CN109897036B - Triazolopyridine compound and preparation method and application thereof - Google Patents
Triazolopyridine compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and relates to a triazolopyridine compound, and a preparation method and application thereof. In particular to a triazolopyridine compound with a structure shown as a general formula I, a stereoisomer and pharmaceutically acceptable salt thereof, wherein R is1、R2、R3、R4As described in the claims and specification. The compound, the stereoisomer, the pharmaceutically acceptable salt and the composition containing the compound have obvious inhibition effect on interaction of PD-1/PD-L1 protein/protein, can treat various diseases such as cancer, virus infection and the like, and can be used for preparing medicines for preventing and/or treating diseases related to PD-1/PD-L1 signal pathways.
Description
The technical field is as follows:
the invention belongs to the technical field of medicines, and relates to triazolopyridine compounds, stereoisomers and pharmaceutically acceptable salts thereof, a preparation method thereof and a pharmaceutical composition containing the compounds. The invention also relates to application of the compounds, stereoisomers and pharmaceutically acceptable salts thereof in preparing medicaments for treating diseases related to the PD-1/PD-L1 signal channel, such as cancers, infectious diseases and autoimmune diseases.
Background art:
immunotherapy is a hotspot field of tumor therapy in recent years, and is the first of ten scientific breakthroughs by Science in 2013. Programmed death receptor 1 (PD-1) is a T cell surface receptor that, when bound to programmed death ligand 1(PD-L1), generates a negative immune regulatory signal that inhibits T cell activation, proliferation, and release of cytokines such as interleukin 2(IL-2), interferon gamma (IFN-. gamma.) (Eur. J. Immunol.,2002,32(3), 634. sup. 643.). A large number of researches show that the tumor microenvironment in a body can induce the up-regulation of PD-1 expression in infiltrated T cells, and the tumor cells highly express PD-L1, so that the signal path mediated by PD-1/PD-L1 is continuously activated, the function of tumor specific CD8+ T cells is inhibited, and the tumor cells cannot be recognized or killed, namely, the tumor cells realize immune escape. Therefore, the targeted blocking of the PD-1/PD-L1 protein/protein interaction can restore the function of the T cell, and lead the T cell to re-recognize and kill the tumor cell.
Immunotherapy based on PD-1/PD-L1 is of great interest, and currently approved commercially available PD-1/PD-L1 monoclonal antibodies include Pembrolizumab by Moshadong, Nivolumab by Baume Shinobo, Avelumab by Merck, Durvalumab by Asricon, Atezolizumab by Roche, and the like. The monoclonal antibodies have shown significant efficacy in the treatment of a variety of tumor types, and approved indications include melanoma, non-small cell lung cancer, gastric cancer, urothelial cancer, and the like. With the development of clinical research, monoclonal antibody drugs are expected to realize breakthrough in more indications.
Although monoclonal antibody drugs have shown advantages in clinical treatment, there are also significant drawbacks such as difficulty in preparation and purification, and high production cost; is easy to be decomposed by protease and has short half-life period; can not be taken orally, and can only be taken by injection; the immunogenicity of monoclonal antibodies leads to severe toxic side effects. Compared with biological macromolecular drugs, the small molecular compound is chemically modified, so that the pharmacokinetic properties of the small molecular compound are controllable, and the small molecular compound has larger exploration and optimization space in the aspects of production process, administration mode and the like. Therefore, the development of small molecule inhibitors targeting the PD-1/PD-L1 protein/protein interaction is a viable option for the realization of immunotherapy.
At present, small-molecule PD-1/PD-L1 inhibitors are developed at an early stage, and therefore, the development of small-molecule PD-1/PD-L1 inhibitors with novel chemical structures is urgently needed.
The invention content is as follows:
the inventors design and synthesize a series of triazolopyridine compounds based on the reference. The activity research result shows that the compound can obviously inhibit the interaction of PD-1/PD-L1 protein/protein.
The invention relates to a triazolopyridine compound with a general formula I, a stereoisomer and a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R1selected from unsubstituted or substituted by R5Substituted phenyl groups,
R5Independently selected from halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, cyano, hydroxy, carboxy, amino;
R2selected from halogen, cyano, (C)1-C4) An alkyl group;
R3、R4independently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group(C1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) An alkyl group; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl may optionally be substituted with 1-3R6Substitution;
or R3、R4And the nitrogen atom to which they are attached form a 3-to 7-membered nitrogen-containing heterocyclic ring; the nitrogen-containing heterocycle may be optionally substituted with 1 to 3R7Substitution;
R6independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino and (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, (C)1-C4) An acyl group;
R7independently selected from hydrogen, hydroxy, carboxy, amino, carbamoyl, (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alcoxyl formyl group and hydroxyl group (C)1-C4) An alkyl group.
The invention preferably relates to triazolopyridine compounds with general formula I, stereoisomers and pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R1selected from phenyl which is unsubstituted or substituted by halogen, methyl or methoxy,
R2Selected from halogen, cyano, (C)1-C4) An alkyl group;
R3、R4independently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) An alkyl group; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl may optionally be substituted with 1-3R6Substitution;
or R3、R4And the nitrogen atom to which they are attached form a 3-to 7-membered nitrogen-containing heterocyclic ring; the nitrogen-containing heterocycle may be optionally substituted with 1 to 3R7Substitution;
R6independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino and (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, (C)1-C4) An acyl group;
R7independently selected from hydrogen, hydroxy, carboxy, amino, carbamoyl, (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alcoxyl formyl group and hydroxyl group (C)1-C4) An alkyl group.
More preferably, the invention relates to triazolopyridine compounds of general formula I, stereoisomers and pharmaceutically acceptable salts thereof, wherein,
R1selected from phenyl which is unsubstituted or substituted by 1-3 halogen, methyl, methoxy,
R2Selected from halogen, cyano, methyl;
R3、R4independently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) An alkyl group; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl may optionally be substituted with 1-3R6Substitution;
or R3、R4And the nitrogen atom to which they are attached form a 5-6 membered nitrogen containing heterocyclic ring; the nitrogen-containing heterocycle may be optionally substituted with 1 to 3R7Substitution;
R6independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino and (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkane (I) and its preparation methodOxycarbonyl radical (C)1-C4) Alkyl, (C)1-C4) An acyl group;
R7independently selected from hydrogen, hydroxy, carboxy, amino, carbamoyl, (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alcoxyl formyl group and hydroxyl group (C)1-C4) An alkyl group.
The invention particularly preferably relates to triazolopyridine compounds with general formula I, stereoisomers and pharmaceutically acceptable salts thereof, wherein,
R1selected from phenyl which is unsubstituted or substituted by 1-3 halogen, methyl, methoxy,
R2Selected from chlorine, cyano, methyl;
the triazolopyridines of general formula i according to the invention and the stereoisomers and pharmaceutically acceptable salts thereof are preferably selected from the following compounds, but these compounds are not meant to limit the invention in any way:
in addition, the present invention also includes prodrugs of the compounds of the present invention. Prodrugs of the compounds of the present invention are derivatives of formula i which may themselves be less active or even inactive, but which, upon administration, are converted to the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis, or otherwise).
The triazolopyridine compound with the general formula I, the stereoisomer and the pharmaceutically acceptable salt thereof comprise salts formed by inorganic acid, organic acid and alkali metal ions; 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, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, or p-toluenesulfonic acid; the alkali metal ions are selected from lithium ions, sodium ions or potassium ions.
"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "Nitrogen-containing heterocycle" refers to a monocyclic or polycyclic ring system containing a nitrogen atom, the ring system being non-aromatic or aromatic.
The invention can contain the triazolopyridine compound of the formula I, the stereoisomer and the pharmaceutically acceptable salt thereof as active ingredients, and the compound is mixed with a pharmaceutically acceptable carrier or excipient to prepare the composition. Such carriers or excipients include diluents, binders, wetting agents, disintegrants, lubricants, glidants and the like as are well known in the art. Diluents include, but are not limited to, starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, dibasic calcium phosphate, and the like; wetting agents include water, ethanol, isopropanol, and the like; binders include, but are not limited to, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyethylene glycol, and the like; disintegrants include, but are not limited to, dry starch, microcrystalline cellulose, low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, sodium lauryl sulfate, and the like; lubricants and glidants include, but are not limited to, talc, silicon dioxide, polyethylene glycol, and the like.
The pharmaceutical composition of the present invention can be formulated into several dosage forms including, but not limited to, injections, tablets, capsules, and the like.
The triazolopyridine compound, the stereoisomer and the pharmaceutically acceptable salt thereof can be combined with other active ingredients for use, so that a better treatment effect is achieved.
The invention also provides application of the triazolopyridine compound with the general formula I, the stereoisomer and the pharmaceutically acceptable salt thereof in preparing medicaments for preventing and/or treating diseases related to the PD-1/PD-L1 signal pathway. The diseases related to the PD-1/PD-L1 signal channel are selected from cancers, infectious diseases and autoimmune diseases. The cancer is selected from lung cancer, skin cancer, blood tumor, glioma, digestive system tumor, breast cancer, lymphoma, nervous system tumor, and melanoma; the infectious diseases are selected from bacterial infection and viral infection; the autoimmune disease is selected from organ specific autoimmune disease and systemic autoimmune disease. Wherein the organ-specific autoimmune disease comprises chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, ulcerative colitis and acute idiopathic polyneuritis, and the systemic autoimmune disease comprises rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis and autoimmune hemolytic anemia.
The positive progress effects of the invention are as follows: the triazolopyridine compound has a novel chemical structure, has high inhibitory activity on PD-1/PD-L1 protein/protein interaction in-vitro research, and can be used for treating and preventing various diseases such as cancer and the like.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way.
The following synthetic schemes outline and describe the preparation of the derivatives of formula I of the present invention, all starting materials prepared by the procedures described in these schemes, by procedures well known to those of ordinary skill in the organic chemistry art, or are commercially available. All of the final derivatives of the invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All the variable factors applied in these procedures are as defined in the claims.
(a) Substituted aniline derivative 1 and benzene, substituted benzene or heteroaromatic boric acid or boric acid ester are used as raw materials, and an intermediate 2 is obtained through Suzuki coupling reaction;
(b) reacting 5-bromo-2-chloronicotinic acid methyl ester 3 serving as a raw material with hydrazine hydrate to obtain an intermediate 4;
(c) taking the intermediate 4 as a raw material, and reacting with trimethyl orthoformate to obtain a triazolopyridine intermediate 5;
(d) taking the intermediate 5 as a raw material, and carrying out hydrolysis reaction under an alkaline condition to obtain a carboxylic acid intermediate 6;
(e) taking the intermediate 6 and the intermediate 2 as raw materials, and carrying out amidation reaction under the condition of a condensing agent to obtain an intermediate 7; or preparing acyl chloride from the intermediate 6 and reacting with the intermediate 2 to obtain an intermediate 7;
(f) taking the intermediate 7 as a raw material, and carrying out Suzuki coupling reaction on the intermediate 7 and vinyl boronic acid pinacol ester to obtain an intermediate 8;
(g) taking the intermediate 8 as a raw material, and preparing an aldehyde compound intermediate 9 under the oxidation conditions of sodium periodate and the like;
(h) taking the intermediate 9 as a raw material, and reacting the intermediate with an amine compound HNR3R4Condensing and reducing under the action of sodium cyanoborohydride or sodium triacetoxyborohydride to obtain the target compound with the general formula I.
Said R1、R2、R3、R4Is as defined in the claims. In intermediate 1, when R2Is (C)1-C4) Alkane (I) and its preparation methodWhen the group is selected, X is chlorine, bromine or iodine; when R is2When is cyano, X is bromine or iodine; when R is2When chlorine is used, X is bromine or iodine; when R is2When it is bromine, X is iodine.
The triazolopyridine compound with the general formula I can be prepared according to the reaction route.
The specific implementation mode is as follows:
in the following examples, methods of preparing some of the compounds are depicted. It is to be understood that the following methods, as well as other methods known to those of ordinary skill in the art, can be applied to the preparation of all of the compounds described herein. The examples are intended to illustrate, but not to limit, the scope of the invention.
Example 1: 6- (((2-hydroxyethyl) amino) methyl) -N- (2-methyl- [1,1' -biphenyl ] -3-yl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-1)
Step 1: 2-methyl- [1,1' -biphenyl ] -3-amine
3-bromo-2-methylaniline (15g, 0.081mol), phenylboronic acid (12.2g, 0.1mol), palladium acetate (1.82g, 8.1mmol) and potassium carbonate (24.9g, 0.18mol) were added to a mixed solution of ethanol/water (volume ratio 1:1, 100mL) in N at room temperature2The reaction was stirred for 5 hours with protection. After the reaction is finished, the mixture is filtered by suction, filtrate is evaporated to dryness, and column chromatography separation is carried out to obtain light yellow solid 12.6g with the yield of 85.2 percent.
Step 2: 5-bromo-2-hydrazinonicotinic acid methyl ester
Methyl 5-bromo-2-chloronicotinate (13.55g, 0.054mol) was dissolved in 1, 4-dioxane (150mL) at room temperature, hydrazine hydrate (6g, 0.096mol) was added, and the reaction was carried out at 60 ℃ for 3 hours. After the reaction was completed, 50mL of water was added to the solution, stirred for 0.5 hour, filtered by suction, and dried to obtain 10.2g of a yellow solid with a yield of 77.4%.
And step 3: 6-bromo- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxylic acid methyl ester
Methyl 5-bromo-2-hydrazinonicotinate (5g, 0.02mol) was dissolved in trimethyl orthoformate (25mL) and reacted at 100 ℃ for 12 hours. The reaction solution was cooled to room temperature, stirred for 0.5 h, filtered, washed with water and dried to give 4.6g of a white solid with a yield of 88.5%.
And 4, step 4: 6-bromo- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxylic acid
Methyl 6-bromo- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxylate (1g, 0.004mol) was dissolved in methanol (5mL) at room temperature, and 1mol/L aqueous NaOH solution (10mL) was added to the solution, and the mixture was heated to reflux for 0.5 hour. Cooling the reaction liquid to room temperature, evaporating to remove methanol, adding a small amount of water into the system, adjusting the pH to 5-6 with dilute hydrochloric acid, stirring for 20 minutes, and performing suction filtration to obtain 0.67g of white solid with the yield of 70.9%.
And 5: 6-bromo-N- (2-methyl- [1,1' -biphenyl ] -3-yl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
6-bromo- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxylic acid (2.18g, 9mmol), 2-methyl- [1,1' -biphenyl ] -3-amine (1.65g, 9.5mmol), HATU (5.13g, 13.5mmol), N-diisopropylethylamine (2.32g, 18mmol) were dissolved in N, N-dimethylformamide (15mL) at room temperature, and the reaction was stirred for 15 hours. After the reaction, the reaction solution was poured into a large amount of water, stirred for 20 minutes, filtered, washed with water, dried, and separated by column chromatography to obtain 2.97g of a yellow solid with a yield of 81.3%.
Step 6: n- (2-methyl- [1,1' -biphenyl ] -3-yl) -6-vinyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
Reacting 6-bromo-N- (2-methyl- [1,1' -biphenyl) at room temperature]-3-yl) - [1,2,4]Triazolo [4,3-a]Pyridine-8-carboxamide (2.3g, 5.7mmol), Vinylboronic acid pinacol ester (0.96g, 6.2mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.42g, 0.57mmol) and cesium carbonate (3.4g, 10.3mmol) are dissolved in a mixed solution of 1, 4-dioxane/water (volume ratio 3: 1, 10mL), and N is added2The reaction is carried out for 2 hours at 90 ℃ under protection. The reaction solution was cooled to room temperature, extracted with ethyl acetate, the organic layer was evaporated to dryness, and separated by column chromatography to give 1.21g of a white solid with a yield of 60%.
And 7: 6-formyl-N- (2-methyl- [1,1' -biphenyl ] -3-yl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
Reacting N- (2-methyl- [1,1' -biphenyl) at room temperature]-3-yl) -6-vinyl- [1,2,4]Triazolo [4,3-a]Pyridine-8-carboxamide (0.65g, 1.8mmol) is dissolved in a mixed solution of 1, 4-dioxane/water (volume ratio 5: 1, 10mL), and 2% OsO is rapidly added4After stirring the aqueous solution (3.5mL) for 5 minutes, sodium periodate (1.54g, 7.2mmol) was added and the reaction was stirred at room temperature for 9 hours. Suction filtration gave 0.41g of pale yellow solid in 64.2% yield.
And 8: 6- (((2-hydroxyethyl) amino) methyl) -N- (2-methyl- [1,1' -biphenyl ] -3-yl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (example 1)
6-formyl-N- (2-methyl- [1,1' -biphenyl ] -3-yl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (0.08g, 0.22mmol) was dissolved in DMF at room temperature, ethanolamine (0.067g, 1.1mmol) and glacial acetic acid (0.02g, 0.33mmol) were added, and the reaction was stirred for 2 hours. Sodium cyanoborohydride (0.07g, 1.1mmol) was added to the system, and the reaction was stirred at 25 ℃ for 12 hours. Adding water into the reaction solution, extracting with dichloromethane, evaporating the solvent to dryness, and performing column chromatography to obtain 0.032g of white solid with the yield of 35.6%.
ESI-MS m/z:402.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),9.20(s,1H),8.77(s,1H),8.56(d,J＝1.3Hz,1H),8.20(d,J＝7.9Hz,1H),7.48(t,J＝7.3Hz,2H),7.43–7.29(m,4H),7.10(d,J＝7.1Hz,1H),4.63(s,1H),3.99(s,2H),3.52(d,J＝4.8Hz,2H),3.17(d,J＝4.6Hz,1H),2.67(t,J＝5.7Hz,2H),2.35(s,3H).
The compounds of examples 2-9 were prepared according to the synthesis procedure of example 1, starting from 6-formyl-N- (2-methyl- [1,1' -biphenyl ] -3-yl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide by reaction with various amine compounds followed by reduction with sodium cyanoborohydride or sodium triacetoxyborohydride.
Example 2: 6- (((2-hydroxyethyl) (methyl) amino) methyl) -N- (2-methyl- [1,1' -biphenyl ] -3-yl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-2)
ESI-MS m/z:416.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ11.40(s,1H),9.19(s,1H),8.75(s,1H),8.48(d,J＝1.3Hz,1H),8.19(d,J＝7.9Hz,1H),7.48(t,J＝7.5Hz,2H),7.42–7.33(m,4H),7.09(d,J＝7.3Hz,1H),4.51(t,J＝5.4Hz,1H),3.72(s,2H),3.56(q,J＝6.0Hz,2H),2.54(t,J＝6.1Hz,2H),2.35(s,3H),2.24(s,3H).
Example 3: 6- (((2, 3-dihydroxypropyl) (methyl) amino) methyl) -N- (2-methyl- [1,1' -biphenyl ] -3-yl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-3)
ESI-MS m/z:446.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ11.40(s,1H),9.20(s,1H),8.75(s,1H),8.48(s,1H),8.20(d,J＝8.0Hz,1H),7.48(t,J＝7.5Hz,2H),7.40(t,J＝7.4Hz,1H),7.38–7.36(m,2H),7.34(d,J＝7.9Hz,1H),7.09(d,J＝7.5Hz,1H),4.54(br,2H),3.74(s,2H),3.69(dd,J＝9.9,5.0Hz,1H),3.38(d,J＝5.3Hz,1H),3.32(d,J＝5.8Hz,1H),2.54(dd,J＝12.8,4.6Hz,1H),2.40(dd,J＝12.7,7.1Hz,1H),2.35(s,3H),2.25(s,3H).
Example 4: trans-6- (((4-hydroxycyclohexyl) amino) methyl) -N- (2-methyl- [1,1' -biphenyl ] -3-yl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-4)
ESI-MS m/z:456.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ11.40(s,1H),9.14(s,1H),8.74(s,1H),8.53(s,1H),8.20(d,J＝7.8Hz,1H),7.48(t,J＝6.8Hz,2H),7.43–7.32(m,4H),7.10(d,J＝7.1Hz,1H),4.47(s,1H),3.91(s,2H),3.43(s,1H),2.41(s,1H),2.35(s,3H),1.90(d,J＝8.5Hz,2H),1.80(d,J＝9.3Hz,2H),1.24(s,1H),1.18–1.03(m,4H).
Example 5: n- (2-methyl- [1,1' -biphenyl ] -3-yl) -6- (((2-sulfamoylethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-5)
ESI-MS m/z:465.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ11.40(s,1H),9.18(s,1H),8.75(s,1H),8.54(t,J＝14.7Hz,1H),8.21(t,J＝15.1Hz,1H),7.60–7.23(m,6H),7.09(d,J＝7.4Hz,1H),6.82(s,2H),3.93(s,2H),3.19(t,J＝7.1Hz,2H),2.92(t,J＝7.1Hz,2H),2.35(s,3H),1.23(s,1H).
Example 6: n- (2-methyl- [1,1' -biphenyl ] -3-yl) -6- (((2- (methanesulfonamido) ethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-6)
ESI-MS m/z:479.2[M+H]+；
Example 7: ((8- ((2-methyl- [1,1' -biphenyl ] -3-yl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) -D-alanine (I-7)
ESI-MS m/z:430.2[M+H]+；
Example 8: ((8- ((2-methyl- [1,1' -biphenyl ] -3-yl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) -L-alanine (I-8)
ESI-MS m/z:430.2[M+H]+；
Example 9: (S) -3-hydroxy-4- (((8- ((2-methyl- [1,1' -biphenyl ] -3-yl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) amino) butanoic acid (I-9)
ESI-MS m/z:460.2[M+H]+；
Example 10: n- (2-cyano- [1,1' -biphenyl ] -3-yl) -6- (((2-hydroxyethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-10)
Step 1: 3-amino- [1,1' -biphenyl ] -2-carbonitrile
2-amino-6-bromobenzonitrile (15.88g, 0.081mol), phenylboronic acid (12.2g, 0.1mol), palladium acetate (1.82g, 8.1mmol) and potassium carbonate (24.9g, 0.18mol) were added to a mixed solution of ethanol/water (volume ratio 1:1, 100mL) in N at room temperature2The reaction was stirred for 8 hours with protection. After the reaction is finished, the mixture is filtered, filtrate is evaporated to dryness, and the white solid is obtained by column chromatography separation, wherein the yield is 76.4%.
Step 2: 6-bromo-N- (2-cyano- [1,1' -biphenyl ] -3-yl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
6-bromo- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxylic acid (5g, 0.021mol), 3-amino- [1,1' -biphenyl ] -2-carbonitrile (3.88g, 0.02mol), HATU (11.8g, 0.031mol), N-diisopropylethylamine (5.42g, 0.042mol) were dissolved in N, N-dimethylformamide (50mL) at room temperature, and the reaction was stirred for 12 hours. After the reaction, the reaction solution was poured into a large amount of water, stirred for 30 minutes, filtered, washed with water, dried, and separated by column chromatography to obtain 6.94g of a yellow solid with a yield of 79.2%.
And step 3: n- (2-cyano- [1,1' -biphenyl ] -3-yl) -6-vinyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
Reacting 6-bromo-N- (2-cyano- [1,1' -biphenyl) at room temperature]-3-yl) - [1,2,4]Triazolo [4,3-a]Pyridine-8-carboxamide (2.38g, 5.7mmol), Vinylboronic acid pinacol ester (0.96g, 6.2mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.42g, 0.57mmol) and cesium carbonate (3.4g, 10.4mmol) are dissolved in a mixed solution of 1, 4-dioxane/water (volume ratio 3: 1, 20mL), and N is added2The reaction is carried out for 3 hours at 90 ℃ under protection. Cooling the reaction solution to room temperature, extracting with dichloromethane, evaporating to dry the organic layer, and separating by column chromatography to obtain white solid0.96g of the product was obtained, and the yield was 46.1%.
And 4, step 4: n- (2-cyano- [1,1' -biphenyl ] -3-yl) -6-formyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
Reacting N- (2-cyano- [1,1' -biphenyl) at room temperature]-3-yl) -6-vinyl- [1,2,4]Triazolo [4,3-a]Pyridine-8-carboxamide (0.66g, 1.8mmol) is dissolved in a mixed solution of 1, 4-dioxane/water (volume ratio 5: 1, 15mL), and 2% OsO is rapidly added4After stirring the aqueous solution (3.5mL) for 10 minutes, sodium periodate (1.54g, 7.2mmol) was added and the reaction was stirred at room temperature for 10 hours. Suction filtration gave 0.51g of a yellow solid in 77.2% yield.
And 5: n- (2-cyano- [1,1' -biphenyl ] -3-yl) -6- (((2-hydroxyethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (example 10)
N- (2-cyano- [1,1' -biphenyl ] -3-yl) -6-formyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (0.08g, 0.22mmol) was dissolved in DMF at room temperature, ethanolamine (0.067g, 1.1mmol) and glacial acetic acid (0.02g, 0.33mmol) were added, and the reaction was stirred for 2 hours. Sodium cyanoborohydride (0.07g, 1.1mmol) was added to the system, and the reaction was stirred at 25 ℃ for 12 hours. Adding water into the reaction solution, extracting with dichloromethane, evaporating the solvent to dryness, and performing column chromatography to obtain 0.025g of white solid with the yield of 27.3%.
ESI-MS m/z:413.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),9.17(s,1H),8.75(s,1H),8.41(d,J＝1.2Hz,1H),8.19(d,J＝7.7Hz,1H),7.49(m,2H),7.47–7.16(m,4H),7.10(d,J＝7.6Hz,1H),4.67(s,1H),3.82(s,2H),3.55(d,J＝4.8Hz,2H),3.21(d,J＝4.7Hz,1H),2.67(m,2H).
According to the synthetic method of example 10, the compounds of examples 11-14 were prepared by reacting N- (2-cyano- [1,1' -biphenyl ] -3-yl) -6-formyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide as a starting material with various amine compounds and then reducing with sodium cyanoborohydride or sodium triacetoxyborohydride.
Example 11: ((8- ((2-cyano- [1,1' -biphenyl ] -3-yl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) -D-alanine (I-13)
ESI-MS m/z:441.2[M+H]+；
Example 12: ((8- ((2-cyano- [1,1' -biphenyl ] -3-yl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) -D-serine (I-14)
ESI-MS m/z:457.2[M+H]+；
Example 13: ((8- ((2-cyano- [1,1' -biphenyl ] -3-yl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) -D-threonine (I-15)
ESI-MS m/z:471.2[M+H]+；
Example 14: (S) -N- (cyano- [1,1' -biphenyl ] -3-yl) -6- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-16)
ESI-MS m/z:453.2[M+H]+；
Example 15: n- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylphenyl) -6- (((2-hydroxyethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-17)
Step 1: 3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylaniline
At room temperature, 3-bromo-2-methylaniline (1.89g, 10.21mmol), 2- (2, 3-dihydrobenzo [ b ]][1,4]Dioxin-6-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (4.02g, 15.32mmol) and [1, 1-bis (diphenylphosphino) ferrocene]Palladium dichloride (0.74g, 1.02mmol), potassium carbonate (4.23g, 30.63mmol) were added to a dioxane/water mixed solution (volume ratio 2: 1, 30mL) in N2The reaction was stirred at 100 ℃ for 10 hours under protection. After the reaction, the mixture is filtered by suction, the filtrate is evaporated to dryness, and the white solid is obtained by column chromatography separation, wherein the yield is 62.1 percent.
Step 2: 6-bromo-N- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylphenyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
6-bromo- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxylic acid (5g, 0.021mol), 3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylaniline (5.06g, 0.021mol), HATU (11.8g, 0.031mol), N-diisopropylethylamine (5.4g, 0.042mol) were dissolved in N, N-dimethylformamide (50mL) at room temperature, and the reaction was stirred for 12 hours. After the reaction, the reaction solution was poured into a large amount of water, stirred for 30 minutes, filtered, washed with water, dried, and separated by column chromatography to obtain 8.7g of a pale yellow solid with a yield of 89.3%.
And step 3: n- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylphenyl) -6-vinyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
Reacting 6-bromo-N- (3- (2, 3-dihydrobenzo [ b ]) at room temperature][1,4]Dioxin-6-yl) -2-methylphenyl) - [1,2,4]Triazolo [4,3-a]Pyridine-8-carboxamide (3g, 6.5mmol), Vinylboronic acid pinacol ester (1.1g, 7.2mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.48g, 0.65mmol) and cesium carbonate (3.81g, 11.7mmol) are dissolved in a mixed solution of 1, 4-dioxane/water (volume ratio 3: 1, 30mL), and N is added2The reaction is carried out for 3 hours at 90 ℃ under protection. The reaction solution was cooled to room temperature, extracted with dichloromethane, the organic layer was evaporated to dryness, and separated by column chromatography to give 1.61g of a yellow solid with a yield of 60.2%.
And 4, step 4: n- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylphenyl) -6-formyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
Reacting N- (3- (2, 3-dihydrobenzo [ b ]) at room temperature][1,4]Dioxin-6-yl) -2-methylphenyl) -6-vinyl- [1,2,4]Triazolo [4,3-a]Pyridine-8-carboxamide (0.62g, 1.5mmol) is dissolved in a mixed solution of 1, 4-dioxane/water (volume ratio 5: 1, 15mL), and 2% OsO is rapidly added4After stirring the aqueous solution (3mL) for 10 minutes, sodium periodate (1.28g, 6mmol) was added and the reaction was stirred at room temperature for 8 hours. Suction filtration and drying are carried out to obtain 0.52g of off-white solid with the yield of 83.7 percent.
And 5: n- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylphenyl) -6- (((2-hydroxyethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (example 15)
N- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylphenyl) -6-formyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (0.09g, 0.22mmol) was dissolved in dichloromethane (8mL) at room temperature, ethanolamine (0.067g, 1.1mmol) and glacial acetic acid (0.02g, 0.33mmol) were added, and the reaction was stirred for 2 hours. Sodium triacetoxyborohydride (0.07g, 1.1mmol) was added to the system, and the reaction was stirred at 25 ℃ for 12 hours. Adding water into the reaction solution, extracting with dichloromethane, evaporating the solvent to dryness, and performing column chromatography to obtain 0.04g of white solid with the yield of 17.5%.
ESI-MS m/z:460.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ11.37(s,1H),9.16(s,1H),8.74(s,1H),8.52(s,1H),8.15(d,J＝7.9Hz,1H),7.30(t,J＝7.5Hz,1H),7.05(d,J＝7.4Hz,1H),6.93(d,J＝8.1Hz,1H),6.85–6.78(m,2H),4.52(s,1H),4.29(s,4H),3.92(s,2H),3.49(d,J＝4.9Hz,2H),2.61(t,J＝4.9Hz,2H),2.35(s,3H),1.23(s,1H).
The compounds of examples 16-21 were prepared according to the synthesis procedure of example 15, starting from N- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylphenyl) -6-formyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide, by reaction with various amine compounds and reduction with sodium triacetoxyborohydride.
Example 16: n- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylphenyl) -6- (((2-hydroxyethyl) (methyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-18)
ESI-MS m/z:474.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ11.37(s,1H),9.20(s,1H),8.75(s,1H),8.47(s,1H),8.14(d,J＝7.8Hz,1H),7.30(t,J＝7.7Hz,1H),7.05(d,J＝7.4Hz,1H),6.93(d,J＝8.1Hz,1H),6.85–6.79(m,2H),4.50(s,1H),4.29(s,4H),3.72(s,2H),3.56(d,J＝5.5Hz,2H),2.35(s,3H),2.23(s,3H),1.23(s,2H).
Example 17: 6- (((2-acetamidoethyl) amino) methyl) -N- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylphenyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-19)
ESI-MS m/z:501.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ11.38(s,1H),9.16(s,1H),8.75(s,1H),8.53(s,1H),8.15(d,J＝8.0Hz,1H),7.82(s,1H),7.31(t,J＝7.8Hz,1H),7.06(d,J＝7.5Hz,1H),6.94(d,J＝8.2Hz,1H),6.85(d,J＝1.8Hz,1H),6.81(dd,J＝8.2,1.8Hz,1H),4.30(s,4H),3.91(s,2H),3.16(dd,J＝12.1,6.1Hz,2H),2.58(t,J＝6.4Hz,2H),2.36(s,3H),1.80(s,3H).
Example 18: n- (3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylphenyl) -6- (((2- (methanesulfonamido) ethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-20)
ESI-MS m/z:537.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ11.38(s,1H),9.18(s,1H),8.76(s,1H),8.53(s,1H),8.15(d,J＝8.0Hz,1H),7.31(t,J＝7.8Hz,1H),7.06(d,J＝7.5Hz,1H),6.98(s,1H),6.94(d,J＝8.2Hz,1H),6.85(d,J＝1.8Hz,1H),6.81(dd,J＝8.2,1.9Hz,1H),4.30(s,4H),3.92(s,2H),3.08(d,J＝5.3Hz,2H),2.92(s,3H),2.67(t,J＝6.3Hz,2H),2.36(s,3H).
Example 19: ((8- ((3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylphenyl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) -D-alanine (I-21)
ESI-MS m/z:488.2[M+H]+；
Example 20: ((8- ((3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylphenyl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) -L-alanine (I-22)
ESI-MS m/z:488.2[M+H]+；
Example 21: (S) -4- (((8- ((3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -2-methylphenyl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) amino) -3-hydroxybutyric acid (I-23)
ESI-MS m/z:518.2[M+H]+；
Example 22: n- (2-cyano-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) -6- (((2-hydroxyethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-24)
Step 1: 2-amino-6- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzonitrile
2-amino-6-bromobenzonitrile (2g,10.2mmol), 2- (2, 3-dihydrobenzo [ b ] at room temperature][1,4]Dioxin-6-yl) -4,4,5, 5-tetramethyl-1, 3, 2-diheterooxocyclopentaneborane (2.94g,11.22mmol), tetrakis (triphenylphosphine) palladium (1.18g,1.02mmol), cesium carbonate (6.65g,20.4mmol) was added to a mixed solution of toluene/ethanol/water (volume ratio 3: 3: 1, 23 mL). In N2The reaction mixture was stirred at 95 ℃ for 12 hours under protection. After the reaction, the mixture is filtered by suction, the filtrate is evaporated to dryness, and the white solid is obtained by column chromatography separation, wherein the yield is 62.1 percent.
Step 2: 6-bromo-N- (2-cyano-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
6-bromo- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxylic acid (1g, 4.15mmol) was dissolved in thionyl chloride (15mL) at room temperature, and the reaction was stirred at 80 ℃ for 4 hours. After the reaction, the reaction solution was evaporated to dryness to obtain a yellow solid. The resulting yellow solid was dissolved in dichloromethane (15mL), added dropwise slowly under ice-bath conditions to a solution of 2-amino-6- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) benzonitrile (1.05g, 4.15mmol) and triethylamine (1.05g, 10.38mmol) in dichloromethane (10mL), and the reaction was stirred at room temperature for 1 hour. After the reaction is finished, adding a large amount of dichloromethane into the reaction solution, stirring for 1 hour on a platform, adding water to wash the organic layer, and evaporating the organic layer to dryness to obtain a light yellow solid. Dissolving the crude product in ethanol, stirring at 80 deg.C for half an hour, filtering, and drying to obtain yellow solid 0.89g with yield of 45.3%.
And step 3: n- (2-cyano-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) -6-vinyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
Reacting 6-bromo-N- (2-cyano-3- (2, 3-dihydrobenzo [ b ]) at room temperature][1,4]Dioxin-6-yl) phenyl) - [1,2,4]Triazolo [4,3-a]Pyridine-8-carboxamide (3.09g, 6.5mmol), Vinylboronic acid pinacol ester (1.1g, 7.2mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.48g, 0.65mmol) and cesium carbonate (3.81g, 11.7mmol) are dissolved in a mixed solution of 1, 4-dioxane/water (volume ratio 3: 1, 30mL), and N is added2The reaction is carried out for 3 hours at 90 ℃ under protection. The reaction solution was cooled to room temperature, extracted with dichloromethane, the organic layer was evaporated to dryness, and separated by column chromatography to give 1.75g of a yellow solid with a yield of 63.7%.
And 4, step 4: n- (2-cyano-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) -6-formyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
Reacting N- (2-cyano-3- (2, 3-dihydrobenzo [ b ]) at room temperature][1,4]Dioxin-6-yl) phenyl) -6-vinyl- [1,2,4]Triazolo [4,3-a]Pyridine-8-carboxamide (0.63g, 1.5mmol) is dissolved in a mixed solution of 1, 4-dioxane/water (volume ratio 5: 1, 15mL), and 2% OsO is rapidly added4After stirring the aqueous solution (3mL) for 10 minutes, sodium periodate (1.28g, 6mmol) was added and the reaction was stirred at room temperature for 12 hours. Suction filtration and drying are carried out to obtain 0.58g of off-white solid with the yield of 90.2 percent.
And 5: n- (2-cyano-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) -6- (((2-hydroxyethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (example 22)
N- (2-cyano-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) -6-formyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (0.094g, 0.22mmol) was dissolved in DMF at room temperature, ethanolamine (0.067g, 1.1mmol) and glacial acetic acid (0.02g, 0.33mmol) were added, and the reaction was stirred for 2 hours. Sodium cyanoborohydride (0.07g, 1.1mmol) was added to the system, and the reaction was stirred at 25 ℃ for 12 hours. Adding water into the reaction solution, extracting with dichloromethane, evaporating the solvent to dryness, and performing column chromatography to obtain 0.029g of white solid with the yield of 27.6%.
ESI-MS m/z:471.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ11.99(s,1H),9.21(s,1H),8.74(s,1H),8.55(s,1H),8.31(d,J＝8.2Hz,1H),7.80(t,J＝8.0Hz,1H),7.39(d,J＝7.6Hz,1H),7.14(s,1H),7.10(d,J＝7.5Hz,1H),7.03(d,J＝8.3Hz,1H),4.52(s,1H),4.33(s,4H),3.93(s,2H),3.50(d,J＝5.2Hz,2H),2.62(t,J＝5.5Hz,2H).
The compounds of examples 23-28 were prepared according to the synthesis procedure of example 22, starting from N- (2-cyano-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) -6-formyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide, by reaction with various amine compounds and reduction with sodium triacetoxyborohydride.
Example 23: n- (2 cyano-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) -6- (((2-hydroxyethyl) (methyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-25)
ESI-MS m/z:485.2[M+H]+；
Example 24: 6- (((2-acetamidoethyl) amino) methyl) -N- (2-cyano-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-26)
ESI-MS m/z:512.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ11.99(s,1H),9.20(s,1H),8.75(s,1H),8.54(s,1H),8.32(s,1H),7.82(s,2H),7.40(s,1H),7.23–7.02(m,3H),4.33(s,4H),3.91(s,2H),3.16(s,2H),2.58(s,2H),1.80(s,3H).
Example 25: n- (2-cyano-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) -6- (((2- (methanesulfonamido) ethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-27)
ESI-MS m/z:548.2[M+H]+；
Example 26: ((8- ((2-cyano-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) -D-alanine (I-28)
ESI-MS m/z:499.2[M+H]+；
Example 27: ((8- ((2-cyano-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) -L-alanine (I-29)
ESI-MS m/z:499.2[M+H]+；
Example 28: (S) -4- (((8- ((2-cyano-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) amino) -3-hydroxybutyric acid (I-30)
ESI-MS m/z:529.2[M+H]+；
The procedure is as in example 15, using 3-bromo-2-chloroaniline instead of 3-bromo-2-methylaniline in the first step, the compound of example 29-31 was prepared by Suzuki coupling reaction with 2- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan to give 2-chloro-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) aniline, followed by amidation with 6-bromo- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxylic acid, coupling with pinacol ester of vinyl borate, oxidation with sodium periodate, and reductive amination with an amine compound.
Example 29: 6- (((2-acetamidoethyl) amino) methyl) -N- (2-chloro-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-33)
ESI-MS m/z:521.2[M+H]+；
Example 30: ((8- ((2-chloro-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) -D-alanine (I-34)
ESI-MS m/z:508.1[M+H]+；
Example 31: (S) -1- ((8- ((2-chloro-3- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) phenyl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) piperidine-2-carboxylic acid (I-37)
ESI-MS m/z:548.2[M+H]+；
Example 32: 6- (((2-hydroxyethyl) amino) methyl) -N- (2-methyl-3- (1-methyl-1H-indazol-4-yl) phenyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-38)
Step 1: 2-methyl-3- (1-methyl-1H-indazol-4-yl) aniline
3-bromo-2-methylaniline (12g, 0.065mol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole (33.5g, 0.13mol), palladium acetate (1.46g, 6.5mmol), and potassium carbonate (26.9g, 0.195mol) were added to a mixed solution of ethanol/water (volume ratio 1:1, 200mL) at room temperature in N2The reaction was stirred for 6 hours with protection. After the reaction, the mixture is filtered, the filtrate is evaporated to dryness, and the white solid is obtained by column chromatography separation, wherein the yield is 63.9 percent.
Step 2: 6-bromo-N- (2-methyl-3- (1-methyl-1H-indazol-4-yl) phenyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
6-bromo- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxylic acid (10g, 0.042mol), 2-methyl-3- (1-methyl-1H-indazol-4-yl) aniline (9.49g, 0.04mol), HATU (22.8g, 0.06mol), N-diisopropylethylamine (10.3g, 0.08mol) were dissolved in N, N-dimethylformamide (20mL) at room temperature, and the reaction was stirred for 13 hours. After the reaction is finished, pouring the reaction solution into a large amount of water, stirring for 30 minutes, carrying out suction filtration, washing a filter cake with water, drying, and carrying out column chromatography separation to obtain 13.7g of light yellow solid, wherein the yield is 71.9%.
And step 3: n- (2-methyl-3- (1-methyl-1H-indazol-4-yl) phenyl) -6-vinyl- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
At room temperature, 6-bromo-N- (2-methyl-3- (1-methyl-1H-indazol-4-yl) phenyl) - [1,2, 4-]Triazolo [4,3-a]Pyridine-8-carboxamide (2g, 4.3mmol), Vinylboronic acid pinacol ester (0.73g, 4.7mmol), [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.31g, 0.43mmol) and cesium carbonate (2.5g, 7.7mmol) are dissolved in a mixed solution of 1, 4-dioxane/water (volume ratio 3: 1, 15mL), and N is added2The reaction is carried out for 5 hours at 90 ℃ under protection. The reaction solution was cooled to room temperature, extracted with dichloromethane, the organic layer was evaporated to dryness, and separated by column chromatography to give 1.19g of a white solid with a yield of 67.7%.
And 4, step 4: 6-formyl-N- (2-methyl-3- (1-methyl-1H-indazol-4-yl) phenyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide
Reacting N- (2-methyl-3- (1-methyl-1H-indazol-4-yl) phenyl) -6-vinyl- [1,2,4] at room temperature]Triazolo [4,3-a]Pyridine-8-carboxamide (0.73g, 1.8mmol) dissolved in 1, 4-dioxoAdding 2% OsO rapidly into mixed solution of hexacyclic ring and water (volume ratio is 5: 1, 8mL)4After stirring the aqueous solution (3.5mL) for 5 minutes, sodium periodate (1.54g, 7.2mml) was added and the reaction was stirred at room temperature for 5 hours. Suction filtration to obtain light yellow solid 0.53g, yield 72.3%.
And 5: 6- (((2-hydroxyethyl) amino) methyl) -N- (2-methyl-3- (1-methyl-1H-indazol-4-yl) phenyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (example 32)
6-formyl-N- (2-methyl-3- (1-methyl-1H-indazol-4-yl) phenyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (0.09g, 0.22mmol) was dissolved in DMF at room temperature, ethanolamine (0.067g, 1.1mmol) and glacial acetic acid (0.02g, 0.33mmol) were added, and the reaction was stirred for 2 hours. Sodium cyanoborohydride (0.07g, 1.1mmol) was added to the system, and the reaction was stirred at 25 ℃ for 15 hours. Adding water into the reaction solution, extracting with dichloromethane, evaporating the solvent to dryness, and performing column chromatography to obtain 0.02g of white solid with the yield of 20.1%.
The compounds of examples 33 and 34 were prepared according to the synthesis of example 32 starting from 6-formyl-N- (2-methyl-3- (1-methyl-1H-indazol-4-yl) phenyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide by reaction with various amine compounds and reduction with sodium cyanoborohydride.
Example 33: 6- (((2-acetamidoethyl) amino) methyl) -N- (2-methyl-3- (1-methyl-1H-indazol-4-yl) phenyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-40)
ESI-MS m/z:497.2[M+H]+；
Example 34: ((8- ((2-methyl-3- (1-methyl-1H-indazol-4-yl) phenyl) carbamoyl) - [1,2,4] triazolo [4,3-a ] pyridin-6-yl) methyl) -D-alanine (I-41)
ESI-MS m/z:484.2[M+H]+；
Following the procedure of example 1, benzidine derivatives were prepared in a first step by Suzuki coupling reaction of 3-bromo-2-methylaniline with substituted phenylboronic acid instead of phenylboronic acid, followed by amidation with 6-bromo- [1,2,4] triazolo [4,3-a ] pyridine-8-carboxylic acid, coupling of the vinylboronic acid pinacol ester, sodium periodate oxidation, and reductive amination with ethanolamine to give the compounds of examples 35-39.
Example 35: n- (2,4 '-dimethyl- [1,1' -biphenyl ] -3-yl) -6- (((2-hydroxyethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-42)
ESI-MS m/z:416.2[M+H]+；
Example 36: n- (2' -fluoro-3 ' -methoxy-2-methyl- [1,1' -biphenyl ] -3-yl) -6- (((2-hydroxyethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-43)
ESI-MS m/z:450.2[M+H]+；
Example 37: n- (3 '-bromo-2-methyl- [1,1' -biphenyl ] -3-yl) -6- (((2-hydroxyethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-44)
ESI-MS m/z:480.1[M+H]+；
Example 38: n- (4 '-chloro-2-methyl- [1,1' -biphenyl ] -3-yl) -6- (((2-hydroxyethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-45)
ESI-MS m/z:436.2[M+H]+；
Example 39: n- (3',4' -dimethoxy-2-methyl- [1,1' -biphenyl ] -3-yl) -6- (((2-hydroxyethyl) amino) methyl) - [1,2,4] triazolo [4,3-a ] pyridine-8-carboxamide (I-46)
ESI-MS m/z:462.2[M+H]+；
Study of the biological Activity of the Compound of the present invention
Homogeneous Time-Resolved Fluorescence (HTRF) assays were used to examine the ability of the compounds of the invention to inhibit the PD-1/PD-L1 interaction. The Detection kit is purchased from CisBio (CAT #63ADK000 CPACPEG) and comprises Anti-Tag 1-captate, Anti-Tag2-XL665/d2, Tag1-PD-L1, Tag2-PD-1, Dilution Buffer, Detection Buffer and other reagents required by experiments.
The experimental steps are as follows: PD-1 recombinant protein and PD-L1 recombinant protein were diluted to 500nM and 50nM, respectively, with Dilution Buffer. 4mM DMSO-solubilized small molecule compound was diluted 20-fold to 200uM with Dilution Buffer. Four-fold gradient Dilution with Dilution Buffer containing 5% DMSO. Concurrent Dilution of 600uM with Dilution Buffer the DMSO-solubilized PD-1/PD-L1 inhibitor was 20-fold to 30uM diluted in a four-fold gradient with Dilution Buffer containing 5% DMSO. To 384 wells, 2uL of diluted test compound, 4uL of diluted PD-1, and 4uL of diluted PDL-1 were added in that order. Mixing, and standing at room temperature for 15 min. Diluting anti-Tag1-Eu with Detection buffer3+(1:25) and anti-Tag2-XL665(1: 100). The diluted detection reagent was then mixed in equal volume, and 10. mu.L of antibody mixture was added to each reaction well. And (5) sealing the membrane and incubating for 2h at room temperature. Fluorescence signals (320nm stimulation, 665nm, 615nm emission) were detected with an envision (perkinelmer) instrument. Detection of 8-12 concentrations.
The results of the compounds' activity in inhibiting the PD-1/PD-L1 interaction are shown in Table 1.
TABLE 1 Activity Range or IC for the inhibition of the PD-1/PD-L1 interaction by the Compounds of the invention50。
The ranges are as follows: a-1 nM-100 nM; b-100.01 nM-1 μ M; c ═ 1.01 μ M to 20 μ M.
HTRF test results indicate that the example compounds significantly inhibited PD-1/PD-L1 interaction at the molecular level. Is expected to show a positive effect in treating diseases associated with the interaction of PD-1/PD-L1.
Claims (17)
1. Triazolopyridine compounds with general formula I, stereoisomers and pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R1selected from unsubstituted or substituted by R5Substituted phenyl groups,
R5Independently selected from halogen, (C)1-C4) Alkyl, (C)1-C4) An alkoxy group;
R2selected from halogen, cyano, (C)1-C4) An alkyl group;
R3、R4independently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) An alkyl group; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl may optionally be substituted with 1-3R6Substitution;
or R3、R4And the nitrogen atom to which they are attached form a 3-to 7-membered nitrogen-containing heterocyclic ring; the nitrogen-containing heterocycle may be optionally substituted with 1 to 3R7Substitution;
R6independently selected from hydrogen, halogen, hydroxyl and (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) An alkyl group;
R7independently selected from hydrogen, hydroxyl, carboxyl and (C)1-C4) Alkyl, (C)1-C4) Alkoxy, hydroxy (C)1-C4) An alkyl group.
2. Triazolopyridines of general formula I according to claim 1 and the stereoisomers and pharmaceutically acceptable salts thereof, wherein,
R1selected from phenyl which is unsubstituted or substituted by 1-3 halogen, methyl, methoxy,
3. Triazolopyridines of general formula i according to claim 1 or 2 and the stereoisomers and pharmaceutically acceptable salts thereof, wherein,
R2selected from halogen, cyano, (C)1-C4) An alkyl group.
4. Triazolopyridines of general formula i according to claim 1 or 2 and the stereoisomers and pharmaceutically acceptable salts thereof, wherein,
R2selected from chlorine, cyano and methyl.
5. Triazolopyridines of general formula i according to claim 1 or 2 and the stereoisomers and pharmaceutically acceptable salts thereof, wherein,
R3、R4independently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) An alkyl group; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl may optionally be substituted with 1-3R6Substitution;
or R3、R4And the nitrogen atom to which they are attached form a 5-6 membered nitrogen containing heterocyclic ring; the nitrogen-containing heterocycle may be optionally substituted with 1 to 3R7And (4) substitution.
6. Triazolopyridines of general formula I according to claim 3 and the stereoisomers and pharmaceutically acceptable salts thereof, wherein,
R3、R4independently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) An alkyl group; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl may optionally be substituted with 1-3R6Substitution;
or R3、R4And the nitrogen atom to which they are attached form a 5-6 membered nitrogen containing heterocyclic ring; the nitrogen-containing heterocycle may be optionally substituted with 1 to 3R7And (4) substitution.
7. The triazolopyridines of general formula I and the stereoisomers and pharmaceutically acceptable salts thereof according to claim 4, wherein,
R3、R4independently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) An alkyl group; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl may optionally be substituted with 1-3R6Substitution;
or R3、R4And the nitrogen atom to which they are attached form a 5-6 membered nitrogen containing heterocyclic ring; the nitrogen-containing heterocycle may be optionally substituted with 1 to 3R7And (4) substitution.
8. The triazolopyridines and stereoisomers and pharmaceutically acceptable salts thereof according to claim 1,2, 6 or 7, wherein,
selected from:
9. the triazolopyridines and stereoisomers and pharmaceutically acceptable salts thereof according to claim 3, wherein,
selected from:
10. the triazolopyridines and stereoisomers and pharmaceutically acceptable salts thereof according to claim 4, wherein,
selected from:
11. the triazolopyridines and stereoisomers and pharmaceutically acceptable salts thereof according to claim 5, wherein,
selected from:
12. the following triazolopyridine compounds and stereoisomers and pharmaceutically acceptable salts thereof:
13. a pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 12 and stereoisomers thereof and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or excipient.
14. Use of a compound according to any one of claims 1 to 12, and stereoisomers and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 13, for the manufacture of a medicament for the prevention and/or treatment of diseases associated with the PD-1/PD-L1 signalling pathway.
15. The use of claim 14, wherein the disease associated with the PD-1/PD-L1 signaling pathway is selected from the group consisting of cancer, infectious disease, and autoimmune disease.
16. The use of claim 15, wherein the cancer is selected from the group consisting of lung cancer, skin cancer, hematological tumors, digestive system tumors, breast cancer, lymphoma, nervous system tumors, melanoma; the infectious diseases are selected from bacterial infection and viral infection; the autoimmune disease is selected from organ specific autoimmune disease and systemic autoimmune disease, the organ specific autoimmune disease comprises chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, ulcerative colitis and acute idiopathic polyneuritis, and the systemic autoimmune disease comprises rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis and autoimmune hemolytic anemia.
17. The use of claim 16, wherein the tumor of the nervous system is a glioma.
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