CN106588922B - Two substitution octahydro -1,6- naphthyridine type compounds and its preparation method and application - Google Patents
Two substitution octahydro -1,6- naphthyridine type compounds and its preparation method and application Download PDFInfo
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- 0 CCCIC1N(*)CCc2c1cccn2 Chemical compound CCCIC1N(*)CCc2c1cccn2 0.000 description 2
- WHTVZABQJPCUOW-UHFFFAOYSA-N CC(C(CC1)=CCCCC1C(N(CCCN(CC1)CC2C1N(Cc(cc1)ccc1F)CCC2)c1ccccc1)=O)=O Chemical compound CC(C(CC1)=CCCCC1C(N(CCCN(CC1)CC2C1N(Cc(cc1)ccc1F)CCC2)c1ccccc1)=O)=O WHTVZABQJPCUOW-UHFFFAOYSA-N 0.000 description 1
- WWKBLVCANBBVON-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC2C1N(Cc1ccccc1)CCC2)=O Chemical compound CC(C)(C)OC(N(CC1)CC2C1N(Cc1ccccc1)CCC2)=O WWKBLVCANBBVON-UHFFFAOYSA-N 0.000 description 1
- VICULRIXUPYWNY-UHFFFAOYSA-N Cc(cc1)ccc1N(CCCN(CC1)CC2C1N(Cc(cc1)ccc1F)CCC2)C(C(CC1)CCN1C(C(F)(F)F)=O)=O Chemical compound Cc(cc1)ccc1N(CCCN(CC1)CC2C1N(Cc(cc1)ccc1F)CCC2)C(C(CC1)CCN1C(C(F)(F)F)=O)=O VICULRIXUPYWNY-UHFFFAOYSA-N 0.000 description 1
- WLRYQVSZZMEIDA-UHFFFAOYSA-N O=C(C(CC1)CCN1C(C(F)(F)F)=O)N(CCCN(CC1)CC2C1N(Cc(cc1)ccc1F)CCC2)c(cc1)ccc1Cl Chemical compound O=C(C(CC1)CCN1C(C(F)(F)F)=O)N(CCCN(CC1)CC2C1N(Cc(cc1)ccc1F)CCC2)c(cc1)ccc1Cl WLRYQVSZZMEIDA-UHFFFAOYSA-N 0.000 description 1
- PPFMOQXBRPBLCQ-UHFFFAOYSA-N OC(C(CC1)CCN1C(C(F)(F)F)=O)N(CCCN(CC1)CC2C1N(Cc1ccccc1)CCC2)c1ccccc1 Chemical compound OC(C(CC1)CCN1C(C(F)(F)F)=O)N(CCCN(CC1)CC2C1N(Cc1ccccc1)CCC2)c1ccccc1 PPFMOQXBRPBLCQ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
Two substitution 1,6 naphthyridine type compounds of octahydro and its preparation method and application, belong to medical compounds technical field.The two substitution 1,6 naphthyridine type compounds of octahydro that formula (I) represents.First using 1 benzyl piepridine, 4 ketone as raw material, cyclization, deprotection are coupled through metal catalytic, Boc is protected, and metallic sodium catalysis reduces, and nucleophilic displacement of fluorine introduces substituted benzyl, deprotection, and finally affine substitution generates formula (I) compound.The compounds of this invention has good inhibiting effect to the virus infection of HIV 1.R1For acetyl group, trifluoroacetyl group；R2For H, Cl, methyl, methoxyl group, R3For H, Cl, methyl；R4For H, F, cyano group, carboxylate methyl ester.
Description
Technical field
The present invention relates to 1- substitutions-N- (3- (1- substituted benzyl octahydro -1,6- naphthyridines) propyl group)-N- substituted phenylpiperidines -
4- amides compounds and preparation method thereof and the application as HIV-1CCR5 antagonists, belong to medical compounds technical field.
Background technology
Acquired immunodeficiency syndrome (Acquired Immune Deficiency Syndrome), abbreviation AIDS
(AIDS), it is to be caused by infecting human immunodeficiency virus type 1 viral (HIV-1) infection, progressively destroy the weight of human immune system
Big communicable disease.By 2012, whole world survival HIV patient still had 35,300,000 people, dies of AIDS virus correlation disease
Patient's number 1,600,000, only 2011 with regard to 2,300,000 people of new infections.By in by the end of October, 2012, China survival HIV-1 the infected and
Aids patient about 780,000, wherein AIDS patients 15.4 ten thousand.
The life cycle of HIV-1 includes adhesion, shell of undressing, reverse transcription, cyclisation, integration, transcription, translation, core granule dress
Match somebody with somebody and finally assemble and sprout.The course of infection of HIV-1:HIV-1 passes through its surface glycoprotein gp120 and cell first
Membrane receptor CD4 combines closely, and the conformation of gp120 memebrane proteins is changed and is exposed, and then gp120 memebrane proteins can be with host
Cooperative expert systems CCR5 or CXCR4 on cell membrane are combined, and are induced the gp41 occurred conformations on HIV-1 coatings to change, are exposed it
Fusogenic peptide and with cell membrane interaction, make viromembrane and cell membrane fusion, then slough film and nucleocapsid, viral nucleic acid is invaded
Enter cell.The reproduction process of HIV-1:Inhibition of HIV RNA forms the double-stranded DNA of wire, is cyclized into and closes under reverse transcriptase catalysis
The double-stranded DNA of conjunction, the latter are transported to nucleus, are incorporated into the chromosome of host cell, form provirus, the virus of transcription
MRNA translates into virus protein and then is processed through proteolytic enzyme, and envelope protein is glycosylated in endoplasmic reticulum, forms gp120, gp41
Deng albumen, albumen and geneome RNA are assembled into new virion near cell membrane, and host is left in the form of budding, complete
Into the life cycle of itself.
Therefore, for HIV infection cell different phase the characteristics of, following several anti-HIV-1 medicines can be designed：1) virus with
Target cell combines inhibitor and fusion inhibitor；2) viral reverse transcriptase inhibitor；3) HIV-1 integrase inhibitors；4)HIV-1
Protease inhibitors；5) HIV-1 maturations inhibitor.
Up to the present, 29 kinds of the treatment AIDS single, drug of clinic is approved by the fda in the United States for, in addition by these
The compound preparation of medicine composition has 6 kinds, based on reverse transcriptase inhibitor and protease inhibitors.It is clinically more common at present
Method be HAART cures i.e. highly efficient anti-virus therapy, but due to the toxic side effect of medicine, the resistance to the action of a drug of virus the problems such as is difficult
To solve, therefore, new and effective, the less toxic treating AIDS medicine tool of research is of great significance.
CCR5 (CC-chemokine receptor 5) is a member of the cellular chemokine receptors of G-protein coupling,
It is one of accessory receptor of HIV-1 invasion cells.Research is found, in the resistive crowds of some R5 types HIV-1, CCR5
The code area of gene has lacked 32 pairs of bases (CCR5 △ 32), and the crowd of 32 homozygote genotypes of CCR5 △ 32/CCR5 △ does not feel
Dye HIV-1, and the infected rate of crowd of 32 heterozygote genotypes of CCR5/CCR5 △ also lower than general population 35%, and body
Physiological function is unaffected.This explanation CCR5 is the ideal targets for designing anti-HIV-1 medicines.
So far, the CCR5 antagonists of document report mainly have two classes:One kind is macromolecular antagonist, another kind of being
Learn the small molecular antagonists of synthesis.Divided by structure type, small molecule CCR5 inhibitor can be divided into eight classes, benzocyclohepta alkenes
Compound, piperidines, spiral diketone piperidines etc..
2007, the small molecule CCR5 inhibitor Maraviroc of pfizer companies research and development ratified to list through FDA, becomes
Small molecule anti-AIDS drug (Meanwell, the N.A. for the targeting CCR5 that first success lists；Kadow,J.F.Drug
evaluation:Maraviroc,achemokine CCR5receptor antagonist for the treatment of
HIV infection and AIDS.Curr.Opin.Invest.Drugs 2007,8,669–681)。
4- piperidines -1- butylamine micromolecular CCR5 antagonists the TAK-220 of Takeda companies research and development has biology well
Active and higher oral administration biaavailability (Imamura, S.；Ichikawa,T.；Nishikawa,Y.；et
al.Discovery of a piperidine-4-carboxamide CCR5antagonist(TAK-220)with highly
potent anti-HIV-1activity.J.Med.Chem.2006,49,2784-2793)。
WO 2005121145 (A2) (publication date：On December 22nd, 2015) disclose a series of 4- nafoxidines bridged ring -1-
Butylamine class CCR5 inhibitor, has good antiviral activity.
The content of the invention
The object of the present invention is to provide 1- substitutions-N- (3- (1- substituted benzyl octahydro -1,6- piperidines) propyl group)-N- substituted benzenes
Phenylpiperidines -4- amides compounds and preparation method thereof and the application as anti-HIV-1 CCR5 antagonists.
The present invention provides 1- substitutions-N- (3- (1- substituted benzyl octahydro -1,6- piperidines) propyl group)-N- that formula (I) represents
Substituted phenylpiperidines -4- amides compounds and preparation method thereof and the application as anti-HIV-1 CCR5 antagonists.
Wherein,
R1For 1) acetyl group；
2) trifluoroacetyl group；
R2For 1)-H,
2)-Cl,
3) methyl,
4) methoxyl group,
R3For 1)-H,
2)-Cl,
3) methyl；
R4For 1)-H,
2)-F,
3) cyano group,
4) carboxylate methyl ester.
The compounds of this invention is respectively provided with the inhibitory action to HIV-1 virus infection, the inhibition of which part compound
Significantly.
1- substitutions-N- (3- (1- substituted benzyl octahydro -1,6- piperidines) propyl group)-N- substituted-phenyl piperazines provided by the invention
The preparation method of pyridine -4- amides compounds comprises the following steps：
(a) 1- benzyl piepridines -4- ketone, through chloride hydrate copper catalysis, is reacted with 2-propynyl amine and generated in absolute ethyl alcohol
6- benzyl -5,6,7,8- tetrahydrochysene -1,6- the naphthyridines that formula (II) represents；
(b) compound that formula (II) represents is in acetic acid, and 5, the 6,7,8- tetra- of the generation formula (III) expression of palladium carbon catalytic hydrogenation
Hydrogen -1,6- naphthyridines；
(c) compound represented toward formula (III) adds toluene and sodium hydrate aqueous solution, is generated with di-tert-butyl dicarbonate
7,8- dihydro -1,6- naphthyridines -6- the carboxylic acid tert-butyl esters that formula (IV) represents；
(d) compound represented toward formula (IV) is heated to reflux in absolute ethyl alcohol, and adds metal sodium reduction, production
(V) octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters represented；
(e) will formula (V) represent compound in add dichloromethane, sodium carbonate effect under with R4Substituted benzyl bromine is anti-
Should, 1- substituted benzyl octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters that generation formula (VI) represents；
Wherein, R4The group of expression is same as above；
(f) compound that formula (VI) represents is dissolved in dichloromethane, is hydrolyzed under the action of trifluoroacetic acid aqueous solution, generated
The 1- substituted benzyl octahydro -1,6- naphthyridines that formula (VII) represents；
Wherein, R4The group of expression is same as above；
(g) compound that formula (VII) represents is dissolved in acetonitrile, under the action of sodium carbonate and potassium iodide, with formula (VIII)
Intermediate 1- substitutions-N- (3- the chloropropyls)-N- substituted phenylpiperidines -4- acid amides reaction of expression, the 1- that generation formula (I) represents take
Generation-N- (3- (1- substituted benzyl octahydro -1,6- naphthyridines) propyl group)-N- substituted phenylpiperidines -4- acid amides.
Wherein, R1、R2、R3The group of expression is same as above；
Wherein, R1、R2、R3、R4The group of expression is same as above.
The method of the present invention is using industrial common reagent and conventional working condition, and reaction condition is gentle, and step is simple.
The synthetic route of Series I compounds：
Reaction condition:a)2-propynylamine,CuCl2.H2O,EtOH,reflux；b)Pd/C,H2,AcOH,60℃；
c)Boc2O,NaOH,PhMe,H2O,rt；d)Na,EtOH,reflux；e)Substituted PhCH2Br,Na2CO3,DCM,H2O,
rt；f)TFA,DCM,rt；g)Intermediate VIII,Na2CO3,KI,MeCN,reflux.
The compounds of this invention has good inhibiting effect to HIV-1 virus infection.
Embodiment
Representational example includes important information, illustration and guidance below, it is suitable for the present invention in its various reality
Apply mode and its way of equivalent.These embodiments are to help the explanation present invention, and are not intended as, and also should not be construed
To limit its scope.In fact, those skilled in the art by consult herein and pertinent literature cited herein, except those
Illustrated and described here, various modifications of the invention and many further embodiments will be apparent.These are quoted
The content of bibliography all entered herein to help to illustrate state of art by quoting.
Embodiment 1
N- (the chloro- 4- aminomethyl phenyls of 3-)-N- (3- (1- benzyl octahydro -1,6- naphthyridines) propyl group) -1- (2,2,2- trifluoro second
Acyl) piperidines -4- acid amides preparation (I-1)
The preparation of step 1) 6- benzyl -5,6,7,8- tetrahydrochysene -1,6- naphthyridines
1- benzyl piepridine -4- ketone (5g, 26.4mmol) is dissolved in the ethanol of 50mL dryings, adds 2- propine -1- amine
(3.45g, 53.0mmol), adds catalyst Hydrated copper chloride (250mg, 1.5mmol), and it is small to be heated to reflux 7-8 under argon gas protection
When.After system cooling, filtering, filtrate decompression distills precipitation, and remaining oily liquids obtains target product through column chromatography for separation.1H NMR(400MHz,CDCl3) δ 8.39 (d, J=4.4Hz, 1H), 7.41-7.26 (m, 6H), 7.05-7.02 (m, 1H), 3.72
(s, 2H), 3.62 (s, 2H), 3.07 (t, J=6.0Hz, 2H), 2.86 (t, J=6.0Hz, 2H)
The preparation of step 2) 5,6,7,8- tetrahydrochysene -1,6- naphthyridines
By 6- benzyls -5,6,7,8- tetrahydrochysene -1,6- naphthyridines (0.2g, 0.89mmol) are dissolved in 5mL acetic acid, add 10% palladium carbon
(40mg), after hydrogen displacement, system is heated to 60 DEG C, when reaction about 2 is small.Reaction system is filtered, filtrate decompression distillation precipitation, obtains
To crude product without further isolating and purifying, directly carry out next step reaction.
The preparation of step 3) 7,8- dihydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters
5 will obtained in step 2,6,7,8- tetrahydrochysene -1,6- naphthyridines are dissolved in 8mL toluene, add 6mol/L NaOH aqueous solutions
(5mL), adds di-tert-butyl dicarbonate (0.26g, 1.2mmol), is stirred overnight at room temperature.Organic phase is separated, with toluene extraction water
Phase, after merging organic phase, depressurizes precipitation, column chromatography for separation, obtains target product.
The preparation of step 4) octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters
7,8- dihydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters (100mg, 0.43mmol) are dissolved in the ethanol of drying process
(5mL), after being heated to reflux, is slowly added to metallic sodium (300mg, 13.0mmol).After metallic sodium is completely dissolved, reaction can stop
Only.After system is cooled to room temperature, it is poured into water and is quenched, repeatedly extracted with petroleum ether, merge organic phase, depressurizes precipitation.Obtain
Crude product is without further isolating and purifying, you can directly carries out next step reaction.
The preparation of step 5) 1- benzyl octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters
Octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters (1.2g, 5mmol) are dissolved in 15mL dichloromethane, add 15mL saturations
Sodium carbonate liquor, then adds cylite (1.27g, 7.5mmol), system is stirred at room temperature overnight.Separate organic phase and water
Phase, with dichloromethane aqueous phase extracted, merges organic phase, depressurizes precipitation.Column chromatography obtains target compound after purification.1H NMR
(400MHz,CDCl3) δ 7.38-7.17 (m, 5H), 4.35-3.79 (m, 4H), 3.15 (d, J=13.5Hz, 1H), 2.81 (t, J
=18.9Hz, 2H), 2.38 (s, 1H), 2.12 (d, J=10.4Hz, 1H), 1.99-1.81 (m, 2H), 1.59 (dd, J=12.1,
7.8Hz,3H),1.46(s,11H).
The preparation of step 6) 1- benzyl octahydro -1,6- naphthyridines
1- benzyl octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters are dissolved in 3mL dichloromethane, add trifluoroacetic acid
(0.5mL), is stirred overnight at room temperature.Reaction system is depressurized into precipitation, adds saturated sodium bicarbonate aqueous solution, it is multiple with dichloromethane
Extract aqueous systems.After merging organic phase, precipitation is depressurized.Obtained oil product directly carries out down without further isolating and purifying
Single step reaction.
Step 7) N- (3- (1- benzyl octahydro -1,6- naphthyridines) propyl group)-N- (the chloro- 4- aminomethyl phenyls of 3-) -1- (2,2,2- tri-
Acetyl fluoride base) piperidines -4- acid amides preparation
1- benzyl octahydro -1,6- naphthyridines (100mg, 0.43mmol) is dissolved in 15mL acetonitrile solutions, intermediate known to addition
N- (the chloro- 4- aminomethyl phenyls of 3-)-N- (3- chloropropyls) -1- (2,2,2- trifluoroacetyl group) piperidines -4- acid amides (200mg,
0.47mmol), potassium carbonate (300mg, 2.15mmol) and potassium iodide (78mg, 0.47mmol) are added, when system reflux 8 is small.Instead
Answer system to depressurize precipitation, add water, with dichloromethane extraction system, after merging organic phase, depressurize precipitation, column chromatography for separation is pure
Change, obtain target compound.1H NMR(400MHz,CDCl3) δ 7.27 (ddd, J=19.9,13.9,9.8Hz, 7H), 7.02 (d,
J=7.8Hz, 1H), 4.41 (d, J=13.5Hz, 1H), 4.05 (d, J=13.5Hz, 1H), 3.96 (d, J=13.7Hz, 1H),
3.68 (d, J=16.7Hz, 2H), 3.20 (d, J=13.4Hz, 1H), 2.99 (dd, J=27.2,12.7Hz, 2H), 2.80 (dd,
J=26.9,9.3Hz, 2H), 2.66 (t, J=11.7Hz, 1H), 2.49-2.41 (m, 4H), 2.36 (s, 2H), 2.20-1.90
(m,3H),1.86-1.52(m,13H).13C NMR(101MHz,CDCl3)δ173.34,155.32(q),140.80,136.69,
135.33,132.09,129.16,128.46,128.19,126.92,126.42,65.53,58.91,57.03,55.42,
53.46,53.19,48.01,44.84,42.61,40.11,38.72,29.82,28.99,28.83,27.98,25.08,
24.93,19.83.HRMS(ESI)m/z:619.3027calcd for C32H42ClF3N4O2[M+H]+,found 619.3080.
Embodiment 2
N- (3- (1- benzyl octahydro -1,6- naphthyridines) propyl group)-N- (4- chlorphenyls) -1- (2,2,2- trifluoroacetyl groups) piperazine
The preparation (I-2) of pyridine -4- acid amides
Step 1) is to 6) the same as embodiment 1；
1- benzyl octahydro -1,6- naphthyridines (0.42g, 1.82mmol) is dissolved in 30mL acetonitrile solutions, intermediate known to addition
N- (4- chlorphenyls)-N- (3- chloropropyls) -1- (2,2,2- trifluoroacetyl group) piperidines -4- acid amides (0.75g, 1.82mmol), adds
Enter potassium carbonate (1.26g, 9.1mmol) and potassium iodide (0.12g, 1.82mmol), when system reflux 8 is small.Reaction system decompression is de-
It is molten, water is added, with dichloromethane extraction system, merges organic phase, depressurizes precipitation, column chromatographic isolation and purification, obtains target chemical combination
Thing.1H NMR(400MHz,CDCl3) δ 7.46 (d, J=8.5Hz, 2H), 7.33 (d, J=4.1Hz, 5H), 7.22 (d, J=
8.3Hz, 2H), 4.43 (d, J=13.3Hz, 1H), 4.11 (d, J=13.3Hz, 1H), 3.96 (d, J=13.5Hz, 1H), 3.69
(dt, J=14.3,7.0,2H), 3.40-3.13 (m, 2H), 2.95 (t, J=11.5Hz, 3H), 2.61 (dd, J=24.2,
11.0Hz, 3H), 2.49-2.37 (m, 1H), 2.23 (d, J=10.7Hz, 2H), 2.05 (d, J=12.8Hz, 2H), 1.93-
1.59(m,13H).13C NMR(101MHz,CDCl3)δ173.55,155.25(q),140.43,134.36,130.36,
129.53,129.34,128.34,127.32,115.45(q),65.25,58.21,56.77,55.02,53.18,52.78,
47.73,44.77,42.59,39.31,38.75,28.98,28.80,28.51,27.95,24.69,24.38.HRMS(ESI)m/
z:605.2870calcd for C32H40ClF3N4O2,[M+H]+,found605.2875.
Embodiment 3
N- (3- (1- benzyl octahydro -1,6- naphthyridines) propyl group)-N- (4- aminomethyl phenyls) -1- (2,2,2- trifluoroacetyl groups) piperazine
The preparation (I-3) of pyridine -4- acid amides
Step 1) is to 6) the same as embodiment 1；
1- benzyl octahydro -1,6- naphthyridines (0.30g, 1.30mmol) is dissolved in 25mL acetonitrile solutions, intermediate known to addition
N- (4- aminomethyl phenyls)-N- (3- chloropropyls) -1- (2,2,2- trifluoroacetyl group) piperidines -4- acid amides, addition potassium carbonate (0.90g,
6.5mmol) and potassium iodide (0.22g, 1.30mmol), when system reflux 8 is small.Reaction system depressurizes precipitation, adds water, uses dichloro
Methane extraction system, merges organic phase, depressurizes precipitation, column chromatographic isolation and purification, obtains target compound.1H NMR(400MHz,
CDCl3) δ 7.34-7.23 (m, 8H), 7.09 (d, J=8.0Hz, 2H), 4.41 (d, J=13.4Hz, 1H), 4.08 (d, J=
13.5Hz, 1H), 3.95 (d, J=13.8Hz, 1H), 3.74-3.62 (d, J=13.0Hz, 1H), 3.16 (d, J=8.5Hz,
1H), 2.92 (dd, J=27.3,12.8Hz, 3H), 2.62 (t, J=11.4Hz, 1H), 2.49 (dd, J=9.6,5.2Hz, 3H),
2.41 (s, 3H), 2.19 (d, J=10.5Hz, 2H), 2.06-1.54 (m, 16H)13C NMR(101MHz,CDCl3)δ173.87,
155.20(q),139.40,138.46,130.69,129.29,128.28,127.77,127.22,117.90,115.04,
65.15,58.14,56.78,55.09,53.54,52.76,47.56,44.84,42.65,39.33,38.63,29.01,
28.83,28.50,27.69,24.59,24.43,21.08.HRMS(ESI)m/z:585.3416calcd for C33H34F3N4O2
[M+H]+,found 585.3419.
Embodiment 4
N- (3- (1- benzyl octahydro -1,6- naphthyridines) propyl group)-N- phenyl -1- (2,2,2- trifluoroacetyl groups) piperidines -4- acyls
The preparation (I-4) of amine
Step 1) is to 6) the same as embodiment 1；
1- benzyl octahydro -1,6- naphthyridines (0.27g, 1.17mmol) is dissolved in 25mL acetonitrile solutions, intermediate known to addition
N- phenyl-N- (3- chloropropyls) -1- (2,2,2- trifluoroacetyl group) piperidines -4- acid amides (0.52g, 1.40mmol), adds carbonic acid
Potassium (0.81g, 5.9mmol) and potassium iodide (0.19g, 1.17mmol), when system reflux 8 is small.Reaction system depressurizes precipitation, adds
Water, with dichloromethane extraction system, merges organic phase, depressurizes precipitation, column chromatographic isolation and purification, obtains target compound.1H
NMR(400MHz,CDCl3) δ 7.50 (t, J=7.4Hz, 2H), 7.46-7.29 (m, 8H), 5.30 (s, 1H), 4.42 (d, J=
13.3Hz, 1H), 4.17 (s, 1H), 3.94 (d, J=13.7Hz, 1H), 3.74 (d, J=6.5Hz, 2H), 3.43 (s, 2H),
3.17 (s, 1H), 3.07-2.70 (m, 4H), 2.70-2.53 (m, 2H), 2.52-2.09 (m, 7H), 2.01 (d, J=8.9Hz,
2H),1.86-1.61(m,7H).13C NMR(101MHz,CDCl3)δ174.30,155.26,141.51,130.31,129.82,
128.70,128.13,117.90,115.03,64.59,56.90,56.36,54.46,53.50,52.61,52.10,47.22,
44.88,42.66,38.78,37.58,28.86,27.99,27.67,27.29,23.89.HRMS(ESI)m/z:
571.3260calcd for C32H41F3N4O2[M+H]+,found 571.3265.
Embodiment 5
N- (3- (1- benzyl octahydro -1,6- naphthyridines) propyl group)-N- (3,4- dichlorophenyls) -1- (2,2,2- trifluoroacetyl groups)
The preparation (I-5) of piperidines -4- acid amides
Step 1) is to 6) the same as embodiment 1；
1- benzyl octahydro -1,6- naphthyridines (0.27g, 1.17mmol) is dissolved in 25mL acetonitrile solutions, intermediate known to addition
N- (3,4- dichlorophenyl)-N- (3- chloropropyls) -1- (2,2,2- trifluoroacetyl group) piperidines -4- acid amides (0.62g,
1.40mmol), potassium carbonate (0.81g, 5.9mmol) and potassium iodide (0.19g, 1.17mmol) are added, when system reflux 8 is small.Instead
Answer system to depressurize precipitation, add water, with dichloromethane extraction system, merge organic phase, depressurize precipitation, column chromatographic isolation and purification,
Obtain target compound.1H NMR(400MHz,CDCl3) δ 7.59 (d, J=8.3Hz, 1H), 7.52-7.21 (m, 8H), 5.30
(s, 1H), 4.43 (d, J=13.0Hz, 1H), 4.15 (d, J=13.5Hz, 1H), 3.97 (d, J=13.1Hz, 1H), 3.70 (s,
2H), 3.43 (d, J=12.1Hz, 1H), 3.22 (d, J=8.5Hz, 1H), 2.99 (dd, J=23.2,11.4Hz, 3H), 2.75-
2.40 (m, 4H), 2.26 (d, J=12.3Hz, 2H), 2.20-2.07 (m, 2H), 2.00 (d, J=13.5Hz, 3H), 1.80 (dd,
J=27.8,9.2Hz, 7H), 1.63 (d, J=11.6Hz, 2H)13C NMR(101MHz,CDCl3)δ173.48,155.16,
141.28,133.80,132.86,131.85,129.86,129.63,128.46,127.96,127.73,117.87,115.01,
65.17,57.78,56.53,54.72,53.60,52.87,52.53,47.77,44.73,42.52,38.69,28.80,
28.35,28.06,27.93,24.42,23.90.HRMS(ESI)m/z:639.2480calcd forC32H39Cl2F3N4O2[M+H
]+,found 639.2484.
Embodiment 6
N- (3- (1- (4- luorobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- (4- chlorphenyls) -1- (2,2,2- trifluoroacetyls
Base) piperidines -4- acid amides preparation (I-6)
Step 1) is to 4) the same as embodiment 1；
The preparation of step 5) 1- (4- luorobenzyls) octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters
Octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters (3g, 12.5mmol) are dissolved in 30mL dichloromethane, 30mL is added and satisfies
And sodium carbonate liquor, 4- fluorobenzyl bromides (3.53g, 18.75mmol) are then added, system is stirred at room temperature overnight.Separate organic
Mutually with water phase, with dichloromethane aqueous phase extracted, merge organic phase, depressurize precipitation.Column chromatography obtains target compound after purification.1H
NMR(400MHz,CDCl3) δ 7.24 (dd, J=8.1,5.7Hz, 2H), 6.96 (t, J=8.6Hz, 2H), 4.06 (t, J=
33.3Hz, 3H), 3.07 (d, J=13.5Hz, 1H), 2.79 (d, J=11.1Hz, 2H), 2.35 (d, J=11.0Hz, 1H),
2.07 (d, J=11.2Hz, 1H), 1.96-1.79 (m, 2H), 1.67-1.50 (m, 3H), 1.50-1.20 (m, 12H)
The preparation of step 6) 1- (4- luorobenzyls) octahydro -1,6- naphthyridines
1- (4- luorobenzyls) octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters (100mg, 0.29mmol) are dissolved in 3mL dichloromethanes
Alkane, adds trifluoroacetic acid (0.17mL), is stirred overnight at room temperature.Reaction system is depressurized into precipitation, it is molten to add saturated sodium bicarbonate water
Liquid, aqueous systems are repeatedly extracted with dichloromethane.After merging organic phase, precipitation is depressurized.Obtained oil product is without further dividing
From purifying, next step reaction is directly carried out.
Step 7) N- (3- (1- (4- luorobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- (4- chlorphenyls) -1- (2,2,2- tri-
Acetyl fluoride base) piperidines -4- acid amides preparation
1- (4- luorobenzyls) octahydro -1,6- naphthyridines (0.25g, 1.01mmol) is dissolved in 25mL acetonitrile solutions, known to addition
Intermediate N (4- chlorphenyls)-N- (3- chloropropyls) -1- (2,2,2- trifluoroacetyl group) piperidines -4- acid amides (0.50g,
1.21mmol), potassium carbonate (0.70g, 5.05mmol) and potassium iodide (0.17g, 1.01mmol) are added, when system reflux 8 is small.Instead
Answer system to depressurize precipitation, add water, with dichloromethane extraction system, merge organic phase, depressurize precipitation, column chromatographic isolation and purification,
Obtain target compound.1H NMR(400MHz,CDCl3) δ 7.48 (d, J=8.4Hz, 2H), 7.38-7.26 (m, 5H), 7.02
(t, J=8.5Hz, 2H), 4.44 (d, J=12.6Hz, 1H), 4.09 (d, J=13.4Hz, 1H), 3.97 (d, J=13.7Hz,
1H), 3.72 (d, J=6.8Hz, 2H), 3.34 (s, 1H), 3.26 (d, J=10.7Hz, 1H), 3.08 (s, 1H), 2.94 (dd, J
=31.3,11.6Hz, 2H), 2.66 (dd, J=30.5,16.9Hz, 3H), 2.51-2.37 (m, 2H), 2.24 (d, J=
10.6Hz, 1H), 2.03 (dd, J=30.6,22.4Hz, 7H), 1.87-1.59 (m, 8H)13C NMR(101MHz,CDCl3)δ
173.98,163.40,160.96,155.28(q),140.17,134.55,132.46,130.96,130.88,130.47,
129.59,120.75,117.89,115.37,115.16,115.02,112.87,64.83,57.46,55.95,54.71,
52.92,52.52,52.46,47.44,44.77,42.60,38.76,38.49,28.81,28.19,28.15,27.96,
24.15,24.06.HRMS(ESI)m/z:623.2776calcd for C32H39ClF4N4O2[M+H]+,found 623.2776.
Embodiment 7
N- (3- (1- (4- luorobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- (4- aminomethyl phenyls) -1- (2,2,2- trifluoro second
Acyl group) piperidines -4- acid amides preparation (I-7)
Step 1) is to 6) the same as embodiment 6；
1- (4- luorobenzyls) octahydro -1,6- naphthyridines (0.25g, 1.01mmol) is dissolved in 25mL acetonitrile solutions, known to addition
Intermediate N (4- aminomethyl phenyls)-N- (3- chloropropyls) -1- (2,2,2- trifluoroacetyl group) piperidines -4- acid amides (0.50g,
1.21mmol), potassium carbonate (0.70g, 5.05mmol) and potassium iodide (0.17g, 1.01mmol) are added, when system reflux 8 is small.Instead
Answer system to depressurize precipitation, add water, with dichloromethane extraction system, merge organic phase, depressurize precipitation, column chromatographic isolation and purification,
Obtain target compound.1H NMR(400MHz,CDCl3) δ 7.33-7.22 (m, 6H), 7.12 (d, J=7.8Hz, 2H), 7.00
(t, J=8.5Hz, 2H), 4.41 (d, J=12.6Hz, 1H), 4.04 (d, J=13.8Hz, 1H), 3.94 (d, J=13.8Hz,
1H), 3.74-3.63 (m, 2H), 3.29-3.14 (m, 2H), 3.04-2.80 (m, 3H), 2.63 (d, J=9.8Hz, 3H), 2.47
(dd, J=12.6,8.5Hz, 1H), 2.40 (s, 3H), 2.31 (s, 1H), 2.23-2.14 (m, 1H), 1.93 (d, J=22.8Hz,
7H), 1.85-1.74 (m, 3H), 1.70 (d, J=14.4Hz, 3H), 1.61 (s, 3H) ..13C NMR(101MHz,CDCl3)δ
174.06,163.24,160.81,155.30,139.08,138.59,133.49,130.75,130.66,130.58,127.79,
117.91,115.21,115.00,65.03,57.85,56.09,55.03,53.13,52.07,47.50,44.86,42.66,
39.01,38.66,28.84,28.73,28.52,27.97,24.41,21.06.HRMS(ESI)m/z:603.3322calcd
for C33H42F4N4O2[M+H]+,found 603.3329.
Embodiment 8
N- (3- (1- (4- luorobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- (3- chlorine 4- aminomethyl phenyls) -1- (2,2,2- tri-
Acetyl fluoride base) piperidines -4- acid amides preparation (I-8)
Step 1) is to 6) the same as embodiment 6；
1- (4- luorobenzyls) octahydro -1,6- naphthyridines (0.20g, 0.81mmol) is dissolved in 25mL acetonitrile solutions, known to addition
Intermediate N (3- chlorine 4- aminomethyl phenyls)-N- (3- chloropropyls) -1- (2,2,2- trifluoroacetyl group) piperidines -4- acid amides (0.42g,
0.97mmol), potassium carbonate (0.56g, 4.03mmol) and potassium iodide (0.14g, 0.81mmol) are added, when system reflux 8 is small.Instead
Answer system to depressurize precipitation, add water, with dichloromethane extraction system, merge organic phase, depressurize precipitation, column chromatographic isolation and purification,
Obtain target compound.1H NMR(400MHz,CDCl3) δ 7.38-7.27 (m, 5H), 7.24 (s, 1H), 7.16 (d, J=
7.7Hz, 1H), 7.02 (t, J=8.6Hz, 2H), 4.43 (d, J=13.0Hz, 1H), 4.08 (d, J=13.2Hz, 1H), 3.98
(d, J=13.3Hz, 1H), 3.70 (s, 2H), 3.26 (s, 2H), 3.06-2.94 (m, 2H), 2.88 (d, J=11.1Hz, 1H),
2.72-2.57 (m, 3H), 2.54-2.41 (m, 5H), 2.31 (s, 1H), 2.21 (d, J=14.9Hz, 1H), 1.97 (d, J=
42.2Hz, 7H), 1.80 (dd, J=25.8,14.5Hz, 5H), 1.63 (s, 2H)13C NMR(101MHz,CDCl3)δ173.84,
163.33,160.89,155.30,140.48,136.89,135.40,132.88,132.25,130.86,130.78,128.28,
126.58,117.90,115.30,115.09,112.18,65.08,57.83,55.98,54.91,53.02,52.67,47.65,
44.79,42.59,38.82,38.68,28.83,28.53,28.38,27.95,24.37,24.22,19.73.HRMS(ESI)m/
z:637.2932calcd for C33H41ClF4N4O2[M+H]+,found 637.2936.
Embodiment 9
N- (3- (1- (4- luorobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- phenyl -1- (2,2,2- trifluoroacetyl groups) piperazine
The preparation (I-9) of pyridine -4- acid amides
Step 1) is to 6) the same as embodiment 6；
1- (4- luorobenzyls) octahydro -1,6- naphthyridines (0.20g, 0.81mmol) is dissolved in 25mL acetonitrile solutions, known to addition
Intermediate N phenyl-N- (3- chloropropyls) -1- (2,2,2- trifluoroacetyl group) piperidines -4- acid amides (0.36g, 0.97mmol), adds
Enter potassium carbonate (0.56g, 4.03mmol) and potassium iodide (0.14g, 0.81mmol), when system reflux 8 is small.Reaction system decompression is de-
It is molten, water is added, with dichloromethane extraction system, merges organic phase, depressurizes precipitation, column chromatographic isolation and purification, obtains target chemical combination
Thing.1H NMR(400MHz,CDCl3) δ 7.57-7.42 (m, 3H), 7.30 (d, J=7.5Hz, 4H), 7.02 (t, J=8.5Hz,
2H), 4.42 (d, J=13.2Hz, 1H), 4.08 (d, J=13.1Hz, 1H), 3.96 (d, J=13.8Hz, 1H), 3.74 (d, J=
5.1Hz, 2H), 3.36 (s, 1H), 3.25 (s, 1H), 3.09 (s, 1H), 2.92 (dd, J=22.9,11.4Hz, 2H), 2.74 (s,
2H), 2.61 (t, J=11.2Hz, 1H), 2.48 (dd, J=12.6,8.0Hz, 2H), 2.23 (d, J=12.8Hz, 1H), 2.17-
1.92 (m, 7H), 1.86-1.69 (m, 5H), 1.65 (d, J=11.8Hz, 3H)13C NMR(101MHz,CDCl3)δ174.13,
163.38,160.94,155,31,141.67,135.05,132.56,130.83,130.75,130.25,128.66,128.11,
117.91,115.36,115.14,117.91,115.36,115.14,64.81,57.50,55.98,54.82,52.97,
52.54,52.48,47.39,44.82,42.65,38.79,38.46,28.84,28.29,28.19,27.98,24.16.HRMS
(ESI)m/z:589.3166calcd for C32H40F4N4O2[M+H]+,found 589.3165.
Embodiment 10
N- (3- (1- (4- luorobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- (3,4- dichlorophenyls) -1- (2,2,2- trifluoros
Acetyl group) piperidines -4- acid amides preparation (I-10)
Step 1) is to 6) the same as embodiment 6；
1- (4- luorobenzyls) octahydro -1,6- naphthyridines (0.20g, 0.81mmol) is dissolved in 25mL acetonitrile solutions, known to addition
Intermediate N (3,4- dichlorophenyl)-N- (3- chloropropyls) -1- (2,2,2- trifluoroacetyl group) piperidines -4- acid amides (0.45g,
0.97mmol), potassium carbonate (0.56g, 4.03mmol) and potassium iodide (0.14g, 0.81mmol) are added, when system reflux 8 is small.Instead
Answer system to depressurize precipitation, add water, with dichloromethane extraction system, merge organic phase, depressurize precipitation, column chromatographic isolation and purification,
Obtain target compound.1H NMR(400MHz,CDCl3) 7.57 (d, J=8.4Hz, 1H), 7.37 (s, 1H), 7.32-7.25 (m,
3H), 7.19 (d, J=7.6Hz, 1H), 7.00 (t, J=8.6Hz, 2H), 4.42 (d, J=13.3Hz, 1H), 4.01 (dd, J=
27.5,13.6Hz, 2H), 3.77-3.61 (m, 2H), 3.24-3.08 (m, 2H), 3.00 (s, 1H), 2.84 (d, J=10.9Hz,
2H), 2.69 (s, 1H), 2.48 (s, 3H), 2.14 (d, J=10.1Hz, 2H), 1.91 (dt, J=88.7,22.2Hz, 13H),
(1.60 t, J=12.3Hz, 3H)13C NMR(101MHz,CDCl3)δ173.38,163.21,160.77,155.30,141.46,
133.91,132.94,131.76,130.68,130.60,129.92,127.78,117.89,115.17,114.96,65.40,
58.38,56.15,55.06,53.24,52.90,47.97,44.70,42.52,39.51,38.76,29.20,28.81,
28.67,27.95,24.77,24.56.HRMS(ESI)m/z:657.2386calcd for C32H38Cl2F4N4O2[M+H]+,
found 657.2389.
Embodiment 11
N- (3- (1- (4- luorobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- (4- chlorphenyls) -1- Acetylpiperidin -4- acyls
The preparation (I-11) of amine
Step 1) is to 6) the same as embodiment 6；
1- (4- luorobenzyls) octahydro -1,6- naphthyridines (0.30g, 1.21mmol) is dissolved in 30mL acetonitrile solutions, known to addition
Intermediate N (4- chlorphenyls)-N- (3- chloropropyls) -1- Acetylpiperidin -4- acid amides (0.52g, 1.54mmol), adds carbonic acid
Potassium (0.83g, 6.05mmol) and potassium iodide (0.20g, 1.21mmol), when system reflux 8 is small.Reaction system depressurizes precipitation, adds
Enter water, with dichloromethane extraction system, merge organic phase, depressurize precipitation, column chromatographic isolation and purification, obtains target compound.1H
NMR(400MHz,CDCl3) δ 7.43 (d, J=8.1Hz, 2H), 7.32-7.22 (m, 3H), 7.17 (d, J=8.1Hz, 2H),
6.98 (t, J=8.5Hz, 2H), 4.52 (d, J=12.9Hz, 1H), 4.01 (d, J=13.4Hz, 1H), 3.91 (s, 1H), 3.72
(dd, J=29.1,9.6Hz, 3H), 3.13 (d, J=13.5Hz, 1H), 3.05 (d, J=9.4Hz, 1H), 2.89-2.74 (m,
3H), 2.42 (s, 2H), 2.34 (s, 2H), 2.15-2.00 (m, 5H), 1.92 (d, J=8.0Hz, 1H), 1.77 (s, 6H), 1.61
(d, J=30.0Hz, 7H)13C NMR(101MHz,CDCl3)δ173.98,163.40,160.96,155.30(q),140.17,
134.55,132.46,130.96,130.88,130.47,129.59,120.75,117.89,115.37,115.16,115.02,
112.87,64.83,57.46,55.95,54.71,52.92,52.52,52.46,47.44,44.77,42.60,38.76,
38.49,28.81,28.19,28.15,27.96,24.15,24.06.HRMS(ESI)m/z:569.3059calcd for
C32H42ClFN4O2[M+H]+,found 569.3062.
Embodiment 12
N- (3- (1- (4- luorobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- (4- aminomethyl phenyls) -1- Acetylpiperidins -4-
The preparation (I-12) of acid amides
Step 1) is to step 6) with embodiment 6；
1- (4- luorobenzyls) octahydro -1,6- naphthyridines (0.30g, 1.21mmol) is dissolved in 30mL acetonitrile solutions, known to addition
Intermediate N (4- aminomethyl phenyls)-N- (3- chloropropyls) -1- Acetylpiperidin -4- acid amides (0.49g, 1.45mmol), adds carbon
Sour potassium (0.83g, 6.05mmol) and potassium iodide (0.20g, 1.21mmol), when system reflux 8 is small.Reaction system depressurizes precipitation,
Water is added, with dichloromethane extraction system, merges organic phase, depressurizes precipitation, column chromatographic isolation and purification, obtains target compound.1H NMR(400MHz,CDCl3) δ 7.25 (d, J=11.1Hz, 5H), 7.11 (d, J=7.2Hz, 2H), 6.99 (t, J=8.2Hz,
2H), 4.51 (d, J=12.8Hz, 1H), 4.03 (d, J=13.3Hz, 1H), 3.72 (dd, J=19.6,10.7Hz, 3H), 3.17
(d, J=13.0Hz, 2H), 2.95 (s, 1H), 2.81 (t, J=11.8Hz, 2H), 2.60 (s, 2H), 2.45-2.25 (m, 6H),
2.17 (d, J=12.6Hz, 1H), 2.04 (s, 3H), 1.93 (d, J=31.7Hz, 6H), 1.69 (dd, J=41.2,18.1Hz,
9H).13C NMR(101MHz,CDCl3)δ174.06,163.24,160.81,155.30,139.08,138.59,133.49,
130.75,130.66,130.58,127.79,117.91,115.21,115.00,65.03,57.85,56.09,55.03,
53.13,52.67,47.50,44.86,42.66,39.01,38.66,28.84,28.73,28.52,27.97,24.41,
21.06.HRMS(ESI)m/z:549.3605calcd for C33H45FN4O2[M+H]+,found 549.3603.
Embodiment 13
The system of N- (3- (1- (4- luorobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- phenyl -1- Acetylpiperidin -4- acid amides
Standby (I-13)
Step 1) is to step 6) with embodiment 6；
1- (4- luorobenzyls) octahydro -1,6- naphthyridines (0.30g, 1.21mmol) is dissolved in 30mL acetonitrile solutions, known to addition
Intermediate N phenyl-N- (3- chloropropyls) -1- Acetylpiperidin -4- acid amides (0.47g, 1.45mmol), adds potassium carbonate
(0.83g, 6.05mmol) and potassium iodide (0.20g, 1.21mmol), when system reflux 8 is small.Reaction system depressurizes precipitation, adds
Water, with dichloromethane extraction system, merges organic phase, depressurizes precipitation, column chromatographic isolation and purification, obtains target compound.1H
NMR(400MHz,CDCl3) δ 7.46 (t, J=7.4Hz, 2H), 7.43-7.37 (m, 1H), 7.32-7.18 (m, 5H), 6.99 (t,
J=8.6Hz, 2H), 4.51 (d, J=13.0Hz, 1H), 4.02 (d, J=13.5Hz, 1H), 3.81-3.64 (m, 3H), 3.16
(d, J=12.6Hz, 2H), 2.92 (d, J=7.6Hz, 1H), 2.80 (t, J=13.4Hz, 2H), 2.55 (s, 2H), 2.42-
2.19 (m, 3H), 2.14 (d, J=12.4Hz, 1H), 2.04 (s, 3H), 1.92 (d, J=30.3Hz, 6H), 1.80-1.52 (m,
9H).13C NMR(101MHz,CDCl3)δ174.45,168.75,163.16,160.72,141.99,133.88,130.60,
130.52,130.04,128.38,128.09,115.13,114.92,65.18,56.15,55.15,53.21,52.86,
52.79,47.57,45.57,40.71,39.37,29.07,28.87,28.65,28.27,24.63,24.58,21.32.HRMS
(ESI)m/z:535.3448calcd for C32H43FN4O2[M+H]+,found 535.3446.
Embodiment 14
N- (3- (1- (4- luorobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- (the chloro- 4- aminomethyl phenyls of 3-) -1- acetyl group piperazines
The preparation (I-14) of pyridine -4- acid amides
Step 1) is to step 6) with example 6；
1- (4- luorobenzyls) octahydro -1,6- naphthyridines (0.30g, 1.21mmol) is dissolved in 30mL acetonitrile solutions, known to addition
Intermediate N (the chloro- 4- aminomethyl phenyls of 3-)-N- (3- chloropropyls) -1- Acetylpiperidin -4- acid amides (0.54g, 1.45mmol), adds
Enter potassium carbonate (0.83g, 6.05mmol) and potassium iodide (0.20g, 1.21mmol), when system reflux 8 is small.Reaction system decompression is de-
It is molten, water is added, with dichloromethane extraction system, merges organic phase, depressurizes precipitation, column chromatographic isolation and purification, obtains target chemical combination
Thing.1H NMR(400MHz,CDCl3) δ 7.36-7.22 (m, 4H), 7.20 (d, J=1.7Hz, 1H), 7.05-6.94 (m, 3H),
4.51 (d, J=13.5Hz, 1H), 4.00 (d, J=13.5Hz, 1H), 3.75 (s, 1H), 3.66 (dd, J=16.0,7.8Hz,
2H), 3.11 (d, J=13.5Hz, 1H), 3.01 (d, J=10.0Hz, 1H), 2.90-2.71 (m, 3H), 2.42 (s, 3H),
2.39-2.31 (m, 4H), 2.13-1.95 (m, 6H), 1.95-1.84 (m, 1H), 1.74 (d, J=8.1Hz, 4H), 1.68-1.49
(m,9H).13C NMR(101MHz,CDCl3)δ174.05,168.73,163.03,160.60,140.92,136.47,135.19,
134.53,131.98,130.44,130.36,128,41,126.42,115.00,114.79,65.54,58.76,56.26,
55.36,53.41,47.87,45.50,40.65,40.01,39.30,29.73,28.92,28.83,28.26,24.99,
24.89,21.30,19.71.HRMS(ESI)m/z:583.3215calcd for C33H44ClFN4O2[M+H]+,found
583.3214.
Embodiment 15
N- (3- (1- (4- luorobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- (3,4- dichlorophenyls) -1- Acetylpiperidins -
The preparation (I-15) of 4- acid amides
Step 1) is to step 6) with example 6；
1- (4- luorobenzyls) octahydro -1,6- naphthyridines (0.30g, 1.21mmol) is dissolved in 30mL acetonitrile solutions, known to addition
Intermediate N (3,4- dichlorophenyl)-N- (3- chloropropyls) -1- Acetylpiperidin -4- acid amides (0.57g, 1.45mmol), adds
Potassium carbonate (0.83g, 6.05mmol) and potassium iodide (0.20g, 1.21mmol), when system reflux 8 is small.Reaction system decompression is de-
It is molten, water is added, with dichloromethane extraction system, merges organic phase, depressurizes precipitation, column chromatographic isolation and purification, obtains target chemical combination
Thing.1H NMR(400MHz,CDCl3) δ 7.56 (d, J=7.7Hz, 1H), 7.38 (s, 1H), 7.29 (s, 2H), 7.20 (s, 1H),
6.99 (t, J=7.7Hz, 2H), 4.53 (d, J=12.6Hz, 1H), 4.05 (d, J=13.5Hz, 1H), 3.88-3.59 (m,
3H), 3.19 (d, J=13.8Hz, 2H), 2.88 (s, 3H), 2.52 (s, 2H), 2.38 (s, 2H), 2.16 (d, J=12.3Hz,
2H), 2.05 (s, 3H), 1.88 (dd, J=73.4,21.4Hz, 8H), 1.64 (d, J=23.6Hz, 7H)13C NMR(101MHz,
CDCl3)δ174.02,168.74,163.15,160.71,141.54,133.72,133.56,132.70,131.67,130.69,
130.62,129.89,127.82,115.13,114.92,65.24,58.18,56.09,54.96,53.16,52.77,47.79,
45.45,40.57,39.36,29.07,28.83,28.56,28.24,24.66,24.52,21.32.HRMS(ESI)m/z:
603.2669calcd for C32H41Cl2FN4O2[M+H]+,found603.2663.
Embodiment 16
N- (3- (1- (4- luorobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- (4- methoxyphenyls) -1- Acetylpiperidins -
The preparation (I-16) of 4- acid amides
Step 1) is to step 6) with example 6；
1- (4- luorobenzyls) octahydro -1,6- naphthyridines (0.21g, 0.85mmol) is dissolved in 25mL acetonitrile solutions, known to addition
Intermediate N (4- methoxyphenyls)-N- (3- chloropropyls) -1- Acetylpiperidin -4- acid amides (0.30g, 0.85mmol), adds
Potassium carbonate (0.60g, 4.25mmol) and potassium iodide (0.14g, 0.85mmol), when system reflux 8 is small.Reaction system decompression is de-
It is molten, water is added, with dichloromethane extraction system, merges organic phase, depressurizes precipitation, column chromatographic isolation and purification, obtains target chemical combination
Thing.1H NMR(400MHz,CDCl3) δ 7.30-7.21 (m, 3H), 7.08 (d, J=8.7Hz, 2H), 6.96 (dd, J=17.0,
8.7Hz, 4H), 4.51 (d, J=13.2Hz, 1H), 3.99 (d, J=13.5Hz, 1H), 3.85 (s, 3H), 3.75 (d, J=
13.6Hz, 1H), 3.65 (dd, J=14.4,6.8Hz, 2H), 3.08 (d, J=13.5Hz, 1H), 2.97 (d, J=11.3Hz,
1H), 2.87-2.69 (m, 3H), 2.35 (ddd, J=23.7,13.1,7.5Hz, 5H), 2.05 (d, J=12.7Hz, 4H),
2.00-1.86(m,2H),1.79-1.67(m,5H),1.66-1.58(m,4H),1.57-1.43(m,5H).13C NMR
(101MHz,CDCl3)δ174.39,168.71,162.99,160.56,159.13,134.80,130.38,130.30,
129.16,114.98,114.77,65.59,56.53,55.61,55.52,53.51,53.25,47.82,45.52,40.77,
40.33,39.29,30.03,29.07,28.83,28.32,25.18,25.08,21.39.HRMS(ESI)m/z:
565.3554calcd for C33H45FN4O3[M+H]+,found 565.3556.
Embodiment 17
N- (3- (1- (4- luorobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- (3- aminomethyl phenyls) -1- Acetylpiperidins -4-
The preparation (I-17) of acid amides
Step 1) is to step 6) with example 6；
1- (4- luorobenzyls) octahydro -1,6- naphthyridines (0.20g, 0.81mmol) is dissolved in 25mL acetonitrile solutions, known to addition
Intermediate N (3- aminomethyl phenyls)-N- (3- chloropropyls) -1- Acetylpiperidin -4- acid amides (0.32g, 0.97mmol), adds carbon
Sour potassium (0.56g, 4.05mmol) and potassium iodide (0.14g, 0.81mmol), when system reflux 8 is small.Reaction system depressurizes precipitation,
Water is added, with dichloromethane extraction system, merges organic phase, depressurizes precipitation, column chromatographic isolation and purification, obtains target compound.1H NMR(400MHz,CDCl3) δ 7.26 (tdd, J=24.4,16.9,7.6Hz, 5H), 6.97 (t, J=8.5Hz, 4H), 4.50
(d, J=13.2Hz, 1H), 4.00 (d, J=13.5Hz, 1H), 3.75 (d, J=13.2Hz, 1H), 3.66 (dt, J=13.9,
7.0Hz, 2H), 3.09 (d, J=13.5Hz, 1H), 3.00 (d, J=9.8Hz, 1H), 2.78 (dd, J=17.9,10.3Hz,
3H), 2.40 (s, 3H), 2.35 (dd, J=14.0,6.3Hz, 3H), 2.11-1.95 (m, 6H), 1.90 (dd, J=15.3,
11.0Hz, 1H), 1.75 (dd, J=19.3,11.1Hz, 5H), 1.68-1.59 (m, 4H), 1.54 (d, J=8.9Hz, 5H)13C
NMR(101MHz,CDCl3)δ174.03,168.71,162.97,160.54,142.20,140.01,130.36,130.28,
129.59,128.97,128.53,125.09,114.95,114.74,65.67,59.09,56.36,55.66,53.55,
53.29,47.88,45.59,40.73,40.45,39.33,30.16,29.11,28.87,28.34,25.30,25.13,
21.40,21.37.HRMS(ESI)m/z:549.3605calcd for C33H45FN4O2[M+H]+,found 549.3607.
Embodiment 18
N- (3- (1- (4- cyanobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- phenyl -1- Acetylpiperidin -4- acid amides
Prepare (I-18)
Step 1) is to 4) the same as embodiment 1；
The preparation of step 5) 1- (4- cyanobenzyls) octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters
Octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters (0.6g, 2.5mmol) are dissolved in 15mL dichloromethane, 15mL is added and satisfies
And sodium carbonate liquor, 4- cyano group benzyl bromines (0.5g, 2.5mmol) are then added, system is stirred at room temperature overnight.Separate organic phase
With water phase, with dichloromethane aqueous phase extracted, merge organic phase, depressurize precipitation.Column chromatography obtains target compound after purification.1H
NMR(400MHz,CDCl3) δ 7.59 (d, J=8.1Hz, 2H), 7.44 (d, J=8.0Hz, 2H), 4.10 (d, J=14.5Hz,
3H), 3.15 (d, J=14.4Hz, 1H), 2.76 (d, J=10.9Hz, 2H), 2.37 (d, J=10.4Hz, 1H), 1.96 (ddd, J
=26.6,14.1,7.0Hz, 3H), 1.70-1.56 (m, 3H), 1.44 (d, J=14.0Hz, 11H), 1.39-1.23 (m, 2H)
The preparation of step 6) 1- (4- cyanobenzyls) octahydro -1,6- naphthyridines
1- (4- cyanobenzyls) octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters (400mg, 1.13mmol) are dissolved in 10mL bis-
Chloromethanes, adds trifluoroacetic acid (1.5mL), is stirred overnight at room temperature.Reaction system is depressurized into precipitation, adds saturated sodium bicarbonate water
Solution, aqueous systems are repeatedly extracted with dichloromethane.After merging organic phase, precipitation is depressurized.Obtained oil product is without further
Isolate and purify, directly carry out next step reaction.
Step 7) N- (3- (1- (4- cyanobenzyls) octahydro -1,6- naphthyridines) propyl group)-N- phenyl -1- Acetylpiperidins -4-
The preparation of acid amides
1- (4- luorobenzyls) octahydro -1,6- naphthyridines (0.20g, 0.78mmol) is dissolved in 25mL acetonitrile solutions, known to addition
Intermediate N phenyl-N- (3- chloropropyls) -1- Acetylpiperidin -4- acid amides (0.26g, 0.78mmol), adds potassium carbonate
(0.55g, 3.90mmol) and potassium iodide (0.13g, 0.78mmol), when system reflux 8 is small.Reaction system depressurizes precipitation, adds
Water, with dichloromethane extraction system, merges organic phase, depressurizes precipitation, column chromatographic isolation and purification, obtains target compound.1H
NMR(400MHz,CDCl3) δ 7.58 (d, J=8.1Hz, 2H), 7.51-7.36 (m, 6H), 7.19 (d, J=7.3Hz, 2H),
4.51 (d, J=13.2Hz, 1H), 4.06 (d, J=14.4Hz, 1H), 3.79-3.65 (m, 3H), 3.13 (d, J=14.4Hz,
1H), 3.00 (d, J=10.7Hz, 1H), 2.84-2.69 (m, 3H), 2.45-2.24 (m, 4H), 2.10-1.90 (m, 7H),
1.84-1.41(m,15H).13C NMR(101MHz,CDCl3)δ174.57,168.69,145.87,141.79,131.99,
130.09,129.10,128.46,128.08,119.03,110.35,64.87,56.93,55.05,54.01,52.75,
52.67,47.38,45.56,40.66,39.56,39.34,29.29,28.87,28.64,28.25,24.88,24.38,
21.41.HRMS(ESI)m/z:542.3495calcd for C33H43N5O2[M+H]+,found 542.3502.
Embodiment 19
N- (3- (1- (4- methyl formates benzyl) octahydro -1,6- naphthyridines) propyl group)-N- phenyl -1- Acetylpiperidin -4- acyls
The preparation (I-19) of amine
Step 1) is to 4) the same as embodiment 1；
The preparation of step 5) 1- (4- methyl formates benzyl) octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters
Octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters (0.5g, 2.1mmol) are dissolved in 15mL dichloromethane, 15mL is added and satisfies
And sodium carbonate liquor, 4- methyl formate benzyl bromines (0.47g, 2.1mmol) are then added, system is stirred at room temperature overnight.Separation
Organic phase and water phase, with dichloromethane aqueous phase extracted, merge organic phase, depressurize precipitation.Column chromatography obtains target chemical combination after purification
Thing.1H NMR(400MHz,CDCl3) δ 7.97 (d, J=8.1Hz, 2H), 7.38 (d, J=8.1Hz, 2H), 4.09 (d, J=
13.9Hz, 2H), 3.91 (s, 3H), 3.17 (d, J=14.0Hz, 1H), 2.79 (d, J=11.1Hz, 2H), 2.37 (s, 1H),
1.98 (dd, J=17.3,8.9Hz, 2H), 1.89 (dd, J=14.1,6.4Hz, 1H), 1.66-1.54 (m, 3H), 1.44 (d, J
=13.0Hz, 11H), 1.26 (s, 2H)
The preparation of step 6) 1- (4- methyl formates benzyl) octahydro -1,6- naphthyridines
1- (4- methyl formates benzyl) octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters (400mg, 1.03mmol) are dissolved in
10mL dichloromethane, adds trifluoroacetic acid (1.5mL), is stirred overnight at room temperature.Reaction system is depressurized into precipitation, adds unsaturated carbonate
Hydrogen sodium water solution, aqueous systems are repeatedly extracted with dichloromethane.After merging organic phase, precipitation is depressurized.Obtained oil product without
Further isolate and purify, directly carry out next step reaction.
Step 7) N- (3- (1- (4- methyl formates benzyl) octahydro -1,6- naphthyridines) propyl group)-N- phenyl -1- (2,2,2- tri-
Acetyl fluoride base) piperidines -4- acid amides preparation
1- (4- methyl formates benzyl) octahydro -1,6- naphthyridines (0.16g, 0.56mmol) is dissolved in 25mL acetonitrile solutions, is added
Enter known intermediate N phenyl-N- (3- chloropropyls) -1- Acetylpiperidin -4- acid amides (0.18g, 0.56mmol), add carbonic acid
Potassium (0.40g, 2.80mmol) and potassium iodide (0.10g, 0.56mmol), when system reflux 8 is small.Reaction system depressurizes precipitation, adds
Enter water, with dichloromethane extraction system, merge organic phase, depressurize precipitation, column chromatographic isolation and purification, obtains target compound.1H
NMR(400MHz,CDCl3) δ 7.97 (d, J=7.6Hz, 2H), 7.48 (t, J=7.3Hz, 2H), 7.41 (t, J=8.1Hz,
3H), 7.34-7.26 (m, 2H), 4.51 (d, J=12.9Hz, 1H), 4.09 (d, J=14.0Hz, 1H), 3.90 (s, 3H),
3.85-3.68 (m, 3H), 3.38 (s, 1H), 3.22 (d, J=13.9Hz, 1H), 3.12 (d, J=10.5Hz, 1H), 2.83 (dd,
J=18.7,9.7Hz, 4H), 2.64 (s, 1H), 2.43-2.17 (m, 4H), 2.15-1.93 (m, 9H), 1.86 (d, J=
12.1Hz, 1H), 1.72 (s, 2H), 1.63 (d, J=10.5Hz, 5H)13C NMR(101MHz,CDCl3)δ174.99,
168.75,166.97,141.57,130.21,129.56,128.86,128.66,128.11,64.36,57.19,56.90,
54.71,53.58,52.44,52.04,47.15,45.57,40.76,39.36,38.90,28.92,28.56,28.41,
28.27,24.58,23.82,21.41.HRMS(ESI)m/z:575.3597calcd for C34H46N4O4[M+H]+,found
575.3599.
Embodiment 20
HIV-1 inhibitory activity measures
MAGI experimental methods are selected to be measured the Anti-HIV-1 Active of sample.MAGI experimental methods can reflect virus
The duplication situation of a cycle in cell.Strain selects the HIV cape horn fever strains prepared by envelope plasmid and skeleton plasmid.It is used
Cell line is the TZM-bl cells as derived from HeLa cell lines, height expression CD4 acceptors, should containing a beta galactosidase gene
Gene is regulated and controled by HIV-1 long terminal repeats (LTR), for quantitative determining the appeal of laboratory source inhibition of HIV strain, is calculated
Inhibiting rate of the sample to virus.Method is as follows：
(1) by sample compound dissolved dilution to 200 μ g/mL of maximum concentration, through 4 times of serial dilutions to 5 various concentrations.
(2) 96 well culture plates, inoculation TZM-bl cells (6000 cells/well) are taken.
(3) after cell culture overnight, culture medium is suctioned out, adds virus and sample solution per each 50 μ L in hole.Set up disease at the same time
Malicious control group (only plus viral, to be not added with sample) and cell controls group (being not added with virus and sample).
(4) 37 DEG C, 5%CO2It is fixed when culture 40-48 is small in incubator, dyeing.
(5) automatically scanning, counting locus coeruleus number under Olympus inverted microscopes.
(6) inhibiting rate of samples for viral is calculated, the inhibiting rate (%) of samples for viral=(virus control group locus coeruleus is equal
Value-dosing group locus coeruleus average)/virus control group locus coeruleus average × 100.
Its determination of activity the results are shown in Table 1.
Table one, HIV-1 inhibitory activity measurement results
Claims (5)
1. two substitution octahydro -1,6- naphthyridine type compounds, it is characterised in that for 1- substitutions-N- (3- (1- substituted benzyls octahydro -1,
6- naphthyridines) propyl group)-N- substituted phenylpiperidines -4- amides compounds, its structural formula is as follows：
Wherein,
R1For 1) acetyl group,
2) trifluoroacetyl group；
R2For 1)-H,
2)-Cl,
3) methyl,
4) methoxyl group,
R3For 1)-H,
2)-Cl,
3) methyl；
R4For 1)-H,
2)-F,
3) cyano group,
4) carboxylate methyl ester.
2. described in claim 1 two substitution octahydro -1,6- naphthyridine type compounds preparation method, it is characterised in that including with
Lower step：
(a) 1- benzyl piepridines -4- ketone, through chlorination copper catalysis, reacts generation formula (II) table in absolute ethyl alcohol with 2-propynyl amine
6- benzyl -5,6,7,8- tetrahydrochysene -1,6- the naphthyridines shown；
(b) formula (II) represent compound in acetic acid, palladium carbon catalytic hydrogenation generation formula (III) represent 5,6,7,8- tetrahydrochysenes-
1,6- naphthyridines；
(c) compound represented toward formula (III) adds toluene and sodium hydrate aqueous solution, with di-tert-butyl dicarbonate production
(IV) the 7,8- dihydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters represented；
(d) compound represented toward formula (IV) is heated to reflux in absolute ethyl alcohol, and adds metal sodium reduction, generates formula (V) table
Octahydro -1,6- naphthyridines -6- the carboxylic acid tert-butyl esters shown；
(e) will formula (V) represent compound in add dichloromethane, sodium carbonate effect under with R4Substituted benzyl bromine reaction, generation
The 1- substituted benzyl octahydro -1,6- naphthyridines -6- carboxylic acid tert-butyl esters that formula (VI) represents；
(f) compound that formula (VI) represents is dissolved in dichloromethane, is hydrolyzed under the action of trifluoroacetic acid, generate formula (VII) table
The 1- substituted benzyl octahydro -1,6- naphthyridines shown；
(g) compound that formula (VII) represents is dissolved in acetonitrile, under the action of sodium carbonate and potassium iodide, is represented with formula (VIII)
Intermediate 1- substitutions-N- (3- chloropropyls)-N- substituted phenylpiperidines -4- acid amides reaction, generation formula (I) represent 1- substitution -
N- (3- (1- substituted benzyl octahydro -1,6- naphthyridines) propyl group)-N- substituted phenylpiperidines -4- acid amides；
3. method according to claim 2, it is characterised in that step (a) reaction temperature is 78 DEG C, and solvent should use Non-aqueous processing
Ethanol, argon gas protection under react, the reaction time for 7 it is small when；
4. method according to claim 2, it is characterised in that step (d) solvent is the ethanol of Non-aqueous processing, in reflux state
Under, metallic sodium is added, after metallic sodium is completely dissolved, you can reaction was completed.
5. the application of two substitution octahydro -1, the 6- naphthyridine type compounds or its pharmaceutically acceptable salt described in claim 1,
Prepare the application in treatment AIDS-treating medicine.
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