CN110734423B - Indoloquinone indoleamine-2,3-dioxygenase inhibitor and medicinal application thereof - Google Patents

Indoloquinone indoleamine-2,3-dioxygenase inhibitor and medicinal application thereof Download PDF

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CN110734423B
CN110734423B CN201810791681.6A CN201810791681A CN110734423B CN 110734423 B CN110734423 B CN 110734423B CN 201810791681 A CN201810791681 A CN 201810791681A CN 110734423 B CN110734423 B CN 110734423B
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张倩
孔凯敏
孟光荣
刘炳志
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Abstract

The invention belongs to the technical field of medicines, and relates to a compound with indoloquinones and indazoloquinones parent nucleus structures, the structure of the compound is shown as a general formula I, the compound shows good indoleamine-2,3-dioxygenase inhibition activity, the compound has obvious IDO inhibition activity, can be used for preparing indoleamine-2,3-dioxygenase (IDO) inhibitors, and further can be used for preparing medicaments for treating relevant diseases such as high IDO expression or high IDO enzyme activity and the like, in particular to medicaments for immunotherapy of tumors.

Description

Indoloquinone indoleamine-2,3-dioxygenase inhibitor and medicinal application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to a compound with indoloquinones and indazoloquinones parent nucleus structures, which shows good indoleamine-2,3-dioxygenase inhibition activity and can be used for preparing a medicine for clinically treating diseases related to indoleamine-2,3-dioxygenase abnormality.
Background
The prior art discloses that Indoleamine-2,3-Dioxygenase (IDO) is a rate-limiting enzyme for catabolism of tryptophan along the canine uric acid pathway, is widely distributed in tissues and cells of mammals except liver, particularly in antigen presenting cells and placenta tissues, participates in the reaction of regulating T cells, and has immune suppression and immune regulation effects.
Research shows that IDO expression level is low in healthy human body, when the body is infected and inflamed, the IDO expression level is obviously increased under the action of cell factors such as Lipopolysaccharide (LPS) and IFN-gamma, and the IDO expression level is immunoregulation by degrading tryptophan. In recent years, research shows that IDO is closely related to tumor immune escape, and IDO expression is obviously enhanced in various malignant tumor cells such as lung cancer, gastric cancer, ovarian cancer, prostatic cancer, colorectal cancer, pancreatic cancer, cervical cancer and the like. Moreover, enhanced IDO expression is also found in the draining lymphoid junction T cells of most tumors as well as in host lymphocytes, particularly antigen presenting cells. The high expression of IDO can inhibit the activation and proliferation of T cells and the toxicity of metabolites by local tryptophan depletion to induce T cell apoptosis, and can also inhibit the proliferation and activity of T cells by promoting the formation of regulatory T cells (Tregs), thereby inducing the local T cell immune tolerance of tumors and being beneficial to the growth and metastasis of the tumors.
In addition, the IDO is also proved to be closely related to various diseases, such as alzheimer disease, depression, cataract and some immune-related diseases, so that the IDO inhibitor can be applied to the treatment of various major diseases such as tumors, alzheimer disease, depression, cataract and the like, and has wide social and economic benefits.
There are no IDO inhibitors currently approved for clinical use, but a number of IDO inhibitors have been introduced into clinical studies for tumor therapy, including: GDC-0919, NLG802, Indoximod, BMS-986205, SHR-946, KHK-2455, PF-06840003, Incyte Inc's INCB-024360(Epacadostat), which has entered clinical phase three studies, etc., clinical trial results show that IDO inhibitors have great potential for use in tumor therapy in combination with chemotherapeutic drugs. And this combination has created a research hotspot and trend, therefore, the search for highly potent IDO inhibitors for IDO enzyme activity modulation is becoming an important strategy for tumor immunotherapy, in view of the role of IDO in the tumor immune escape mechanism.
Disclosure of Invention
The invention aims to provide a compound shown as a general formula I, or a pharmaceutically acceptable salt, a stereoisomer or a tautomer thereof, or a prodrug thereof:
Figure BDA0001735065430000021
wherein: ring A is selected from benzene ring and naphthaleneA ring, pyridine ring, pyrimidine ring, quinoline ring, aliphatic ring having 3 to 8 carbon atoms, or aliphatic ring having 3 to 8 carbon atoms to which a hetero atom such as O, S or N is inserted; r1Is a substituent on the A ring selected from independent hydrogen, halogen, hydroxyl, amino, nitro, cyano, substituted or unsubstituted alkyl containing 3 to 6 carbon atoms, substituted or unsubstituted alkoxy containing 3 to 6 carbon atoms, or a combination of the above groups; r2And R3Is hydrogen, hydroxy, alkoxy having 3 to 6 carbon atoms, acyloxy having 3 to 6 carbon atoms, substituted or unsubstituted alkyl having 1 to 10 carbon atoms, substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, substituted or unsubstituted alkenyl having 2 to 10 carbon atoms, substituted or unsubstituted aryl having 6 to 12 carbon atoms, substituted or unsubstituted heteroaryl having 3 to 12 carbon atoms, substituted or unsubstituted acyl having 1 to 10 carbon atoms, substituted or unsubstituted sulfonyl having 1 to 10 carbon atoms, or R2And R3Can be linked to form a ring, forming a three to eight membered ring; r4Is hydrogen, alkyl having 1 to 6 carbon atoms, acyl having 1 to 6 carbon atoms, methanesulfonyl, p-toluenesulfonyl; n is 1 to 4, i.e., the length of the connecting chain is 1 to 4 carbon atoms.
The structure of the preferable compound of the compound shown in the general formula I is shown in the general formula II, or pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or prodrug thereof:
Figure BDA0001735065430000031
wherein: r1Is a substituent on the pyridine ring, and can be selected from independent hydrogen, halogen, hydroxyl, amino, nitro, cyano, substituted or unsubstituted alkyl containing 3 to 6 carbon atoms, substituted or unsubstituted alkoxy containing 3 to 6 carbon atoms, or the combination of the groups; r2And R3Is hydrogen, hydroxy, alkoxy having 3 to 6 carbon atoms, acyloxy having 3 to 6 carbon atoms, substituted or unsubstituted alkyl having 1 to 10 carbon atoms, substituted or unsubstituted cycloalkyl having 3 to 6 carbon atoms, substituted or unsubstitutedAlkenyl having 2 to 10 carbon atoms, substituted or unsubstituted aryl having 6 to 12 carbon atoms, substituted or unsubstituted heteroaryl having 3 to 12 carbon atoms, substituted or unsubstituted acyl having 1 to 10 carbon atoms, substituted or unsubstituted sulfonyl having 1 to 10 carbon atoms, or R2And R3Can be linked to form a ring, forming a three to eight membered ring; r4Is hydrogen, alkyl having 1 to 6 carbon atoms, acyl having 1 to 6 carbon atoms, methanesulfonyl, p-toluenesulfonyl; n is 1 to 4, i.e., the length of the connecting chain is 1 to 4 carbon atoms.
The compound shown in the general formula I and the preferable compound shown in the general formula II, or the pharmaceutically acceptable salt, the stereoisomer or the tautomer, or the prodrug thereof are synthesized by the method known in the field.
The invention has carried on the IDO enzyme inhibitory activity test experiment, the result shows, said compound has obvious inhibition to IDO protease, have apparent indoleamine-2,3-dioxygenase (IDO) inhibitory activity, can be used for preparing indolequinone indoleamine-2,3-dioxygenase inhibitor, further prepare and be used for treating IDO high expression or IDO enzyme activity and correlated disease such as increase, used for clinical treatment IDO high expression or IDO enzyme activity and correlated disease such as increase, especially can be used for the immunotherapy of the tumor; the related diseases comprise tumors, Alzheimer's disease, depression, cataract and some immune related diseases.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1.3- (2-aminoethyl) -5- (3-pyridyl) -1H-indole-4, 7-dione
Figure BDA0001735065430000041
1H NMR(400MHz,DMSO-d6)δ12.93(s,1H),8.98-8.88(m,2H),8.58-8.45(m,1H),8.17(m,2H),8.01-7.95(m,1H),7.32(s,1H),7.06(d,J＝8.5Hz,1H),3.06(s,2H),2.52(s,2H).ESI-MS m/z 268(M+H+).。
Example 2.3- (2-aminoethyl) -5- (5-chloro-3-pyridinyl) -1H-indole-4, 7-dione
Figure BDA0001735065430000051
1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),8.97(s,1H),8.91(s,1H),8.18(m,2H),8.05(s,1H),7.32(s,1H),7.06(s,1H),3.06(s,2H),2.52(s,2H).ESI-MS m/z 302(M+H+).。
Example 3- (2-aminoethyl) -5- (5-fluoro-3-pyridinyl) -1H-indole-4, 7-dione
Figure BDA0001735065430000052
1H NMR(400MHz,DMSO-d6)δ12.98(s,1H),9.07(s,1H),8.97(s,1H),8.16(m,2H),8.13(s,1H),7.34(s,1H),7.11(s,1H),3.06(s,2H),2.52(s,2H).ESI-MS m/z 286(M+H+).。
Example 4.3- (2-aminoethyl) -5- (5-cyano-3-pyridinyl) -1H-indole-4, 7-dione
Figure BDA0001735065430000053
1H NMR(400MHz,DMSO-d6)δ12.98(s,1H),9.08(s,1H),8.96(s,1H),8.16(m,2H),8.15(s,1H),7.34(s,1H),7.11(s,1H),3.06(s,2H),2.52(s,2H).ESI-MS m/z 293(M+H+).。
Example 5.3- (2-aminoethyl) -5- (2-methyl-3-pyridinyl) -1H-indole-4, 7-dione
Figure BDA0001735065430000061
1H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.86(d,1H),8.06(m,2H),8.00(s,2H),7.31(s,1H),7.01(s,1H),3.06(s,2H),2.83(s,3H),2.52(s,2H).ESI-MS m/z 282(M+H+).。
Example 6.3- (2-aminoethyl) -5- (6-methyl-3-pyridinyl) -1H-indole-4, 7-dione
Figure BDA0001735065430000062
1H NMR(400MHz,DMSO-d6)δ12.85(s,1H),8.84(s,1H),8.76(m,1H),8.04(m,1H),8.01(s,2H),7.31(s,1H),7.01(s,1H),3.06(s,2H),2.85(s,3H),2.52(s,2H).ESI-MS m/z 282(M+H+).。
Example 7.3- (tert-Butoxycarbonylaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000063
1H NMR(400MHz,DMSO-d6)δ12.66(s,1H),8.66(s,1H),8.62(d,J＝4.1Hz,1H),7.91(d,J＝8.6Hz,1H),7.49-7.46(m,1H),7.12(s,1H),6.86(s,1H),6.81(s,1H),3.18(d,J＝6.1Hz,2H),2.99(t,J＝5.8Hz,2H),1.34(s,9H).ESI-MS m/z 368(M+H+).。
Example 8.3- (Acetaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000071
1H NMR(400MHz,DMSO-d6)δ12.66(s,1H),8.68-8.63(m,2H),7.91(s,2H),7.47(s,1H),7.14(s,1H),6.80(s,1H),3.25(s,2H),2.83(s,2H),1.77(s,3H).ESI-MS m/z 310(M+H+).。
Example 9.3- (pivaloylaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000072
1H NMR(400MHz,DMSO-d6)δ12.67(s,1H),8.67(s,1H),8.63(d,J＝4.4Hz,1H),7.92(d,J＝7.4Hz,1H),7.49(dd,J＝7.6Hz,J＝5.3Hz,1H),7.13(s,1H),6.86(t,J＝4.0Hz,1H),6.81(s,1H),3.18(d,J＝6.1Hz,2H),2.83(t,J＝6.7Hz,2H),1.34(s,9H).ESI-MS m/z 352(M+H+).。
Example 10.3- (benzoylaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000073
1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),8.64-8.61(m,2H),8.52(s,1H),7.88(d,J＝8.0Hz,1H),7.79(d,J＝5.2Hz,2H),7.47-7.41(m,4H),7.13(s,1H),6.80(s,1H),2.96(s,2H),2.48(s,2H).ESI-MS m/z372(M+H+).。
Example 11.3- (benzenesulfonylaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000081
1H NMR(400MHz,DMSO-d6)δ12.66(s,1H),8.65(s,2H),7.89(d,J＝6.3Hz,1H),7.72(s,3H),7.58(d,J＝6.3Hz,1H),7.54-7.50(m,3H),7.11(s,1H),6.79(s,1H),3.10-3.03(m,2H),2.79(s,2H).ESI-MS m/z408(M+H+).。
Example 12.3- (Acrylamidoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000082
1H NMR(400MHz,DMSO-d6)δ12.66(s,1H),8.68-8.63(m,2H),7.91(m,2H),7.47(s,1H),7.14(s,1H),6.80(s,1H),6.49(d,J＝16.8Hz 1H),6.08(m,1H),5.74(m,1H),3.25(s,2H),2.83(s,2H).ESI-MS m/z 322(M+H+).。
Example 13.3- (methylaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000083
1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),8.64(s,1H),8.54(d,J＝6.8Hz,1H),7.96(d,J＝8.9Hz,1H),7.47(s,1H),7.11(s,1H),6.74(s,1H),4.81(s,1H),3.30(s,2H),3.14(s,2H),2.86(s,3H).ESI-MS m/z282(M+H+).。
Example 14.3- (N, N-dimethylaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000091
1H NMR(400MHz,CD3OD)δ8.64(s,1H),8.54(d,J＝6.8Hz,1H),7.96(d,J＝8.9Hz,1H),7.47(s,1H),7.11(s,1H),6.74(s,1H),3.30(s,2H),3.14(s,2H),2.86(s,6H).ESI-MS m/z 296(M+H+).。
Example 15.3- (N-Ethylaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000092
1H NMR(400MHz,CD3OD)δ8.67(s,1H),8.57(d,J＝4.8Hz,1H),8.00(d,J＝7.5Hz,1H),7.52-7.49(m,1H),7.15(s,1H),6.78(s,1H),3.27(s,2H),3.16-3.06(m,4H),3.11(t,J＝7.1Hz,3H).ESI-MS m/z 296(M+H+).。
Example 16.3- (N, N-diethylaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000093
1H NMR(400MHz,CD3OD)δ8.67(s,1H),8.57(d,J＝4.8Hz,1H),8.00(d,J＝7.5Hz,1H),7.52-7.49(m,1H),7.15(s,1H),6.78(s,1H),3.27(s,2H),3.16-3.06(m,6H),3.11(t,J＝7.1Hz,6H).ESI-MS m/z 324(M+H+).。
Example 17.3- (N-isopropylaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000101
1H NMR(400MHz,CD3OD)δ8.62(s,1H),8.53(d,J＝3.7Hz,1H),7.95(d,J＝6.3Hz,1H),7.48-7.45(m,1H),7.10(s,1H),6.74(s,1H),3.38-3.35(m,2H),3.10(d,J＝5.2Hz,3H),2.79(d,J＝5.8Hz,6H).ESI-MS m/z 310(M+H+).。
Example 18.3- (N-tert-butylaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000102
1H NMR(400MHz,CD3OD)δ8.62(s,1H),8.53(d,J＝3.7Hz,1H),7.95(d,J＝6.3Hz,1H),7.48-7.45(m,1H),7.10(s,1H),6.74(s,1H),3.38-3.35(m,2H),2.79(m,2H),1.53(s,9H).ESI-MS m/z 324(M+H+).。
Example 19.3- (1-Piperidylethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000111
1H NMR(400MHz,CD3OD)δ8.68(s,1H),8.56(d,J＝4.8Hz,1H),8.01(d,J＝7.8Hz,1H),7.52-7.49(m,1H),7.15(s,1H),6.78(s,1H),3.27(s,2H),3.16-3.10(m,4H),2.71(m,2H),1.56-1.48(m,6H).ESI-MS m/z 336(M+H+).。
Example 20.3- (N-Cyclohexylaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000112
1H NMR(400MHz,CD3OD)δ8.61(s,1H),8.52(s,1H),7.93(d,J＝7.3Hz,1H),7.45(s,1H),7.09(s,1H),6.71(s,1H),3.23(s,2H),3.09-3.06(m,2H),2.05(s,2H),1.78(s,2H),1.62(d,J＝11.5Hz,1H),1.28-1.14(m,6H).ESI-MS m/z 350(M+H+).。
Example 21.3- (N-neopentyl aminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000113
1H NMR(400MHz,CD3OD)δ8.63(s,1H),8.54(d,J＝4.6Hz,1H),7.96(d,J＝8.2Hz,1H),7.48-7.46(m,1H),7.10(s,1H),6.75(s,1H),3.16(d,J＝7.7Hz,2H),2.88(s,2H),2.21(s,2H),1.02(s,9H)；ESI-MS m/z 338(M+H+).。
Example 22.3- (N-N-butylaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000121
1H NMR(400MHz,CD3OD)δ8.64(s,1H),8.54(s,1H),7.96(d,J＝8.4Hz,1H),7.48(s,1H),7.14(s,1H),6.75(s,1H),3.33(d,J＝9.4Hz,2H),3.20-3.12(m,4H),1.72(s,2H),1.40(d,J＝6.7Hz,2H),0.96(t,J＝6.6Hz,3H).ESI-MS m/z 324(M+H+).。
Example 23.3- (N-phenethylaminoethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000122
1H NMR(400MHz,CD3OD)δ8.64(s,1H),8.53(d,J＝4.8Hz,1H),7.96(d,J＝7.6Hz,1H),7.46-7.43(m,1H),7.24-7.23(m,5H),7.03(s,1H),6.73(s,1H),3.28(d,J＝6.5Hz,2H),3.11(d,J＝10.9Hz,2H),3.01-2.97(m,3H),1.90(s,2H).ESI-MS m/z 372(M+H+).。
Example 24.3- (N, N-dimethylaminomethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000123
1H NMR(400MHz,CD3OD)δ8.64(s,1H),8.54(d,J＝6.8Hz,1H),7.96(d,J＝8.9Hz,1H),7.47(s,1H),7.11(s,1H),6.74(s,1H),3.30(s,2H),3.14(s,6H).ESI-MS m/z 282(M+H+).。
Example 25.3- (1-Piperidylmethyl) -5- (3-pyridine) -1H-indole-4, 7-dione
Figure BDA0001735065430000131
1H NMR(400MHz,CD3OD)δ8.64(s,1H),8.54(d,J＝6.8Hz,1H),7.96(d,J＝8.9Hz,1H),7.47(s,1H),7.11(s,1H),6.74(s,1H),3.30(s,2H),3.14(m,4H),1.86-1.53(m,6H).ESI-MS m/z 322(M+H+).。
Example 26.3- (tert-Butoxycarboxamido ethyl) -5-phenyl-1H-indole-4, 7-dione
Figure BDA0001735065430000132
1H NMR(400MHz,CDCl3)δ9.77(s,1H),7.47-7.44(m,5H),6.93(s,1H),6.67(s,1H),4.81(s,1H),3.42(q,J＝6.5Hz,2H),2.99(t,J＝6.5Hz,2H),1.41(s,9H).ESI-MS m/z 367(M+H+).。
Example 27.3- (tert-Butoxycarboxamido ethyl) -5- (2-methoxyphenyl) -1H-indole-4, 7-dione
Figure BDA0001735065430000133
1H NMR(400MHz,CDCl3)δ10.16(s,1H),7.41-7.36(m,1H),7.18(d,J＝7.1Hz,1H),7.03-6.96(m,2H),6.91(s,1H),6.62(s,1H),4.82(s,1H),3.79(s,3H),3.40(q,J＝6.5Hz,2H),2.96(t,J＝6.4Hz,2H),1.41(s,9H).ESI-MS m/z 397(M+H+).。
Example 28.3- (tert-Butoxycarbonylaminoethyl) -5- (4-methoxyphenyl) -1H-indole-4, 7-dione
Figure BDA0001735065430000141
1H NMR(400MHz,CDCl3)δ9.55(s,1H),7.47(d,J＝8.2Hz,2H),6.96(d,J＝8.2Hz,2H),6.91(s,1H),6.63(s,1H),4.79(s,1H),3.86(s,3H),3.42(q,J＝6.5Hz,2H),2.98(t,J＝6.6Hz,2H),1.41(s,9H).ESI-MS m/z 397(M+H+).。
Example 29.3- (tert-Butoxycarbonylaminoethyl) -5- (2-fluorophenyl) -1H-indole-4, 7-dione
Figure BDA0001735065430000142
1H NMR(400MHz,CDCl3)δ9.75(s,1H),7.42(d,J＝6.7Hz,1H),7.30(d,J＝6.8Hz,1H),7.18(m,2H),6.95(s,1H),6.69(s,1H),4.77(s,1H),3.40(q,J＝6.6Hz,2H),2.98(t,J＝7.4Hz,2H),1.41(s,9H).ESI-MS m/z 385(M+H+).。
Example 30.3- (tert-Butoxycarbonylaminoethyl) -5- (4-fluorophenyl) -1H-indole-4, 7-dione
Figure BDA0001735065430000151
1H NMR(400MHz,CDCl3)δ9.75(s,1H),7.45(d,J＝6.7Hz,2H),7.30(d,J＝6.8Hz,2H),6.95(s,1H),6.69(s,1H),4.77(s,1H),3.40(q,J＝6.6Hz,2H),2.98(t,J＝7.4Hz,2H),1.41(s,9H).ESI-MS m/z385(M+H+).。
Example 31.3- (tert-Butoxycarboxamido ethyl) -5- (4-methylphenyl) -1H-indole-4, 7-dione
Figure BDA0001735065430000152
1H NMR(400MHz,CDCl3)δ9.58(s,1H),7.40(d,J＝6.8Hz,2H),7.25(d,J＝11.3Hz,2H),6.93(s,1H),6.66(s,1H),4.80(s,1H),3.42(q,J＝6.3Hz,2H),2.98(t,J＝6.2Hz,2H),2.42(s,3H),1.42(s,9H).ESI-MS m/z 379(M+H+).。
Example 32.1- (4-Methylbenzenesulfonyl) -3- (tert-butoxyformamidoethyl) -5- (3-pyridine) indole-4, 7-dione
Figure BDA0001735065430000153
1H NMR(400MHz,CDCl3)δ8.54-8.51(m,2H),7.94(d,J＝7.7Hz,2H),7.67(d,J＝7.6Hz,1H),7.59(s,1H),7.25(d,J＝7.5Hz,2H),7.15(d,J＝6.8Hz,1H),6.55(s,1H),4.60(s,1H),3.30(d,J＝6.3Hz,2H),2.89(d,J＝5.4Hz,2H),3.32(s,3H),1.29(s,9H).ESI-MS m/z522(M+H+).。
Example 32.1-methyl-3- (tert-Butoxycarboxamido ethyl) -5- (3-pyridine) indole-4, 7-dione
Figure BDA0001735065430000161
1H NMR(400MHz,CDCl3)δ8.54-8.51(m,2H),7.67(d,J＝7.6Hz,1H),7.59(s,1H),7.15(d,J＝6.8Hz,1H),6.55(s,1H),4.60(s,1H),3.30(d,J＝6.3Hz,2H),2.89(d,J＝5.4Hz,2H),3.32(s,3H),1.29(s,9H).ESI-MS m/z 382(M+H+).。
Example 34.1- (4-Methylbenzenesulfonyl) -3- (tert-butoxycarboxamidoethyl) -5- (4-pyridine) -toluenesulfonyl-indole-4, 7-dione
Figure BDA0001735065430000162
1H NMR(400MHz,CDCl3)δ8.68(d,J＝6.0Hz,2H),8.06(d,J＝8.3Hz,2H),7.71(s,1H),7.37(d,J＝8.2Hz,2H),7.33(d,J＝6.1Hz,2H),6.67(s,1H),4.70(s,1H),3.42(q,J＝6.6Hz,2H),3.00(t,J＝6.6Hz,2H),2.44(s,3H),1.41(s,9H).ESI-MS m/z 522(M+H+).。
Example 35.1-methyl-3- (tert-Butoxycarboxamido ethyl) -5- (4-pyridine) indole-4, 7-dione
Figure BDA0001735065430000171
1H NMR(400MHz,CDCl3)δ8.68(d,J＝6.0Hz,2H),8.06(d,J＝8.3Hz,2H),7.54(s,1H),6.76(s,1H),4.70(s,1H),3.42(q,J＝6.6Hz,2H),3.00(t,J＝6.6Hz,2H),2.44(s,3H),1.41(s,9H).ESI-MS m/z 382(M+H+).。
Example 36.3- (tert-Butoxycarboxamido ethyl) -5- (4-pyridine) indole-4, 7-dione
Figure BDA0001735065430000172
1H NMR(400MHz,CD3OD)δ8.59(s,1H),7.66-7.62(m,3H),7.02(s,1H),6.76(s,1H),3.31(s,2H),2.92(t,J＝6.6Hz,2H),1.38(s,9H).ESI-MS m/z 368(M+H+).。
Example 37: test of the inhibitory Activity of Compounds on IDO enzyme and results
The experimental method comprises the following steps: preparation of Buffer (pH 6.5): 599.9mg of sodium dihydrogen phosphate was added to 1.52mL of 1M potassium hydroxide, and the mixture was diluted with water to 100mL, and the pH was adjusted to 6.5. Preparation of a standard reaction solution: a buffer (pH 6.5) was used as a mother liquor, and 176.12mg of ascorbic acid, 10mg of catalase, 0.325mg of methylene blue, and 4.075mg of L-tryptophan were added. All test compounds were prepared as 10mmol solutions in DMSO, and 10mmol solutions were diluted with Buffer to 100. mu. mol (containing 1% DMSO) for use. Taking a 96-hole blackboard, and adding 80 mu L of standard reaction solution into the test hole, the maximum value control hole and the minimum value control hole; mu.L of the IDO enzyme and 10. mu.L of the test compound solution were added to the test wells, 10. mu.L of the enzyme and 10. mu.L of Buffer were added to the maximum control wells, and 20. mu.L of Buffer was added to the minimum control wells. After being left at 37 ℃ for 1h, the plate was taken out, 20. mu.l of 1M sodium hydroxide solution was added to the wells of a 96-plate, and the plate was left at 60 ℃ for 4h (for the purpose of decomposing N-formylkynurenine into kynurenine), and then the plate was taken out, cooled, and then the fluorescence value was measured by a microplate reader. Inhibition rate (max-measure)/(max-min) × 100%.
The experimental results are as follows:
Figure BDA0001735065430000181
Figure BDA0001735065430000191
the compound has obvious inhibiting effect on IDO protease, can be used for preparing medicaments for treating relevant diseases such as high IDO expression or high IDO enzyme activity and the like, and the relevant diseases comprise tumors, Alzheimer's disease, depression, cataract and the treatment of certain immune-related diseases, especially can be applied to the immunotherapy of tumors.

Claims (8)

1. A compound of formula I:
Figure FDA0003662786560000011
wherein: ring A is selected from benzene ring and pyridine ring; r1Is a substituent on the A ring selected from independent hydrogen, halogen, hydroxyl, amino, nitro, cyano, unsubstituted alkyl containing 3 to 6 carbon atoms, unsubstituted alkoxy containing 3 to 6 carbon atoms, or a combination of the above groups; r2And R3Is hydrogen, hydroxy, alkoxy having 3 to 6 carbon atoms, acyloxy having 3 to 6 carbon atoms, unsubstituted alkyl having 1 to 10 carbon atoms, unsubstituted cycloalkyl having 3 to 6 carbon atoms, unsubstituted alkenyl having 2 to 10 carbon atoms, unsubstituted aryl having 6 to 12 carbon atoms, unsubstituted heteroaryl having 3 to 12 carbon atoms, unsubstituted heteroaryl having 1 to 10 carbon atomsAcyl, unsubstituted sulfonyl containing 1 to 10 carbon atoms, or R2And R3Can be linked to form a ring, forming a three to eight membered ring; r4Is hydrogen, alkyl having 1 to 6 carbon atoms, acyl having 1 to 6 carbon atoms, methanesulfonyl, p-toluenesulfonyl; n is 1 to 4, i.e., the length of the connecting chain is 1 to 4 carbon atoms.
2. A compound of formula i according to claim 1, wherein the compound has the structure of formula ii:
Figure FDA0003662786560000012
wherein: r1Is a substituent on the pyridine ring selected from independent hydrogen, halogen, hydroxyl, amino, nitro, cyano, unsubstituted alkyl containing 3 to 6 carbon atoms, unsubstituted alkoxy containing 3 to 6 carbon atoms, or a combination of the above groups; r2And R3Is hydrogen, hydroxy, alkoxy having 3 to 6 carbon atoms, acyloxy having 3 to 6 carbon atoms, unsubstituted alkyl having 1 to 10 carbon atoms, unsubstituted cycloalkyl having 3 to 6 carbon atoms, unsubstituted alkenyl having 2 to 10 carbon atoms, unsubstituted aryl having 6 to 12 carbon atoms, unsubstituted heteroaryl having 3 to 12 carbon atoms, unsubstituted acyl having 1 to 10 carbon atoms, unsubstituted sulfonyl having 1 to 10 carbon atoms, or R2And R3Can be linked to form a ring, forming a three to eight membered ring; r4Is hydrogen, alkyl having 1 to 6 carbon atoms, acyl having 1 to 6 carbon atoms, methanesulfonyl, p-toluenesulfonyl; n is 1 to 4, i.e., the length of the connecting chain is 1 to 4 carbon atoms.
3. The compound of formula i according to claim 1, further comprising a pharmaceutically acceptable salt thereof, a stereoisomer or a tautomer thereof.
4. A compound of formula i according to claim 1, wherein said compound is a compound of formula i:
Figure FDA0003662786560000021
Figure FDA0003662786560000031
Figure FDA0003662786560000041
5. the use of a compound of formula i according to claim 1 for the preparation of an indoquinone indoleamine-2,3-dioxygenase inhibitor.
6. Use of a compound of formula i according to claim 1 for the preparation of a medicament for the treatment of a disease associated with a high IDO expression or an increased IDO enzyme activity.
7. The use according to claim 6, wherein the disease associated with high IDO expression or increased IDO enzyme activity is tumor, Alzheimer's disease, depression, cataract or immune related diseases.
8. Use of a compound of formula i according to claim 1 for the preparation of a medicament for the immunotherapy of tumors.
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