CN109942505A - Isothiazolinone compound and corresponding uses - Google Patents
Isothiazolinone compound and corresponding uses Download PDFInfo
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Abstract
Purposes the present invention provides a kind of isothiazolinone compound with IDO inhibitory activity and preparation method thereof and pharmaceutically.More particularly to compound shown in formula (I), its pharmaceutically acceptable salt, isomers and prodrug, wherein the definition of each group is as noted in the discussion.The invention further relates to these compound medicine preparations, pharmaceutical composition and its in treatment, alleviation and/or the application for preventing various related diseases, such as tumour, virus infection or autoimmune disease etc. due to caused by immunosupress.Isothiazolinone compound of the invention has preferable IDO inhibitory activity.
Description
Technical field
The present invention relates to pharmaceutical technology fields, in particular to pharmaceutical chemistry synthesis field, in particular to a kind of isothiazoline
Ketone compounds and corresponding uses.
Background technique
Indoleamine 2,3-dioxygenase (Indoleamine 2,3-dioxygenase, hereinafter referred to as " IDO ") was in 1967
It is found in the intestinal tissue of rabbit first, is a kind of enzyme containing heme.Mankind's IDO gene loci is located at No. 8 dye
It on colour solid, is made of 403 amino acid, IDO is that indole ring oxicracking in tryptophan modules can be uniquely catalyzed in addition to liver
Enzyme, therefore be rate-limiting enzyme of the tryptophan along kynurenine approach catabolism.
On the one hand the illness of cancer is the escape due to human body antineoplastic immune, tumour cell infinite multiplication destroys normal
Caused by cell.Popular immunotherapy of tumors in recent years, is the immune system by transferring body, and enhancing tumor microenvironment is anti-
Tumor immunity, thus control and kill tumour cell.The available tumour immunotherapy master in clinical development and in the market at present
If the macromoleculars biological agent such as antibody, and Small molecule immunodulators are because of its relatively simple administration mode and lower research and development
Cost is also developing progressively as an important field of research in tumour immunotherapy.
What is played a major role in tumor immune escape is considered as the kynurenine approach of tryptophan metabolism, it is resulted in pair
The generation of the immune unwanted metabolic products of the inhibition such as the consumption of the responsible tryptophan of local immunosuppression and kynurenine.Therefore dog urine
Propylhomoserin access plays a significant role in immunological regulation, and IDO as L-Trp along the pass of kynurenine pathway oxicracking
Key enzyme, it is considered to be the potential small molecule target spot of popular tumour immunotherapy.A large number of studies show that the unconventionality expression of IDO with
It is related that tumour cell escapes immune system, therefore IDO is inhibited to be expected to become a kind of novel tumor therapeutic strategy.Have five at present
A small-molecule drug is in clinical investigation phase, and in addition there are multiple inhibitor to be in the biological activity test stage.
Lot of experimental data shows that in addition to inhibiting immunotherapy of tumors cancer, it is living can also to enhance T cell for IDO inhibitor
Property, treat and prevent relevant to IDO disease, such as inhibition of HIV infection, autoimmune disease etc..To sum up, exist in view of IDO
Importance in immunosupress, thus the focus that novel IDO inhibitor is always this field forward position scholar's extensive concern is researched and developed,
It is of great significance.
Summary of the invention
The purpose of the invention is to overcome above-mentioned missing in the prior art, provide with good IDO inhibitory activity,
In the isothiazolinone compound for various related diseases caused by immunosupress with prevention or therapeutic effect.
To achieve the goals above, one aspect of the present invention provides a kind of isothiazolinone compound, the different thiophene
Shown in the structural formula of oxazoline ketone compounds such as general formula (I),
Wherein, A ring is nothing or phenyl, five yuan or single six-membered rings heteroaryl, 8-12 member and ring heteroaryl；
R1For hydrogen, substituted or unsubstituted C1-6Alkyl, alkoxy, alkylthio group, halogenated alkyl, halogenated alkoxy, amino,
C3-18Naphthenic base, Heterocyclylalkyl, substituted or unsubstituted phenyl, five yuan or single six-membered rings heteroaryl, substituted or unsubstituted 8-
12 yuan and ring heteroaryl it is one or more, be selected from halogen, amino, cyano, hydroxyl for the substituent group of substituted aryl or heteroaryl
1 to 3 kind in base, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, aryl or heteroaryl；
R2For hydrogen, substituted or unsubstituted C1-6Alkyl, alkoxy, alkylthio group, halogenated alkyl, halogenated alkoxy, amino,
C3-18Naphthenic base, Heterocyclylalkyl, substituted or unsubstituted phenyl, five yuan or single six-membered rings heteroaryl, substituted or unsubstituted 8-
12 yuan and ring heteroaryl it is one or more, be selected from halogen, amino, cyano, hydroxyl for the substituent group of substituted aryl or heteroaryl
1 to 3 kind in base, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, aryl or heteroaryl；
Alternatively, R1And R2Between form that 5-8 member substituted or unsubstituted saturation, part be unsaturated, aromatic rings, for replacing 5-8
Member saturation, part be unsaturated, aromatic rings substituent group is selected from halogen, amino, cyano, hydroxyl, alkyl, alkoxy, halogenated alkyl,
1 to 3 kind in halogenated alkoxy, substituted or unsubstituted aryl or heteroaryl, for substituted aryl or the substituent group of heteroaryl
1 to 3 kind in halogen, amino, cyano, hydroxyl, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy；
R3The reasonable any position of valence link on A ring, R3Selected from hydrogen, alkyl, alkoxy, alkylthio group, halogenated alkyl,
Halogenated alkoxy, amino ,-NHRa, naphthenic base, Heterocyclylalkyl, substituted or unsubstituted phenyl, five yuan or single six-membered rings heteroaryl
Base, substituted or unsubstituted 8-12 member and ring heteroaryl it is one or more, for the substituent group of substituted aryl or heteroaryl select
1 to 3 kind from halogen, amino, cyano, hydroxyl, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy；
Wherein, selected halogen is selected from F, Cl, Br, I；
RaFor-S (O)2NH2, substituted or unsubstituted phenyl, five yuan or single six-membered rings heteroaryl, substituted or unsubstituted 8-
12 yuan and ring heteroaryl it is one or more.
L is selected from linking group C1-6Alkyl, C1-6Alkoxy, C1-6Alkylthio group, C2-6Alkenyl, C2-6Alkynyl, C1-6Amide groups
Alkyl, C1-6Alkylamidoalkyl, C1-6Sulfonylalkyl, C1-6Alkyl sulphonyl, C1-6Sulfonamidoalkyl, C1-6Alkyl sulfonamide
Base, C1-6Alkyl sulfide amido, C1-6Thioamides base alkyl, C1-6Alkylthioamide base, C1-6Carbonylic alkyl, C1-6Alkyl-carbonyl,
C1-6Thiocarbonyl alkyl, C1-6Any one in alkyl thiocarbonyl.
Preferably, the compound isothiazolinone includes following compound:
The present invention provides the isothiazolinone compounds described in one kind in the purposes for preparing IDO inhibitor drug.
The present invention provides the isothiazolinone compounds described in one kind in the drug for preparing the disease that treatment IDO is mediated
Purposes.
Preferably, the disease that the IDO is mediated includes infection, cancer or autoimmune disease.
Preferably, the cancer be osteocarcinoma, lung cancer, gastric cancer, colon cancer, film gland cancer, breast cancer, prostate cancer, lung cancer,
One of the cancer of the brain, oophoroma, bladder cancer, cervix cancer, guilt ball cancer, kidney, head and neck cancer, lymph cancer, leukaemia and cutaneum carcinoma
Or it is a variety of；
The infection be skin infection, alimentary infection, urogenital infections, systemic infection or by influenza,
Hepatitis C Virus, human papilloma virus, cytomegalovirus, Epstein epstein-Barr virus, poliovirus, water disease
It is band-like to grow one of man of virtue and ability's virus, Coxsackie virus and human immunodeficiency virus or a variety of caused virus infections；
The autoimmune disease be rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease,
System chorionitis, dermatomyositis, nodular vasculitis, nephrosis, endocrine related disease, hepatopathy, psoriasis and due to infection cause
One of autoimmune response or a variety of.
The present invention provides a kind of pharmaceutical composition, the pharmaceutical composition include the active component of therapeutically effective amount with
And pharmaceutically acceptable auxiliary material；The active component include isothiazolinone compound of any of claims 1 or 2,
Its isomers, prodrug, stable isotope derivatives or pharmaceutically acceptable salt.
Preferably, the active component further includes the therapeutic agent for cancer, virus infection or autoimmune disease.
The type I compound, its isomers, prodrug, stable isotope derivatives or pharmaceutically acceptable salt or institute
The therapeutic agent and/or treatment method for treating cancer for stating pharmaceutical composition and one or more other types are used in combination；
The therapeutic agent and/or treatment method for treating cancer of other types are Antitubulin, alkylating agent, topological enzyme
I/I I inhibitor, platinum-like compounds, antimetabolitas, hormone and hormone analogs, signal transduction pathway inhibitor, blood vessel are raw
At inhibitor, targeted therapy, immunotherapeutic agent, promote one of apoptosis agent, cell cycle signalling pathways inhibitor and radiotherapy or
It is a variety of.
Preferably, the dosage form of the pharmaceutical composition is capsule, micro-capsule, tablet, granule, pill, dispersion powders, liquid
Body preparation, soft extract, suspending agent, syrup, gelling agent, aerosol, patch, liposome, oral solution, intravenous fluid or muscle
Injection.
Preferably, the isothiazolinone compound, its isomers, prodrug, stable isotope derivatives or medicine
Dosage of the acceptable salt in the pharmaceutical composition is 0.05mg/kg~90mg/kg on.
Using isothiazolinone compound of the invention and corresponding uses, the experimental results showed that, above-mentioned isoxazolines ketone
Compound have the function of inhibit IDO enzyme, show this isoxazolines ketone compounds provided by the invention can treat, alleviate and/
Or prevention IDO mediate related disease include: cancer, virus or it is other infection or autoimmune disease in application.
Specific embodiment
For a further understanding of the present invention, the preferred embodiment of the invention is described below with reference to embodiment, still
It should be appreciated that these descriptions are intended merely to further illustrate the features and advantages of the present invention, rather than to invention claim
Limitation.Those skilled in the art can use for reference present disclosure, be suitably modified realization of process parameters.In particular, it should be pointed out that institute
There are similar replacement and change apparent to those skilled in the art, they are considered as being included in the present invention.
Method and application of the invention is described by preferred embodiment, and related personnel can obviously not depart from the present invention
Hold, in spirit and scope to method described herein and application is modified or appropriate changes and combinations, carrys out implementation and application sheet
Inventive technique.
All raw materials of the present invention, are not particularly limited its source, buying on the market or according to those skilled in the art
The preparation of conventional method known to member.
In order to further illustrate the present invention, below with reference to embodiment to a kind of isoxazolines ketone compounds provided by the invention
The preparation and its application of compound are described in detail, and protection scope of the present invention is not limited by the following examples.
Embodiment 1
The synthesis of N- (replacing benzisothiazole) -2 (3H)-formamides (I -1~I -5)
4- substituted aniline (3mmol) is weighed in dry bottle with two necks, the dissolution of 5mL anhydrous methylene chloride, triphosgene is added
The dichloromethane solution (3mL) of (445mg, 1.5mmol) is slowly added under 0 DEG C of nitrogen protection, and three second are then added dropwise
The dichloromethane solution (3mL) of amine (460 μ L, 3.3mmol) finishes and is warmed to room temperature 30 minutes back spins of stirring except reaction solution, is made
The crude product of 4- substituted phenylisocyanate.
6mL methylene chloride is added thereto and adds 1,2- benzisothiazole-3-ketone (BIT) (272mg, 1.8mmol)
Tetrahydrofuran solution 6mL, the reaction system are warming up to 45 DEG C and react 8 hours.Stop heating, cooling, rotation removes solvent, is added about
10mL acetone, 10mL water ultrasonic mixing precipitate filtering after standing, and filter cake is washed with (acetone: water=1:1), obtain yellow solid crude product,
The crude product is dissolved with a small amount of methylene chloride, obtains product after n-hexane recrystallization.
- 2 (3H)-formamide (I -1) of N- (4- morpholino) -3- oxo benzisothiazole, faint yellow solid, yield are
13%.
1H NMR(400MHz,CDCl3) δ ppm 10.95 (s, 1H), 8.06 (d, J=7.9Hz, 1H), 7.76-7.69 (m,
1H), 7.61 (d, J=8.1Hz, 1H), 7.47 (dd, J=16.4,8.0Hz, 3H), 7.17 (d, J=8.3Hz, 2H), 2.34 (s,
3H)；13C NMR(100MHz,CDCl3)δppm 165.3,148.5,140.8,134.6,134.3,134.2,129.8(2C),
127.5,126.1,125.0,120.7,120.4(2C),21.0；HRMS(ESI)m/z calcd for C15H12N2O2S(M+Na)+
337.1,found 337.1.
3- oxo-N- (p-methylphenyl) benzisothiazole -2 (3H)-formamide (I -2), white solid, yield 75%.
1H NMR(400MHz,CDCl3) δ ppm 10.88 (s, 1H), 8.06 (d, J=7.9Hz, 1H), 7.78-7.69 (m,
1H), 7.61 (d, J=8.1Hz, 1H), 7.51 (d, J=9.0Hz, 2H), 7.46 (t, J=7.5Hz, 1H), 6.93 (d, J=
8.7Hz,2H),3.91-3.84(m,4H),3.22-3.09(m,4H)；13C NMR(100MHz,CDCl3)δppm 165.34
(2C),148.59,140.87,134.2(2C),127.5(2C),126.1(2C),125.1,121.70(2C),120.7(2C),
116.53,66.99,49.82；HRMS(ESI)m/z calcd for C18H17N3O3S(M+H)+356.1069,found
356.1066.
- 2 (3H)-formamide (I -3) of N- (4- (1- isobutyl group -1H- pyrazoles -4- base) phenyl) -3- oxo benzisothiazole,
Yellow solid, yield 26%.
1H NMR(400MHz,DMSO)δppm 7.90(s,1H),7.58(s,1H),7.17-7.05(m,4H),6.57-
6.47 (m, 4H), 3.91 (d, J=7.2Hz, 2H), 2.11-2.06 (m, 1H), 0.80 (d, J=6.7Hz, 6H)；HRMS(ESI)
m/z calcd for C21H20N4O2S(M+H)+393.1,found 393.1.
- 2 (3H)-formamide (I -4) of N- (4- (2- methyl -2H- indazole -4- base) phenyl) -3- oxo benzisothiazole, it is yellow
Color solid, yield 63%.
1H NMR (400MHz, DMSO) δ ppm 11.17 (s, 1H), 8.10 (d, J=8.7Hz, 2H), 7.79-7.62 (m,
7H), 7.52-7.45 (m, 1H), 7.40 (dd, J=8.7,7.0Hz, 1H), 7.19 (d, J=6.6Hz, 1H), 4.29 (s, 3H)；
HRMS(ESI)m/z calcd for C22H16N4O2S(M+H)+401.1072,found 401.1071.
- 2 (3H)-formamide (I -5) of N- (3- (1H-TETRAZOLE -5- base) phenyl) -3- oxo benzisothiazole, white solid,
Yield is 48%.
HRMS(ESI)m/z calcd for C15H10N6O2S(M-H)-337.0508,found 337.0509.
Embodiment 2
- 2 (3H)-formyl of N- ((1- (4- fluorophenyl) -1H-1,2,3- triazole-4-yl) methyl) -3- oxo benzisothiazole
The synthesis of amine (I -6)
Step 1
The synthesis of 1- azido -4- fluorobenzene (6.1)
4- fluoroaniline (1.11g, 10mmol) is dissolved in 20mL acetonitrile, be added under ice bath stirring nitrite tert-butyl (1.55g,
15mmol), azidotrimethylsilane (1.73g, 15mmol) is then added dropwise, finishes and is warmed to room temperature reaction 1 hour and (pays attention to anti-
Should can be highly exothermic, need open reaction).It adds methylene chloride, organic layer washing, saturated common salt washing, after anhydrous sodium sulfate is dry,
Low temperature rotation (can not be spin-dried for, product low boiling point, be easy to be removed by rotation) completely except solvent to 5mL or so, with an overlength silicagel column, two
Pressure column chromatography is not added as eluent in chloromethanes, and sterling collection is concentrated into 5mL or so and directly throws in next step, and yield is about 80%.
Step 2
3- oxo-N- (propyl- 2- alkynes -1- base) benzisothiazole -2 (3H)-formamide (6.2) synthesis
With reference to method Ι -1, white solid 6.2 is obtained, yield is about 80%.
1H NMR(400MHz,CDCl3) δ ppm 9.11 (s, 1H), 8.04 (d, J=8.0Hz, 1H), 7.75-7.67 (m,
1H), 7.58 (d, J=8.1Hz, 1H), 7.49-7.39 (m, 1H), 4.24 (dd, J=5.5,2.5Hz, 2H), 2.30 (t, J=
2.5Hz,1H).
Step 3
The synthesis of compound Ι -6
6.1 (1.5mmol) of 6.2 (232mg, 1mmol) and preparation are added in single port bottle, the dissolution of 10mL methanol is added,
Copper sulphate (11.2mg, 0.07mmol) is added under nitrogen protection and the mixing of sodium ascorbate (27.7mg, 0.14mmol) is water-soluble
Liquid (0.8mL), finishing reaction system, nitrogen protects reaction 12 hours at room temperature, and TLC monitors raw material and disappears, and reaction was completed.Rotation removes solvent,
Add ethyl acetate to extract, washed with 10% ammonium hydroxide (2 × 5mL), is washed, dry, concentration, through silica gel column chromatography (petroleum ether: acetic acid second
Ester: triethylamine=1:1:0.02) purifying, a small amount of ethyl acetate and a large amount of n-hexanes recrystallize to obtain I -6 277mg of yellow solid, produce
Rate is 75%.
1H NMR(400MHz,CDCl3) δ ppm 9.42 (s, 1H), 8.02 (d, J=7.2Hz, 2H), 7.75-7.66 (m,
3H), 7.58 (d, J=8.1Hz, 1H), 7.47-7.38 (m, 1H), 4.81 (d, J=5.9Hz, 2H)；13C NMR(100MHz,
CDCl3) δ ppm 165.6,161.7,151.9,145.7,141.2,134.5,127.9,126.4,125.2,12 3.1 (d, J=
8.6Hz, 2C), 121.5,120.9,117.2 (d, J=23.2Hz, 2C), 100.4,36.5；HRMS(ESI)m/z calcd for
C17H12FN5O2S(M+H)+370.08,found 369.99.
Embodiment 3
N- ((1- (4- fluorophenyl) -1H-1,2,3- triazole-4-yl) methyl) -3- oxo benzisothiazole -2 (3H) is thio
The synthesis of formamide (I -7)
Step 1
The synthesis of propargyl isothiocyanates (7.1)
By propargylamine (3.2mL, 50mmol) and Et3N (6.9mL, 50mmol) is dissolved in 150mL tetrahydrofuran, and ice bath stirs
It mixes lower dropwise addition carbon disulfide (3mL, 50mmol) and reacts 30 minutes at such a temperature, reaction becomes cloudy, and is then added dropwise 30% pair
Oxygen water finishes reaction and becomes clarification.Rotation removes solvent, and add methylene chloride extraction, and washing, organic layer is dry, concentration, through silica gel column chromatography
(petroleum ether: ethyl acetate=8:1) purifies to obtain 7.1 777mg of yellow-white semisolid, yield 16%.
Step 2
The synthesis of 3- oxo-N- (propyl- 2- alkynes -1- base) benzisothiazole -2 (3H) thioformamide (7.2)
7.1 (750mg, 3.02mmol) and BIT (365mg, 2.42mmol) are dissolved in 4mL methylene chloride and 4mL tetrahydrofuran
In, which is warming up to 65 DEG C of back flow reactions 8 hours.Cooling, rotation removes solvent, and about 3mL acetone is added, and 3mL water ultrasound is mixed
It closes, filtering is precipitated after standing, filter cake is washed with (acetone: water=1:1), and filtration cakes torrefaction obtains 7.2 120mg of white-yellowish solid, and yield is
13%.
1H NMR(400MHz,CDCl3) δ ppm 11.33 (s, 1H), 8.00 (d, J=8.0Hz, 1H), 7.74-7.65 (m,
1H), 7.53 (d, J=8.1Hz, 1H), 7.45-7.38 (m, 1H), 4.53 (dd, J=4.9,2.6Hz, 2H), 2.37 (t, J=
2.6Hz,1H).
Step 3
The synthesis of chemical compounds I -7
Reference method Ι -6, solvent replace methanol with dimethyl sulfoxide, obtain Tan solid I -7, yield 21%.
1H NMR(400MHz,CDCl3) δ ppm 11.70 (s, 1H), 8.14 (s, 1H), 7.98 (d, J=10.1Hz, 2H),
7.77-7.65 (m, 5H), 7.52 (d, J=8.1Hz, 1H), 7.44-7.33 (m, 2H), 7.25-7.18 (m, 4H), 5.15 (d, J
=5.6Hz, 2H), 4.94 (s, 2H)；13C NMR(100MHz,CDCl3) δ 177.3,163.4,146.2 (d, J=62.4Hz,
1C), 142.0 (d, J=112.0Hz, 1C), 133.3,126.6,125.0,124.6,122.8 (d, J=28.3Hz, 1C),
121.7 (d, J=2.7Hz, 1C), 121.6 (d, J=2.7Hz, 1C), 120.3,119.3,118.9,115.8 (dd, J=23.3,
15.2Hz,2C),44.8；HRMS(ESI)m/z calcd for C17H12FN5OS2(M+H)+386.0546,found
386.0545.
Embodiment 4
N- ((1- (4- fluorophenyl) -1H-1,2,3- triazole-4-yl) methyl) -3- oxo isothiazole simultaneously [5,4-A] pyridine -2
The synthesis of (3H)-formamide (I -8)
Step 1
The synthesis of 2- sulfydryl-Niacinamide (8.1)
2- mercaptonicotinic acid (5.9g, 38mmol) is dissolved in 60mL toluene, thionyl chloride (13.8mL, 190mmol) is added, is returned
Stream reaction 3 hours.Adding 20mL toluene after cooling concentration, vacuum rotary steam band removes extra thionyl chloride twice；Residue adds ammonium chloride
(7g, 130mmol), ammonium hydroxide (50mL), water (17mL) stir 18 hours at room temperature；It is small to stir 1 at room temperature for then sodium borohydride
When, reaction was completed.With 3M hydrochloric acid about 100mL tune reaction solution pH to 4, there is Precipitation, filter, filter cake washes to obtain yellow solid
8.1 4.3g, yield 74%.
1H NMR (400MHz, DMSO) δ ppm 14.00 (s, 1H), 10.06 (s, 1H), 8.48 (dd, J=7.6,1.9Hz,
1H), 7.94 (td, J=6.2,1.8Hz, 2H), 7.05-6.95 (m, 1H)
Step 2
The synthesis of isothiazole simultaneously [5,4-b] pyridine -3 (2H) -one (8.2)
8.1 (4.3g, 27.9mmol) are dissolved in the 28mL concentrated sulfuric acid, 100 DEG C are reacted 2 hours.Add 70mL ice water after cooling,
Add about 70mL ammonium hydroxide tune pH to 11 with constant pressure addition loophole again, insoluble solids are filtered, 100 DEG C of filtrate are heated to slightly boiled, heating
Lower constant pressure funnel adds about 20mL acetic acid tune pH to 4, and then chill has a large amount of Precipitations, filtering, filter cake washing
Dry, add methylene chloride: methanol (1:1) ultrasound filtration, filter cake collect to obtain 8.2 2.56g of yellow solid, yield 60%.
1H NMR (400MHz, DMSO) δ ppm 8.81 (dd, J=4.6,1.6Hz, 1H), 8.31 (dd, J=8.0,
1.6Hz, 1H), 7.50 (dd, J=8.0,4.6Hz, 1H)
Step 3
Simultaneously [5,4-A] pyridine -2 (3H)-formamide (8.3) synthesis of 3- oxo-N- (propyl- 2- alkynes -1- base) isothiazole
Reference method I -1 obtains yellow solid 8.3, yield 50%.
1H NMR (400MHz, DMSO) δ ppm 9.00 (t, J=5.5Hz, 1H), 8.94 (dd, J=4.7,1.6Hz, 1H),
8.40 (dd, J=8.0,1.6Hz, 1H), 7.58 (dd, J=8.0,4.7Hz, 1H), 4.14 (dd, J=5.7,2.4Hz, 2H),
3.24 (t, J=2.4Hz, 1H)
Step 4
The synthesis of chemical compounds I -8
Reference method I -6, solvent replaces methanol with dimethyl sulfoxide, obtains Tan solid I -8, yield 8%.
1H NMR (400MHz, DMSO) δ ppm 10.87 (s, 1H), 8.74 (t, J=63.9Hz, 2H), 8.19 (t, J=
47.5Hz, 2H), 7.72 (d, J=75.5Hz, 1H), 7.41 (s, 1H), 7.10 (s, 1H), 6.77 (s, 1H), 4.01 (d, J=
20.9Hz,2H).
Embodiment 5
N- ((1- (4- fluorophenyl) -1H-1,2,3- triazole-4-yl) methyl) -3- oxo -4- phenyl benzisothiazole -2
The synthesis of (3H)-formamide (I -9)
Step 1
The synthesis of the bromo- 6- iodo-benzoic acid (9.1) of 2-
2- bromobenzoic acid (8.04g, 40mmol), iodobenzene diacetate (19.3g, 60mmol), palladium acetate (449mg, 2mmol)
It is dissolved in the anhydrous n,N-Dimethylformamide of 80mL with iodine grain (15.2g, 60mmol), 100 DEG C are reacted 24 hours, and reaction was completed.
Cooling, a large amount of ethyl acetate extractions, 0.5M salt pickling, washing, organic layer is dry, concentration, through silica gel column chromatography (petroleum ether: second
Acetoacetic ester=3:1) purify to obtain 9.1 7.32g of rufous liquid, yield 46%.
1H NMR (400MHz, DMSO) δ ppm 7.79 (dd, J=8.0,0.8Hz, 1H), 7.58 (dd, J=8.1,
0.8Hz, 1H), 6.97 (t, J=8.0Hz, 1H)
Step 2
The synthesis of the bromo- 6- iodobenzamide (9.2) of 2-
9.1 (7.32g, 22mmol) are dissolved in 40mL tetrahydrofuran, add 4mL thionyl chloride and catalytic amount N, N- dimethyl methyl
Amide, 3 hours back spins of nitrogen protection back flow reaction remove reaction solution, and residue adds 40mL tetrahydrofuran, ammonia is added dropwise under ice bath stirring
Water 33mL, 3 hours at room temperature.Ethyl acetate is added to extract, saturated sodium bicarbonate is washed, and organic layer is dry, concentration, with a small amount of dichloromethane
Alkane and a large amount of n-hexane recrystallization purifyings obtain 9.2 6.09g of white solid, yield 85%.
1H NMR (400MHz, DMSO) δ ppm 7.97 (s, 1H), 7.84 (dd, J=7.9,0.9Hz, 1H), 7.70 (s,
1H), 7.64 (dd, J=8.0,0.9Hz, 1H), 7.02 (t, J=8.0Hz, 1H)
Step 3
The synthesis of the bromo- 6- iodobenzene formonitrile HCN (9.3) of 2-
9.2 (6g, 18.4mmol) are dissolved in 20mL tetrahydrofuran, add trifluoroacetic anhydride (2.8mL, 20.2mmol) He Sanyi
Amine (3.3mL, 23.9mmol) reacts 2 hours at room temperature.Add 21mL water quenching reaction, rotation removes tetrahydrofuran, a large amount of solid analysis
Out, it filters, filter cake washing and drying obtains 9.3 5.38g of white solid, yield 95%.
1H NMR (400MHz, DMSO) δ ppm 7.88 (d, J=8.0Hz, 1H), 7.67 (d, J=8.1Hz, 1H), 7.12
(t, J=8.1Hz, 1H)
Step 4
The synthesis of bromo- [1,1'- the biphenyl] -2- formonitrile HCN (9.4) of 3-
9.3 (5.3g, 17.2mmol), phenyl boric acid (2.3g, 18.9mmol) and sodium carbonate (3.65g, 34.4mmol) are dissolved in
126mL toluene: ethyl alcohol: water (5:1:1) in the mixed solvent, nitrogen air-blowing add after five minutes four triphenyl phosphorus palladiums (994mg,
0.86mmol), it reacts 6 hours for lower 90 DEG C of whole nitrogen protection, reaction was completed.Cooling, rotation removes solvent, and ethyl acetate is added to extract,
Washing, organic layer is dry, and concentration purifies to obtain white solid through silica gel column chromatography (petroleum ether: methylene chloride=15:1)
9.41.77g yield 40%.
1H NMR (400MHz, CDCl3) δ ppm 7.68 (dd, J=7.8,1.3Hz, 1H), 7.58-7.38 (m, 7H)
Step 5
The synthesis of 3- (ethylmercapto group)-[1,1'- biphenyl] -2- formonitrile HCN (9.5)
Successively 9.4 (1.03g, the 4mmol) of addition in tube sealing, bromoethane (298 μ L, 4mmol), potassium rhodanide (389mg,
4mmol), cuprous bromide (57mg, 0.4mmol), ferrosin (72mg, 0.4mmol), tetrabutylammonium bromide (258mg,
0.8mmol), sodium hydroxide (320mg, 8mmol) and 16mL water, 130 DEG C are reacted 48 hours.It is cooled to room temperature, increasing amount acetic acid
Ethyl ester extraction, washing, organic layer is dry, and concentration purifies to obtain yellow oil through silica gel column chromatography (petroleum ether: methylene chloride=20:1)
9.5 335mg of shape object, yield 40%.
1H NMR (400MHz, DMSO) δ ppm 7.59-7.43 (m, 6H), 7.37 (d, J=8.0Hz, 1H), 7.26 (d, J
=7.7Hz, 1H), 3.10 (q, J=7.4Hz, 2H), 1.41 (t, J=7.4Hz, 3H)
Step 6
The synthesis of 3- (ethylmercapto group)-[1,1'- biphenyl] -2- formonitrile HCN (9.6)
9.5 (201mg, 0.84mmol) are dissolved in 0.8mL chlorobenzene, are added water (18 μ L, 1mmol), sulfonic acid chloride (74 μ L,
0.92mmol), it finishes and rises to 75 DEG C of reactions 1 hour.There are white solid precipitation, cold filtration, filter cake chlorobenzene is washed, whitely dry
9.6 153mg of solid, yield 81%.
1H NMR (400MHz, DMSO) δ ppm 7.98 (d, J=8.1Hz, 2H), 7.65-7.61 (m, 1H), 7.48-7.35
(m, 5H), 7.23 (dd, J=7.2,0.7Hz, 1H)
Step 7
3- oxo -4- phenyl-N- (propyl- 2- alkynes -1- base) benzisothiazole -2 (3H)-formamide (9.7) synthesis
Reference method I -1 obtains yellow solid 9.7, yield 75%.
1H NMR(400MHz,CDCl3) δ ppm 9.06 (s, 1H), 7.71 (t, J=7.7Hz, 1H), 7.57 (dd, J=
8.1,0.6Hz, 1H), 7.48-7.42 (m, 5H), 7.28 (d, J=8.2Hz, 1H), 4.16 (dd, J=5.5,2.5Hz, 2H),
2.22 (t, J=2.5Hz, 1H)
Step 8
The synthesis of chemical compounds I -9
Reference method I -6, solvent replaces methanol with dimethyl sulfoxide, obtains Tan solid I -9, yield 70%.
1H NMR (400MHz, DMSO) δ ppm 9.35 (t, J=5.8Hz, 1H), 7.96 (s, 1H), 7.73-7.65 (m,
3H), 7.57 (d, J=8.1Hz, 1H), 7.48-7.43 (m, 3H), 7.40 (dd, J=6.7,3.0Hz, 2H), 7.28 (s, 1H),
7.23-7.17 (m, 2H), 4.72 (d, J=6.0Hz, 2H)；13C NMR(100MHz,CDCl3)δppm 164.7,163.8,
(161.3,151.7,145.3,144.9,142.1,137.2,133.4,129.4 2C), 128.5 (d, J=7.9Hz, 2C),
127.9 (2C), 122.7 (d, J=8.6Hz, 2C), 121.2,120.8,119.7,116.9,116.7,36.0；HRMS(ESI)m/
z calcd for C23H16FN5O2S(M+H)+446.1087,found 446.1088.
Embodiment 6
- 2 (3H)-formamide of N- ((1- (4- fluorophenyl) -1H-1,2,3- triazole-4-yl) methyl) -3- oxo isothiazole
The synthesis of (I -10)
Step 1
3- oxo-N- (propyl- 2- alkynes -1- base) isothiazole -2 (3H)-formamide (10.1) synthesis
Reference method I -1 obtains yellow solid 10.1, yield 45%.
Step 2
The synthesis of chemical compounds I -10
Reference method I -6, solvent isopropanol instead of methanol obtain yellow solid I -10, yield 17%.
1H NMR(400MHz,CDCl3) δ ppm 9.45 (s, 1H), 8.22 (d, J=6.4Hz, 1H), 7.99 (s, 1H),
7.73-7.67 (m, 2H), 7.25-7.18 (m, 2H), 6.26 (d, J=6.4Hz, 1H), 4.77 (d, J=5.9Hz, 2H)；13C
NMR (100MHz, DMSO) δ ppm 167.9,162.9,150.7,147.6,145.4,133.2 (d, J=2.9Hz, 2C), 122.4
(d, J=8.8Hz, 2C), 121.5,116.7 (d, J=23.2Hz, 2C), 114.6,35.3；HRMS(ESI)m/z calcd for
C13H10FN5O2S(M+NA0)+342.0437,found 342.0435.
Embodiment 7
3- oxo-N- ((3- phenyl -1,2,4- oxadiazoles -5- base) methyl) benzisothiazole -2 (3H)-formamide (I -
11) synthesis
Step 1
The synthesis of 5- (chloromethyl) -3- phenyl -1,2,4- oxadiazoles (11.1)
Hydroxylamine hydrochloride (4.17g, 60mmol) and sodium carbonate (4.07g, 38.4mmol) are dissolved in 50mL water, and benzene is added thereto
The ethanol solution 25mL of formonitrile HCN (2.47g, 24mmol), is warming up to 105 DEG C of back flow reactions 10 hours.It is cooled to room temperature, increasing amount
Ethyl acetate extraction, washing, organic layer is dry, is concentrated to give crude product (E) -2- amino -2- ethylalbenzene oxime.Thereto plus 40mL bis-
Chloromethanes dissolves, and adds n,N-diisopropylethylamine (5.58g, 43.2mmol) under ice bath stirring, chloracetyl chloride is added dropwise
(2.44g, 21.6mmol) is finished and is risen to back flow reaction 18 hours.Cooling, ethyl acetate extraction, washing, organic layer is dry, dense
Contracting, through silica gel column chromatography (petroleum ether: ethyl acetate=20:1) purify 11.1 3.13g of weak yellow liquid, two step yields are
67%.
1H NMR (400MHz, CDCl3) δ ppm 8.09 (dd, J=8.0,1.6Hz, 2H), 7.54-7.45 (m, 3H),
4.75(s,2H).
Step 2
The synthesis of 2- ((3- phenyl -1,2,4- oxadiazoles -5- base) methyl) isoindoline -1,3- diketone (11.2)
11.1 (2.92g, 15mmol) are dissolved in 25mL n,N-Dimethylformamide, in batches plus phthalimide
Potassium (2.78g, 15mmol), 60 DEG C are reacted 4 hours.It is cooling, add 100mL water, ultrasound, a large amount of precipitatings generate, filtering, filter cake washing
Dry white 11.2 2.84g of yellow solid, yield 62%.
1H NMR (400MHz, CDCl3) δ ppm 8.04-8.00 (m, 2H), 7.95 (dd, J=5.5,3.1Hz, 2H),
7.80 (dd, J=5.5,3.1Hz, 2H), 7.49-7.41 (m, 3H), 5.18 (s, 2H)
Step 3
The synthesis of (3- phenyl -1,2,4- oxadiazoles -5- base) methylamine (11.3)
11.2 (2.74g, 9mmol) are dissolved in 40mL ethyl alcohol, add 80% hydrazine hydrate (675mg, 10.8mmol), back flow reaction
4 hours, reaction was completed.Cooling, rotation removes solvent, adds water, is adjusted to alkalinity, is extracted with ethyl acetate, dry, is concentrated to give white solid
11.3 1.45g, yield 92%.
1H NMR(400MHz,CDCl3)δppm 8.11-8.03(m,2H),7.51-7.41(m,3H),4.14(s,2H).
Step 4
The synthesis of chemical compounds I -11
Reference method I -1 need to extend to 8 hours when preparing isocyanates, obtain white solid I -11, yield 73%.
1H NMR (400MHz, DMSO) δ ppm 9.56 (t, J=5.7Hz, 1H), 8.01 (dd, J=17.2,8.1Hz,
4H), 7.81 (t, J=8.2Hz, 1H), 7.61-7.48 (m, 4H), 4.96 (d, J=5.8Hz, 2H)；13C NMR(100MHz,
DMSO)δppm 177.2,167.7,164.4,151.2,140.9,134.2,131.7,129.3(2C),127.0(2C),
126.7,126.2,126.0,124.4,122.2,37.0；HRMS(ESI)m/z calcd for C17H12N4O3S(M+NA0)+
375.0528,found375.0530.
Embodiment 8
- 2 (3H)-formamide (I -12) of N- (1- ((3- fluorophenyl) sulfonyl) piperidin-4-yl) -3- oxo benzisothiazole
Synthesis
Step 1
1- ((3- fluorophenyl) sulfonyl) piperidin-4-yl) t-butyl carbamate (12.1) synthesis
4- t-butoxycarbonyl amino piperidines (2.5g, 12.5mmol) and triethylamine (5.2mL, 37.5mmol) are dissolved in 20mL bis-
In chloromethanes, the dichloromethane solution 10mL of 3- fluorophenylsulfonyl chloride (1.74mL, 13.1mmol) is added dropwise under ice bath stirring, finishes liter
To room temperature reaction 5 hours.Ethyl acetate is added to extract, 1M salt pickling, saturated sodium bicarbonate, washing, organic layer is dry, is concentrated, warp
Silica gel column chromatography (petroleum ether: ethyl acetate=8:1) purifies to obtain 12.1 4.1g of white solid, yield 92%.
1H NMR(400MHz,CDCl3) δ ppm 7.55-7.49 (m, 2H), 7.44 (d, J=7.7Hz, 1H), 7.34-7.27
(m, 1H), 4.46 (s, 1H), 3.69 (d, J=10.8Hz, 2H), 3.39 (d, J=5.7Hz, 1H), 2.47 (t, J=11.3Hz,
2H), 1.97 (d, J=15.5Hz, 2H), 1.48 (ddd, J=24.1,11.6,4.0Hz, 2H), 1.40 (s, 9H)
Step 2
The synthesis of 1- ((3- fluorophenyl) sulfonyl) piperidines -4- amine (12.2)
12.1 (3g, 8.37mmol) are dissolved in 6mL methylene chloride, add trifluoroacetic acid 6mL, are reacted at room temperature 3 hours, are terminated anti-
It answers.Rotation removes solvent, adds water, is adjusted to alkalinity, is extracted with dichloromethane, dry, is concentrated to give 12.2 2.22g of white solid, yield is
93%.
1H NMR(400MHz,CDCl3) δ ppm 8.50 (t, J=5.5Hz, 1H), 8.33 (d, J=7.7Hz, 1H), 8.04
(t, J=7.4Hz, 1H), 7.78 (d, J=5.8Hz, 1H), 7.69 (d, J=5.1Hz, 2H), 4.08 (dd, J=5.7,2.4Hz,
2H).
Step 3
The synthesis of chemical compounds I -12
Reference method I -1 obtains white solid I -12, yield 20%.
1H NMR(400MHz,CDCl3) δ 8.92 (d, J=7.4Hz, 1H), 7.99 (d, J=7.9Hz, 1H), 7.74-7.66
(m, 1H), 7.56 (dd, J=10.7,8.7Hz, 3H), 7.48 (dd, J=9.6,1.6Hz, 1H), 7.43 (t, J=7.6Hz,
1H), 7.35-7.30 (m, 1H), 3.88-3.77 (m, 1H), 3.75-3.70 (m, 2H), 2.62 (td, J=12.1,2.6Hz,
2H), 2.12 (dd, J=13.1,3.5Hz, 2H), 1.74 (ddd, J=24.1,10.9,4.0Hz, 2H)；13C NMR(100MHz,
CDCl3) δ ppm 165.3,162.6 (d, J=252Hz, 1C), 150.5,140.8,138.4 (d, J=6.5Hz, 1C), 134.1,
131.1 (d, J=7.8Hz, 1C), 127.3,126.0,124.9,123.4 (d, J=3.3Hz, 1C), 120.6,120.2 (d, J=
21.2Hz, 1C), 115.0 (d, J=24.1Hz, 1C), 47.2,45.0 (2C), 31.4 (2C)；HRMS(ESI)m/z calcd
for C19H18FN3O4S2(M+Na)+458.1,found 458.1.
Embodiment 9
The synthesis of 3- oxo-N- (2- (sulphamoylamino) ethyl) benzisothiazole -2 (3H)-formamide (I -13)
Step 1
1- ((3- fluorophenyl) sulfonyl) piperidin-4-yl) t-butyl carbamate (13.1) synthesis
Synthetic method is with I -1, and alkali replaces triethylamine with saturated sodium bicarbonate, obtains white solid 411mg 13.1, and yield is
90%.
1H NMR (400MHz, DMSO) δ ppm 9.03 (s, 1H), 8.02 (d, J=7.9Hz, 1H), 7.70 (t, J=
7.7Hz, 1H), 7.58 (d, J=8.1Hz, 1H), 7.43 (t, J=7.3Hz, 1H), 4.91 (s, 1H), 3.57 (dd, J=11.6,
5.8Hz, 2H), 3.38 (dd, J=11.2,5.5Hz, 2H), 1.43 (s, 9H)
Step 2
The synthesis of -2 (3H)-formamide (13.2) of N- (2- amino-ethyl) -3- oxo benzisothiazole
It weighs and trifluoroacetic acid is added under 13.1 (337mg, 1mmol) ice baths: in the mixed solution 4mL of water (9:1), then turning
To room temperature reaction 2 hours, reaction was completed.Rotation removes reaction solution, and add methylene chloride extraction, and saturated sodium bicarbonate is washed, and washes, dry,
Concentration purifies to obtain 13.2 221mg of white solid, yield through silica gel plate separation (methylene chloride: methanol: ammonium hydroxide=10:1:0.1)
It is 93%.
Step 3
(N- (2- (3- oxo -2,3- dihydrobenzo [d] isothiazole -2- formamido) ethyl) sulfamoyl) carbamic acid
The synthesis of the tert-butyl ester (13.3)
Chlorosulphonyl isocyanate (78 μ L, 0.88mmol) is dissolved in 3mL methylene chloride, the tert-butyl alcohol is added dropwise under ice bath stirring
The dichloromethane solution of (85 μ L, 0.88mmol) finishes and is warmed to room temperature reaction 1.5 hours, and N-Aoc chloride solution is made.
13.2 (190mg, 0.8mmol) are dissolved in 3mL methylene chloride, and N-Aoc chloride solution obtained is slowly added to it at -15 DEG C
In, stirring has solid generation after ten minutes, then triethylamine (945 μ L, 4mmol) is added dropwise thereto, finishes and is warmed to room temperature reaction 10
Minute, precipitating dissolution, solution becomes clarification, fully reacting.With 1M hydrochloric acid tune pH to 7, ethyl acetate is added to extract, washed, it is dry, it is dense
Contracting, silica gel plate separation (methylene chloride: methanol: ammonium hydroxide=20:1:0.2) purify white solid 13.3117mg, yield are
35%.
1H NMR (400MHz, DMSO) δ ppm 7.57 (d, J=8.0Hz, 1H), 7.31 (q, J=7.7Hz, 2H), 7.03
(t, J=8.0Hz, 1H), 3.22-3.17 (m, 2H), 2.84 (t, J=6.0Hz, 2H), 1.03 (s, 9H)
Step 4
The synthesis of chemical compounds I -13
Reference method 13.2 obtains white solid I -13, yield 15%.
1H NMR (400MHz, DMSO) δ ppm 9.00-8.89 (m, 1H), 7.99 (dd, J=26.5,8.0Hz, 2H),
7.80 (t, J=8.3Hz, 1H), 7.50 (t, J=7.6Hz, 1H), 7.46 (s, 1H), 6.75 (t, J=5.9Hz, 1H), 6.59
(s, 2H), 3.47 (q, J=6.1Hz, 2H), 3.08 (dd, J=11.7,5.7Hz, 2H)；13C NMR(100MHz,DMSO)δppm
164.2,150.9,140.7,133.9,126.4,126.0,124.7,122.0,54.9,41.9；HRMS(ESI)m/z calcd
for C10H12N4O4S2(M+Na)+339.0198,found 339.0197.
Embodiment 10
2- ((1- (substituted-phenyl) -1H-1,2,3- triazole-4-yl) first (or second) base) benzisothiazole -3 (2H) -one (I -
14~I -16) synthesis
Step 1
The synthesis of 5- (chloromethyl) -3- (3- trifluoromethyl) -1,2,4- thiadiazoles (14.1 and 15.1)
AIT (2.27g, 15mmol) is dissolved in 150mL acetonitrile, is added potassium carbonate (4.15g, 30mmol), is reacted 30 at room temperature
After minute, add bromine second (or third) alkynes (22.5mmol), reacts 4 hours at room temperature, reaction was completed.Add ethyl acetate to extract, wash,
Organic layer is dry, and concentration purifies to obtain product through silica gel column chromatography (petroleum ether: methylene chloride=1:1)；
2- (propyl- 2- alkynes -1- base) benzisothiazole -3 (2H) -one (14.1), white solid, yield 38%.
1H NMR(400MHz,CDCl3) δ ppm 8.05-8.00 (m, 1H), 7.64-7.60 (m, 1H), 7.56 (d, J=
8.1Hz, 1H), 7.42-7.38 (m, 1H), 4.69 (d, J=2.6Hz, 2H), 2.44 (t, J=2.6Hz, 1H)
2- (butyl- 3- alkynes -1- base) benzisothiazole -3 (2H) -one (15.1), yellow solid, yield 13%.
Step 2
The synthesis of chemical compounds I -14~I -16
With reference to method I -6
2- (2- (1- (4- fluorophenyl) -1H-1,2,3- triazole-4-yls) methyl) benzisothiazole -3 (2H) -one (I -14),
Yellow solid, yield 79%.
1H NMR(400MHz,CDCl3)δppm 8.08-8.00(m,2H),7.72-7.64(m,2H),7.64-7.58(m,
1H), 7.54 (d, J=8.1Hz, 1H), 7.44-7.38 (m, 1H), 7.23-7.15 (m, 2H)；13C NMR(100MHz,CDCl3)δ
Ppm 165.5,163.9,161.4,144.0,140.8,132.3,126.8,125.8,124.1,12 2.7 (d, J=8.7Hz,
2C), 121.8,120.7,116.9 (d, J=23.2Hz, 2C), 39.1；HRMS(ESI)m/z calcd for C16H11FN4OS(M
+H)+327.07,found 326.83.
2- (2- (1- (4- fluorophenyl) -1H-1,2,3- triazole-4-yls) ethyl) benzisothiazole -3 (2H) -one (I -15),
Yellow solid, yield 79%.
1H NMR(400MHz,CDCl3) δ ppm 8.02 (d, J=7.9Hz, 1H), 7.84 (s, 1H), 7.69-7.62 (m,
2H), 7.62-7.56 (m, 1H), 7.52 (d, J=8.1Hz, 1H), 7.39 (dd, J=11.4,4.4Hz, 1H), 7.22-7.15
(m, 2H), 4.31 (t, J=7.0Hz, 2H), 3.29 (t, J=7.0Hz, 2H)；13C NMR(100MHz,CDCl3)δppm
165.7,162.5 (d, J=249Hz, 1C), 144.9,140.5,133.5 (d, J=3.1Hz, 1C), 132.0,126.7,
125.7,124.5,122.5 (d, J=8.6Hz, 2C), 120.5,120.3,116.8 (d, J=23.2Hz, 2C), 43.2,26.0；
HRMS(ESI)m/z calcd for C17H13FN4OS(M+H)+341.0872,found 341.0871.
2- ((1- (4- fluorophenyl) -1H-1,2,3- triazole-4-yls) methyl) benzisothiazole -3 (2H) -one (I -16), it is yellow
Color solid, yield 84%.
1H NMR (400MHz, DMSO) δ ppm 10.97 (s, 1H), 8.58 (s, 1H), 7.93 (dd, J=26.9,7.9Hz,
2H), 7.68 (t, J=7.2Hz, 2H), 7.53-7.26 (m, 2H), 7.11 (d, J=8.0Hz, 1H), 5.19 (s, 2H)；HRMS
(ESI)m/z calcd for C16H11ClN4O2S(M+H)+359.0369,found 359.0367.
Embodiment 11
2- ((5- (substituted-phenyl) -1,2,4- thiadiazoles -3- base) methyl) benzisothiazole -3 (2H) -one (I -17 and I -
18) synthesis
Step 1
5- (substituted-phenyl) -1,3,4- dislikes the synthesis of thiazole -2- ketone (17.1 and 18.1)
Substituted benzamide (10mmol) is dissolved in 80mL toluene, chlorination carbonyl mesyl chloride (1.57g, 12mmol), is returned
After stream reaction 6 hours, reaction was completed.Rotation removes solvent, adds pentane: ether=1:1 ultrasound, freezing are stood, and filtering, filtrate weighs again
Crystallization merges filter cake and obtains product.
5- (3- trifluoromethyl) -1,3,4- dislikes thiazole -2- ketone (17.1), pale solid, yield 70%.
1H NMR(400MHz,CDCl3) δ ppm 8.25 (s, 1H), 8.16 (d, J=7.9Hz, 1H), 7.83 (d, J=
7.9Hz, 1H), 7.66 (t, J=7.9Hz, 1H).
5- (5- chlorine-2-hydroxyl phenyl) -1,3,4- dislikes thiazole -2- ketone (18.1), white solid, yield 70%.
1H NMR(400MHz,CDCl3) δ 9.74 (s, 1H), 7.70 (d, J=2.6Hz, 1H), 7.43 (s, 1H), 7.03 (d,
J=8.9Hz, 1H)
Step 2
The synthesis of 5- (chloromethyl) -3- (substituted-phenyl) -1,2,4- thiadiazoles (17.2 and 18.2)
17.1 or 18.1 (6.88mmol) are dissolved in 17mL chloroacetonitrile (40 equivalent), after back flow reaction 36 hours, reaction solution
Concentration, purifies to obtain product through silica gel column chromatography (petroleum ether: methylene chloride=10:1).
5- (chloromethyl) -3- (3- trifluoromethyl) -1,2,4- thiadiazoles (17.2), faint yellow solid, yield are
53%.
1H NMR(400MHz,CDCl3) δ ppm 8.56 (s, 1H), 8.46 (d, J=7.8Hz, 1H), 7.73 (d, J=
7.8Hz, 1H), 7.61 (t, J=7.8Hz, 1H), 5.00 (s, 2H)
5- (chloromethyl) -3- (5- chlorine-2-hydroxyl phenyl) phenyl) -1,2,4- thiadiazoles (18.2), yellow solid, yield
It is 32%.
1H NMR(400MHz,CDCl3) δ ppm 10.73 (s, 1H), 8.23 (d, J=2.6Hz, 1H), 7.33 (d, J=
11.5Hz, 1H), 7.01 (d, J=8.8Hz, 1H), 5.01 (s, 2H)
Step 3
The synthesis of chemical compounds I -17 and I -18
17.2 or 18.2 (3mmol) are dissolved in 10mL acetone, are added sodium iodide (675mg, 4.5mmol), and back flow reaction 4 hours
Afterwards, add ethyl acetate to extract, wash, organic layer is dry, is concentrated to give crude product N- (2- iodine ethyl) -3- oxo benzisothiazole -2
(3H)-formamide.BIT (378mg, 2.5mmol) and potassium carbonate (518mg, 3.75mmol) are dissolved in 4mL DMF, room temperature reaction
After 30 minutes plus previous step crude product, 150W, 100 DEG C microwave reaction 20 minutes, reaction was completed.Add ethyl acetate to extract, washes, have
Machine layer is dry, and concentration purifies to obtain product through silica gel column chromatography (petroleum ether: methylene chloride: triethylamine=1:1:0.02).
2- ((5- (3- trifluoromethyl) -1,2,4- thiadiazoles -3- base) methyl) benzisothiazole -3 (2H) -one (I -
17), faint yellow solid, yield 32%.
1H NMR(400MHz,CDCl3) δ ppm 8.56 (s, 1H), 8.46 (d, J=7.8Hz, 1H), 7.73 (d, J=
7.8Hz, 1H), 7.61 (t, J=7.8Hz, 1H), 5.00 (s, 2H)；13C NMR(100MHz,CDCl3)δppm 187.6,
171.7,161.3,152.5,133.4,131.6,131.5,131.3,129.4,129.3,12 7.1 (q, J=3.7Hz, 1C),
125.4 (q, J=3.8Hz, 1C), 125.1,124.6,123.1,120.5,66.4；HRMS(ESI)m/z calcd for
C17H10F3N3OS2(M+H)+394.0,found 394.0.
2- ((5- (5- chlorine-2-hydroxyl phenyl) -1,2,4- thiadiazoles -3- base) methyl) benzisothiazole -3 (2H) -one (I -
18), yellow solid, yield 10%.
1H NMR(400MHz,CDCl3) δ ppm 10.91 (s, 1H), 8.30 (s, 1H), 8.00 (d, J=8.6Hz, 1H),
7.84 (d, J=9.1Hz, 1H), 7.59 (t, J=7.8Hz, 1H), 7.51-7.42 (m, 1H), 7.32 (d, J=8.5Hz, 1H),
7.02 (d, J=9.3Hz, 1H), 6.07 (s, 2H)；HRMS(ESI)m/z calcd for C16H10ClN3O2S2(M+H)+376.0,
found 376.0.
Embodiment 12
- 2 (3H)-sulfonamide of N- (2- (3- cyclopropyl isoxazole -5- base) ethyl) -4- (naphthalene -1- base) -3 oxo isothiazole
(I-19) synthesis
Step 1
The synthesis of 3- (benzyloxy) -4- bromine isothiazole (19.1)
3- benzyloxy isothiazole (590mg, 3mmol) is dissolved in anhydrous MeCN (10mL), and be added NBS (588mg,
3.3mmol).Mixture is stirred at room temperature 7 days.Mixture is concentrated into about 50 DEG C.1mL and EtOAc is added.It will be organic molten
Liquid H2O washing, is then washed with brine and uses MgSO4It is dry, concentration, through silica gel column chromatography (petroleum ether: toluene=2:1~1:
1) product is purified to obtain.
3- (benzyloxy) -4- bromine isothiazole (19.1), transparent oil, yield 88%.
1H NMR(400MHz,CDCl3): δ 5.40 (s, 2H), 7.27-7.43 (m, 5H), 8.20 (s, 1H)
Step 2
The synthesis of 3- (naphthalene -1- base) isothiazole -3 (2H) -one (19.2)
Stir 19.1 (297mg, 1.1mmol), 1- naphthalenylboronic acid (567mg, 3.3mmol, 3 equivalent) and powdered K2CO3
The mixture of (228mg, 1.65mmol, 1.5 equivalent).Under nitrogen atmosphere, by the Pd in dry and degassing DMF (2ml)
(OAc)2(12mg, 5mol%) is heated to about 100 DEG C, until not having raw material to remain (TLC).Mixture is cooled to about 20 DEG C.
It is diluted with DCM (15ml), uses H2O (4 × 10ml) washing.Organic layer is separated, obtains product through column chromatographic purifying.
3- (naphthalene -1- base) isothiazole -3 (2H) -one (19.2), transparent oil, yield 77%.
1H NMR(400MHz,CDCl3):δ7.98–7.90(m,3H),7.69–7.59(m,3H),7.48(s,1H),7.06
(s,1H),6.88(s,1H).
Step 3
The synthesis of -2 (3H)-sulfonamide (19.3) of N- (butyl- 3- alkynes -1- base) -4- (naphthalene -1- base) -3 oxo isothiazole
By the DCM (2ml) of 19.2 (102mg, the 0.495mmol) and triethylamine (69 μ L, 0.495mmol, 1 equivalent) of stirring
Solution is cooled to about 0 DEG C.Reaction mixture is added in 3- propine -1- base sulfamic acid chloride (165mg, 0.99mmol, 2 equivalent).
Reaction mixture is maintained at about 100 DEG C of stirrings, until there is no raw material to remain (TLC).It is pure through column chromatography (hexane-DCM=5:3)
Change to obtain product.
- 2 (3H)-sulfonamide (19.3) of N- (butyl- 3- alkynes -1- base) -4- (naphthalene -1- base) -3 oxo isothiazole, pale yellow colored solid
Body, yield 24%.
1H NMR(400MHz,CDCl3):δ7.98–7.86(m,3H),7.77–7.64(m,3H),7.46(m,1H),6.84
(m,1H),6.32(s,1H),2.87(m,2H),2.46m,2H),1.99(m,1H).
Step 4
The synthesis of compound I-19
To N- hydroxyl cyclopropane carbimide chlorine (3mmol) ethyl acetate solution (7mL) in be added 19.3 (6mmol) and
Solid sodium bicarbonate (840mg, 10mmol).Mixture is stirred at room temperature until halogenated oxime disappears；It is monitored and is reacted by TLC
Process.(eluent: 20% ethyl acetate/hexamethylene).Slurries are poured into water, organic layer is separated, water phase further uses ether
(2 × 20mL) extraction.Organic extract liquid is dry with anhydrous sodium sulfate, concentration, through silica gel column chromatography (petroleum ether: methylene chloride: three
Ethamine=1:1:0.02) obtain product.
- 2 (3H)-sulfonamide of N- (2- (3- cyclopropyl isoxazole -5- base) ethyl) -4- (naphthalene -1- base) -3 oxo isothiazole
(I-19), faint yellow solid, yield 51%.
1H NMR(400MHz,CDCl3):δ7.93–7.85(m,3H),7.73–7.62(m,3H),7.43(m,1H),6.85
(m, 1H), 6.81 (m, 1H), 4.74 (m, 1H), 3.01 (m, J=2.7Hz, 4H), 2.21 (m, 1H), 1.11 (m, J=
124.7Hz,4H).
Embodiment 13
Inhibitory activity research of the isothiazolinone compound to IDO enzyme.
Test method reference literature [Yue E W, Douty B, Wayland B, et al.Discovery of potent
competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo
pharmacodynamic activity and efficacy in a mouse melanoma model[J].Journal of
Medicinal Chemistry,2009,52(23):7364-7367.]。
IDO is catalyzed the indole ring oxicracking of tryptophan, generates N'- formylkynurenine.Method as described in the literature,
20mM ascorbate, the 50mM kaliumphosphate buffer (pH6.5) of 3.5 μM of methylenum careuleum and 0.2mg/mL catalase is being added
It is middle to be measured at room temperature using 20nM IDO and 2mM L-Trp.Due to the formation of N'- formylkynurenine, pass through company
It is continuous to track the absorbance increase at 321nm to record initial reaction rate.It is right that test is divided into blank control group, sample sets and the positive
According to group；I -1~I -18 dimethyl sulphoxide solution of 10 μM and 0.1 μM concentration is added in sample sets and positive controls simultaneously；It is empty
The dimethyl sulfoxide of same volume is added in white control group.Every group of progress parallel test twice, the results are shown in Table 1.
Inhibitory activity of the 1 isothiazolinone compound of table to IDO enzyme
| Compound | 10 μM of inhibiting rates (%) | 0.1 μM of inhibiting rate (%) |
| Ⅰ-1 | Preferably | Generally |
| Ⅰ-2 | Well | Generally |
| Ⅰ-3 | Generally | Generally |
| Ⅰ-4 | Generally | Generally |
| Ⅰ-5 | Well | Generally |
| Ⅰ-6 | Preferably | Generally |
| Ⅰ-7 | Preferably | Generally |
| Ⅰ-8 | Generally | Generally |
| Ⅰ-9 | Well | Generally |
| Ⅰ-10 | Well | Generally |
| Ⅰ-11 | Preferably | Generally |
| Ⅰ-12 | Generally | Generally |
| Ⅰ-13 | Well | Generally |
| Ⅰ-14 | Well | Generally |
| Ⅰ-15 | Well | Generally |
| Ⅰ-16 | Well | Generally |
| Ⅰ-17 | Well | Generally |
| Ⅰ-18 | Well | Generally |
| Ⅰ-19 | Preferably | Generally |
Preferable: compound inhibiting rate is good between 76%~100%: compound inhibiting rate between 51%~75%,
General: compound inhibiting rate is between 0~50%.
By 1 result of table, as it can be seen that most numerical expression (I) compound has IDO enzyme under 10 μM of concentration, inhibitory activity is good,
There is certain inhibitory activity to IDO enzyme under 0.1 μM of concentration, wherein there are 4 compounds to inhibit effect preferable IDO.
In this description, the present invention is described with reference to its specific embodiment.But it is clear that can still make
Various modifications and alterations are without departing from the spirit and scope of the invention.Therefore, specification should be considered as illustrative rather than limit
Property processed.
Claims (10)
1. a kind of isothiazolinone compound, which is characterized in that the structural formula of the isothiazolinone compound is such as logical
Shown in formula (I),
Wherein, A ring is nothing or phenyl, five yuan or single six-membered rings heteroaryl, 8-12 member and ring heteroaryl；
R1For hydrogen, substituted or unsubstituted C1-6Alkyl, alkoxy, alkylthio group, halogenated alkyl, halogenated alkoxy, amino, C3-18Ring
Alkyl, Heterocyclylalkyl, substituted or unsubstituted phenyl, five yuan or single six-membered rings heteroaryl, substituted or unsubstituted 8-12 member are simultaneously
Ring heteroaryl it is one or more, for the substituent group of substituted aryl or heteroaryl be selected from halogen, amino, cyano, hydroxyl, alkane
1 to 3 kind in base, alkoxy, halogenated alkyl, halogenated alkoxy, aryl or heteroaryl；
R2For hydrogen, substituted or unsubstituted C1-6Alkyl, alkoxy, alkylthio group, halogenated alkyl, halogenated alkoxy, amino, C3-18Ring
Alkyl, Heterocyclylalkyl, substituted or unsubstituted phenyl, five yuan or single six-membered rings heteroaryl, substituted or unsubstituted 8-12 member are simultaneously
Ring heteroaryl it is one or more, for the substituent group of substituted aryl or heteroaryl be selected from halogen, amino, cyano, hydroxyl, alkane
1 to 3 kind in base, alkoxy, halogenated alkyl, halogenated alkoxy, aryl or heteroaryl；
Alternatively, R1And R2Between form that 5-8 member substituted or unsubstituted saturation, part be unsaturated, aromatic rings, for replacing 5-8 member full
With part is unsaturated, substituent group of aromatic rings is selected from halogen, amino, cyano, hydroxyl, alkyl, alkoxy, halogenated alkyl, halogenated
1 to 3 kind in alkoxy, substituted or unsubstituted aryl or heteroaryl, the substituent group for substituted aryl or heteroaryl is selected from
Halogen, amino, cyano, hydroxyl, alkyl, alkoxy, halogenated alkyl, 1 to 3 kind in halogenated alkoxy；
R3The reasonable any position of valence link on A ring, R3Selected from hydrogen, alkyl, alkoxy, alkylthio group, halogenated alkyl, halogenated
Alkoxy, amino ,-NHRa, naphthenic base, Heterocyclylalkyl, substituted or unsubstituted phenyl, five yuan or single six-membered rings heteroaryl, take
Generation or unsubstituted 8-12 member and ring heteroaryl it is one or more, for the substituent group of substituted aryl or heteroaryl be selected from halogen
Element, amino, cyano, hydroxyl, alkyl, alkoxy, halogenated alkyl, 1 to 3 kind in halogenated alkoxy；
Wherein, selected halogen is selected from F, Cl, Br, I；
RaFor-S (O)2NH2, substituted or unsubstituted phenyl, five yuan or single six-membered rings heteroaryl, substituted or unsubstituted 8-12 member
And ring heteroaryl is one or more.
L is selected from linking group C1-6Alkyl, C1-6Alkoxy, C1-6Alkylthio group, C2-6Alkenyl, C2-6Alkynyl, C1-6Amido alkyl,
C1-6Alkylamidoalkyl, C1-6Sulfonylalkyl, C1-6Alkyl sulphonyl, C1-6Sulfonamidoalkyl, C1-6Alkylsulfonamido, C1-6
Alkyl sulfide amido, C1-6Thioamides base alkyl, C1-6Alkylthioamide base, C1-6Carbonylic alkyl, C1-6Alkyl-carbonyl, C1-6Sulphur
For carbonylic alkyl, C1-6Any one in alkyl thiocarbonyl.
2. isothiazolinone compound according to claim 1, which is characterized in that the compound isothiazolinone
Class includes following compound:
3. isothiazolinone compound described in a kind of claims 1 or 2 is in the purposes of preparation IDO inhibitor drug.
4. isothiazolinone compound described in a kind of claims 1 or 2 is in the drug of the preparation treatment IDO disease mediated
Purposes.
5. purposes according to claim 4, which is characterized in that the disease that the IDO is mediated include infection, cancer or
Autoimmune disease.
6. purposes according to claim 5, which is characterized in that the cancer is osteocarcinoma, lung cancer, gastric cancer, colon cancer, film
Gland cancer, breast cancer, prostate cancer, lung cancer, the cancer of the brain, oophoroma, bladder cancer, cervix cancer, guilt ball cancer, kidney, head and neck cancer, lymph
One of cancer, leukaemia and cutaneum carcinoma are a variety of；
The infection is skin infection, alimentary infection, urogenital infections, systemic infection or by influenza, the third type
Hepatitis virus, human papilloma virus, cytomegalovirus, Epstein epstein-Barr virus, poliovirus, water disease are band-like
Grow one of man of virtue and ability's virus, Coxsackie virus and human immunodeficiency virus or a variety of caused virus infections；
The autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, system
Chorionitis, dermatomyositis, nodular vasculitis, nephrosis, endocrine related disease, hepatopathy, psoriasis and due to infect caused by oneself
One of body immune response is a variety of.
7. a kind of pharmaceutical composition, which is characterized in that the pharmaceutical composition include therapeutically effective amount active component and
Pharmaceutically acceptable auxiliary material；The active component include isothiazolinone compound of any of claims 1 or 2, its
Isomers, prodrug, stable isotope derivatives or pharmaceutically acceptable salt.
8. pharmaceutical composition according to claim 7, which is characterized in that the active component further include for cancer,
The therapeutic agent of infection or autoimmune disease.
9. pharmaceutical composition according to claim 7, which is characterized in that the dosage form of the pharmaceutical composition be capsule,
Micro-capsule, tablet, granule, pill, dispersion powders, liquid preparation, soft extract, suspending agent, syrup, gelling agent, aerosol, patch
Agent, liposome, oral solution, intravenous fluid or intramuscular injection.
10. pharmaceutical composition according to claim 7, which is characterized in that the isothiazolinone compound, its is different
The dosage of structure body, prodrug, stable isotope derivatives or pharmaceutically acceptable salt in the pharmaceutical composition is
0.05mg/kg~90mg/kg.
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| US11883499B2 (en) | 2022-02-01 | 2024-01-30 | Akos Biosciences, Inc. | Cannabinoid conjugate molecules |
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| CN113292510A (en) * | 2021-06-07 | 2021-08-24 | 中国药科大学 | Benzisothiazole compound for inhibiting hypoxia inducible factor 2 activity, preparation method and application thereof |
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| US11660348B1 (en) | 2022-02-01 | 2023-05-30 | Akos Biosciences, Inc. | Cannabinoid conjugate molecules |
| US11883499B2 (en) | 2022-02-01 | 2024-01-30 | Akos Biosciences, Inc. | Cannabinoid conjugate molecules |
| US11944686B2 (en) | 2022-02-01 | 2024-04-02 | Akos Biosciences, Inc. | Cannabinoid conjugate molecules |
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