CN110128415A - Indoline-like compound as immunomodulator and preparation method thereof - Google Patents

Indoline-like compound as immunomodulator and preparation method thereof Download PDF

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CN110128415A
CN110128415A CN201910475329.6A CN201910475329A CN110128415A CN 110128415 A CN110128415 A CN 110128415A CN 201910475329 A CN201910475329 A CN 201910475329A CN 110128415 A CN110128415 A CN 110128415A
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秦铭泽
宫平
赵燕芳
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Shenyang Pharmaceutical University
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Abstract

The invention belongs to pharmaceutical technology field, it is related to being used as the indoline-like compound of immunomodulator and its stereoisomer and pharmaceutically acceptable salt, their preparation method and the pharmaceutical composition containing the compound.The invention further relates to such compound and its stereoisomer and pharmaceutically acceptable salt preparation treat disorders such as cancers related with PD-1/PD-L1 signal path, infectious diseases, autoimmune disease drug in terms of purposes.The indoline-like compound and its stereoisomer and pharmaceutically acceptable salt structure are as follows, and wherein substituent group Cy, Q, X, Y, Z has the meaning provided in the description.The indoline-like compound and its stereoisomer, pharmaceutically acceptable salt or pharmaceutical composition have obvious inhibiting effect to PD-1/PD-L1 albumen/protein-interacting, can be used for preparing the drug of a variety of diseases such as treatment disorders such as cancers related with PD-1/PD-L1 albumen/protein-interacting, virus infection.

Description

Indoline-like compound as immunomodulator and preparation method thereof
Technical field:
The invention belongs to pharmaceutical technology field, it is related to indoline-like compound and its alloisomerism as immunomodulator Body and pharmaceutically acceptable salt, their preparation method and the pharmaceutical composition containing the compound.The present invention is also It is logical in preparation treatment and PD-1/PD-L1 signal to be related to such compound and its stereoisomer and pharmaceutically acceptable salt The related disorders such as cancers in road, infectious diseases, autoimmune disease drug in terms of purposes.
Background technique:
Immunization therapy is the hot fields of oncotherapy in recent years, was chosen as ten big sciences by " Science " in 2013 and dashes forward First of broken.Programmed death receptor 1 (programmed death 1, PD-1) is T cell surface receptor, when its with it is procedural dead It dies when ligand 1 (PD-L1) is combined and generates negative immune adjustment signal, to inhibit T cell activation, proliferation and interleukins The release (Eur.J.Immunol., 2002,32 (3), 634-643.) of the cell factors such as 2 (IL-2), interferon gamma (IFN-γ). A large number of studies show that the intracorporal tumor microenvironment of machine can induce PD-1 expression up-regulation in the T cell of infiltration, while tumour cell is high PD-L1 is expressed, the signal path sustained activation for causing PD-1/PD-L1 to mediate, tumour-specific CD8+T cell function is suppressed So that it cannot identification or killing tumor cell, i.e. tumour cell realize immunologic escape.Therefore targeting blocks PD-1/PD-L1 egg White/protein-interacting can restore T cell function, it is made to re-recognize simultaneously killing tumor cell.
Immunotherapy based on PD-1/PD-L1 attracts attention, and the PD-1/PD-L1 monoclonal antibody for the listing that gone through at present includes The Pembrolizumab of Mo Shadong, the Nivolumab of Bristol Myers Squibb, the Avelumab of Merck, AstraZeneca Durvalumab, Atezolizumab of Roche etc..Above-mentioned monoclonal antibody shows obvious treatment in the treatment of kinds of tumors type Effect, approved indication includes melanoma, non-small cell lung cancer, gastric cancer, bladder transitional cell carcinoma etc..With opening for clinical research Exhibition, monoclonal antibody medicine, which is expected to realize in more indications, to be broken through.
Although monoclonal antibody medicine shows advantage in clinical treatment, it is as tired in prepared and purified that there is also apparent defects Hardly possible, production cost are high；Easily by proteases for decomposing, half-life short；It cannot take orally, it can only drug administration by injection；The immunogenicity of monoclonal antibody Lead to serious toxic side effect.Compared to biopharmaceutical macromolecular drug, small molecule compound pharmacokinetic after chemical modification It is controllable to learn property, in addition production technology, in terms of also with bigger exploration and optimization space.Therefore, it develops Targeting PD-1/PD-L1 albumen/protein-interacting micromolecular inhibitor is the feasibility option for realizing immunization therapy.
Small molecule PD-1/PD-L1 inhibitor research and development at present are at early stage, the PD-L1 inhibitor AC-170 of Curis In clinical I phase, Bristol Myers Squibb, Incyte micromolecular inhibitor also in the preclinical study stage.Therefore, there is an urgent need to open Send out the small molecule PD-1/PD-L1 inhibitor with novel chemical structure.
The present inventor has designed and synthesized a series of new indoline-like compounds.Activity research the result shows that, such change PD-1/PD-L1 albumen/protein-interacting can be significantly inhibited by closing object.
Summary of the invention:
The present invention relates to the indoline-like compound and its stereoisomer and pharmaceutically acceptable salt of general formula I,
Wherein,
Cy is selected from 6-10 member aryl or 5-12 unit's heteroaryl, or isThe 5-12 unit's heteroaryl contains 1-3 A hetero atom selected from N, O or S；The 6-10 member aryl, 5-12 unit's heteroaryl orIt can be optionally by 1-3 R1It takes Generation；
R1Independently selected from hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, cyano, hydroxyl, carboxyl, amino；It is described (C1-C4) alkyl, (C1-C4) alkoxy can be optionally by 1-3 R2Replace；
R2Independently selected from hydrogen, halogen, (C1-C4) alkyl, hydroxyl, amino, carboxyl, or
Ra、RbIndependently selected from hydrogen, (C1-C4) alkyl, (C3-C8) naphthenic base, hydroxyl (C1-C4) alkyl, amino (C1-C4) Alkyl, carbamoyl (C1-C4) alkyl, amino-sulfonyl (C1-C4) alkyl, methylsulfonyl amido (C1-C4) alkyl, carboxyl (C1- C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl, tetrahydropyran -4-base；(the C1-C4) alkyl, (C3-C8) cycloalkanes Base, hydroxyl (C1-C4) alkyl, amino (C1-C4) alkyl, carbamoyl (C1-C4) alkyl, amino-sulfonyl (C1-C4) alkyl, Methylsulfonyl amido (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl, tetrahydropyran -4-base It can be optionally by 1-3 R3Replace；
Or Ra、RbThe nitrogen-containing heterocycle of a 3-7 member is formed together with the nitrogen-atoms being connected with them, preferably 5-6 member contains Azacyclo-；The nitrogen-containing heterocycle contains the 1-3 hetero atoms for being selected from N, O or S；The nitrogen-containing heterocycle can be optionally by 1-3 R4Replace；
R3Independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, (C1-C4) alkyl, hydroxyl (C1-C4) alkyl, (C1-C4) Alkoxy (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl, (C1-C4) acyl group；
R4Independently selected from hydrogen, hydroxyl, carboxyl, amino, carbamyl, (C1-C4) alkyl, (C1-C4) alkoxy, (C1- C4) alkoxyl formyl, hydroxyl (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl；
X is selected from N or CH；
Y is selected from N or CR5；
R5Selected from hydrogen, halogen, (C1-C4) alkyl, or
Z is CR6；
R6Selected from hydrogen, (C1-C4) alkyl, or
Rc、RdIndependently selected from hydrogen, (C1-C4) alkyl, (C3-C8) naphthenic base, hydroxyl (C1-C4) alkyl, amino (C1-C4) Alkyl, carbamoyl (C1-C4) alkyl, amino-sulfonyl (C1-C4) alkyl, methylsulfonyl amido (C1-C4) alkyl, carboxyl (C1- C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl, tetrahydropyran -4-base；(the C1-C4) alkyl, (C3-C8) cycloalkanes Base, hydroxyl (C1-C4) alkyl, amino (C1-C4) alkyl, carbamoyl (C1-C4) alkyl, amino-sulfonyl (C1-C4) alkyl, Methylsulfonyl amido (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl, tetrahydropyran -4-base It can be optionally by 1-3 R7Replace；
Or Rc、RdThe nitrogen-containing heterocycle of a 3-7 member is formed together with the nitrogen-atoms being connected with them, preferably 5-6 member contains Azacyclo-；The nitrogen-containing heterocycle contains the 1-3 hetero atoms for being selected from N, O or S；The nitrogen-containing heterocycle can be optionally by 1-3 R8Replace, carbon atom can be by oxo on ring；
R7Independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, (C1-C4) alkyl, hydroxyl (C1-C4) alkyl, (C1-C4) Alkoxy (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl, (C1-C4) acyl group；
R8Independently selected from hydrogen, hydroxyl, carboxyl, amino, carbamyl, (C1-C4) alkyl, (C1-C4) alkoxy, (C1- C4) alkoxyl formyl, hydroxyl (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl；
Q is selected from O, S or NR9；
R9Selected from hydrogen or (C1-C4) alkyl.
Present invention is preferably related to the indoline-like compounds and its stereoisomer of general formula I and pharmaceutically acceptable Salt, wherein
Cy is selected from:
The Cy can be optionally by 1-3 R1Replace；
R1Independently selected from hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, cyano, hydroxyl, carboxyl, amino；It is described (C1-C4) alkyl, (C1-C4) alkoxy can be optionally by 1-3 R2Replace；
R2Independently selected from hydrogen, halogen, (C1-C4) alkyl, hydroxyl, amino, carboxyl, or
It is selected from:
X is selected from N or CH；
Y is selected from N or CR5；
R5Selected from hydrogen, halogen, (C1-C4) alkyl, or
Z is CR6；
R6Selected from hydrogen, (C1-C4) alkyl, or
Rc、RdIndependently selected from hydrogen, (C1-C4) alkyl, (C3-C8) naphthenic base, hydroxyl (C1-C4) alkyl, amino (C1-C4) Alkyl, carbamoyl (C1-C4) alkyl, amino-sulfonyl (C1-C4) alkyl, methylsulfonyl amido (C1-C4) alkyl, carboxyl (C1- C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl, tetrahydropyran -4-base；(the C1-C4) alkyl, (C3-C8) cycloalkanes Base, hydroxyl (C1-C4) alkyl, amino (C1-C4) alkyl, carbamoyl (C1-C4) alkyl, amino-sulfonyl (C1-C4) alkyl, Methylsulfonyl amido (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl, tetrahydropyran -4-base It can be optionally by 1-3 R7Replace；
Or Rc、RdThe nitrogen-containing heterocycle of a 3-7 member is formed together with the nitrogen-atoms being connected with them, preferably 5-6 member contains Azacyclo-；The nitrogen-containing heterocycle contains the 1-3 hetero atoms for being selected from N, O or S；The nitrogen-containing heterocycle can be optionally by 1-3 R8Replace, carbon atom can be by oxo on ring；
R7Independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, (C1-C4) alkyl, hydroxyl (C1-C4) alkyl, (C1-C4) Alkoxy (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl, (C1-C4) acyl group；
R8Independently selected from hydrogen, hydroxyl, carboxyl, amino, carbamyl, (C1-C4) alkyl, (C1-C4) alkoxy, (C1- C4) alkoxyl formyl, hydroxyl (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl；
Q is selected from O, S or NR9；
R9Selected from hydrogen or (C1-C4) alkyl.
The present invention is more preferably related to the indoline-like compound and its stereoisomer and pharmaceutically acceptable of general formula I Salt, wherein
Cy is selected from: The Cy can be optionally by 1-3 R1Replace；
R1Independently selected from hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, cyano, hydroxyl, carboxyl, amino；It is described (C1-C4) alkyl, (C1-C4) alkoxy can be optionally by 1-3 R2Replace；
R2Independently selected from hydrogen, halogen, (C1-C4) alkyl, hydroxyl, amino, carboxyl, or
It is selected from:
X is selected from N or CH；
Y is selected from N or CR5；
R5Selected from hydrogen, (C1-C4) alkyl；
Z is CR6；
R6Selected from hydrogen or
It is selected from:
Q is S.
The present invention is more particularly preferably related to the indoline-like compound of general formula I and its stereoisomer and pharmaceutically may be used The salt of receiving, wherein
Cy is The Cy can be optionally by 1-3 R1Replace；
R1Independently selected from hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, cyano, hydroxyl, carboxyl, amino；It is described (C1-C4) alkyl, (C1-C4) alkoxy can be optionally by 1-3 R2Replace；
R2Independently selected from hydrogen, halogen, (C1-C4) alkyl, hydroxyl, amino, carboxyl, or
It is selected from:
X is selected from N or CH；
Y is selected from N or CR5；
R5Selected from hydrogen, (C1-C4) alkyl；
Z is CR6；
R6Selected from hydrogen or
It is selected from:
Q is S.
Simultaneously, the present invention be also more particularly preferably related to indoline-like compound and its stereoisomer of general formula I with And pharmaceutically acceptable salt, wherein
Cy is selected from: The Cy can be optionally by 1-3 A R1Replace；
R1Independently selected from hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy；(the C1-C4) alkyl, (C1-C4) Alkoxy can be optionally by 1-3 R2Replace；
R2Independently selected from halogen or
It is selected from:
X is selected from N or CH；
Y is selected from N or CH；
Z is CR6；
R6Selected from hydrogen or
It is selected from:
Q is S.
The sulfonylindoline compounds and its stereoisomer and pharmaceutically acceptable salt of general formula I of the present invention preferably are selected from following Compound, but these compounds are not meant to any limitation of the invention:
In addition, the invention also includes the prodrugs of the compounds of this invention.The prodrug of the compounds of this invention is the derivative of general formula I Object, their own may have weaker activity even without activity, but upon administration, in physiological conditions (such as pass through Metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
The indoline-like compound and its stereoisomer and pharmaceutically acceptable salt of above-described general formula I, institute The pharmaceutically acceptable salt stated includes the salt formed with inorganic acid, Organic Acid and Base metal ion；The inorganic acid is selected from: Hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid；The organic acid is selected from: succinic acid, fumaric acid, maleic acid, lactic acid, apple Acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid or p-methyl benzenesulfonic acid；Affiliated alkali metal ion is selected from lithium ion, sodium ion Or potassium ion.
" halogen " refers to fluorine, chlorine, bromine or iodine in the present invention；" alkyl " refers to the alkyl of linear chain or branched chain；" heteroaryl " is Refer to containing carbon atom and heteroatomic monocycle or polycyclic cyclic annular system, and cyclic annular system has armaticity, heteroatomic type It is as claimed in claim with number；Represent substituent group junction.
The present invention can the indoline-like compound containing above formula I and its stereoisomer and pharmaceutically acceptable salt As active constituent, composition is prepared by mixing into pharmaceutically acceptable carrier or excipient.The carrier or excipient packet Include diluent well known in the art, adhesive, wetting agent, disintegrating agent, lubricant, glidant etc..Diluent includes but is not limited to Starch, dextrin, sucrose, glucose, lactose, mannitol, sorbierite, xylitol, calcium monohydrogen phosphate etc.；Wetting agent include water, ethyl alcohol, Isopropanol etc.；Adhesive includes but is not limited to starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatin Slurry, sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, polyethylene glycol etc.；Disintegrating agent includes but is not limited to dry Starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium, carboxylic first Base sodium starch, dodecyl sodium sulfate etc.；Lubricant and glidant include but is not limited to talcum powder, silica, polyethylene glycol Deng.
Pharmaceutical composition of the invention can be configured to several dosage form, the dosage form include but is not limited to injection, tablet, Capsule etc..
Indoline-like compound of the invention and its stereoisomer and pharmaceutically acceptable salt can be with other work Property ingredient is applied in combination, to reach more preferably therapeutic effect.
The present invention also provides the indoline-like compounds and its stereoisomer and pharmaceutically acceptable salt of general formula I Application in the drug that preparation prevention and/or treatment have related disorders with PD-1/PD-L1 signal path.Described and PD-1/ The related disease of PD-L1 signal path is selected from cancer, infectious diseases, autoimmune disease.The cancer be selected from liver cancer, Lung cancer, cutaneum carcinoma, neoplastic hematologic disorder, glioma, digestive system tumor, breast cancer, lymthoma, nervous system neoplasm, melanoma； The infectious diseases is selected from bacterium infection, virus infection；The autoimmune disease is selected from organ specificity, system Property autoimmunity disease.Wherein, the organ specific autoimmune disease includes chronic lymphocytic thyroiditis, thyroid gland function Energy hyperfunction, insulin-dependent diabetes mellitus, ulcerative colitis, acute idiopathic polyneuritis, the systematicness itself are exempted from Epidemic disease includes rheumatoid arthritis, systemic loupus erythematosus, systemic vasculitis, autoimmune hemolytic anemia.
The positive effect of the present invention is that: indoline-like compound of the invention has novel chemical structure, and There is very high inhibitory activity to PD-1/PD-L1 interaction in research in vitro, can be used for the treatment of a variety of diseases such as cancer And prevention.
Examples provided hereinafter and preparation example further elucidate and illustrate the present invention compound and its preparation side Method.It should be appreciated that the range of following examples and preparation example does not limit the scope of the invention in any way.
Following synthetic route is summarized and describes the preparation of I derivative of formula of the invention, and all raw materials all pass through Mode described in these processes, by organic chemistry filed it is well-known to the ordinarily skilled artisan method preparation or it is commercially available. Derivative of the invention is prepared by method described in these processes or by similar method, these methods It is that organic chemistry filed is well-known to the ordinarily skilled artisan.Determine in the whole variable factors such as claim applied in these processes Justice.
Route one:
(a) using the bromo- 1H- indoles of 4- and benzene, substituted benzene or hetero-aromatic ring boric acid or borate as raw material, pass through Suzuki- Intermediate 2 is made in Miyaura coupling reaction；
(b) it is raw material with intermediate 2, indoline intermediate 3 is made under reducing agent such as sodium cyanoborohydride effect；
(c) heterocyclic carboxylic acid using intermediate 3 and containing formoxyl passes through amidation process as raw material under the conditions of condensing agent The intermediate 4 containing formoxyl is made；
It (d) is raw material with intermediate 4, with aminated compounds condensation and sodium cyanoborohydride or sodium triacetoxy borohydride The lower reduction of effect or the target compound that general formula I is further made by nucleophilic substitution or carbonylation.
Route two:
(e) heterocyclic carboxylic acid using intermediate 3 and containing halogen passes through amidation process system as raw material under the conditions of condensing agent Obtain intermediate 5；
(f) it is raw material with intermediate 5, is obtained with vinyl boronic acids pinacol ester or tributylvinyl tin by coupling reaction To intermediate 6；
(g) it is raw material with intermediate 6, the intermediate 4 containing formoxyl is made under osmium reagent and oxidant effect；
It (h) is raw material with intermediate 4, with aminated compounds condensation and sodium cyanoborohydride or sodium triacetoxy borohydride Effect is lower to restore the target compound that general formula I is made.
Route three:
(i) using the bromo- 1H- indoles of 4- as raw material, indoline intermediate is made under reducing agent such as sodium cyanoborohydride effect 7；
(j) using intermediate 7 and benzene, substituted benzene or hetero-aromatic ring boric acid or borate as raw material, pass through Suzuki-Miyaura Intermediate 3 is made in coupling reaction；
(k) heterocyclic carboxylic acid using intermediate 3 and containing ethylidene ether structure is anti-by amidation under the conditions of condensing agent as raw material Intermediate 8 should be made；
(l) it is raw material with intermediate 8, is deprotected the intermediate 4 containing formoxyl is made in acid condition；
It (m) is raw material with intermediate 4, with aminated compounds condensation and sodium cyanoborohydride or sodium triacetoxy borohydride The lower reduction of effect or the target compound that general formula I is further made by nucleophilic substitution or carbonylation.
Route four:
(n) heterocyclic carboxylic acid using intermediate 7 and containing ethylidene ether structure is anti-by amidation under the conditions of condensing agent as raw material Intermediate 9 should be made；
(o) it is raw material with intermediate 9, is deprotected the intermediate 10 containing formoxyl is made in acid condition；
It (p) is raw material with intermediate 10, with aminated compounds condensation and sodium cyanoborohydride or triacetoxy boron hydride Intermediate 11 is made in lower restore of sodium effect.
(q) using intermediate 11 and benzene, substituted benzene or hetero-aromatic ring boric acid or borate as raw material, pass through Suzuki-Miyaura Coupling reaction or the target compound that general formula I is further made by nucleophilic substitution or carbonylation.
Route five:
(r) heterocyclic carboxylic acid using intermediate 7 and containing formoxyl passes through amidation process as raw material under the conditions of condensing agent The intermediate 10 containing formoxyl is made；
(s) using intermediate 10 and benzene, substituted benzene or hetero-aromatic ring boric acid or borate as raw material, pass through Suzuki-Miyaura Further intermediate 4 is made by nucleophilic substitution in coupling reaction；
It (t) is raw material with intermediate 4, with aminated compounds condensation and sodium cyanoborohydride or sodium triacetoxy borohydride Effect is lower to restore the target compound that general formula I is made.
Route six:
(u) using intermediate 7 and replace heterocyclic carboxylic acid as raw material, under the conditions of condensing agent by amidation process be made in Mesosome 11；
(v) using intermediate 11 and benzene, substituted benzene or hetero-aromatic ring boric acid or borate as raw material, pass through Suzuki-Miyaura Coupling reaction or the target compound that general formula I is further made by nucleophilic substitution.
Route seven:
(w) using intermediate 9 and benzene, substituted benzene or hetero-aromatic ring boric acid or borate as raw material, pass through Suzuki-Miyaura Further intermediate 8 is made by nucleophilic substitution in coupling reaction.
(x) it is raw material with intermediate 8, is deprotected the intermediate 4 containing formoxyl is made in acid condition；
It (y) is raw material with intermediate 4, with aminated compounds condensation and sodium cyanoborohydride or sodium triacetoxy borohydride The lower reduction of effect or the target compound that general formula I is further made by being carbonylated.
The definition of described Cy, Q, X, Y, Z are as claimed in claim.In intermediate 5, A is chlorine, bromine or iodine.
The method or similar that indoline-like compound with general formula I of the invention can be described according to above-mentioned reaction route Method be prepared.
Specific embodiment:
Below in an example, the method for the preparation part compound is depicted.It will be appreciated that following methods and affiliated Other methods known to the those of ordinary skill in field may be applicable to the preparation of all compounds of the present invention.Embodiment It is intended to illustrate and be not intended to limit the scope of the invention.
Embodiment 1:(2- (((2- hydroxyethyl) amino) methyl) thiazole -5- base) (4- Phenylindole quinoline -1- base) formyl
Step 1:4- phenyl -1H- indoles
At room temperature, by the bromo- 1H- indoles (7g, 35.9mmol) of 4-, phenyl boric acid (4.38g, 35.9mmol), four (triphenyls Phosphine) palladium (1.24g, 1.07mmol), potassium carbonate (14.89g, 107.7mmol) be dissolved in dioxane and water (volume ratio 4:1, In the mixed solvent 200mL).Under nitrogen protection, 60 DEG C are warming up to react 10 hours.It is cooled to room temperature, pads suction filtered through kieselguhr, Filtrate is extracted with dichloromethane, organic layer saturated common salt water washing, is concentrated under reduced pressure, and column chromatography for separation obtains white solid 4.28g, Yield 61.7%.1H NMR(600MHz,DMSO-d6) δ 11.27 (s, 1H), 7.67 (d, J=7.3Hz, 2H), 7.49 (t, J= 7.7Hz, 2H), 7.42 (t, J=5.9Hz, 2H), 7.37 (t, J=7.4Hz, 1H), 7.18 (t, J=7.6Hz, 1H), 7.08 (d, J=7.1Hz, 1H), 6.55 (s, 1H).
Step 2:4- Phenylindole quinoline
At room temperature, 4- phenyl -1H- indoles (3g, 15.54mmol) is dissolved in glacial acetic acid (20mL), is slowly added to cyano Sodium borohydride (2.93g, 46.61mmol) reacts at room temperature 3 hours.Under ice bath, pH to 9-10, second are adjusted with 40%NaOH solution Acetoacetic ester extraction, organic layer saturated common salt water washing are concentrated under reduced pressure, and column chromatography for separation obtains white solid 2.09g, yield 68.9%.1H NMR(600MHz,DMSO-d6) δ 7.47-7.40 (m, 4H), 7.36-7.29 (m, 1H), 7.00 (t, J=7.7Hz, 1H), 6.59 (d, J=7.1Hz, 1H), 6.51 (d, J=7.7Hz, 1H), 5.59 (s, 1H), 3.39 (t, J=8.4Hz, 2H), 2.97 (t, J=8.4Hz, 2H).
Step 3:(2- bromo thiazole -5- base) (4- Phenylindole quinoline -1- base) formyl
By 4- Phenylindole quinoline (1g, 5.13mmol), 2- bromo thiazole -5- carboxylic acid (1.06g, 5.13mmol) and 2- (7- oxygen Change benzotriazole)-N, N, N', the dry DMF of N'- tetramethylurea hexafluorophosphate (HATU, 2.93g, 7.7mmol) addition In (20mL), after being stirred at room temperature uniformly, it is added n,N-diisopropylethylamine (1.33g, 10.26mmol), reacts at room temperature 3 hours. Reaction solution is poured into ice water, is stirred at room temperature half an hour, filters, obtains pale solid 1.51g, yield 76.7%.1H NMR(600MHz,DMSO-d6)δ8.27(s,1H),8.08(s,1H),7.51-7.45(m,4H),7.42-7.37(m,1H), 7.35 (t, J=7.9Hz, 1H), 7.15 (d, J=7.6Hz, 1H), 4.41 (t, J=8.1Hz, 2H), 3.26 (t, J=8.1Hz, 2H)。
Step 4:(4- Phenylindole quinoline -1- base) (2- vinylthiazole -5- base) formyl
At room temperature, by (2- bromo thiazole -5- base) (4- Phenylindole quinoline -1- base) formyl (0.5g, 1.3mmol), tributyl Vinyl tin (0.46g, 1.43mmol), tetrakis triphenylphosphine palladium (0.15g, 0.13mmol) and cesium carbonate (0.76g, 2.34mmol) it is dissolved in the in the mixed solvent of Isosorbide-5-Nitrae-dioxane/water (volume ratio 3:1,15mL), the lower 100 DEG C of reactions of nitrogen protection 3.5 hour.Reaction solution is cooled to room temperature, Isosorbide-5-Nitrae-dioxane is evaporated off.Reaction solution, saturated common salt washing is extracted with ethyl acetate Organic layer is washed, organic layer is evaporated, column chromatography for separation obtains yellow solid 0.2g, yield 46.3%.1H NMR(600MHz,DMSO-d6) δ 8.37 (s, 1H), 8.09 (s, 1H), 7.48 (dd, J=9.4,5.1Hz, 4H), 7.41 (dt, J=12.6,6.8Hz, 1H), 7.34 (t, J=7.8Hz, 1H), 7.14 (d, J=7.4Hz, 1H), 7.01 (dd, J=17.5,10.9Hz, 1H), 6.23 (d, J= 17.5Hz, 1H), 5.73 (d, J=11.0Hz, 1H), 4.42 (s, 2H), 3.25 (t, J=8.1Hz, 2H).
Step 5:5- (4- Phenylindole quinoline -1- formoxyl) thiazole -2- formaldehyde
By (4- Phenylindole quinoline -1- base) (2- vinylthiazole -5- base) formyl (0.6g, 1.8mmol), two hydration osmic acids Potassium (0.13g, 0.36mmol) is dissolved in the in the mixed solvent of Isosorbide-5-Nitrae-dioxane/water (volume ratio 5:1,12mL), is stirred at room temperature 5 points Sodium metaperiodate (1.54g, 7.2mmol) is added after clock, is stirred to react at room temperature 3 hours.Reaction solution is poured into water, is stirred, Filter to obtain light yellow solid 0.52g, yield 86.6%.1H NMR(600MHz,DMSO-d6)δ8.73(s,1H),7.52-7.46 (m, 5H), 7.43-7.33 (m, 3H), 7.18 (d, J=7.5Hz, 1H), 4.40 (t, J=7.9Hz, 2H), 3.26 (t, J= 8.1Hz,2H)。
Step 6:(2- (((2- hydroxyethyl) amino) methyl) thiazole -5- base) (4- Phenylindole quinoline -1- base) formyl is (in fact Apply example 1)
At room temperature, by 5- (4- Phenylindole quinoline -1- formoxyl) thiazole -2- formaldehyde (0.2g, 0.6mmol), ethanol amine (0.18g, 3mmol), glacial acetic acid (0.054g, 0.9mmol) are added to the mixing of methylene chloride/methanol (volume ratio 1:1,7mL) It in solvent, reacts at room temperature 3 hours, is added sodium cyanoborohydride (0.19g, 3mmol), the reaction was continued at room temperature 10 hours.To Add water in reaction solution, organic solvent is evaporated off, methylene chloride extraction is added, solvent, column layer is evaporated off in saturated common salt water washing organic layer Analysis separates to obtain white solid 0.062g, yield 27.2%.
ESI-MS m/z:380.1[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.26(s,1H),7.51-7.45(m, 5H), 7.39 (ddd, J=8.4,5.9,2.4Hz, 1H), 7.33 (t, J=7.9Hz, 1H), 7.13 (d, J=7.5Hz, 1H), 4.56 (t, J=5.3Hz, 1H), 4.38 (t, J=8.2Hz, 2H), 4.04 (s, 2H), 3.50 (q, J=5.5Hz, 2H), 3.24 (t, J=8.1Hz, 2H), 2.69 (t, J=5.7Hz, 2H).
According to the synthetic method of embodiment 1, using 5- (4- Phenylindole quinoline -1- formoxyl) thiazole -2- formaldehyde as raw material, lead to It crosses and is reacted with N- (2- amino-ethyl) acetamide, then the compound of embodiment 2 is prepared through sodium cyanoborohydride reduction.
Embodiment 2:N- (2- (((5- (4- Phenylindole quinoline -1- formoxyl) thiazol-2-yl) methyl) amino) ethyl) second Amide
ESI-MS m/z:421.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.26(s,1H),7.83(s,1H), 7.48 (dd, J=9.0,5.2Hz, 4H), 7.39 (ddd, J=8.2,5.9,2.3Hz, 1H), 7.33 (t, J=7.8Hz, 1H), 7.13 (d, J=7.6Hz, 1H), 4.39 (t, J=8.2Hz, 2H), 4.01 (s, 2H), 3.24 (t, J=8.1Hz, 2H), 3.16 (q, J=6.2Hz, 2H), 2.66 (t, J=6.4Hz, 2H), 1.80 (s, 3H).
Embodiment 3:(5- (((2- hydroxyethyl) amino) methyl) thiophene -2- base) (4- Phenylindole quinoline -1- base) formyl
Step 1:5- (4- Phenylindole quinoline -1- formoxyl) thiophene -2-formaldehyde
By 4- Phenylindole quinoline (2g, 10.25mmol), 5- formylthien -2- carboxylic acid (2.08g, 13.33mmol), HATU (5.85g, 15.38mmol) is dissolved in DMF (30mL), and 20min is stirred at room temperature, and will enter n,N-diisopropylethylamine (6.62g, 51.26mmol), in room temperature reaction 3 hours.Reaction solution is poured into water, is stirred 10 minutes, is filtered, it is solid to obtain brown color Body 2.51g, yield 73.4%.ESI-MS m/z:334.1[M+H]+。
Step 2:(5- (((2- hydroxyethyl) amino) methyl) thiophene -2- base) (4- Phenylindole quinoline -1- base) formyl is (in fact Apply example 3)
At room temperature, by 5- (4- Phenylindole quinoline -1- formoxyl) thiophene -2-formaldehyde (0.1g, 0.3mmol), ethanol amine (0.092g, 1.5mmol), glacial acetic acid (0.027g, 0.45mmol) are added to methylene chloride/methanol (volume ratio 1:1,5mL) In the mixed solvent reacts at room temperature 5 hours, is added sodium cyanoborohydride (0.095g, 1.5mmol), the reaction was continued at room temperature 10 Hour.Add water into reaction solution, organic solvent is evaporated off, methylene chloride extraction is added, saturated common salt water washing organic layer is evaporated off molten Agent, column chromatography for separation obtain white solid 0.035g, yield 30.7%.
ESI-MS m/z:379.1[M+H]+；1H NMR(600MHz,DMSO-d6) δ 8.05 (d, J=7.7Hz, 1H), 7.60 (d, J=3.6Hz, 1H), 7.53-7.45 (m, 4H), 7.43-7.37 (m, 1H), 7.32 (t, J=7.8Hz, 1H), 7.11 (d, J =7.5Hz, 1H), 7.05 (d, J=3.3Hz, 1H), 4.54 (s, 1H), 4.40 (t, J=8.1Hz, 2H), 3.95 (s, 2H), 3.49 (d, J=4.0Hz, 2H), 3.24 (t, J=8.0Hz, 2H), 2.64 (t, J=5.7Hz, 2H).
According to the synthetic method of embodiment 3, using 5- (4- Phenylindole quinoline -1- formoxyl) thiophene -2-formaldehyde as raw material, lead to It crosses and is reacted from different aminated compounds, then the compound of embodiment 4-7 is prepared through sodium cyanoborohydride reduction.
Embodiment 4:N- (2- (((5- (4- Phenylindole quinoline -1- formoxyl) thiophene -2- base) methyl) amino) ethyl) second Amide
ESI-MS m/z:420.2[M+H]+；1H NMR(600MHz,DMSO-d6) δ 8.04 (d, J=7.8Hz, 1H), 7.80 (s, 1H), 7.59 (d, J=3.7Hz, 1H), 7.51-7.45 (m, 4H), 7.41-7.36 (m, 1H), 7.32 (t, J=7.8Hz, 1H), 7.10 (d, J=7.6Hz, 1H), 7.03 (d, J=3.5Hz, 1H), 4.39 (t, J=8.1Hz, 2H), 3.91 (s, 2H), 3.23 (t, J=8.0Hz, 2H), 3.13 (dd, J=12.2,6.2Hz, 2H), 2.59 (t, J=6.4Hz, 2H), 1.79 (s, 3H).
Embodiment 5:N- (2- (((5- (4- Phenylindole quinoline -1- formoxyl) thiophene -2- base) methyl) amino) ethyl) first Sulfonamide
ESI-MS m/z:456.1[M+H]+。
Embodiment 6:((5- (4- Phenylindole quinoline -1- formoxyl) thiophene -2- base) methyl)-D-Ser
ESI-MS m/z:423.1[M+H]+。
Embodiment 7:((5- (4- Phenylindole quinoline -1- formoxyl) thiophene -2- base) methyl)-D-alanine
ESI-MS m/z:407.1[M+H]+。
Embodiment 8:(5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) (4- Phenylindole quinoline -1- base) formyl
Step 1:5- formyl thiazole -2- carboxylic acid, ethyl ester
At room temperature, ethyl thiooxamate (5g, 37.59mmol) and 2- bromine malonaldehyde (5.64g, 37.59mmol) are added Enter into glycol dimethyl ether (120mL), continues to be stirred to react 10 hours.Water is added into reaction solution, methylene chloride extraction is satisfied With brine It organic layer, washed organic layer, solvent evaporated obtains yellow-brown solid 3.94g, yield 56.6%.1H NMR (600MHz,DMSO-d6) δ 10.15 (s, 1H), 8.87 (s, 1H), 4.42 (q, J=7.1Hz, 2H), 1.35 (t, J=7.1Hz, 3H)。
Step 2:5- formyl thiazole -2- carboxylic acid
At room temperature, by 5- formyl thiazole -2- carboxylic acid, ethyl ester (1g, 5.41mmol) be added tetrahydrofuran/water (volume ratio 4: 1,5mL) in the mixed solvent is added lithium hydroxide (0.26g, 10.81mmol), is stirred to react 1 hour.Tetrahydrofuran is evaporated off, It is extracted with dichloromethane, water layer adjusts pH to 5-6 with dilute hydrochloric acid, is evaporated water layer, obtains faint yellow solid 0.57g, yield 67.3%. ESI-MS m/z:158.0[M+H]+。
Step 3:2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- formaldehyde
At room temperature, by 4- Phenylindole quinoline (1.5g, 7.69mmol), 5- formyl thiazole -2- carboxylic acid (1.45g, 9.23mmol), HATU (4.39g, 11.53mmol) is dissolved in DMF (30mL), is stirred 20min, will be entered n,N-diisopropylethylamine (4.96g, 38.44mmol), in room temperature reaction 2.5 hours.Reaction solution is poured into water, is stirred 10 minutes, filters, obtains brown color Solid 2.12g, yield 82.7%.1H NMR(600MHz,DMSO-d6) δ 10.15 (s, 1H), 8.87 (s, 1H), 8.25 (d, J= 8.0Hz, 1H), 7.52-7.47 (m, 4H), 7.40 (dd, J=12.9,7.2Hz, 2H), 7.21 (d, J=7.5Hz, 1H), 4.70 (t, J=8.1Hz, 2H), 3.29 (t, J=8.1Hz, 2H).
Step 4:(5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) (4- Phenylindole quinoline -1- base) formyl is (in fact Apply example 8)
At room temperature, by 2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- formaldehyde (0.1g, 0.3mmol), ethanol amine (0.092g, 1.5mmol), glacial acetic acid (0.027g, 0.45mmol) are added to methylene chloride/methanol (volume ratio 1:1,5mL) In the mixed solvent reacts at room temperature 7 hours, is added sodium cyanoborohydride (0.095g, 1.5mmol), the reaction was continued at room temperature 12 Hour.Add water into reaction solution, organic solvent is evaporated off, methylene chloride extraction is added, saturated common salt water washing organic layer is evaporated off molten Agent, column chromatography for separation obtain white solid 0.022g, yield 19.3%.
ESI-MS m/z:380.1[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.23(s,1H),7.91(s,1H), 7.80 (s, 1H), 7.49 (q, J=7.8Hz, 4H), 7.38 (dt, J=15.3,7.2Hz, 2H), 7.16 (d, J=7.6Hz, 1H), 4.68 (t, J=7.9Hz, 2H), 3.98 (s, 2H), 3.26 (t, J=8.1Hz, 2H), 3.13 (dd, J=11.8,5.8Hz, 2H), 2.58 (t, J=6.3Hz, 2H), 1.79 (s, 3H).
According to the synthetic method of embodiment 8, using 2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- formaldehyde as raw material, lead to It crosses and is reacted from different aminated compounds, then the compound of embodiment 9-21 is prepared through sodium cyanoborohydride reduction.
Embodiment 9:(5- (((2- hydroxyethyl) (methyl) amino) methyl) thiazol-2-yl) (4- Phenylindole quinoline -1- Base) formyl
ESI-MS m/z:394.2[M+H]+。
Embodiment 10:N- (2- (((2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- base) methyl) amino) ethyl) second Amide
ESI-MS m/z:421.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.23(s,1H),7.91(s,1H), 7.80 (s, 1H), 7.49 (q, J=7.8Hz, 4H), 7.38 (dt, J=15.3,7.2Hz, 2H), 7.16 (d, J=7.6Hz, 1H), 4.68 (t, J=7.6Hz, 2H), 3.98 (s, 2H), 3.26 (t, J=8.1Hz, 2H), 3.13 (dd, J=11.8,5.8Hz, 2H), 2.58 (t, J=6.3Hz, 2H), 1.79 (s, 3H).
Embodiment 11:2- (((2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- base) methyl) amino) ethane -1- sulphur Amide
ESI-MS m/z:443.1[M+H]+。
Embodiment 12:N- (2- (((2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- base) methyl) amino) ethyl) first Sulfonamide
ESI-MS m/z:457.1[M+H]+。
Embodiment 13:((2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- base) methyl)-D-Ser
ESI-MS m/z:424.1[M+H]+。
Embodiment 14:((2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- base) methyl)-D-Thr
ESI-MS m/z:438.1[M+H]+。
Embodiment 15:((2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- base) methyl)-D-alanine
ESI-MS m/z:408.1[M+H]+。
Embodiment 16:((2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- base) methyl)-l-Alanine
ESI-MS m/z:408.1[M+H]+。
Embodiment 17:(S) -3- hydroxyl -4- (((2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- base) methyl) ammonia Base) butyric acid
ESI-MS m/z:438.2[M+H]+。
Embodiment 18:(S)-(5- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) thiazol-2-yl) (4- Phenylindole Quinoline -1- base) formyl
ESI-MS m/z:420.2[M+H]+。
Embodiment 19:((2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- base) methyl)-L-PROLINE
ESI-MS m/z:434.2[M+H]+。
Embodiment 20:(S) -1- ((2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- base) methyl) piperidines -2- carboxylic acid
ESI-MS m/z:448.2[M+H]+。
Embodiment 21:(4- Phenylindole quinoline -1- base) (5- (((tetrahydro -2H- pyrans -4- base) amino) methyl) thiazole -2- Base) formyl
ESI-MS m/z:420.2[M+H]+。
Embodiment 22:3- ((2- (4- Phenylindole quinoline -1- formoxyl) thiazole -5- base) methyl) oxazolidine -2- ketone
At room temperature, by (5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) (4- Phenylindole quinoline -1- base) formyl (embodiment 8,0.1g, 0.26mmol) is dissolved in dehydrated alcohol (8mL), and sodium ethoxide (1M, 0.53mL, 0.53mmol) is slowly added dropwise With the mixed solution of diethyl carbonate (0.31g, 2.64mmol), it is warming up to back flow reaction 7 hours.Acetic acid is added into system, Solvent is evaporated off, methylene chloride is added, organic phase is evaporated off, and column chromatography for separation obtains white solid 0.046g, yield 42.6% in washing.
ESI-MS m/z:406.1[M+H]+。
Intermediate: the bromo- 1,3,4- thiadiazoles -2- carboxylic acid of 5-
Under ice bath, bromo- 1,3,4- thiadiazoles -2- carboxylic acid, ethyl ester (1g, 4.24mmol) of 5-, NaOH (1g, 25mmol) are added Enter to the in the mixed solvent of methanol/water (volume ratio 4:1,15mL).Reaction solution continues to be stirred to react 2 hours at room temperature.Xiang Ti Dilute hydrochloric acid is added in system and adjusts pH to 6, solvent is evaporated off and obtains white solid 0.79g, yield 89.7% can be directly used in next step.
The synthetic method of similar embodiment 1, using 4- Phenylindole quinoline as raw material, by with bromo- 1,3,4- thiadiazoles -2- of 5- Carboxylic acyloxy amination, tributylvinyl tin coupling, sodium periodate oxidation and aminated compounds are through sodium cyanoborohydride reduction amination The compound of embodiment 23-27 is prepared.
Embodiment 23:(5- (((2- hydroxyethyl) amino) methyl) -1,3,4- thiadiazoles -2- base) (4- Phenylindole quinoline - 1- yl) formyl
ESI-MS m/z:381.1[M+H]+。
Embodiment 24:N- (2- (((5- (4- Phenylindole quinoline -1- formoxyl) -1,3,4- thiadiazoles -2- base) methyl) ammonia Base) ethyl) acetamide
ESI-MS m/z:422.2[M+H]+。
Embodiment 25:N- (2- (((5- (4- Phenylindole quinoline -1- formoxyl) -1,3,4- thiadiazoles -2- base) methyl) ammonia Base) ethyl) Methanesulfomide
ESI-MS m/z:458.1[M+H]+。
Embodiment 26:((5- (4- Phenylindole quinoline -1- formoxyl) -1,3,4- thiadiazoles -2- base) methyl)-D-Ser
ESI-MS m/z:425.1[M+H]+。
Embodiment 27:((5- (4- Phenylindole quinoline -1- formoxyl) -1,3,4- thiadiazoles -2- base) methyl)-D-alanine
ESI-MS m/z:409.2[M+H]+。
Embodiment 28:(4- (benzo [d] oxazole -5- base) indoline -1- base) (5- (((2- hydroxyethyl) amino) methyl) Thiazol-2-yl) formyl
Step 1:5- (1,3- dioxolanes -2- base) thiazole -2- carboxylic acid, ethyl ester
At room temperature, by 5- formyl thiazole -2- carboxylic acid, ethyl ester (3g, 16.22mmol), ethylene glycol (3.5g, 56.42mmol), p-methyl benzenesulfonic acid monohydrate (0.25g, 1.32mmol) is dissolved in toluene (20mL), is warming up to 110 DEG C of reactions 3 Hour.Toluene is evaporated off, residue is dissolved with methylene chloride, is had respectively with saturated sodium bicarbonate solution and saturated common salt water washing Machine layer is evaporated off solvent and obtains yellow-brown solid 2.17g, yield 58.4%.1H NMR(600MHz,DMSO-d6)δ8.17(s,1H), 6.24 (s, 1H), 4.38 (q, J=7.1Hz, 2H), 4.09-4.03 (m, 2H), 4.02-3.96 (m, 2H), 1.34 (dt, J= 11.7,4.5Hz,3H)。
Step 2:5- (1,3- dioxolanes -2- base) thiazole -2- carboxylic acid
At room temperature, 5- (1,3-dioxolane -2- base) thiazole -2- carboxylic acid, ethyl ester (2.17g, 9.47mmol) is dissolved in tetrahydro The in the mixed solvent of furans/water (volume ratio 4:1,20mL) is added lithium hydroxide (0.68g, 28.42mmol), and it is anti-to continue stirring It answers 6 hours.Tetrahydrofuran is evaporated off, water layer is extracted with dichloromethane, water layer dilute hydrochloric acid adjusts pH to 6, and extracting n-butyl alcohol merges Organic layer is evaporated off solvent and obtains tenne solid 0.75g, yield 39.4%.ESI-MS m/z:202.0[M+H]+。
Step 3:(5- (1,3- dioxolanes -2- base) thiazol-2-yl) (4--bromo indole quinoline -1- base) formyl
At room temperature, by 4--bromo indole quinoline (0.57g, 2.89mmol), 5- (1,3-dioxolane -2- base) thiazole -2- carboxylic acid (0.7g, 3.47mmol), HATU (1.65g, 4.34mmol) are dissolved in DMF (20mL), are stirred 20min, will be entered N, N- diisopropyl Base ethamine (1.87g, 14.48mmol), in room temperature reaction 3 hours.Reaction solution is poured into water, is stirred 10 minutes, filters, obtains orange Brown solid 1.01g, yield 91.8%.1H NMR(600MHz,DMSO-d6) δ 8.22-8.14 (m, 2H), 7.34 (d, J= 8.0Hz, 1H), 7.22 (t, J=8.0Hz, 1H), 6.23 (s, 1H), 4.73 (t, J=8.1Hz, 2H), 4.09-4.03 (m, 2H), 4.03-3.98 (m, 2H), 3.19 (t, J=8.3Hz, 2H).
Step 4:2- (4--bromo indole quinoline -1- formoxyl) thiazole -5- formaldehyde
At room temperature, by (5- (1,3-dioxolane -2- base) thiazol-2-yl) (4--bromo indole quinoline -1- base) formyl (1.01g, 2.66mmol), p-methyl benzenesulfonic acid (0.91g, 5.29mmol) is dissolved in the in the mixed solvent of acetone/water (volume ratio 3:2,10mL), It is reacted 2.5 hours in 70 DEG C.Reaction solution is poured into ice water and is stirred 10 minutes, is filtered, it is dry, faint yellow solid 0.84g is obtained, is received Rate 94.1%.ESI-MS m/z:337.0[M+H]+。
Step 5:(4--bromo indole quinoline -1- base) (5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) formyl
At room temperature, by 2- (4--bromo indole quinoline -1- formoxyl) thiazole -5- formaldehyde (0.84g, 2.5mmol), ethanol amine Mixing to methylene chloride/water (volume ratio 1:1,10mL) is added in (0.76g, 12.5mmol) and glacial acetic acid (0.23g, 3.75mmol) In bonding solvent, continue stirring 5 hours.Sodium cyanoborohydride (0.79g, 12.5mmol) is added into system, continues at room temperature Reaction 12 hours.Add water into reaction solution, organic solvent is evaporated off, methylene chloride is added and extracts, saturated common salt water washing organic layer, Solvent is evaporated off, column chromatography for separation obtains faint yellow solid 0.52g, yield 54.6%.1H NMR(600MHz,DMSO-d6)δ8.18(d, J=8.1Hz, 1H), 7.92 (s, 1H), 7.32 (d, J=8.0Hz, 1H), 7.21 (t, J=8.1Hz, 1H), 4.73 (t, J= 8.2Hz, 2H), 4.51 (t, J=5.4Hz, 1H), 4.00 (s, 2H), 3.46 (q, J=5.7Hz, 2H), 3.18 (t, J=8.4Hz, 2H), 2.60 (t, J=5.7Hz, 2H).
Step 6:(4- (benzo [d] oxazole -5- base) indoline -1- base) (5- (((2- hydroxyethyl) amino) methyl) thiophene Azoles -2- base) formyl (embodiment 28)
At room temperature, by (4--bromo indole quinoline -1- base) (5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) formyl (0.5g, 1.31mmol), 5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolanes -2- base) benzo [d] oxazole (0.48g, 1.97mmol), [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (0.067g, 0.092mmol) and carbonic acid Sodium (0.28g, 2.62mmol) be added to dioxane/water (volume ratio 3:1,15mL) in the mixed solvent, under nitrogen protection It is reacted 4 hours in 80 DEG C.Filtering, is evaporated off solvent, column chromatography for separation obtains white solid 0.15g, yield 27.2%.
ESI-MS m/z:421.1[M+H]+；1H NMR(600MHz,DMSO-d6) δ 8.82 (s, 1H), 8.25 (d, J= 7.0Hz, 1H), 7.94-7.90 (m, 2H), 7.87 (d, J=8.4Hz, 1H), 7.56 (dd, J=8.4,1.5Hz, 1H), 7.38 (t, J=7.8Hz, 1H), 7.22 (d, J=7.4Hz, 1H), 4.69 (t, J=7.8Hz, 2H), 4.52 (t, J=5.3Hz, 1H), 4.00 (s, 2H), 3.47 (q, J=5.6Hz, 2H), 3.29 (t, J=8.2Hz, 2H), 2.61 (t, J=5.7Hz, 2H).
The synthetic method of similar embodiment 28, with (4--bromo indole quinoline -1- base) (5- (((2- hydroxyethyl) amino) methyl) Thiazol-2-yl) formyl and benzene, substituted benzene or hetero-aromatic ring boric acid or borate be raw material, it is coupled by Suzuki-Miyaura anti- The compound of embodiment 29-43 should be prepared.
Embodiment 29:(5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (1- methyl-1 H- indazole -4- Base) indoline -1- base) formyl
ESI-MS m/z:434.2[M+H]+。
Embodiment 30:(4- (1H- indoles -4- base) indoline -1- base) (5- (((2- hydroxyethyl) amino) methyl) thiophene Azoles -2- base) formyl
ESI-MS m/z:419.2[M+H]+。
Embodiment 31:(5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (6- methoxypyridine -2- base) Indoline -1- base) formyl
ESI-MS m/z:411.1[M+H]+。
Embodiment 32:(4- (1H- pyrroles [2,3-b] pyridine -5- base) indoline -1- base) (5- (((2- hydroxyethyl) ammonia Base) methyl) thiazol-2-yl) formyl
ESI-MS m/z:420.1[M+H]+。
Embodiment 33:(4- (2,3- dihydrobenzo [b] [1,4] dioxin -6- base) indoline -1- base) (5- (((2- hydroxyl Ethyl) amino) methyl) thiazol-2-yl) formyl
ESI-MS m/z:438.1[M+H]+。
Embodiment 34:(4- (benzo [d] thiazole -5- base) indoline -1- base) (5- (((2- hydroxyethyl) amino) methyl) Thiazol-2-yl) formyl
ESI-MS m/z:437.1[M+H]+。
Embodiment 35:(4- (benzo [d] oxazole -6- base) indoline -1- base) (5- (((2- hydroxyethyl) amino) methyl) Thiazol-2-yl) formyl
ESI-MS m/z:421.1[M+H]+。
Embodiment 36:(4- (benzo [d] thiazole -6- base) indoline -1- base) (5- (((2- hydroxyethyl) amino) methyl) Thiazol-2-yl) formyl
ESI-MS m/z:437.1[M+H]+。
Embodiment 37:(5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (quinoxalin-6-yl) indoline- 1- yl) formyl
ESI-MS m/z:432.1[M+H]+。
Embodiment 38:(5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (quinoline -3- base) indoline -1- Base) formyl
ESI-MS m/z:431.2[M+H]+。
Embodiment 39:(5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (thiophene -2- base) indoline -1- Base) formyl
ESI-MS m/z:386.1[M+H]+。
Embodiment 40:(5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (4- (trifluoromethoxy) phenyl) Indoline -1- base) formyl
ESI-MS m/z:464.1[M+H]+。
Embodiment 41:(4- (the fluoro- 3- methoxyphenyl of 2-) indoline -1- base) (5- (((2- hydroxyethyl) amino) first Base) thiazol-2-yl) formyl
ESI-MS m/z:428.1[M+H]+。
Embodiment 42:(5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (3- methoxyl group -2- methylbenzene Base) indoline -1- base) formyl
ESI-MS m/z:424.2[M+H]+。
Embodiment 43:(4- (3,4- Dimethoxyphenyl) indoline -1- base) (5- (((2- hydroxyethyl) amino) methyl) Thiazol-2-yl) formyl
ESI-MS m/z:440.2[M+H]+。
Embodiment 44:N- (2- (((2- (4- (benzo [d] oxazole -5- base) indoline -1- formoxyl) thiazole -5- base) first Base) amino) ethyl) acetamide
Step 1:4--bromo indole quinoline
At room temperature, the bromo- 1H- indoles (17g, 87.19mmol) of 4- is dissolved in glacial acetic acid (15mL), is stirred 10 minutes.It will Sodium cyanoborohydride (16.32g, 258.92mmol) is slowly added to reaction solution.It finishes, continues that reaction 1 hour is stirred at room temperature.To It is 8-9 that sodium hydroxide solution is added in system to pH, and methylene chloride extracts, and organic layer is evaporated off in saturated common salt water washing organic layer, Column chromatographs to obtain yellow oil 9.88g, yield 57.5%.ESI-MS m/z:198.0[M+H]+。
Step 2:5- (indoline -4- base) benzo [d] oxazole
At room temperature, by 4--bromo indole quinoline (1g, 5.08mmol), 5- (4,4,5,5- tetramethyls -1,3, penta boron of 2- dioxane Alkane -2- base) benzo [d] oxazole (1.87g, 7.61mmol), [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (0.26g, 0.36mmol) and sodium carbonate (1.08g, 10.15mmol) are added to dioxane/water (volume ratio 3:1,15mL) In the mixed solvent is reacted 5 hours in 80 DEG C under nitrogen protection.Filtering, is evaporated off solvent, column chromatography for separation obtains white solid 0.71g, yield 59.1%.ESI-MS m/z:237.1[M+H]+。
Step 3:(5- (1,3- dioxolanes -2- base) thiazol-2-yl) (4- (benzo [d] oxazole -5- base) indoline -1- Base) formyl
At room temperature, by 5- (indoline -4- base) benzo [d] oxazole (0.7g, 2.96mmol), 5- (1,3-dioxolane -2- Base) thiazole -2- carboxylic acid (0.72g, 3.56mmol), HATU (1.69g, 4.45mmol) be dissolved in DMF (20mL), 20min is stirred, N,N-diisopropylethylamine (1.92g, 14.82mmol) will be entered, in room temperature reaction 2.5 hours.Reaction solution is poured into water, is stirred It 10 minutes, filters, obtains faint yellow solid 1.06g, yield 85.7%.ESI-MS m/z:420.1[M+H]+。
Step 4:2- (4- (benzo [d] oxazole -5- base) indoline -1- formoxyl) thiazole -5- formaldehyde
At room temperature, by (5- (1,3-dioxolane -2- base) thiazol-2-yl) (4- (benzo [d] oxazole -5- base) indoline - 1- yl) formyl (1g, 2.39mmol), p-methyl benzenesulfonic acid (0.82g, 4.77mmol) be dissolved in acetone/water (volume ratio 3:2,10mL) In the mixed solvent, in 70 DEG C react 3 hours.Reaction solution is poured into ice water and is stirred 10 minutes, is filtered, it is dry, it obtains faint yellow Solid 0.8g, yield 89.7%.ESI-MS m/z:376.1[M+H]+。
Step 5:N- (2- (((2- (4- (benzo [d] oxazole -5- base) indoline -1- formoxyl) thiazole -5- base) methyl) Amino) ethyl) acetamide (embodiment 44)
At room temperature, by 2- (4- (benzo [d] oxazole -5- base) indoline -1- formoxyl) thiazole -5- formaldehyde (0.1g, 0.27mmol), N- (2- amino-ethyl) acetamide (0.14g, 1.33mmol), glacial acetic acid (0.024g, 0.4mmol) are added to two The in the mixed solvent of chloromethanes/methanol (volume ratio 1:1,5mL) reacts at room temperature 5 hours, addition sodium cyanoborohydride (0.084g, 1.33mmol), the reaction was continued at room temperature 13 hours.Add water into reaction solution, organic solvent is evaporated off, methylene chloride extraction is added It takes, saturated common salt water washing organic layer, solvent is evaporated off, column chromatography for separation obtains white solid 0.04g, yield 32.7%.
ESI-MS m/z:462.2[M+H]+。
According to the synthetic method of embodiment 44, with 2- (4- (benzo [d] oxazole -5- base) indoline -1- formoxyl) thiazole - 5- formaldehyde is raw material, and embodiment 45- is prepared by reacting from different aminated compounds, then through sodium cyanoborohydride reduction 50 compound.
Embodiment 45:2- (((2- (4- (benzo [d] oxazole -5- base) indoline -1- formoxyl) thiazole -5- base) methyl) Amino) ethane -1- sulfonamide
ESI-MS m/z:484.1[M+H]+。
Embodiment 46:N- (2- (((2- (4- (benzo [d] oxazole -5- base) indoline -1- formoxyl) thiazole -5- base) first Base) amino) ethyl) Methanesulfomide
ESI-MS m/z:498.1[M+H]+。
Embodiment 47:((2- (4- (benzo [d] oxazole -5- base) indoline -1- formoxyl) thiazole -5- base) methyl)-D- Serine
ESI-MS m/z:465.1[M+H]+。
Embodiment 48:((2- (4- (benzo [d] oxazole -5- base) indoline -1- formoxyl) thiazole -5- base) methyl)-D- Alanine
ESI-MS m/z:449.1[M+H]+。
Embodiment 49:((2- (4- (benzo [d] oxazole -5- base) indoline -1- formoxyl) thiazole -5- base) methyl)-L- Alanine
ESI-MS m/z:449.1[M+H]+。
Embodiment 50:(4- (benzo [d] oxazole -5- base) indoline -1- base) (5- (((tetrahydro -2H- pyrans -4- base) ammonia Base) methyl) thiazol-2-yl) formyl
ESI-MS m/z:461.2[M+H]+。
The preparation method of similar embodiment 22, with (4- (benzo [d] oxazole -5- base) indoline -1- base) (5- (((2- hydroxyl Base ethyl) amino) methyl) thiazol-2-yl) formyl (embodiment 28) be raw material, the compound of embodiment 51 is prepared.
Embodiment 51:3- ((2- (4- (benzo [d] oxazole -5- base) indoline -1- formoxyl) thiazole -5- base) methyl) is disliked Oxazolidine -2- ketone
ESI-MS m/z:447.1[M+H]+。
Embodiment 52:(R)-(5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (3- (3- (3- hydroxyl pyrrole Cough up alkane -1- base) propoxyl group) -2- aminomethyl phenyl) indoline -1- base) formyl
The bromo- 3- of step 1:1- (3- bromine propoxyl group) -2- methylbenzene
At room temperature, by 1,3- dibromopropane (75.24g, 376.4mmol), the bromo- 2- methylphenol (7g, 37.64mmol) of 3- It is added into acetone (300mL) with potassium carbonate (14.02g, 101.63mmol), reaction 7 days is stirred at room temperature.Filtering, removes under reduced pressure Filtrate, column chromatograph to obtain colourless liquid 10.28g, yield 89.3%.ESI-MSm/z:307.0[M+H]+。
Penta boron of step 2:2- (3- (3- bromine propoxyl group) -2- aminomethyl phenyl) -4,4,5,5- tetramethyl -1,3,2- dioxane Alkane
At room temperature, by the bromo- 3- of 1- (3- bromine propoxyl group) -2- methylbenzene (5g, 16.34mmol), connection boric acid pinacol ester (6.23g, 24.52mmol), [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (0.84g, 1.14mmol) and potassium acetate (4.81g, 49.03mmol) is added into Isosorbide-5-Nitrae-dioxane (60mL).Under nitrogen protection, it is reacted 20 hours in 80 DEG C.It crosses Filter, is evaporated off solvent, column chromatography for separation obtains white solid 3.91g, yield 67.6%.ESI-MS m/z:355.1[M+H]+。
Step 3:(4- (3- (3- bromine propoxyl group) -2- aminomethyl phenyl) indoline -1- base) (5- (((2- hydroxyethyl) ammonia Base) methyl) thiazol-2-yl) formyl
At room temperature, by (4--bromo indole quinoline -1- base) (5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) formyl (0.5g, 1.31mmol), 2- (3- (3- bromine propoxyl group) -2- aminomethyl phenyl) -4,4,5,5- tetramethyls -1,3,2- dioxane penta Borine (0.7g, 1.97mmol), [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (0.067g, 0.092mmol) and carbon Sour sodium (0.28g, 2.62mmol) is added to the in the mixed solvent of dioxane/water (volume ratio 3:1,15mL), in nitrogen protection Under in 80 DEG C react 7 hours.Filtering, is evaporated off solvent, column chromatography for separation obtains white solid 0.22g, yield 31.3%.ESI-MS m/z:530.1[M+H]+。
Step 4:(R)-(5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (3- (3- (3- hydroxypyrrole Alkane -1- base) propoxyl group) -2- aminomethyl phenyl) indoline -1- base) formyl (embodiment 52)
At room temperature, by (4- (3- (3- bromine propoxyl group) -2- aminomethyl phenyl) indoline -1- base) (5- (((2- hydroxyethyl) Amino) methyl) thiazol-2-yl) formyl (0.1g, 0.19mmol), (R) -3- hydroxy-pyrrolidine hydrochloride (0.34g, 2.74mmol), n,N-diisopropylethylamine (0.44g, 3.4mmol) is dissolved in methanol (7mL), and reaction solution is heated to 70 DEG C of reactions 15 hours.Solvent is evaporated off, methylene chloride is added into system, organic layer is evaporated off in saturated common salt water washing, and column chromatographs faint yellow Solid 0.027g, yield 26.7%.
ESI-MS m/z:537.3[M+H]+。
According to the synthetic method of embodiment 52, with (4- (3- (3- bromine propoxyl group) -2- aminomethyl phenyl) indoline -1- base) (5- (((2- hydroxyethyl) amino) methyl) thiazol-2-yl) formyl is raw material, by passing through parent from different aminated compounds The compound of embodiment 53 and embodiment 54 is prepared in core substitution reaction.
Embodiment 53:2- (3- hydroxyl -1- (3- (3- (1- (5- (((2- hydroxyethyl) amino) methyl) thiazole -2- formyl Base) indoline -4- base) -2- methylphenoxy) propyl) pyrrolidin-3-yl) acetic acid
ESI-MS m/z:595.3[M+H]+。
Embodiment 54:(3- (3- (1- (5- (((2- hydroxyethyl) amino) methyl) thiazole -2- formoxyl) indoline -4- Base) -2- methylphenoxy) propyl)-D-Ser
ESI-MS m/z:555.2[M+H]+。
The compounds of this invention biological activity research
It is tested using homogeneous phase time discrimination fluorescence (Homogenouse Time-Resolved Fluorescence, HTRF) To detect the ability that the compounds of this invention inhibits PD-1/PD-L1 interaction.Detection kit is bought in CisBio company, In include Anti-Tag1-Cyptate, Anti-Tag2-XL665/d2, Tag1-PD-L1, Tag2-PD-1, Dilution Reagent needed for Buffer, Detection Buffer etc. are tested.
Experimental procedure: PD-1 recombinant protein and PD-L1 recombinant protein are diluted to 500nM with Dilution Buffer respectively And 50nM.The small molecule compound 20 dissolved with Dilution Buffer dilution 4mM DMSO is again to 200uM.With containing 5% Tetra- times of gradient dilutions of Dilution Buffer of DMSO.It is dissolved simultaneously with Dilution Buffer dilution 600uM DMSO PD-1/PD-L1 inhibitor 20 is again to 30uM, with tetra- times of gradient dilutions of Dilution Buffer containing 5%DMSO.Successively to 384 The PD-1 that untested compound, the 4uL that 2uL has diluted have diluted and the PDL-1 that 4uL has diluted are added in hole.It mixes well, room temperature Place 15min.Anti-Tag1-Eu is diluted with Detection buffer3+(1:25) and anti-Tag2-XL665 (1:100). Then 10 μ L antibody mixed liquors are added in the good detection reagent of isometric mixed diluting, every reacting hole.Sealer is incubated at room temperature 2h.With ENVISION (Perkinelmer) instrument detects fluorescence signal (320nm stimulation, 665nm, 615nm transmitting).Each chemical combination quality testing Survey 8-12 concentration.
Compound inhibits the Activity Results of PD-1/PD-L1 interaction to be shown in Table 1.
1 the compounds of this invention of table inhibits the field of activity or IC of PD-1/PD-L1 interaction50Value.Range is as follows: A= 1nM-100nM；B=100.01nM-1 μM；C=1.01 μM -20 μM.
HTRF test result shows that embodiment compound can significantly inhibit PD-1/PD-L1 interaction in molecular level.

Claims (10)

1. the indoline-like compound and its stereoisomer and pharmaceutically acceptable salt of general formula I,
Wherein,
Cy is selected from 6-10 member aryl or 5-12 unit's heteroaryl, or isThe 5-12 unit's heteroaryl contains 1-3 Hetero atom selected from N, O or S；The 6-10 member aryl, 5-12 unit's heteroaryl orIt can be optionally by 1-3 R1It takes Generation；
R1Independently selected from hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, cyano, hydroxyl, carboxyl, amino；Described (C1-C4) alkyl, (C1-C4) alkoxy can be optionally by 1-3 R2Replace；
R2Independently selected from hydrogen, halogen, (C1-C4) alkyl, hydroxyl, amino, carboxyl, or
Ra、RbIndependently selected from hydrogen, (C1-C4) alkyl, (C3-C8) naphthenic base, hydroxyl (C1-C4) alkyl, amino (C1-C4) alkyl, Carbamoyl (C1-C4) alkyl, amino-sulfonyl (C1-C4) alkyl, methylsulfonyl amido (C1-C4) alkyl, carboxyl (C1-C4) alkane Base, (C1-C4) alkoxyl formyl (C1-C4) alkyl, tetrahydropyran -4-base；(the C1-C4) alkyl, (C3-C8) naphthenic base, hydroxyl (C1-C4) alkyl, amino (C1-C4) alkyl, carbamoyl (C1-C4) alkyl, amino-sulfonyl (C1-C4) alkyl, Methanesulfomide Base (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl, tetrahydropyran -4-base can optional quilt 1-3 R3Replace；
Or Ra、RbThe nitrogen-containing heterocycle of a 3-7 member, preferably 5-6 member nitrogen-containing hetero are formed together with the nitrogen-atoms being connected with them Ring；The nitrogen-containing heterocycle contains the 1-3 hetero atoms for being selected from N, O or S；The nitrogen-containing heterocycle can be optionally by 1-3 R4It takes Generation；
R3Independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, (C1-C4) alkyl, hydroxyl (C1-C4) alkyl, (C1-C4) alkoxy (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl, (C1-C4) acyl group；
R4Independently selected from hydrogen, hydroxyl, carboxyl, amino, carbamyl, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alcoxyl Formoxyl, hydroxyl (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl；
X is selected from N or CH；
Y is selected from N or CR5；
R5Selected from hydrogen, halogen, (C1-C4) alkyl, or
Z is CR6；
R6Selected from hydrogen, (C1-C4) alkyl, or
Rc、RdIndependently selected from hydrogen, (C1-C4) alkyl, (C3-C8) naphthenic base, hydroxyl (C1-C4) alkyl, amino (C1-C4) alkyl, Carbamoyl (C1-C4) alkyl, amino-sulfonyl (C1-C4) alkyl, methylsulfonyl amido (C1-C4) alkyl, carboxyl (C1-C4) alkane Base, (C1-C4) alkoxyl formyl (C1-C4) alkyl, tetrahydropyran -4-base；(the C1-C4) alkyl, (C3-C8) naphthenic base, hydroxyl (C1-C4) alkyl, amino (C1-C4) alkyl, carbamoyl (C1-C4) alkyl, amino-sulfonyl (C1-C4) alkyl, Methanesulfomide Base (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl, tetrahydropyran -4-base can optional quilt 1-3 R7Replace；
Or Rc、RdThe nitrogen-containing heterocycle of a 3-7 member, preferably 5-6 member nitrogen-containing hetero are formed together with the nitrogen-atoms being connected with them Ring；The nitrogen-containing heterocycle contains the 1-3 hetero atoms for being selected from N, O or S；The nitrogen-containing heterocycle can be optionally by 1-3 R8It takes In generation, carbon atom can be by oxo on ring；
R7Independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, (C1-C4) alkyl, hydroxyl (C1-C4) alkyl, (C1-C4) alkoxy (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl, (C1-C4) acyl group；
R8Independently selected from hydrogen, hydroxyl, carboxyl, amino, carbamyl, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alcoxyl Formoxyl, hydroxyl (C1-C4) alkyl, carboxyl (C1-C4) alkyl, (C1-C4) alkoxyl formyl (C1-C4) alkyl；
Q is selected from O, S or NR9；
R9Selected from hydrogen or (C1-C4) alkyl.
2. the indoline-like compound and its stereoisomer of general formula I as described in claim 1 and pharmaceutically acceptable Salt, wherein
Cy is selected from: The Cy can be optionally by 1-3 R1 Replace；
R1Independently selected from hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, cyano, hydroxyl, carboxyl, amino；Described (C1-C4) alkyl, (C1-C4) alkoxy can be optionally by 1-3 R2Replace；
R2Independently selected from hydrogen, halogen, (C1-C4) alkyl, hydroxyl, amino, carboxyl, or
3. the indoline-like compound and its stereoisomer of general formula I as claimed in claim 1 or 2 and pharmaceutically acceptable Salt, wherein
It is selected from:
4. the indoline-like compound and its stereoisomer and pharmacy of the general formula I as described in claim 1-3 any one Upper acceptable salt, wherein
X is selected from N or CH；
Y is selected from N or CR5；
R5Selected from hydrogen, (C1-C4) alkyl；
Z is CR6；
R6Selected from hydrogen or
Q is S.
5. the indoline-like compound and its stereoisomer and pharmacy of the general formula I as described in claim 1-4 any one Upper acceptable salt, wherein
It is selected from:
6. indoline-like compound as described below and its stereoisomer and pharmaceutically acceptable salt:
7. a kind of pharmaceutical composition, described pharmaceutical composition includes any one of the claim 1-6 as effective component institute Compound and its stereoisomer and pharmaceutically acceptable salt, carrier or the excipient stated.
8. any one of the claim 1-6 compound and its stereoisomer and pharmaceutically acceptable salt or right It is required that pharmaceutical composition described in 7 is in preparation prevention and/or the drug for the treatment of disease related with PD-1/PD-L1 signal path In application.
9. application according to claim 8, disease related with PD-1/PD-L1 signal path is selected from cancer, infectious disease Disease, autoimmune disease.
10. application according to claim 9, the cancer is selected from liver cancer, lung cancer, cutaneum carcinoma, neoplastic hematologic disorder, colloid Tumor, digestive system tumor, breast cancer, lymthoma, nervous system neoplasm, melanoma；The infectious diseases is selected from bacterium Infection, virus infection；The autoimmune disease is selected from organ specificity, Autoimmune diseases.Wherein, the device Official's specific autoimmune diseases include chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent glycosuria Disease, ulcerative colitis, acute idiopathic polyneuritis, the Autoimmune diseases include rheumatoid arthritis, Systemic loupus erythematosus, systemic vasculitis, autoimmune hemolytic anemia.
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