG C, reduced iron powder is added, is stirred to react, be warming up to 100 DEG C-
110 DEG C the reaction was continued, post-processes to obtain intermediate 45；
The molar ratio of the intermediate 44 and reduced iron powder is 1:2-20；
I., intermediate 45 is added to the NaH of iodomethane and 1.3 equivalents that 1.3 equivalents are added into anhydrous DMF, under ice bath, room temperature
Under be stirred to react, post-process to obtain intermediate 46 after reaction；
The reaction route of above step is as follows:
Wherein, the alkali compounds of step f and g is selected from Na2CO3、K2CO3、CsCO3, NaOAc or KOAc.
8. the described in any item dihydro pteridinone-sulfonic acid amide derivatives of Claims 1-4 and its pharmaceutically acceptable salt are made
For application of the BRD4 protein inhibitor in anti-tumor drug preparation.
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