CN109438347A - A kind of cyano quinolines class IDO1 inhibitor, preparation method and application - Google Patents
A kind of cyano quinolines class IDO1 inhibitor, preparation method and application Download PDFInfo
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Abstract
The present invention relates to a kind of cyano quinolines class IDO1 inhibitor, preparation method and application, cyano quinolines class IDO1 inhibitor is compounds of formula I or its pharmaceutically acceptable salt.The preparation method is as follows: being obtained by mercaptan acid III and the chlorine atom in compound II through nucleophilic substitution reaction by the process of compound II prepare compound IV；By the process of compound IV prepare compound I, it is condensed to yield by substituted aniline V with carboxyl.The inhibitor is used to treat the immunosuppressive related disease of the mediation of indole amine 2,3-dioxygenase 1.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of derivative containing cyano quinolines, its is pharmaceutically acceptable
Salt, its synthetic method and its application in medicine.
Background technique
Immunologic test point inhibitor (Immune checkpoint inhibitors) and Chimeric antigen receptor T cell
The success of (CAR-T cell) therapy clinically shows that tumour immunotherapy has advantage efficiently, safe
(Schadendorf D.et al.J.Clin.Oncol.,2015,33:1889-1894；Yang Y.J.Clin.Invest.,
2015,125:3335-3337).However for such bio-pharmaceutical, clinically applies there are still certain defect, wrap
Include response rate it is low, cannot using oral therapies, it is expensive (Mullard A.Nat.Rev.Drug Discov., 2015,14:
739；Kreamer KM, et al.J Adv Pract Oncol, 2014,5:418-431) etc..Therefore, research and development are for immune inspection
The small-molecule drug for making an inventory for the treatment of can play supplement and potential synergistic effect to the clinical application of macromolecular bio-pharmaceutical.
Tryptophan (Trp) is a kind of essential amino acid of human body internal protein synthesis, and 95% or more Trp passes through dog urinary ammonia
Sour approach (kynurenine pathway, KP) metabolism, is finally metabolized as kynurenic acid (kynurenic acid), nicotinoyl
Amine adenine-dinucleotide (NAD) and xanthurenic acid (4,8-Er Qiangjikuilinjiasuan) (xanthurenic acid) isoreactivity metabolite, to be grown to cell
Generate a series of important physiological actions (Routy JP, Routy B, Graziani GM, et al.Int.J.Tryptophan
Res.,2016,9:67-77).Wherein, indoleamine 2,3-dioxygenase 1 (Indoleamine 2,3-dioxygenase 1,
It IDO1) is the first rate-limiting enzyme (Mellor AL, the et al.Nat Rev for regulating and controlling tryptophan catabolism KP access outside liver
Immunol,2004,4:762-774).IDO1 is a kind of monomeric protein comprising heme, by 403 amino acid residues
Composition, including two fold α-helixstructure domain, big structure domain include catalytic pocket, substrate can in catalytic pocket with IDO1
The effects of hydrophobic (Rohrig UF, et al.J.Med.Chem., 2015,58:9421) occurs.IDO1 is in vivo under normal circumstances
In low expression level, when interferon (IFN-α, IFN-β and IFN-γ), interleukin (IL-1 and IL-2), tumor necrosis factor
(TNF) etc. when cytokine profiles induction IDO1 level increases, tryptophan will be extensively metabolized, to inhibit human body to parasitism
Property, the pathogen such as viral, bacillary, fungoid immune response, human body will be in the immunosuppressive condition of morbid state
(Banzola,I.et al.Front.Immunol.,2018,9:1051).IDO1 mainly passes through two aspect mediated immunity suppressions
System: on the one hand, IDO1 exhausts local T rp, causes T cell Cycle Arrest；On the other hand, the resolution of Trp causes metabolism to produce
Object (such as kynurenin, Kyn's) builds up, and activation aryl hydrocarbon receptor (AhR) etc. further activates regulatory T-cell (Treg
) and then depression effect T cell (Munn DH, et al.J Exp Med, 1999,189:1363-1372 cell；Mezrich JD,
et al.J Immunol,2010,185:3190-3198)。
Studies have shown that IDO1 high expression in many tumours, in addition, IDO1 is again often associated with prognosis mala
(Okamoto A,et al.Clin Cancer Res,2005,11:6030-6039).In fact, inhibit IDO1 activity for
Oncotherapy has significant facilitation, and IDO1 inhibitor is clinically combined with PD-1, PD-L1 inhibitor to improve at present
Curative effect (Marin-Acevedo JA, et al.J.Hematol.Oncol., 2018,11:39).
Disclosed selectivity IDO1 inhibitor patent application includes WO2010005958, WO2015173764,
WO2016155545, WO2016073770 and WO2018184392 etc..
IDO1 inhibitor has a good application prospect as drug in pharmaceuticals industry, but not yet finds at present well
IDO1 inhibitor is as marketed drug.In order to reach better oncotherapy effect, it is intended that develop high-efficiency low-toxicity of new generation
Selective IDO1 inhibitor, show excellent effect and effect, excellent medicine generation absorbs activity.
Summary of the invention
The present invention is directed to find high structure novel, activity, Small side effects and resisting with good pharmacokinetic properties to swell
Tumor candidate compound.These compounds are by being applied alone or being combined with other anti-tumor drugs, so that it is existing antitumor to reach raising
Curative effect of medication and the effect for reducing dosage and toxicity.
The invention discloses compounds of formula I, its stereoisomer or its pharmaceutically acceptable salts.
Wherein:
R1Selected from hydrogen atom, cyano, amino, nitro, halogen, C1~C4Alkoxy, substituted or unsubstituted C1~C5Alkyl；
The C wherein replaced1~C5In alkyl, substituent group is selected from one or more of halogen, amino, nitro, hydroxyl or cyano；
R2Selected from hydrogen atom, cyano, amino, nitro, halogen, C1~C4Alkoxy, substituted or unsubstituted C1~C5Alkyl,
Substituted or unsubstituted aryl；The C wherein replaced1~C5In alkyl, substituent group is selected from halogen, amino, nitro, hydroxyl or cyano
One or more of；
N is selected from 1,2,3,4.
In a preferred embodiment of the invention, in which:
R1Selected from hydrogen atom, fluorine atom, chlorine atom, bromine atom, methoxyl group, methyl；
R2Selected from hydrogen atom, fluorine atom, chlorine atom, bromine atom, phenyl；
N represents 1,2.
The pharmaceutically acceptable salt of the compound of logical formula (I) of the present invention refers to the compound and medicine of logical formula (I)
On it is acceptable acid formed acid-addition salts, the 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:
1 preferred compound of table
Another object of the present invention is to provide the preparation methods of compound shown in logical formula (I):
Wherein: R1, R2, n is defined as above described.
By the process of compound II prepare compound IV, by the chlorine atom in mercaptan acid III and compound II through nucleophilic
Substitution reaction obtains；Acid binding agent used in nucleophilic substitution is sodium carbonate, potassium carbonate, sodium hydroxide or triethylamine, preferably carbonic acid
Potassium；Solvent for use is tetrahydrofuran, methylene chloride, n,N-Dimethylformamide, dimethyl sulfoxide, preferably dimethyl sulfoxide.
By the process of compound IV prepare compound I, dehydrating condensation is carried out with carboxyl by substituted aniline V and is obtained；It is used
Condensing agent be dicyclohexylcarbodiimide (DCC), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDCI),
N, N'- diisopropylcarbodiimide (DIC), preferably EDCI；Catalyst or activator are 4-dimethylaminopyridine (DMAP), 1- hydroxyl
Base benzotriazole (HOBT), preferably HOBT；Solvent is methylene chloride, n,N-Dimethylformamide, dimethyl sulfoxide, preferably N, N-
Dimethylformamide.
More specific method includes:
Wherein: R1, R2, n is defined as above described.
By the process of compound VI prepare compound VII, reaction reagent is phosphorus oxychloride, n,N-Dimethylformamide.
By the process of compound VII prepare compound II, reaction reagent is ammonium hydroxide, and oxidant is iodine or lead tetra-acetate or oxygen
Gas, solvent are tetrahydrofuran.
The process of compound II prepare compound IV, reactant are mercaptan acid III, and acid binding agent is sodium carbonate, potassium carbonate, hydrogen
Sodium oxide molybdena or triethylamine, solvent are tetrahydrofuran, methylene chloride, n,N-Dimethylformamide, dimethyl sulfoxide.
By the process of compound IV prepare compound I, reactant is substituted aniline V, and condensing agent DCC, EDCI, DIC are urged
Agent or activator are DMAP, HOBT, and solvent is methylene chloride, n,N-Dimethylformamide, dimethyl sulfoxide.
The pharmaceutically acceptable salt of the compound of Formula I can by with equal chemical equivalents or excess acid (inorganic acid or
Organic acid) in suitable solvent or solvent compositions react be made.The acid includes but is not limited to hydrogen chloride, hydrogen bromide, sulphur
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.The solvent includes but is not limited to methanol, ethyl alcohol, methylene chloride, acetone, ethyl acetate, toluene
Or tetrahydrofuran, or any several mixed solvents.
The present invention provides a kind of pharmaceutical compositions comprising the active component of medicine effective quantity and pharmaceutically acceptable
Auxiliary material；The active component includes one of compound of Formula I and pharmaceutically acceptable salt or a variety of.The pharmaceutical composition
In object, the auxiliary material includes pharmaceutically acceptable carrier, diluent and/or excipient.
Pharmaceutical composition can be made to various types of administration unit dosage forms according to therapeutic purposes, such as tablet, pill, powder
Agent, liquid, suspension, lotion, granule, granule, capsule and injection (solution or suspension) etc., preferred tablet, capsule, liquid
Body, suspension and injection (solution or suspension).
The modes such as oral, injection can be used in the administration mode of compound of the present invention clinically.
Generally, the compound of the present invention is for when treating, people to be 1-1000mg/ days with dosage range.It can also be according to agent
The difference and disease severity of type, dosage exceed the range.
The present invention also provides compounds shown in general formula I to prepare the application in 1 inhibitor of indole amine 2,3-dioxygenase.
The present invention also provides compounds shown in general formula I in the immune suppression for treating the mediation of indole amine 2,3-dioxygenase 1
Application in the related disease of system.
The immunosuppressive related disease that indole amine 2,3-dioxygenase 1 of the present invention mediates includes cancer, virus
Infection, neurodegenerative disease, cataract, organ-graft refection, depression or autoimmune disease.The wherein preferred lung of cancer
Cancer, melanoma, head and neck cancer, clear-cell carcinoma, bladder transitional cell carcinoma.The preferred HIV infection of virus infection.Neurodegenerative disease preferred Ah
The silent disease in Wurz sea.
Unless otherwise stated, the following term used in the specification and in the claims has meaning discussed below:
Term " alkyl " indicates the aliphatic group of the saturation of 1-20 carbon atom, including straight chain and branched group (this specification
In the digital scope mentioned, such as " 1-5 " refers to the group, is at this time alkyl, can contain 1 carbon atom, 2 carbon atoms, 3
A carbon atom etc., until including 5 carbon atoms).Alkyl can be substituted or unsubstituted.It, should when being the alkyl replaced
Substituent group is preferably one or more, and more preferable 1-3, most preferably 1 or 2 substituent group.
Term " alkoxy " expression-O-(unsubstituted alkyl) and-O-(unsubstituted naphthenic base).Representative example includes
But be not limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..
Term " halogen " indicates fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine, bromine.
Term " amino " expression-NH2Group.
Term " nitro " expression-NO2Group.
Term " hydroxyl " expression-OH group.
Term " cyano " expression-CN group.
Term " aryl " indicates the full carbon monocycle or fused polycycle group of 1 to 12 carbon atom, the π electricity with total conjugated
Subsystem.The non-limiting example of aryl has phenyl, naphthalene and anthryl.Aryl can be substituted or unsubstituted.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.
Embodiment 1
It is prepared by (VII-1) of the chloro- 3- quinoline aldehyde of step 1:2-
DMF (9.1g, 125mmol, 2.5equiv) is added in reaction flask, 10min is stirred under ice bath, is added dropwise
POCl3(30.4g, 200mmol, 4equiv) and reacting liquid temperature is controlled no more than 5 DEG C, be added dropwise under rear ice bath and continue to stir
Until reaction solution solidifies completely, antifebrin (6.8g, 50mmol, 1equiv) is added and is slowly risen after stirring 10min at room temperature
Temperature reacts 3h to 75 DEG C.Excessive POCl is removed under reduced pressure after TLC detection fully reacting3, viscous fluid, which pours into, uses NaHCO in ice water3It adjusts
PH value is saved to 5-6, filters to obtain VI-1 (6.8g, yield 71%).HRMS m/z[M+H]+calculated for C10H6ClNO:
192.0211,found:192.0213.1H NMR(300MHz,DMSO-d6): δ=10.39 (s, 1H ,-CHO), 9.01 (s, 1H ,-
), ArH 8.30 (d, J=8.2Hz, 1H ,-ArH), 8.07-7.97 (m, 2H ,-ArH), 7.77 (t, J=7.5Hz, 1H ,-ArH)
ppm。
The preparation of step 2:2- chloroquinoline -3- formonitrile HCN (II-1)
VII-1 (3.8g, 20mmol, 1equiv) is dissolved in THF, be added 25% ammonium hydroxide (6.8mL, 100mmol,
5equiv) and I2(6.0g, 24mmol, 1.2equiv) reacts 3h at 25 DEG C.Reaction solution is poured into after TLC detection fully reacting
It is saturated Na2S2O3In aqueous solution, there are a large amount of solids to be precipitated, filter to obtain V-2 (2.4g, yield 63%).HRMS m/z[M+H]+
calculated for C10H5ClN2:189.0214,found:189.0222.1H NMR(300MHz,DMSO-d6): δ=9.28
(s, 1H ,-ArH), 8.16 (d, J=8.3Hz, 1H ,-ArH), 8.10-8.02 (m, 2H ,-ArH), 7.83 (t, J=7.3Hz,
1H,–ArH)ppm。
Embodiment 2
The preparation of step 1:3- ((3- cyano quinolines -2- base) is thio) propionic acid (II-1)
Thioglycolic acid (1.1g, 12mmol, 1.2equiv) is dissolved in DMSO, stirs 10min at room temperature, is slowly divided
It criticizes and K is added2CO3(6.9g, 50mmol, 5equiv) continuation stir 30min at room temperature, dropwise instill II-1 (1.9g, 10mmol,
It is to slowly warm up to 60 DEG C after DMSO dilution 1equiv), reacts 3h.By bodies such as reaction solution additions after TLC detection fully reacting
In ponding, 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, wash organic phase 2
It is secondary, it removes ethyl acetate under reduced pressure and obtains crude product, recrystallize to obtain IV-1 (2.1g, yield 86%).HRMS m/z[M+H]+
calculated for C12H8N2O2S:245.0379,found:245.0391.1H NMR(300MHz,DMSO-d6): δ=
12.88 (s, 1H ,-COOH), 9.01 (s, 1H ,-ArH), 8.02 (d, J=8.1Hz, 1H ,-ArH), 7.95-7.87 (m, 2H ,-
), ArH 7.66 (t, J=7.1Hz, 1H ,-ArH), 4.20 (s, 2H ,-CH2 -) ppm.
The preparation of step 2:2- ((3- cyano quinolines -2- base) is thio)-phenyl acetanilide,Phenacetylaniline (CPU-Q1)
By IV-1 (0.24g, 1mmol, 1equiv), EDCI (0.25g, 1.3mmol, 1.3equiv) and HOBT (0.04g,
0.3mmol, 0.3equiv) be dissolved in DMF, no more than 10 DEG C at react 30min.Addition aniline (0.10g, 1.1mmol,
1.1equiv) reaction solution color is deepened afterwards, and reaction is stayed overnight at room temperature.Reaction solution is poured into water after TLC detection fully reacting, is taken out
Filter, filter cake column chromatograph to obtain CPU-Q1 (180mg, yield 56%).m.p.226–228℃.HRMS m/z[M+H]+calculated
for C18H13N3OS:320.0852,found:320.0850.1H NMR(300MHz,DMSO-d6): δ=10.45 (s, 1H ,-
NH -), 8.99 (s, 1H ,-ArH), 8.00 (d, J=8.2Hz, 1H ,-ArH), 7.88 (s, 2H ,-ArH), 7.62 (d, J=
8.0Hz, 3H ,-ArH), 7.31 (t, J=7.8Hz, 2H ,-ArH), 7.05 (t, J=7.3Hz, 1H ,-ArH), 4.33 (s, 2H ,-
CH2–)ppm.13C NMR(75MHz,DMSO-d6): δ=165.83,157.22,147.64,144.14,138.99,133.64,
128.88,128.76,127.35,127.05,123.75,123.38,119.13,115.65,104.41,35.08ppm。
Embodiment 3
2- (3- cyano quinolines -2- base) sulfenyl)-N- (4- fluorophenyl) acetamide (CPU-Q2) preparation
Outside with 4- fluoroaniline (0.11g, 1.1mmol, 1.1equiv) substitution aniline, method identical with compound CPU-Q1
(with embodiment 2, step 2) synthesizes compound CPU-Q2 (120mg, yield 36%).m.p.250–252℃.HRMS m/z[M+H]+
calculated for C18H12FN3OS:338.0758,found:338.1H NMR(300MHz,DMSO-d6): δ=10.51
(s, 1H ,-NH -), 9.01 (s, 1H ,-ArH), 8.01 (d, J=9.0Hz, 1H ,-ArH), 7.93-7.85 (m, 2H ,-ArH),
7.66-7.61 (m, 3H ,-ArH), 7.16 (t, J=9.0Hz, 2H ,-ArH), 4.32 (s, 2H ,-CH2–)ppm。
Embodiment 4
The preparation of 2- ((3- cyano -6- methylquinoline -2- base) sulfenyl)-N- (4- fluorophenyl) acetamide (CPU-Q3)
Antifebrin, 4- fluoroaniline is replaced to replace outside aniline with 4- exalgine, using the identical preparation of CPU-Q1
Method synthesizes compound CPU-Q3 (130mg, yield 38%).m.p.247–250℃.HRMS m/z[M+H]+calculated
for C19H14FN3OS:352.0914,found:352.0910.1H NMR(300MHz,DMSO-d6): δ=10.46 (s, 1H ,-
NH -), 8.89 (s, 1H ,-ArH), 7.77 (d, J=6.0Hz, 3H ,-ArH), 7.63-7.59 (m, 2H ,-ArH), 7.14 (t, J=
9.0Hz,2H,–ArH),4.29(s,2H,–CH2–),2.51(s,3H,–CH3)ppm。
Embodiment 5
The preparation of 2- ((3- cyano -8- methylquinoline -2- base) sulfenyl)-N- (4- fluorophenyl) acetamide (CPU-Q4)
Antifebrin, 4- fluoroaniline is replaced to replace outside aniline with 2- exalgine, using the identical preparation of CPU-Q1
Method synthesizes compound CPU-Q4 (121mg, yield 35%).m.p.243–246℃.HRMS m/z[M+H]+calculated
for C19H14FN3OS:352.4069,found:352.4064.1H NMR(300MHz,DMSO-d6): δ=10.43 (s, 1H ,-
NH -), 8.95 (s, 1H ,-ArH), 7.82 (d, J=6.0Hz, 1H ,-ArH), 7.71 (d, J=6.0Hz, 1H ,-ArH), 7.62-
7.48 (m, 3H ,-ArH), 7.14 (t, J=9.0Hz, 2H ,-ArH), 4.31 (s, 2H ,-CH2–),2.56(s,3H,–CH3)ppm.
Embodiment 6
The preparation of 2- ((3- cyano -6- fluorine quinoline -2- base) sulfenyl)-N- (4- fluorophenyl) acetamide (CPU-Q5)
Antifebrin, 4- fluoroaniline is replaced to replace outside aniline with 4- fluoroacetanilide, using the identical preparation side CPU-Q1
Method synthesizes compound CPU-Q5 (142mg, yield 40%).m.p.218–220℃.HRMS m/z[M+H]+calculated for
C18H11F2N3OS:356.0664,found:356.0662.1H NMR(300MHz,DMSO-d6): δ=10.57 (s, 1H ,-NH-),
9.09 (s, 1H ,-ArH), 8.11 (d, J=6.0Hz, 1H ,-ArH), 7.69-7.54 (m, 2H ,-ArH), 7.38-7.26 (m,
2H ,-ArH), 7.15 (t, J=9.0Hz, 2H ,-ArH), 4.35 (s, 2H ,-CH2–)ppm。
Embodiment 7
The preparation of 2- ((3- cyano -6- methoxy quinoline -2- base) sulfenyl)-N- (4- fluorophenyl) acetamide (CPU-Q6)
Antifebrin, 4- fluoroaniline is replaced to replace outside aniline with 4- p-methoxyacetanilide, using the identical system of CPU-Q1
Preparation Method synthesizes compound CPU-Q6 (126mg, yield 33%).m.p.232–235℃.HRMS m/z[M+H]+calculated
for C19H14FN3O2S:368.0864,found:368.0863.1H NMR(300MHz,DMSO-d6): δ=10.44 (s, 1H ,-
NH -), 8.85 (s, 1H ,-ArH), 7.79 (d, J=9.0Hz, 1H ,-ArH), 7.63-7.53 (m, 3H ,-ArH), 7.40 (d, J=
3.0Hz, 1H ,-ArH), 7.14 (t, J=9.0Hz, 2H ,-ArH), 4.27 (s, 2H ,-CH2–),3.88(s,3H,–CH3)ppm。
Embodiment 8
The preparation of N- (3- chlorphenyl) -2- ((3- cyano quinolines -2- base) is thio) acetamide (CPU-Q7)
Outside with 3- chloroaniline (0.14g, 1.1mmol, 1.1equiv) substitution aniline, method identical with compound CPU-Q1
(with embodiment 2, step 2) synthesizes compound CPU-Q7 (170mg, yield 48%).m.p.>250℃.HRMS m/z[M+H]+
calculated for C18H12ClN3OS:354.0462,found:354.0463.1H NMR(300MHz,DMSO-d6): δ=
9.67 (s, 1H ,-NH -), 9.20 (s, 1H ,-ArH), 8.11 (d, J=9.0Hz, 2H ,-ArH), 7.97 (t, J=2.1Hz, 1H ,-
), ArH 7.88 (t, J=7.7Hz, 1H ,-ArH), 7.72 (s, 2H ,-CH2–),7.69–7.64(m,2H,–ArH),7.38(t,J
=8.1Hz, 1H ,-ArH), 7.15 (d, J=7.9Hz, 1H ,-ArH) ppm.13C NMR(75MHz,DMSO-d6): δ=163.94,
159.26,148.27,147.08,140.54,132.71,131.29,130.94,130.03,129.19,127.71,125.85,
125.69,124.59,122.98,120.30,119.20,95.28ppm。
Embodiment 9
The preparation of N- (3- bromophenyl) -2- ((3- cyano quinolines -2- base) is thio) acetamide (CPU-Q8)
Outside with 3- bromaniline (0.19g, 1.1mmol, 1.1equiv) substitution aniline, method identical with compound CPU-Q1
(with embodiment 2, step 2) synthesizes compound CPU-Q8 (160mg, yield 40%).m.p.190–192℃.HRMS m/z[M+H]+
calculated for C18H12BrN3OS:397.9957,found:397.9954.1H NMR(300MHz,DMSO-d6): δ=
10.63 (s, 1H ,-NH -), 9.01 (s, 1H ,-ArH), 8.03-7.83 (m, 4H ,-ArH), 7.64 (t, J=7.4Hz, 1H ,-
), ArH 7.53 (d, J=7.7Hz, 1H ,-ArH), 7.32-7.24 (m, 2H ,-ArH), 4.33 (s, 2H ,-CH2–)ppm.13C NMR
(75MHz,DMSO-d6): δ=166.30,157.10,147.62,144.20,140.56,133.69,130.82,128.91,
127.31,127.10,126.00,123.77,121.56,121.42,117.86,115.63,104.37,35.06ppm。
Embodiment 10
The preparation of N- ([1,1 '-xenyl] -4- base) -2- ((3- cyano quinolines -2- base) is thio) acetamide (CPU-Q9)
Outside with 4- aminobphenyl (0.19g, 1.1mmol, 1.1equiv) substitution aniline, side identical with compound CPU-Q1
(with embodiment 2, step 2) synthesizes compound CPU-Q9 (180mg, yield 46%) to method.m.p.>250℃.HRMS m/z[M+H]+
calculated for C24H17N3OS:396.1165,found:396.1163.1H NMR(300MHz,DMSO-d6): δ=
10.60 (s, 1H ,-NH -), 9.03 (s, 1H ,-ArH), 8.02 (d, J=8.1Hz, 1H ,-ArH), 7.90 (s, 2H ,-ArH),
7.74-7.63 (m, 7H ,-ArH), 7.44 (t, J=7.6Hz, 2H ,-ArH), 7.33 (t, J=7.3Hz, 1H ,-ArH), 4.36
(s,2H,–CH2–)ppm.13C NMR(75MHz,DMSO-d6): δ=165.91,157.23,147.65,144.19,139.59,
138.47,135.03,133.69,128.91,128.86,127.36,127.08,126.98,126.21,123.76,119.46,
115.67,104.39,35.14ppm。
Embodiment 11
The preparation of 3- ((3- cyano quinolines -2- base) is thio)-N- Phenylpropionamide (CPU-Q10)
It is replaced outside thioglycolic acid with 3- mercaptopropionic acid, compound CPU- is synthesized using the identical preparation method of CPU-Q1
Q10 (180mg, yield 54%).m.p.226–228℃.HRMS m/z[M+H]+calculated for C19H15N3OS:
334.1009,found:334.1004.1H NMR(300MHz,DMSO-d6): δ=10.01 (s, 1H ,-NH -), 9.00 (s, 1H ,-
), ArH 8.03-7.90 (m, 3H ,-ArH), 7.69-7.58 (m, 3H ,-ArH), 7.30 (t, J=7.7Hz, 2H ,-ArH), 7.04
(t, J=7.6Hz, 1H ,-ArH), 3.65 (t, J=6.9Hz, 2H ,-S-CH2), 2.90 (t, J=6.9Hz, 2H ,-CH2- C=
O–)ppm.13C NMR(75MHz,DMSO-d6): δ=169.24,157.56,147.82,144.15,139.01,133.56,
128.85,128.68,127.64,126.98,123.71,123.12,118.97,115.74,104.93,35.44,
25.30ppm。
Embodiment 12
The preparation of 3- ((3- cyano quinolines -2- base) is thio)-N- (4- fluorophenyl) propionamide (CPU-Q11)
Thioglycolic acid, 4- fluoroaniline is replaced to replace outside aniline with 3- mercaptopropionic acid, using the identical preparation side CPU-Q1
Method synthesizes compound CPU-Q11 (210mg, yield 60%).m.p.235–237℃.HRMS m/z[M+H]+calculated
for C19H14FN3OS:352.0914,found:352.0912.1H NMR(300MHz,DMSO-d6): δ=10.06 (s, 1H ,-
NH -), 8.97 (s, 1H ,-ArH), 8.03-7.90 (m, 3H ,-ArH), 7.68-7.58 (m, 3H ,-ArH), 7.13 (t, J=
8.7Hz, 2H ,-ArH), 3.65 (t, J=6.8Hz, 2H ,-S-CH2), 2.89 (t, J=6.8Hz, 2H ,-CH2- C=O -)
ppm.13C NMR(75MHz,DMSO-d6): δ=169.14,157.88 (d, Ar-F, J=238.3Hz), 157.53,147.82,
(144.10,135.39 d, J=2.3Hz), 133.54,128.83,127.63,126.97,123.71,120.74 (d, J=
7.8Hz), 115.72,115.54 (d, J=22.0Hz), 104.93,35.39,25.32ppm.
Embodiment 13
The preparation of N- (3- chlorphenyl) -3- ((3- cyano quinolines -2- base) is thio) propionamide (CPU-Q12)
Thioglycolic acid, 3- chloroaniline is replaced to replace outside aniline with 3- mercaptopropionic acid, using the identical preparation side CPU-Q1
Method synthesizes compound CPU-Q12 (200mg, yield 54%).m.p.200–202℃.HRMS m/z[M+H]+calculated
for C19H14ClN3OS:368.0619,found:368.0615.1H NMR(300MHz,DMSO-d6): δ=10.22 (s, 1H ,-
NH–),8.98(s,1H,–ArH),8.02–7.89(m,3H,–ArH),7.83(s,1H,–ArH),7.68–7.63(m,1H,–
), ArH 7.43 (d, J=8.3Hz, 1H ,-ArH), 7.33 (t, J=8.1Hz, 1H ,-ArH), 7.10 (d, J=8.0Hz, 1H ,-
), ArH 3.66 (t, J=6.7Hz, 2H ,-S-CH2), 2.92 (t, J=6.7Hz, 2H ,-CH2- C=O -) ppm.13C NMR
(75MHz,DMSO-d6): δ=169.69,157.47,147.78,144.11,140.40,133.52,133.02,130.38,
128.83,127.62,126.96,123.69,122.83,118.44,117.32,115.72,104.91,35.55,
25.17ppm。
Embodiment 14
The preparation of N- (3- bromophenyl) -3- ((3- cyano quinolines -2- base) is thio) propionamide (CPU-Q13)
Thioglycolic acid, 3- bromaniline is replaced to replace outside aniline with 3- mercaptopropionic acid, using the identical preparation side CPU-Q1
Method synthesizes compound CPU-Q13 (200mg, yield 49%).m.p.216–218℃.HRMS m/z[M+H]+calculated
for C19H14BrN3OS:412.0114,found:412.0111.1H NMR(300MHz,DMSO-d6): δ=10.20 (s, 1H ,-
NH -), 8.99 (s, 1H ,-ArH), 8.03-7.90 (m, 4H ,-ArH), 7.66 (t, J=7.4Hz, 1H ,-ArH), 7.47 (d, J=
7.4Hz, 1H ,-ArH), 7.29-7.24 (m, 2H ,-ArH), 3.65 (t, J=6.6Hz, 2H ,-S-CH2), 2.91 (t, J=
6.7Hz,2H,–CH2- C=O -) ppm.13C NMR(75MHz,DMSO-d6): δ=169.68,157.47,147.79,144.14,
140.54,133.54,130.70,128.84,127.62,126.98,125.74,123.71,121.51,121.30,117.70,
115.72,104.92,35.54,25.17ppm。
Embodiment 15
The preparation of N- ([1,1 '-xenyl] -4- base) -3- ((3- cyano quinolines -2- base) is thio) propionamide (CPU-Q14)
Thioglycolic acid, 4- aminobphenyl is replaced to replace outside aniline with 3- mercaptopropionic acid, using the identical preparation of CPU-Q1
Method synthesizes compound CPU-Q14 (200mg, yield 49%).m.p.>250℃.HRMS m/z[M+H]+calculated for
C25H19N3OS:410.1322,found:410.1324.1H NMR(300MHz,DMSO-d6): δ=10.11 (s, 1H ,-NH -),
8.98 (s, 1H ,-ArH), 8.03-7.90 (m, 3H ,-ArH), 7.71-7.63 (m, 7H ,-ArH), 7.44 (t, J=7.4Hz,
2H ,-ArH), 7.32 (t, J=7.4Hz, 1H ,-ArH), 3.67 (t, J=6.8Hz, 2H ,-S-CH2), 2.93 (t, J=
6.7Hz,2H,–CH2- C=O -) ppm.13C NMR(75MHz,DMSO-d6): δ=169.32,157.56,147.82,144.15,
139.64,138.49,134.77,133.56,128.85,127.65,126.97,126.88,126.18,123.71,119.40,
119.34,115.75,104.93,35.51,25.31ppm。
It is the pharmacology test and result of part of compounds of the present invention below:
One, inhibitory activity of the part of compounds of the present invention to hIDO1
Experimental method:
The 50mmol kaliumphosphate buffer that secure ph is 6.5, is added and reaches sodium ascorbate 25mmol, methylene blue
10 μM, 100 μ g/mL of catalase, 100 μM of L-Trp.The diluted compound of series of concentrations is added in 96 orifice plates, every hole adds
The IDO1 enzyme for entering extraction guarantees that every hole final volume is 200 μ L, 37 DEG C of incubation 1h.Take 140 μ L supernatants that 96 new orifice plates are added
In, 10 μ L, 30% trichloroacetic acid solution or 1N NaOH aqueous solution is added in 60 DEG C of hydrolysis 30min in every hole.After hydrolysis in
10000rpm is centrifuged 10min at 0 DEG C.When being hydrolyzed with trichloroacetic acid, takes in 100 μ L supernatants and new 96 hole transparent panel, add 100 μ L
The paradime thylaminobenzaldehyde acetum of 2% (w/v), mixes 2min at room temperature, and the absorbance in every hole is surveyed at 480nm.With
NaOH takes 100 μ L supernatants in white 96 orifice plates when hydrolyzing, the emitted luminescence intensity of 460nm is surveyed under 360nm exciting light.Use L-
Kynurenin is that reference substance makes two standard curves.Prepare series of concentrations reference substance (200,100,50,25,12.5,
6.25,3.12,1.56 μm of ol), the paradime thylaminobenzaldehyde of 100 μ L and 2% isometric (w/v) are taken under (1) each concentration
Acetum mixes, and surveys absorbance at 480nm.(2) with 100 μ L are taken in 96 hole blanks under each concentration, in 360nm excitation
The emitted luminescence intensity of 460nm is surveyed under light.Nonlinear regression (Graphpad prism) generates IC to analyze data50Value.Using upper
Method is stated, the IDO1 inhibitory activity of compound is measured, wherein IC50It is as follows, and with being currently in II phase clinical trial
IDO1 inhibitor NLG0919 is control.
Experimental result is as shown in table 2.
Inhibitory activity IC of the part of compounds of the present invention of table 2 to hIDO150
As can be seen from Table 2, part of compounds of the present invention has good inhibitory activity to hIDO1.
Two, the measurement of part of compounds of the present invention IDO1 protease inhibiting activity intracellular to Hela
Experimental method:
With 1640 cell culture fluid of RPMI containing 10%FBS by Hela cell culture to logarithmic phase, simultaneously with pancreatin digestion
It is 5 × 10 that concentration, which is made,4The cell suspension of a/mL, in the case where guaranteeing every 5000 cells in hole by cell inoculation transparent
It is put in 37 DEG C of cell incubators and is cultivated for 24 hours in 96 orifice plates.It is adherent and grow form in 96 orifice plates to cell, discard former training
Base is supported, IFN-γ human interferon (hole 20ng/) and the diluted compound of series of concentrations are added in 96 orifice plates and (guarantee every hole end body
Product is 200 μ L) it is put in cell incubator and cultivates 48h.140 μ L culture solution supernatants in former 96 orifice plates are moved into 96 new orifice plates
In, the trichloroacetic acid aqueous solution that 10 μ L 6.1N are added in every hole hydrolyzes 30min at 60 DEG C.96 orifice plates are put in after hydrolysis
In centrifuge, 20min is centrifuged with 4000rpm at 0 DEG C.100mL supernatant is moved to 96 new hole transparent panels after centrifugation
In, the paradime thylaminobenzaldehyde acetum of 100 μ L 2% (w/v) is added in every hole, 2min is mixed at room temperature, at 480nm
Survey the absorbance in every hole.It is reference substance production standard curve with L- kynurenin.Prepare series of concentrations reference substance (200,100,
50,25,12.5,6.25,3.12,1.56 μM), take under each concentration 100 μ L and 2% isometric (w/v) to dimethylamino
Benzaldehyde acetum mixes, and surveys absorbance at 480nm.It is raw that data are analyzed with nonlinear regression (Graphpad prism)
At IC50Value.3 multiple holes of experimental setup.Using the above method, the IDO1 inhibitory activity of compound is measured, wherein IC50
It is as follows.It uses and is currently in the IDO1 inhibitor NLG0919 of II phase clinical trial as control.
Experimental result is as shown in table 3:
IDO1 inhibitory activity IC of the part of compounds of the present invention of table 3 based on Hela cell50
As shown in Table 3, IDO1 inhibitory activity IC of the part of compounds of the present invention based on Hela cell50It is substantially better than current place
In the IDO1 inhibitor NLG0919 of II phase clinical trial.
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 (10)
1. compounds of formula I or its pharmaceutically acceptable salt:
Wherein:
R1Selected from hydrogen atom, cyano, amino, nitro, halogen, alkoxy, substituted or unsubstituted C1~C5Alkyl；Wherein replace
Base is selected from one or more of halogen, amino, nitro, hydroxyl or cyano；
R2Selected from hydrogen atom, cyano, amino, nitro, halogen, alkoxy, substituted or unsubstituted C1~C5Alkyl, substitution or not
Substituted aryl；Wherein substituent group is selected from one or more of halogen, amino, nitro, hydroxyl or cyano；
N is selected from 1,2,3,4.
2. compounds of formula I or its pharmaceutically acceptable salt according to claim 1, which is characterized in that R1Selected from hydrogen original
Son, fluorine atom, chlorine atom, bromine atom, methoxyl group, methyl；R2Selected from hydrogen atom, fluorine atom, chlorine atom, bromine atom, phenyl.
3. compounds of formula I or its pharmaceutically acceptable salt according to claim 1, which is characterized in that wherein n is represented
1、2。
4. compounds of formula I according to claim 1 or its pharmaceutically acceptable salt, which is characterized in that pharmaceutically
Acceptable salt refers to compounds of formula I and the acid-addition salts that pharmaceutically acceptable acid is formed, and the acid includes: chlorination
Hydrogen, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, first
Sulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or ferulic acid.
5. compound described in general formula I or its pharmaceutically acceptable salt are most preferably following any structure:
6. the preparation method of compound shown in general formula I:
Wherein: R1、R2, n definition with described in claim 1；
By the process of compound II prepare compound IV, by the chlorine atom in mercaptan acid III and compound II through affine substitution
Reaction obtains；By the process of compound IV prepare compound I, it is condensed to yield by substituted aniline V with carboxyl.
7. 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.
8. compound described in claim 1 or its pharmaceutically acceptable salt or pharmaceutical composition as claimed in claim 6 are being made
Application in standby 1 inhibitor of indole amine 2,3-dioxygenase.
9. compound described in claim 1 or its pharmaceutically acceptable salt or pharmaceutical composition as claimed in claim 6 are being made
The application being ready for use in the drug for the immunosuppressive related disease that treatment indole amine 2,3-dioxygenase 1 mediates.
10. application according to claim 9, which is characterized in that the immune suppression that the indoleamine 2,3-dioxygenase 1 mediates
The related disease of system includes cancer, virus infection, neurodegenerative disease, cataract, organ-graft refection, depression or itself exempts from
Epidemic disease disease.
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