CN109574920A - - 6 cyclopropyl pyridine class IDO1 inhibitor of 3- itrile group and application thereof - Google Patents
- 6 cyclopropyl pyridine class IDO1 inhibitor of 3- itrile group and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Abstract
The present invention relates to -6 cyclopropyl pyridine class IDO1 inhibitor of 3- itrile group and application thereof, inhibitor is that compounds of formula I or its pharmaceutically acceptable salt, n represent 1-4；R represents hydrogen, halogen, methyl, C1~C4Alkoxy, cyano, nitro, C1~C4Alkyl.- 6 cyclopropyl pyridine class IDO1 inhibitor structure of 3- itrile group of the invention is novel, activity is high, Small side effects and has good pharmacokinetic properties, can be used as antitumor candidate compound.These compounds are by being applied alone or being combined with other anti-tumor drugs, to have the function that improve existing anti-tumor drug curative effect and reduce dosage and toxicity.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of indoles amine -2,3- with nitrogen-containing benzoheterocycle structure
Dioxygenase 1 (IDO1) inhibitor and application thereof.
Background technique
Indoles amine -2,3- dioxygenase 1 (Indoleamine-2,3-dioxygenase 1, IDO1) is in immune tolerance
It plays an important role, just becomes the novel targets of tumour immunotherapy.IDO1 is (Trp) generation of essential amino acids tryptophan in human body
The crucial rate-limiting enzyme thanked is widely present in human body and respectively organizes and over-express in kinds of tumors tissue.Mistake in tumor tissues
The IDO1 of degree expression causes Trp exhaustion in tumor microenvironment, inhibits the Proliferation, Differentiation of T cell with this, to inhibit immune system
To the immune response of tumour.Research shows that combination IDO1 inhibitor, not only can be enhanced the curative effect of conventional chemotherapy, while energy
Synergistic effect is generated with radiotherapy.In addition, this illustrates use research shows that the mouse of ido1 gene knockout can healthily survive
IDO1 inhibitor will not generate the serious side effect based on mechanism.Therefore, the research and development of 1 inhibitor of Novel IDO for
The treatment of tumour has great importance.
The first step of tryptophan degradation is that tryptophan is oxidized to N- formoxyl-L- kynurenin, it is by IDO and color ammonia
Acid -2,3- dioxygenase (tryptophan 2,3-dioxygenase, TDO) both heme dependent form dioxygenases
What one such mediation generated.In both dioxygenases, IDO is considered as the inspection for adjusting the oxidation reaction and occurring
Point, there is the performance with effect is the main reason for human body generates immunosupress power.IDO is further divided into IDO1 and IDO2.
IDO1 is in low expression level in vivo under normal circumstances, when interferon (IFN-α, IFN-β and IFN-γ), interleukin (IL-1 and
IL-2), when the cytokine profiles such as tumor necrosis factor (TNF) induction IDO1 level increases, tryptophan will be extensively metabolized, from
And inhibiting human body to the immune response of the pathogen such as parasitics, viral, bacillary, fungoid, human body will exempt from morbid state
Epidemic disease holddown.
The high expression of IDO1 reduces the concentration of tryptophan in cell micro-environment in most of tumour cells, so that color ammonia
The T cell synthesis that acid relies on was stagnated in the G1 phase, and T cell proliferation is suppressed, to inhibit the immune system of human body to tumour
The lethal effect of tissue.Meanwhile having cytotoxic tryptophan metabolite and can generate direct dissolution to T cell and making
With.Therefore, IDO1 is exempted in the occurrence and development with tumour in tumour immunity and is played an important role.
In some chronic diseases such as acquired immunodeficiency syndrome (AIDS), multiple types depression, Alzheimer
In disease etc., IDO1 is also considered as one of the reason of promoting progression of the disease.High-caliber interferon-induced IDO1 high expression.Dry
Under the continuous activation for disturbing element, IDO1 reduces the availability of free serum tryptophan, to reduce the generation of serotonin.Add
The Kynurenine metabolism object with neural activity accumulation, a variety of neurological conditions and mental handicape generation one touching is
Hair.
Since IDO1 has been demonstrated closely related with a variety of disease incidence mechanism, IDO1 inhibitor can be used for treating
IDO1 mediate tryptophan metabolic pathway pathological characteristics disease, these diseases include and be not limited only to malignant tumour, from
Body immunity disease, alzheimer's disease and schizophrenia.IDO1 inhibitor has wide development prospect as drug, so
And there is not suitable IDO1 inhibitor to list as drug so far, therefore find new and effective IDO1 inhibitor with weight
The theory significance and application value wanted.
Summary of the invention
The invention discloses a kind of compounds of nitrogen-containing benzoheterocycle structure, are -6 cyclopropyl pyridine class IDO1 of 3- itrile group
Inhibitor.Compounds of formula I, structural formula are as follows:
N represents 1-4；
R represents hydrogen, halogen, methyl, C1~C4Alkoxy, cyano, nitro, C1~C4Alkyl.
Pharmaceutically acceptable salt refers to compounds of formula I and the acid-addition salts that pharmaceutically acceptable acid is formed, institute
State acid include: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid,
Acetic acid, maleic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or ferulic acid.
Currently preferred part of compounds such as the following table 1:
The R of 1 preferred compound of table, n selection
The present invention also includes hydrate, stereoisomer, solvate and the pharmaceutically acceptable salt of compound of Formula I
Deng.
Preferably, n represents 1.R represents halogen.
A kind of pharmaceutical composition, wherein containing compound above-mentioned or its pharmaceutically acceptable salt and pharmaceutically acceptable
Carrier.Compound of the present invention can add pharmaceutically acceptable carrier and common pharmaceutical formulation is made, as tablet,
Fragrance, sweetener, liquid or solid filler or diluent etc. can be added in capsule, pulvis, syrup, liquor, suspending agent, injection
Common medicinal supplementary material.
The present invention also provides aforesaid compound or its pharmaceutically acceptable salts or pharmaceutical composition above-mentioned in preparation Yin
Application in 1 inhibitor of diindyl amine 2,3- dioxygenase.Especially, it is used to prepare what treatment indoles amine -2,3- dioxygenase mediated
The purposes of the drug of the disease of tryptophan metabolic pathway.The disease for the tryptophan metabolic pathway that indoles amine -2,3- dioxygenase mediates
Disease is malignant tumour, autoimmune disease, alzheimer's disease or schizophrenia.
The administration mode of compound of the present invention clinically can be using modes such as oral, injections.
Generally, the compound of the present invention is for when treating, people to be 1mg~1000mg/ days with dosage range.It can also basis
The difference and disease severity of dosage form, dosage exceed the range.
Compared with the existing technology, -6 cyclopropyl pyridine class IDO1 inhibitor structure of 3- itrile group of the invention is novel, activity is high,
Small side effects and have good pharmacokinetic properties, can be used as antitumor candidate compound.These compounds by being applied alone or
It is combined with other anti-tumor drugs, to have the function that improve existing anti-tumor drug curative effect and reduce dosage and toxicity.
Specific embodiment
Below by way of specific embodiment, the invention will be further described.
The preparation of intermediate compound I -2
By the chloro- nicotinonitrile of 2- (3.0g, 21.7mmol, 1eq), ethylene-acetic acid (9.3g, 108.3mmol, 5eq) and
Silver nitrate (1.1g, 6.5mmol, 0.3eq) is dissolved in 10% dilute sulfuric acid of 30mL, stirs 30min at room temperature, is slowly added dropwise
Enter the aqueous solution of ammonium persulfate (9.9g, 43.4mmol, 2eq), overnight, TLC detects fully reacting for reaction at room temperature.Post-processing:
PH to 8-9 is adjusted with ammonium hydroxide, is filtered, filtrate is extracted with ethyl acetate 3 times, and organic phase with saturated common salt water washing 1 time, steam by decompression
Except ethyl acetate obtains I-2 (3.5g, yield 90%).
The preparation of intermediate compound I -3
Thioglycolic acid (1.1g, 12mmol, 1.2eq) is dissolved in DMSO, stirs 10min at room temperature, slowly in batches
K is added2CO330min is stirred in (6.9g, 50mmol, 5eq) continuation at room temperature, is instilled dropwise II-1 (1.8g, 10mmol, 1eq)
It is to slowly warm up to 60 DEG C after DMSO dilution, reacts 4h, TLC detects fully reacting.Post-processing: isometric water is added in reaction solution
In, with salt acid for adjusting pH value to 1-2, there are a large amount of grease to be precipitated, be extracted with ethyl acetate water phase 3 times, washes organic phase 2 times,
It removes ethyl acetate under reduced pressure and obtains -3 crude product of intermediate compound I, grease column layer obtains I-3 (2.0g, yield 85%).
Embodiment 1
The preparation of 2- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio)-phenyl acetanilide,Phenacetylaniline (1)
By II-2 (0.46g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g,
0.6mmol, 0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, be added aniline (0.20g, 2.2mmol, 1.1eq)
Reaction solution color is deepened afterwards, and overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered,
Filter cake column chromatographs to obtain crude product, and crude product recrystallizes to obtain 1 (140mg, yield 57%) with petroleum ether-ethyl acetate system.m.p.223-
225℃.HRMS m/z[M+H]+calculated for C17H15N3OS:310.1009,found:310.1019.1H NMR
(300MHz,DMSO-d6) δ: 9.31 (s, 1H ,-NH-), 8.32 (d, J=8.4Hz, 1H ,-ArH), 7.67 (d, J=8.0Hz,
2H,-ArH),7.36-7.29(m,5H,-ArH,-S-CH2- C=O-), 7.07 (t, J=7.2Hz, 1H ,-ArH), 2.25-2.19
(m,1H,-CH(CH2)2-),1.07-1.01(m,4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:164.22,
163.96,158.83,147.03,138.96,130.63,128.33,123.65,123.29,121.11,117.61,95.32,
17.19,10.68ppm.
Embodiment 2
The preparation of compound 2
The preparation of 2- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio)-N- (4- fluorophenyl) acetamide
By I-3 (0.46g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, aniline (0.24g, 2.2mmol, 1.1eq) reaction solution afterwards is added
Color burn, overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered, filter cake column layer
Crude product is analysed to obtain, crude product recrystallizes to obtain 2 (160mg, yields 61%) with petroleum ether-ethyl acetate system.m.p.198-200℃
.HRMS m/z[M+H]+calculated for C17H14FN3OS:328.0914,found:328.0926.1H NMR
(300MHz,DMSO-d6) δ: 9.42 (s, 1H ,-NH-), 8.33 (d, J=8.4Hz, 1H ,-ArH), 7.69 (dd, J=7.9,
5.1Hz,2H,-ArH),7.36(m,3H,-ArH,-S-CH2- C=O-), 7.16 (t, J=8.9Hz, 2H ,-ArH), 2.28-
2.19(m,1H,-CH(CH2)2-),1.07-1.02(m,4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:
(164.28,163.93,158.82,158.17 d, Ar-F, J=238.3Hz), 147.14,135.24 (d, J=2.8Hz),
(130.66,123.61,122.99 d, J=7.8Hz), 117.65,114.90 (d, J=22.0Hz), 94.93,17.19,
10.75ppm.
Embodiment 3
The preparation of compound 3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio)-N- Phenylpropionamide (3)
By compound I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g,
0.6mmol, 0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, be added aniline (0.20g, 2.2mmol, 1.1eq)
Reaction solution color is deepened afterwards, and overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered,
Filter cake column chromatographs to obtain crude product, and crude product recrystallizes to obtain 3 (160mg, yields 50%) with petroleum ether-ethyl acetate system.m.p.154-
156℃.HRMS m/z[M+H]+calculated for C18H17N3OS:324.1165,found:324.1175.1H NMR
(300MHz,DMSO-d6) δ: 9.94 (s, 1H ,-NH-), 8.01 (d, J=8.0Hz, 1H ,-ArH), 7.58 (d, J=7.4Hz,
2H ,-ArH), 7.32-7.25 (m, 3H ,-ArH), 7.03 (t, J=7.2Hz ,-ArH), 3.44 (t, J=6.8Hz, 2H ,-S-
CH2), 2.75 (t, J=6.8Hz, 2H ,-CH2- C=O-), 2.26-2.17 (m, 1H ,-CH (CH2)2-),1.13-1.09(m,
4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:169.10,167.03,160.67,141.10,138.99,
128.67,123.13,119.02,117.56,116.00,102.55,35.94,24.94,17.38,11.49ppm.
Embodiment 4
Compound 3- ((3- cyano -4,6- Bicyclopropyl pyridine -2- base) is thio)-N- (4- fluorophenyl) propionamide (LWTW-
And the preparation of 3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio)-N- (4- fluorophenyl) propionamide (4) 207)
By II-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g,
0.6mmol, 0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, be added 4- fluoroaniline (0.24g, 2.2mmol,
1.1eq) reaction solution color is deepened afterwards, and overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water
In, it filters, filter cake column chromatographs to obtain crude product, and crude product recrystallizes to obtain 4 (180mg, yields 66%) with petroleum ether-ethyl acetate system.
m.p.140-142℃.HRMS m/z[M+H]+calculated for C18H16FN3OS:342.1071,found:
342.1064.1H NMR(300MHz,DMSO-d6) δ: 10.05 (s, 1H ,-NH-), 8.02 (d, J=8.0Hz, 1H ,-ArH),
7.62 (dd, J=9.0,5.1Hz, 2H ,-ArH), 7.26 (d, J=8.0Hz, 1H ,-ArH), 7.15 (t, J=8.9Hz, 2H ,-
), ArH 3.46 (t, J=6.8Hz, 2H ,-S-CH2), 2.76 (t, J=6.8Hz, 2H ,-CH2- C=O-), 2.26-2.18 (m,
1H,-CH(CH2)2-),1.15-1.10(m,4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:169.00,
166.99,160.64,157.87 (d, Ar-F, J=238.1Hz), 141.04,135.39 (d, J=2.4Hz), 120.72 (d, J
=7.7Hz), 117.53,115.99,115.20 (d, J=22.1Hz), 102.55,35.85,24.92,17.38,11.50ppm.
Embodiment 5
The preparation of compound N-(4- chlorphenyl) -3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio) propionamide (5)
By I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, it is anti-afterwards that 4- chloroaniline (0.28g, 2.2mmol, 1.1eq) is added
Liquid color burn is answered, overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered, filter cake
Column chromatographs to obtain crude product, and crude product recrystallizes to obtain 5 (220mg, yields 62%) with petroleum ether-ethyl acetate system.m.p.155-157
℃.HRMS m/z[M+H]+calculated for C18H16ClN3OS:358.0775,found:358.0783.1H NMR
(300MHz,DMSO-d6) δ: 10.09 (s, 1H ,-NH-), 8.02 (d, J=7.9Hz, 1H ,-ArH), 7.61 (d, J=8.9Hz,
2H ,-ArH), 7.35 (d, J=8.8Hz, 2H ,-ArH), 7.26 (d, J=8.0Hz, 1H ,-ArH), 3.44 (t, J=6.8Hz,
2H,-S-CH2), 2.75 (t, J=6.8Hz, 2H ,-CH2- C=O-), 2.25-2.17 (m, 1H ,-CH (CH2)2-),1.11-
1.08(m,4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:169.30,167.04,160.60,141.11,
137.92,128.60,126.66,120.53,117.59,116.00,102.55,35.96,24.83,17.37,11.51ppm.
Embodiment 6
The preparation of compound N-(4- bromophenyl) -3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio) propionamide (6)
By I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, it is anti-afterwards that 4- bromaniline (0.38g, 2.2mmol, 1.1eq) is added
Liquid color burn is answered, overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered, filter cake
Column chromatographs to obtain crude product, and crude product recrystallizes to obtain 6 (160mg, yields 40%) with petroleum ether-ethyl acetate system.m.p.164-166
℃.HRMS m/z[M+H]+calculated for C18H16BrN3OS:402.0270,found:402.0272.1H NMR
(300MHz,DMSO-d6) δ: 10.12 (s, 1H ,-NH-), 8.02 (d, J=8.0Hz, 1H ,-ArH), 7.57 (d, J=9.0Hz,
2H ,-ArH), 7.48 (d, J=9.0Hz, 2H ,-ArH), 7.27 (d, J=8.0Hz, 1H ,-ArH), 3.44 (t, J=6.7Hz,
2H,2H,-S-CH2), 2.76 (t, J=6.7Hz, 2H ,-CH2- C=O-), 2.26-2.17 (m, 1H ,-CH (CH2)2-),1.11-
1.09(m,4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:169.32,167.03,160.60,141.11,
138.33,131.50,120.89,117.59,116.00,114.66,102.53,35.97,24.81,17.37,11.53ppm.
Embodiment 7
The preparation of compound 3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio)-N- (4- tolyl) propionamide (7)
By I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, after 4- methylaniline (0.24g, 2.2mmol, 1.1eq) is added
Reaction solution color is deepened, and overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered, filter
Cake column chromatographs to obtain crude product, and crude product recrystallizes to obtain 7 (180mg, yields 53%) with petroleum ether-ethyl acetate system.m.p.156-158
℃.HRMS m/z[M+H]+calculated for C19H19N3OS:338.1322,found:338.1319.1H NMR
(300MHz,DMSO-d6) δ: 9.88 (s, 1H ,-NH-), 8.02 (d, J=8.0Hz, 1H ,-ArH), 7.46 (d, J=8.1Hz,
2H ,-ArH), 7.27 (d, J=8.0Hz, 1H ,-ArH), 7.10 (d, J=8.1Hz, 2H ,-ArH), 3.43 (t, J=6.8Hz,
2H,-S-CH2), 2.72 (t, J=6.8Hz, 2H ,-CH2- C=O-), 2.24-2.17 (m, 4H ,-CH3,-CH(CH2)2-),
1.11-1.09(m,4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:168.84,167.03,160.68,
141.11,136.50,131.98,129.05,118.98,117.58,116.02,102.50,35.84,24.95,20.39,
17.37,11.53ppm.
Embodiment 8
Compound 3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio)-N- (4- methoxyphenyl) propionamide (8)
Preparation by I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, be added 4- aminoanisole (0.28g, 2.2mmol, 1.1eq)
Reaction solution color is deepened afterwards, and overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered,
Filter cake column chromatographs to obtain crude product, and crude product recrystallizes to obtain 8 (180mg, yields 51%) with petroleum ether-ethyl acetate system.m.p.155-
157℃.HRMS m/z[M+H]+calculated for C19H19N3O2S:354.1271,found:354.1266.1H NMR
(300MHz,DMSO-d6) δ: 9.83 (s, 1H ,-NH-), 8.02 (d, J=7.9Hz, 1H ,-ArH), 7.49 (d, J=8.5Hz,
2H ,-ArH), 7.27 (d, J=7.9Hz, 1H ,-ArH), 6.87 (d, J=8.5Hz, 2H ,-ArH), 3.71 (s, 3H ,-O-CH3),
3.43 (t, J=6.8Hz, 2H ,-S-CH2), 2.70 (t, J=6.9Hz, 2H ,-CH2- C=O-), 2.22-2.20 (m, 1H ,-CH
(CH2)2-),1.12-1.09(m,4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:168.54,167.03,
160.69,155.07,141.11,132.18,120.51,117.57,116.03,113.78,102.51,55.09,35.75,
25.02,17.37,11.52ppm.
Embodiment 9
Compound N-([1,1'- xenyl] -4- base) -3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio) propionamide
(9) preparation
By I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, after 4- aminobphenyl (0.38g, 2.2mmol, 1.1eq) is added
Reaction solution color is deepened, and overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered, filter
Cake column chromatographs to obtain crude product, and crude product recrystallizes to obtain 9 (150mg, yields 38%) with petroleum ether-ethyl acetate system.m.p.200-202
℃.HRMS m/z[M+H]+calculated for C24H21N3OS:400.1478,found:400.1477.1H NMR
(300MHz,DMSO-d6) δ: 10.08 (s, 1H ,-NH-), 8.03 (d, J=7.9Hz, 1H ,-ArH), 7.70-7.61 (m, 6H ,-
), ArH 7.44 (t, J=7.5Hz, 2H ,-ArH), 7.35-7.26 (m, 2H ,-ArH), 3.46 (t, J=7.0Hz, 2H ,-S-
CH2), 2.78 (t, J=6.8Hz, 2H ,-CH2- C=O-), 2.27-2.18 (m, 1H ,-CH (CH2)2-),1.14-1.10(m,
4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:169.19,167.05,160.65,141.13,139.65,
138.47,134.78,128.85,126.89,126.19,119.35,117.60,116.02,102.53,35.98,24.93,
17.38,11.54ppm.
Embodiment 10
The preparation of compound 3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio)-N- (3- fluorophenyl) propionamide (10)
By I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, it is anti-afterwards that 3- fluoroaniline (0.24g, 2.2mmol, 1.1eq) is added
Liquid color burn is answered, overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered, filter cake
Column chromatographs to obtain crude product, and crude product recrystallizes to obtain LWTW-216 (160mg, yield 47%) with petroleum ether-ethyl acetate system.
m.p.121-123℃.HRMS m/z[M+H]+calculated for C18H16FN3OS:342.1071,found:
342.1070.1H NMR(300MHz,DMSO-d6) δ: 10.20 (s, 1H ,-NH-), 8.02 (d, J=8.0Hz, 1H ,-ArH),
7.60 (d, J=11.8Hz, 1H ,-ArH), 7.38-7.26 (m, 3H ,-ArH), 6.87 (t, J=8.7Hz, 1H ,-ArH), 3.44
(t, J=6.8Hz, 2H ,-S-CH2), 2.77 (t, J=6.8Hz, 2H ,-CH2- C=O-), 2.26-2.18 (m, 1H ,-CH
(CH2)2-),1.12-1.09(m,4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:169.55,167.04,
162.08 (d, Ar-F, J=239.7Hz), 160.58,141.12,140.67 (d, J=11.0Hz), 130.34 (d, J=
9.4Hz), 117.60,116.00,114.66 (d, J=2.2Hz), 109.58 (d, J=21.0Hz), 105.74 (d, J=
26.1Hz),102.53,35.99,24.76,17.37,11.53ppm.
Embodiment 11
The preparation of compound N-(3- chlorphenyl) -3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio) propionamide (11)
By I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, it is anti-afterwards that 3- chloroaniline (0.28g, 2.2mmol, 1.1eq) is added
Liquid color burn is answered, overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered, filter cake
Column chromatographs to obtain crude product, and crude product recrystallizes to obtain LWTW-217 (170mg, yield 48%) with petroleum ether-ethyl acetate system.
m.p.142-144℃.HRMS m/z[M+H]+calculated for C18H16ClN3OS:358.0775,found:
358.0769.1H NMR(300MHz,DMSO-d6) δ: 10.19 (s, 1H ,-NH-), 8.03 (d, J=8.0Hz, 1H ,-ArH),
7.82 (s, 1H ,-ArH), 7.42 (d, J=8.7Hz, 1H ,-ArH), 7.36-7.26 (m, 2H ,-ArH), 7.11 (d, J=
8.2Hz, 1H), 3.44 (t, J=6.8Hz, 2H ,-S-CH2), 2.76 (t, J=6.8Hz, 2H ,-CH2- C=O-), 2.26-2.18
(m,1H,-CH(CH2)2-),1.12-1.09(m,4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:169.57,
167.04,160.57,141.12,140.38,133.02,130.42,122.85,118.43,117.61,117.31,116.00,
102.54,35.99,24.78,17.37,11.52ppm.
Embodiment 12
The preparation of compound N-(3- bromophenyl) -3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio) propionamide (12)
By I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, it is anti-afterwards that 3- bromaniline (0.38g, 2.2mmol, 1.1eq) is added
Liquid color burn is answered, overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered, filter cake
Column chromatographs to obtain crude product, and crude product recrystallizes to obtain 12 (150mg, yields 37%) with petroleum ether-ethyl acetate system.m.p.140-142
℃.HRMS m/z[M+H]+calculated for C18H16BrN3OS:402.0270,found:402.0262.1H NMR
(300MHz,DMSO-d6) δ: 10.14 (s, 1H ,-NH-), 8.02 (d, J=8.0Hz, 1H ,-ArH), 7.95 (s, 1H ,-ArH),
7.46 (d, J=7.5Hz, 1H ,-ArH), 7.30-7.22 (m, 3H ,-ArH), 3.44 (t, J=6.8Hz, 2H ,-S-CH2-),
2.76 (t, J=6.9Hz, 2H ,-CH2- C=O-), 2.26-2.18 (m, 1H ,-CH (CH2)2-),1.12-1.09(m,4H,-CH2-
CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:169.55,167.04,160.56,141.13,140.51,130.73,
125.75,121.52,121.27,117.69,117.62,116.00,102.54,35.98,24.78,17.37,11.53ppm.
Embodiment 13
The preparation of compound 3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio)-N- (3- tolyl) propionamide (13)
By I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, after 3- methylaniline (0.24g, 2.2mmol, 1.1eq) is added
Reaction solution color is deepened, and overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered, filter
Cake column chromatographs to obtain crude product, and crude product recrystallizes to obtain 13 (170mg, yields 50%) with petroleum ether-ethyl acetate system.m.p.143-
145℃.HRMS m/z[M+H]+calculated for C19H19N3OS:338.1322,found:338.1321.1H NMR
(300MHz,DMSO-d6) δ: 9.90 (s, 1H ,-NH-), 8.03 (d, J=8.0Hz, 1H ,-ArH), 7.44 (s, 1H ,-ArH),
7.35 (d, J=8.1Hz, 1H ,-ArH), 7.27 (d, J=8.0Hz, 1H ,-ArH), 7.17 (t, J=7.8Hz, 1H ,-ArH),
6.86 (d, J=7.5Hz, 1H ,-ArH), 3.43 (t, J=6.8Hz, 2H ,-S-CH2), 2.73 (t, J=6.7Hz, 2H ,-CH2-C
=O-), 2.27-2.18 (m, 4H ,-CH3,-CH(CH2)2-),1.13-1.09(m,4H,-CH2-CH2-)ppm.13C NMR
(75MHz,DMSO-d6)δ:169.03,167.03,160.67,141.11,138.92,137.83,128.51,123.82,
119.52,117.58,116.17,116.02,102.51,35.90,24.96,21.16,17.37,11.53ppm.
Embodiment 14
Compound 3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio)-N- (3- methoxyphenyl) propionamide (14)
Preparation by I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, be added 3- aminoanisole (0.28g, 2.2mmol, 1.1eq)
Reaction solution color is deepened afterwards, and overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered,
Filter cake column chromatographs to obtain crude product, and crude product recrystallizes to obtain LWTW-220 (210mg, yield 59%) with petroleum ether-ethyl acetate system.
m.p.114-116℃.HRMS m/z[M+H]+calculated for C19H19N3O2S:354.1271,found:
354.1265.1H NMR(300MHz,DMSO-d6) δ: 9.96 (s, 1H ,-NH-), 8.01 (d, J=8.0Hz, 1H ,-ArH),
7.29-7.09 (m, 4H ,-ArH), 6.62 (d, J=8.1Hz, 1H ,-ArH), 3.72 (s, 3H ,-O-CH3), 3.43 (t, J=
7.0Hz,2H,-S-CH2), 2.74 (t, J=6.9Hz, 2H ,-CH2- C=O-), 2.26-2.17 (m, 1H ,-CH (CH2)2-),
1.12-1.10(m,4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:169.17,167.03,160.66,
159.46,141.11,140.16,129.47,117.58,116.01,111.25,108.59,104.75,102.52,54.90,
35.96,24.88,17.37,11.52ppm.
Embodiment 15
The preparation of compound 3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio)-N- (2- tolyl) propionamide (15)
By I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, after 2-aminotoluene (0.24g, 2.2mmol, 1.1eq) is added
Reaction solution color is deepened, and overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered, filter
Cake column chromatographs to obtain crude product, and crude product recrystallizes to obtain LWTW-221 (160mg, yield 47%) with petroleum ether-ethyl acetate system.
m.p.147-149℃.HRMS m/z[M+H]+calculated for C19H19N3OS:338.1322,found:
338.1315.1H NMR(300MHz,DMSO-d6) δ: 9.37 (s, 1H ,-NH-), 8.04 (d, J=8.0Hz, 1H ,-ArH), 7.36
(d, J=7.7Hz, 1H ,-ArH), 7.28 (d, J=8.0Hz, 1H ,-ArH), 7.22-7.06 (m, 3H ,-ArH), 3.44 (t, J=
7.0Hz,2H,-S-CH2), 2.76 (t, J=7.0Hz, 2H ,-CH2- C=O-), 2.27-2.19 (m, 4H ,-CH (CH2)2-,-
CH3),1.14-1.10(m,4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:169.08,167.03,160.68,
141.11,136.13,131.78,130.24,125.87,125.19,125.12,117.63,116.02,102.55,35.32,
25.19,17.83,17.35,11.53ppm.
Embodiment 16
Compound 3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio)-N- (2- methoxyphenyl) propionamide (16)
Preparation by I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, be added 2- aminoanisole (0.28g, 2.2mmol, 1.1eq)
Reaction solution color is deepened afterwards, and overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered,
Filter cake column chromatographs to obtain crude product, and crude product recrystallizes to obtain 16 (200mg, yields 57%) with petroleum ether-ethyl acetate system.m.p.108-
110℃.HRMS m/z[M+H]+calculated for C19H19N3O2S:354.1271,found:354.1262.1H NMR
(300MHz,DMSO-d6) δ: 9.20 (s, 1H ,-NH-), 8.01 (d, J=8.0Hz, 1H ,-ArH), 7.95 (d, J=8.1Hz,
1H ,-ArH), 7.26 (d, J=8.0Hz, 1H ,-ArH), 7.09-7.01 (m, 2H ,-ArH), 6.90 (t, J=7.6Hz, 1H ,-
ArH),3.81(s,3H,-O-CH3), 3.43 (t, J=7.0Hz, 2H ,-S-CH2), 2.81 (t, J=6.9Hz, 2H ,-CH2- C=
O-),2.23-2.17(m,1H,-CH(CH2)2-),1.14-1.08(m,4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-
d6)δ:169.35,167.02,160.74,149.52,141.07,127.10,124.33,122.02,120.13,117.56,
116.04,111.09,102.46,55.54,35.66,25.02,17.36,11.54ppm.
Embodiment 17
Compound N-(the chloro- 4- fluorophenyl of 3-) -3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio) propionamide (17)
Preparation
By I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 2.6eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, be added the chloro- 4- fluoroaniline of 3- (0.32g, 2.2mmol,
1.1eq) reaction solution color is deepened afterwards, and overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water
In, it filters, filter cake column chromatographs to obtain crude product, and crude product recrystallizes to obtain LWTW-223 (180g, yield with petroleum ether-ethyl acetate system
48%).m.p.152-154℃.HRMS m/z[M+H]+calculated for C18H15ClFN3OS:376.0681,found:
376.0688.1H NMR(300MHz,DMSO-d6) δ: 10.21 (s, 1H ,-NH-), 8.03 (d, J=8.0Hz, 1H ,-ArH),
7.92 (d, J=7.0Hz, 1H ,-ArH), 7.47-7.34 (m, 2H ,-ArH), 7.27 (d, J=8.0Hz, 1H ,-ArH), 3.44
(t, J=6.8Hz, 2H ,-S-CH2), 2.75 (t, J=6.7Hz, 2H ,-CH2- C=O-), 2.26-2.17 (m, 1H ,-CH
(CH2)2-),1.12-1.09(m,4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:169.43,167.04,
160.54,152.95 (d, Ar-F, J=240.8Hz), 141.13,136.19 (d, J=2.8Hz), 120.31,119.19 (d, J
=6.7Hz), 119.05 (d, J=17.7Hz), 117.62,116.93 (d, J=21.6Hz), 116.00,102.55,35.91,
24.77,17.36,11.52ppm.
Embodiment 18
Compound N-(the bromo- 4- fluorophenyl of 3-) -3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio) propionamide (18)
Preparation
By I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, be added the bromo- 4- fluoroaniline of 3- (0.42g, 2.2mmol,
1.1eq) reaction solution color is deepened afterwards, and overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water
In, it filters, filter cake column chromatographs to obtain crude product, and crude product recrystallizes to obtain LWTW-224 (200mg, yield with petroleum ether-ethyl acetate system
48%).m.p.166-168℃.HRMS m/z[M+H]+calculated for C18H15BrFN3OS:420.0176,found:
420.0174.1H NMR(300MHz,DMSO-d6)δ:10.19(s,1H,-NH-),8.04-8.01(m,2H,-ArH),7.49-
7.47 (m, 1H ,-ArH), 7.36-7.26 (m, 2H ,-ArH), 3.44 (t, J=6.7Hz, 2H ,-S-CH2), 2.75 (t, J=
6.7Hz,2H,-CH2- C=O-), 2.26-2.17 (m, 1H ,-CH (CH2)2-),1.12-1.09(m,4H,-CH2-CH2-)
ppm.13C NMR(75MHz,DMSO-d6) δ: 169.40,167.04,160.55,154.03 (d, Ar-F, J=239.2Hz),
141.12,136.43 (d, J=2.8Hz), 123.09,119.86 (d, J=2.8Hz), 117.62,116.70 (d, J=
22.9Hz), 116.00,107.52 (d, J=21.7Hz), 102.55,35.91,24.79,17.37,11.52ppm.
Embodiment 19
Compound 3- ((3- cyano -6- cyclopropyl pyridine -2- base) is thio)-N- (3,5- dibromo phenyl) propionamide (19)
Preparation by I-3 (0.50g, 2mmol, 1eq), EDCI (0.50g, 2.6mmol, 1.3eq) and HOBT (0.08g, 0.6mmol,
0.3eq) be dissolved in DMF, no more than 10 DEG C at react 30min, be added 3,5- dibromo aniline (0.56g, 2.2mmol, 1.1eq)
Reaction solution color is deepened afterwards, and overnight, TLC detects fully reacting for reaction at room temperature.Post-processing: reaction solution is poured into water, and is filtered,
Filter cake column chromatographs to obtain crude product, and crude product recrystallizes to obtain LWTW-225 (150mg, yield 31%) with petroleum ether-ethyl acetate system.
m.p.175-177℃.HRMS m/z[M+H]+calculated for C18H15Br2N3OS:479.9375,found:
479.9375.1H NMR(300MHz,DMSO-d6) δ: 10.28 (s, 1H ,-NH-), 8.02 (d, J=8.0Hz, 1H ,-ArH),
7.82 (s, 2H ,-ArH), 7.50 (s, 1H ,-ArH), 7.27 (d, J=7.9Hz, 1H ,-ArH), 3.43 (t, J=6.7Hz, 2H ,-
S-CH2), 2.77 (t, J=6.7Hz, 2H ,-CH2- C=O-), 2.24-2.19 (m, 1H ,-CH (CH2)2-),1.11-1.10(m,
4H,-CH2-CH2-)ppm.13C NMR(75MHz,DMSO-d6)δ:169.90,167.03,160.49,141.51,141.12,
127.68,122.35,120.22,117.63,115.99,102.56,36.09,24.66,17.37,11.53ppm.
It is the pharmacology test and result of part of compounds of the present invention below:
(1) measurement experiment of IDO1 inhibitory activity
There is the human indoleamine 2,3-dioxygenase (IDO) of N- terminal His tag in expression in escherichia coli, extract and pure
Change IDO1.The oxidation scission of the pyrrole ring of IDO1 catalysis tryptophan indole ring obtains N '-formoxyl kynurenin.On 96 orifice plates
By 50mM kaliumphosphate buffer (pH 6.5), 40mM vitamin C, 400 μ g/mL catalases, 20 μM of methylenum careuleum and IDO1 enzyme
Mixing.Substrate L-Trp and sample to be tested are added into above-mentioned mixed liquor.Reaction carries out 60min at 37 DEG C, is added 30%
(w/v) trichloroacetic acid makes reaction terminating.96 orifice plates heat 15min at 65 DEG C, are allowed to complete to urinate from formylkynurenine to dog
The conversion of propylhomoserin, then 6000rpm rotates 5min.Every hole is taken out 100 μ L supernatants and is transferred in 96 new orifice plates, is added 2%
(w/v) acetic acid solution of p- (dimethylamino) benzaldehyde, kynurenin, which reacts generation yellow color, microplate reader can be used to exist
480nm observation, acquired results utilize IC50(nM) software for calculation calculates.Using the above method, to the IDO1 inhibitory activity of compound
It is measured, IC50(nM) as follows, and use be currently in the IDO inhibitor INCB024360 of III clinical trial phase as pair
According to.Compound numbers respectively refer to the product of embodiment 1-19 preparation in table 1.
Inhibitory activity IC of the part of compounds of the present invention of table 1 to IDO50(nM)
| Compound numbers | IC50(nM) | Compound numbers | IC50(nM) |
| 1 | 146 | 11 | 427 |
| 2 | 726 | 12 | 581 |
| 3 | 438 | 13 | 730 |
| 4 | 381 | 14 | 973 |
| 5 | 592 | 15 | 841 |
| 6 | 393 | 16 | 580 |
| 7 | 721 | 17 | 507 |
| 8 | 792 | 18 | 428 |
| 9 | 861 | 19 | 243 |
| 10 | 190 | INCB024360 | 72 |
Seen from table 1, part of compounds of the present invention has good inhibitory activity, and opposite III clinical trial phase to IDO1
IDO inhibitor INCB024360, the inhibitory activity of the compounds of this invention is obviously more preferable.
(2) measurement experiment of the IDO inhibitory activity based on Hela cell
At 37 DEG C, cell is stored in, 5%CO is provided2The wet incubator of control in.It is measured as follows: by 5000/ hole
Density, by Hela cell inoculation in 96 well culture plates, and overnight incubation.Second day, by IFN-γ (final concentration 50ng/mL) and
The serial dilutions (200 μ L culture medium of total volume) of compound add to cell.After incubating 48h, by 140 μ L supernatants/Kong Yizhi
In 96 new orifice plates.10 μ L 6.1N trichloroacetic acids are mixed into each hole, incubate the N- formoxyl dog that 30min is generated with IDO at 50 DEG C
Urinary ammonia acid is hydrolyzed to kynurenin.Then reaction mixture is centrifuged to remove sediment by 10min with 6000rpm.It will be on 100 μ L
Clear liquid/hole moves in another 96 orifice plate, mixes with 100 μ L 2% (w/v) paradime thylaminobenzaldehydes in acetic acid, in 480nm
Measure the yellow that kynurenin generates.Make standard with L- kynurenin.With 100 μ L culture mediums prepare titer (240,120,60,
30,15,7.5,3.75,1.87 μM), and they are mixed with 2% isometric (w/v) paradime thylaminobenzaldehyde.Measurement is each
Inhibition percentage under a concentration obtains IC using nonlinear regression analysis data50(μM) value, and faced with the III phase is currently in
The IDO1 inhibitor INCB024360 of bed test is as control.
IDO inhibitory activity IC of the part of compounds of the present invention of table 2 based on Hela cell50(μM)
| Compound numbers | IC50(nM) | Compound numbers | IC50(nM) |
| 1 | 130 | 11 | 147 |
| 5 | 230 | 15 | 101 |
| 10 | 59 | INCB024360 | 15 |
As can be seen from Table 2, part of compounds of the present invention has good inhibitory activity, and opposite III clinical trial phase to IDO1
IDO inhibitor INCB024360, the inhibitory activity of the compounds of this invention is obviously more preferable.
The above is only a preferred embodiment of the present invention, it should be pointed out that: for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (8)
1. compounds of formula I or its pharmaceutically acceptable salt:
N represents 1-4；
R represents hydrogen, halogen, methyl, C1~C4Alkoxy, cyano, nitro, C1~C4Alkyl.
2. the compound of claim 1 or its pharmaceutically acceptable salt, which is characterized in that n represents 1.
3. the compound of claim 1 or its pharmaceutically acceptable salt, which is characterized in that R represents halogen.
4. compound described in general formula I described in claim 1 or its pharmaceutically acceptable salt are most preferably following any structure:
。
5. a kind of pharmaceutical composition, wherein the compound containing claim 1 or its pharmaceutically acceptable salt and pharmaceutically may be used
The carrier of receiving.
6. pharmaceutical composition described in compound described in claim 1 or its pharmaceutically acceptable salt or claim 5 is being made
Application in standby 1 inhibitor of indole amine 2,3-dioxygenase.
7. it is double that any compound or its pharmaceutically acceptable salt in Claims 1-4 are used to prepare treatment indoles amine -2,3-
The purposes of the drug of the disease for the tryptophan metabolic pathway that oxygenase mediates.
8. the purposes of claim 7, which is characterized in that the disease for the tryptophan metabolic pathway that indoles amine -2,3- dioxygenase mediates
Disease is malignant tumour, autoimmune disease, alzheimer's disease or schizophrenia.
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| CN109574920B (en) | 2022-03-04 |
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