CN112279835B - Aromatic ring or aromatic heterocyclic imidazole compound, preparation method and pharmaceutical application thereof - Google Patents
Aromatic ring or aromatic heterocyclic imidazole compound, preparation method and pharmaceutical application thereof Download PDFInfo
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Abstract
The invention relates to a compound containing an aromatic ring or aromatic heterocyclic imidazole structure or pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and medical application of the compound. The compound has the function of specifically exciting the STING protein, and can be used for preparing medicaments for treating diseases related to the STING protein function, such as malignant tumors, virus infection and the like.
Description
Technical Field
The invention relates to the field of medicines, in particular to a compound containing an aromatic ring or aromatic heterocyclic imidazole structure or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound in preparing medicines for treating diseases related to the function of STING protein.
Background
The innate immune system plays an important role in identifying pathogens and stimulating acquired immune protection, and pathogen-associated molecular patterns (PAMPs) are identified through various Pattern Recognition Receptors (PRRs) to resist the invasion of foreign pathogenic microorganisms, thereby constituting a first line of defense of a human body against pathogens, which includes a series of cellular actions and related mechanisms.
Interferon gene stimulatory molecules (STING) are transmembrane proteins, usually forming dimers and in a self-inhibitory state. When stimulated by partial ligands (such as cyclic dinucleotides and CDNs), the molecular configuration is changed and activated, thereby recruiting TANK-binding kinase 1 (TBK 1) in cytoplasm, mediating phosphorylation of interferon regulatory factor 3 (IRF-3) by TBK1, leading to the formation of interferon (interferon-beta, IFN-beta) and other various cytokines (cytokines), and further regulating non-specific immune response.
The STING protein plays an important role as a member of a pattern recognition receptor in the non-specific immune system, it promotes interferon production, and it plays a role in connection with the TBK1-IRF3 signaling pathway. More importantly, in the tumor cell microenvironment, nonspecific immune signaling is a key step in tumor-specific T cell activation and tumor-infiltrating lymphocyte infiltration, with type I IFN playing a key role in tumor-activated T cell activation. Meanwhile, the STING protein agonist can also activate immune cells including dendritic cells and the like, change the tumor microenvironment, induce the generation of tumor specific T cells, trigger the immune response of an organism to the tumor cells, and play an important role in a non-specific immune signal path.
The STING protein has obvious species selectivity, and the natural ligand molecule Cyclic Dinucleosides (CDNs) of the human STING protein are unstable, are easily degraded by various nucleases and phosphodiesterases and have poor pharmaceutical performance; moreover, activation of the interferon synthesis pathway also brings about a series of side reactions such as skin allergy, flu-like syndrome, hematopoietic system changes, and the like.
In recent years, tumor immunotherapy has become the greatest development focus of the global pharmaceutical industry, and the STING protein-mediated physiological immune pathway activates the human body innate immune system from a wider layer, so that the protein is expected to be applicable to different groups of various cancers, and even used for treating other diseases besides cancers, such as viral infection, bacterial infection and serving as an immune adjuvant. Therefore, with the recent increase of the number of patients with cancer year by year, there is a need to find a novel human-derived STING protein agonist having high activity and good drug potency.
Disclosure of Invention
The invention provides a compound containing an aromatic ring or aromatic heterocyclic imidazole structure or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound in preparing a medicament for treating diseases related to the function of STING protein.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides a compound shown as a general formula (I) or a pharmaceutically acceptable salt thereof:
wherein, the first and the second end of the pipe are connected with each other,
x is selected from C or N; with the proviso that when X is N, R4Is absent; when X is C, R4Selected from hydrogen, hydroxy, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted C1-8Alkoxy, substituted or unsubstituted C3-8A cycloalkoxy group; the substituent is selected from C1-8Alkoxy radical, C3-8Cycloalkoxy, N-morpholinyl straight C1-8An alkyl group;
y is selected from CH or N;
R1selected from hydrogen, carboxyl, carbomethoxy, substituted or unsubstituted carbamoyl; the substituent is selected from C1-8Alkyl or C3-8A cycloalkyl group;
R3selected from the group consisting of quinoline rings, isoquinoline rings, N-substituted or unsubstituted indole rings, substituted or unsubstituted aromatic heterocycles, substituted or unsubstituted aliphatic rings, substituted or unsubstituted aliphatic heterocycles; the aromatic ring, the aromatic heterocyclic ring, the aliphatic ring or the aliphatic heterocyclic ring is selected from five-membered rings and six-membered rings; the substituent is selected from C1-8Alkyl radical, C3-8A cycloalkyl group; the aromatic heterocycle or aliphatic heterocycle contains 1-3 heteroatoms, and the heteroatoms are selected from N;
R2selected from the group consisting of substituents having the following structures:
-(CH2)m-CH3，-(CH2)m-NH-CO2-Ra
wherein m is selected from 2, 3 or 4;
ra is selected from tert-butyl and benzyl.
Further, a compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that C is1-8The alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and isopentyl; said C is3-8The cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl; said C is1-8The alkoxy is selected from methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy; said C is3-8The cycloalkoxy group is selected from the group consisting of cyclopropyloxy, cyclobutyloxy, cyclopentyloxy.
Further, a compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that Ra is selected from the group consisting of tert-butyl, benzyl; m is selected from 2, 3 or 4.
The pharmaceutically acceptable salt is selected from organic acid salts or inorganic acid salts, including but not limited to hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, malate, fumarate, tartrate or methanesulfonate.
As a preferred embodiment of the present invention, the compound of formula (I) has the following structure:
in another aspect of the technical solution of the present invention, a method for synthesizing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is provided, wherein the synthetic route is as follows:
route (1):
reagents and conditions: (a) ammonia water, 50 ℃; (b) r2NH2Potassium carbonate, N-methylpyrrolidone, 120 ℃; (c) zinc powder, acetic acid, dichloromethane and room temperature; (d) nitrile bromide, methanol, 60 ℃; (e) r3COOH, 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate, N-diisopropylethylamine, N-dimethylformamide;
route (2):
reagents and conditions: (a) boron tribromide, dichloromethane, room temperature; (b) r4' Cl, potassium carbonate, N, N-dimethylformamide, 120 ℃; (c) benzyl N- (3-aminopropyl) carbamate, potassium carbonate, N-methylpyrrolidone, 120 ℃; (d) zinc powder, acetic acid, dichloromethane and room temperature; (e) bromine compoundNitrile conversion, methanol, 60 ℃; (f) r3COOH, 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate, N-diisopropylethylamine, N-dimethylformamide;
or
Route (3):
reagents and conditions: (a) n-tert-butoxycarbonyl-1, 3-propanediamine, potassium carbonate, N-methylpyrrolidone, 120 ℃; (b) hydrogen, palladium on carbon, dichloromethane, room temperature; (c) nitrile bromide, methanol, 60 ℃; (d) 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid, 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate, N-diisopropylethylamine, N-dimethylformamide; (e)0.5N lithium hydroxide solution, methanol, room temperature; (f) ethyl chloroformate, triethylamine, tetrahydrofuran, room temperature; tetrahydrofuran solution of amine, room temperature;
wherein R is1、R2、R3As defined in any one of claims 1 to 6; r is4' is selected from substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted C1-8Alkoxy, substituted or unsubstituted C3-8A cycloalkoxy group; the substituent is selected from C1-8Alkoxy radical, C3-8Cycloalkoxy, N-morpholinyl straight C1-8An alkyl group.
In another aspect of the technical scheme of the invention, a pharmaceutical composition is provided, wherein the pharmaceutical composition comprises a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The invention also provides application of the compound shown as the general formula (I) or pharmaceutically acceptable salt thereof in preparing medicines for treating diseases related to the function of the STING protein.
The other aspect of the technical scheme of the invention is to provide the application of the compound shown as the general formula (I) or the pharmaceutically acceptable salt thereof in preparing the medicines for treating tumor or virus infection diseases.
Advantageous technical effects
Examples 10, 11, 18, 19, 20 and 21 in the technical scheme of the invention have obvious agonistic activity on STING protein, can activate a STING protein signal pathway, mediate I-type interferon, interleukin-6 and downstream related cytokine secretion, further cause immune response of an organism to tumor cells and regulate non-specific immune response.
Detailed Description
Example 1
N- (5-carbamoyl-7-methoxy-1-propyl-1H-benzo [ d ] imidazol-2-yl) quinoline-2-carboxamide
(1) Preparation of 4-chloro-3-methoxy-5-nitrobenzamide
Methyl 3-methoxy-4-propylamino-5-nitrobenzoate (1g,4.1mmol) and 50ml of ammonia (28%, 50ml) were added in turn to a bottle, and the mixture was heated to 50 ℃ under the protection of argon and reacted for 5 hours. The reaction is cooled to room temperature, after a large amount of light yellow solid is separated out, the pressure is reduced and the filtration is carried out, the filter cake is washed by ether and dried to obtain 0.715g of light yellow solid, the yield is 75.6 percent, and the melting point is 215-.
1H NMR(400MHz,DMSO-d6)δ8.29(s,1H),8.05(d,J＝1.64Hz,1H),7.88(d,J＝1.56Hz,1H),7.78(s,1H),4.02(s,3H).
MS(ESI)m/z 231.0(M+H)+.
(2) Preparation of 3-methoxy-5-nitro-4-propylaminobenzamide
4-chloro-3-methoxy-5-nitrobenzamide (1g,4mmol), propylamine (0.715mL,8.7mmol) and potassium carbonate (1.8g, 13mmol) were dissolved in a 100mL sealed tube and reacted at 100 ℃ for 6 hours by dissolving in 20mL of N-methylpyrrolidone. Cooling the reaction to room temperature, adding saturated ammonium chloride solution to quench the reaction, separating out brick-red solid, filtering under reduced pressure, washing the filter cake with ether, and drying to obtain brick-red solid 0.887g, yield 87.6%, and melting point 180-182 ℃.
1H NMR(400MHz,DMSO-d6)δ8.18(d,J＝1.9Hz,1H),8.00(s,1H),7.67(t,J＝5.8Hz,1H),7.54(d,J＝1.8Hz,1H),7.30(s,1H),3.88(s,3H),3.65(t,J＝7.0Hz,2H),1.70–1.60(m,2H),0.85(t,J＝7.4Hz,3H).
MS(ESI)m/z 254.1(M+H)+.
(3) Preparation of 3-amino-5-methoxy-4-propylaminobenzamide
3-methoxy-5-nitro-4-propylaminobenzamide (1.0g,4.0mmol) was dissolved in 30ml of methanol, Pd/C (0.1g, 10%) was added thereto, and hydrogen gas was introduced thereinto to react at 25 ℃ for 6 hours. Filtering with diatomite to remove Pd/C, concentrating the reaction solution, and performing column chromatography separation, wherein an eluent is dichloromethane: methanol 10:1, 0.71g of white solid powder is obtained, the yield is 79.2%, and the melting points are 102-104 ℃.
1H NMR(400MHz,DMSO-d6)δ7.60(s,1H),6.96(s,1H),6.86(d,J＝1.8Hz,1H),6.79(d,J＝1.8Hz,1H),4.63(s,2H),3.76(s,3H),2.90(t,J＝7.0Hz,2H),1.46–1.37(m,2H),0.87(t,J＝7.4Hz,3H).
MS(ESI)m/z 224.1(M+H)+.
(4) Preparation of 2-amino-7-methoxy-1-propyl-1H-benzo [ d ] imidazole-5-amide
3-amino-5-methoxy-4-propylaminobenzamide (0.227g,1.02mmol) and cyanogen bromide (0.13g,1.2mmol) were dissolved in 25ml of methanol and heated to 60 ℃ under the protection of argon for reaction for 5 hours. Cooling the reaction to room temperature, adding saturated potassium carbonate solution to adjust the pH value to 7-8, separating out a large amount of white solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 0.197g of white solid, wherein the yield is 77.6%, and the melting point is 273-.
1H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.39(d,J＝1.2Hz,1H),7.10(d,J＝1.1Hz,1H),7.05(s,1H),6.40(s,2H),4.08(t,J＝7.2Hz,2H),3.88(s,3H),1.69–1.60(m,2H),0.84(t,J＝7.4Hz,3H).
MS(ESI)m/z 249.1(M+H)+.
(5) Preparation of the title Compound
2-amino-7-methoxy-1-propyl-1H-benzo [ d]Imidazole-5-amide (0.2g,0.81mmol), quinoline-2-carboxylic acid (0.168g,0.97mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.368g,0.97mmol), N, N-diisopropylethylamine (0.54ml,3.25mmol) were dissolved in 10ml of N, N-dimethylformamide and reacted for 5 hours with stirring at room temperature. Adding saturated ammonium chloride solution 30ml after reaction, precipitating a large amount of yellow solid, vacuum filtering, washing filter cake with diethyl ether, drying to obtain yellow solid 0.154g, yield 47%, and melting point>300℃。1H NMR(400MHz,DMSO-d6)δ8.57(d,J＝8.5Hz,1H),8.35(d,J＝8.5Hz,1H),8.18(d,J＝8.4Hz,1H),7.94(d,J＝8.0Hz,1H),7.88(s,1H),7.66–7.60(m,2H),7.55(t,J＝7.5Hz,1H),7.16(s,1H),7.04(s,1H),4.41(t,J＝6.5Hz,2H),3.93(s,3H),1.81–1.72(m,2H),0.85(t,J＝7.4Hz,3H).
HRMS calcd.For C22H22N5O3(M+H)+404.17172,found 404.17084.
Example 2
N- (5-carbamoyl-7-methoxy-1-propyl-1H-benzo [ d ] imidazol-2-yl) isoquinoline-1-amide
(1) Preparation of the title Compound
2-amino-7-methoxy-1-propyl-1H-benzo [ d ] imidazole-5-amide (0.2g,0.81mmol), isoquinoline-1-carboxylic acid (0.168g,0.97mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.368g,0.97mmol), N, N-diisopropylethylamine (0.54ml,3.25mmol) was dissolved in 10ml of N, N-dimethylformamide and stirred at room temperature for reaction for 5H. After the reaction is finished, 30ml of saturated ammonium chloride solution is added, a large amount of light orange solid is separated out, the pressure reduction and the suction filtration are carried out, the filter cake is washed by ethyl ether and dried to obtain 0.149g of light orange solid, the yield is 45.5 percent, and the melting point is 251-.
1H NMR(400MHz,DMSO-d6)δ8.57–8.51(m,1H),8.37(d,J＝5.7Hz,1H),7.89(d,J＝8.2Hz,1H),7.74(d,J＝1.2Hz,1H),7.70–7.66(m,2H),7.54(t,J＝7.7Hz,1H),7.11(d,J＝1.1Hz,1H),7.01(s,1H),4.18(t,J＝6.6Hz,2H),3.88(s,3H),1.69–1.60(m,2H),0.77(t,J＝7.4Hz,3H).
HRMS calcd.For C22H22N5O3(M+H)+404.17044,found 404.17172.
Example 3
7-methoxy-2- (2-pyridylamido) -1-propyl-1H-benzo [ d ] imidazole-5-amide
(1) Preparation of the title Compound
2-amino-7-methoxy-1-propyl-1H-benzo [ d ] imidazole-5-amide (0.2g,0.81mmol), pyridine-2-carboxylic acid (0.120g,0.97mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.368g,0.97mmol), and N, N-diisopropylethylamine (0.54ml,3.25mmol) were dissolved in 10ml of N, N-dimethylformamide and stirred at room temperature for reaction for 8H. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of white solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 183mg of white solid, wherein the yield is 64.1 percent, and the melting point is more than 300 ℃.
1H NMR(400MHz,DMSO-d6)δ8.65(d,J＝4.0Hz,1H),8.40(d,J＝7.8Hz,1H),7.88(t,J＝7.8Hz,1H),7.83(s,2H),7.50–7.37(m,1H),7.19(s,1H),7.13(s,1H),4.36(t,J＝6.7Hz,2H),3.94(s,3H),1.80–1.71(m,2H),0.86(t,J＝7.4Hz,3H).
HRMS calcd.For C18H20N5O3(M+H)+354.15607,found 354.15649.
Example 4
7-methoxy-1-propyl-2- (pyridazine-3-carboxamido) -1H-benzo [ d ] imidazole-5-amide
(1) Preparation of the title Compound
2-amino-7-methoxy-1-propyl-1H-benzo [ d ] imidazole-5-amide (0.2g,0.81mmol), pyridazine-3-carboxylic acid (0.12g,0.97mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.368g,0.97mmol), N, N-diisopropylethylamine (0.54ml,3.25mmol) were dissolved in 10ml of N, N-dimethylformamide and reacted for 8.5H with stirring at room temperature. After the reaction, 30ml of saturated ammonium chloride solution was added, a large amount of yellow solid precipitated, and the reaction mixture was filtered under reduced pressure, and the filter cake was washed with ether and dried to obtain a yellow solid, which was prepared by the method of step (5) in example 3, 177mg of gray solid was obtained, the yield was 61.7%, and the melting point was 268 ℃ and 270 ℃.
1H NMR(400MHz,DMSO-d6)δ9.33(s,1H),8.32(d,J＝8.36Hz,1H),7.98(s,1H),7.83(s,1H),7.73(s,1H),7.37(s,1H),7.31(s,1H),4.37–4.27(m,2H),3.96(s,3H),1.81–1.75(m,2H),0.83(t,J＝6.7Hz,3H).
HRMS calcd.For C17H19N6O3(M+H)+355.15131,found 355.15167.
Example 5
7-methoxy-2- (1-methyl-1H-imidazole-5-carboxamido) -1-propyl-1H-benzo [ d ] imidazole-5-amide
(1) Preparation of the title Compound
2-amino-7-methoxy-1-propyl-1H-benzo [ d ] imidazole-5-amide (0.2g,0.81mmol), 1-methyl-1H-imidazole-5-carboxylic acid (0.122g,0.97mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.368g,0.97mmol), N, N-diisopropylethylamine (0.54ml,3.25mmol) were dissolved in 10ml of N, N-dimethylformamide and reacted for 5H with stirring at room temperature. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of gray solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 156mg of gray solid, wherein the yield is 54.2%, and the melting point is more than 300 ℃.
1H NMR(400MHz,DMSO-d6)δ12.71(s,1H),7.98(s,1H),7.72(s,1H),7.64(s,1H),7.61(s,1H),7.38(s,1H),7.33(s,1H),4.31(t,J＝6.9Hz,2H),3.98(s,3H),3.97(s,3H),1.82–1.73(m,2H),0.90(t,J＝7.4Hz,3H).
HRMS calcd.For C17H21N6O3(M+H)+357.16697,found 357.16702.
Example 6
7-methoxy-2- (1-methyl-1H-indole-2-carboxamido) -1-propyl-1H-benzo [ d ] imidazole-5-amide
(1) Preparation of the title Compound
2-amino-7-methoxy-1-propyl-1H-benzo [ d ] imidazole-5-amide (0.2g,0.81mmol), 1-methylindole-2-carboxylic acid (0.17g,0.97mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.368g,0.97mmol), N, N-diisopropylethylamine (0.54ml,3.25mmol) was dissolved in 10ml of N, N-dimethylformamide and reacted for 6.5H with stirring at room temperature. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of gray solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 235mg of gray solid, wherein the yield is 71.8 percent, and the melting point is more than 300 ℃.
1H NMR(400MHz,DMSO-d6)δ12.78(s,1H),7.95(s,1H),7.68–7.59(m,2H),7.49(d,J＝8.3Hz,1H),7.36(s,1H),7.31–7.28(m,2H),7.23(t,J＝7.5Hz,1H),7.04(t,J＝7.3Hz,1H),4.34(t,J＝6.5Hz,2H),4.16(s,3H),3.96(s,3H),1.84–1.75(m,2H),0.90(t,J＝7.2Hz,3H).
HRMS calcd.For C22H24N5O3(M+H)+406.18737,found 406.18637.
Example 7
7-methoxy-2- (3-phenylalanyl) -1-propyl-1H-benzo [ d ] imidazole-5-amide
(1) Preparation of the title Compound
2-amino-7-methoxy-1-propyl-1H-benzo [ d ] imidazole-5-amide (0.2g,0.81mmol), phenylpropionic acid (0.146g,0.97mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.368g,0.97mmol), N, N-diisopropylethylamine (0.54ml,3.25mmol) were dissolved in 10ml of N, N-dimethylformamide and reacted for 4.5H with stirring at room temperature. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of white solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 203mg of white solid, wherein the yield is 65.8 percent, and the melting point is more than 300 ℃.
1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),7.98(s,1H),7.77(s,1H),7.33(s,1H),7.30–7.27(m,5H),7.22–7.17(m,1H),4.00(t,J＝9.1Hz,2H),3.95(s,3H),2.94(t,J＝7.4Hz,2H),2.76(t,J＝7.2Hz,2H),1.72–1.51(m,2H),0.67(t,J＝7.1Hz,3H).
HRMS calcd.For C21H25N4O3(M+H)+381.19212,found 381.19214.
Example 8
(3- (5-carbamoyl-7-methoxy-2- (quinoline-2-carboxamido) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of benzyl (3- ((4-carbamoyl-2-methoxy-6-nitrophenyl) amino) propyl) carbamate
4-chloro-3-methoxy-5-nitrobenzamide (3g,13mmol), benzyl N- (3-aminopropyl) carbamate (4.88mL,26mmol) and potassium carbonate (5.4g, 40mmol) were dissolved in 25mL of N-methylpyrrolidone in a 100mL sealed tube and reacted at 110 ℃ for 8 hours. The reaction is cooled to room temperature, saturated ammonium chloride solution is added to quench the reaction, brick red solid is separated out, the pressure is reduced and the filtration is carried out, the filter cake is washed by ethyl ether and dried to obtain 4.76g of brick red solid, the yield is 90.8 percent, and the melting point is 153-.
1H NMR(400MHz,DMSO-d6)δ8.20(d,J＝1.9Hz,1H),8.02(s,1H),7.78(t,J＝5.9Hz,1H),7.54(d,J＝1.7Hz,1H),7.39–7.26(m,7H),5.76(s,1H),4.99(s,2H),3.86(s,3H),3.48(q,J＝6.6Hz,2H),3.03(q,J＝6.4Hz,2H),1.69–1.63(m,2H).
MS(ESI)m/z 403.1(M+H)+.
(2) Preparation of benzyl (3- ((2-amino-4-carbamoyl-6-methoxyphenyl) amino) propyl) carbamate
Benzyl (3- ((4-carbamoyl-2-methoxy-6-nitrophenyl) amino) propyl) carbamate (6.54g,16mmol) was dissolved in 50ml of methanol, zinc powder (10g, 160mmol) was added, glacial acetic acid (9.2ml, 160mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 8 h. Filtering with diatomite to remove zinc powder, concentrating the reaction solution, and adding saturated sodium bicarbonate solution to adjust the pH value to be neutral. The mixture was extracted three times with dichloromethane, washed 2 times with distilled water, 1 time with saturated sodium chloride solution and dried over sodium sulfate. Concentrating, separating by column chromatography, and eluting with dichloromethane: methanol 10:1, 4.12g of white solid is obtained, the yield is 69.2%, and the melting point is 135-137 ℃.
1H NMR(400MHz,DMSO-d6)δ7.61(s,1H),7.39–7.28(m,5H),6.97(s,1H),6.86(d,J＝1.9Hz,1H),6.79(d,J＝1.9Hz,1H),5.01(s,2H),4.66(s,2H),3.75(s,3H),3.07(q,J＝6.6Hz,2H),2.94(t,J＝6.6Hz,2H),1.56–1.49(m,2H).
MS(ESI)m/z 373.1(M+H)+.
(3) Preparation of benzyl (3- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) carbamate
Benzyl (3- ((2-amino-4-carbamoyl-6-methoxyphenyl) amino) propyl) carbamate (5g,13mmol), cyanogen bromide (1.71g,16mmol) were dissolved in 40ml methanol and heated to 60 ℃ under argon for 5h reaction. Cooling the reaction to room temperature, adding saturated potassium carbonate solution to adjust the pH value to 7-8, separating out a large amount of white solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 4.2g of white solid, wherein the yield is 81.3%, and the melting point is 218-.1H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.39(d,J＝1.2Hz,1H),7.37–7.27(m,5H),7.09(d,J＝1.3Hz,1H),7.06(s,1H),6.44(s,2H),5.02(s,2H),4.14(t,J＝7.3Hz,2H),3.84(s,3H),3.04(q,J＝6.6Hz,2H),1.82–1.75(m,2H).
MS(ESI)m/z 398.1(M+H)+.
(4) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.25g,0.63mmol), quinoline-2-carboxylic acid (0.132g,0.76mmol), 2- (7-oxybenzotriazole) -N, N, N ', N ' -tetramethyluronium hexafluorophosphate (0.289g,0.76mmol), N, N ' -diisopropylethylamine (0.42ml,2.5mmol) were dissolved in 10ml N, N-dimethylformamide and the reaction was stirred at room temperature for 6H. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of light yellow solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 0.201g of light yellow solid, wherein the yield is 57.8 percent, and the melting point is 213-.
1H NMR(400MHz,DMSO-d6)δ13.04(s,1H),11.26(s,0.84H),8.65(d,J＝8.2Hz,1H),8.44–8.36(m,2H),8.24–8.14(m,4H),8.05–7.60(m,12H),7.40(d,J＝14.7Hz,3H),7.30–7.19(m,12H),5.02(s,2.3H),4.84(s,2H),4.54–4.44(m,2.37H),4.37–4.27(m,2H),3.98(s,3.45H),3.96(s,3H),3.16–3.10(m,2.31H),3.05–2.97(m,2H),2.01–1.90(m,4.38H).
HRMS calcd.For C30H29N6O5(M+H)+553.21939,found 553.21918.
Example 9
(3- (5-carbamoyl-2- (isoquinoline-1-carboxamido) -7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.25g,0.63mmol), isoquinoline-1-carboxylic acid (0.132g,0.76mmol), 2- (7-oxybenzotriazole) -N, N, N ', N ' -tetramethyluronium hexafluorophosphate (0.289g,0.76mmol), N, N ' -diisopropylethylamine (0.42ml,2.5mmol) was dissolved in 10ml N, N-dimethylformamide and the reaction was stirred at room temperature for 5H. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of yellow solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 0.192g of yellow solid, wherein the yield is 55.2 percent, and the melting point is 181-182 ℃.
1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.47(s,1H),8.04(s,2H),7.91–7.77(m,3H),7.76–7.69(m,1H),7.42(s,1H),7.37–7.30(m,6H),4.98(s,2H),4.37(t,J＝6.3Hz,2H),3.97(s,3H),3.04–3.00(m,2H),1.97–1.85(m,2H).
HRMS calcd.For C30H29N6O5(M+H)+553.21939,found 553.21997.
Example 10
(3- (5-carbamoyl-7-methoxy-2- (2-pyridylamido) -1H-benzo [ d)]Imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.25g,0.63mmol), pyridine-2-carboxylic acid (0.94g,0.76mmol), 2- (7-oxybenzotriazole) -N, N, N ', N ' -tetramethyluronium hexafluorophosphate (0.289g,0.76mmol), N, N ' -diisopropylethylamine (0.42ml,2.5mmol) were dissolved in 10ml N, N-dimethylformamide and the reaction was stirred at room temperature for 5.5H. After the reaction, 30ml of saturated ammonium chloride solution is added, a large amount of gray solid is separated out, the pressure reduction and the suction filtration are carried out, the filter cake is washed by ether and dried to obtain 171mg of gray solid, the yield is 54.1 percent, and the melting point is 244-245 ℃.
1H NMR(400MHz,DMSO-d6)δ12.95(s,1.75H),11.11(s,1H),8.77(s,1H),8.65(s,1H),8.47(s,1H),8.22–8.13(m,3H),8.08–8.01(m,4H),7.95–7.80(m,3H),7.71(s,3H),7.54–7.29(m,25.76H),5.10(s,3.71H),4.92(s,2H),4.48–4.41(m,3.76H),4.29–4.22(m,2H),3.98(s,5.52H),3.96(s,3H),3.07–2.96(m,5.68H),1.95–1.83(m,5.68H).
HRMS calcd.For C26H27N6O5(M+H)+503.20374,found 503.20343.
Example 11
(3- (5-carbamoyl-7-methoxy-2- (pyridazine-3-carboxamido) -1H-benzo [ d ] imidazol-1-yl) propyl) amino
Carboxylic acid benzyl ester
(1) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.25g,0.63mmol), pyridazine-3-carboxylic acid (0.95g,0.76mmol), 2- (7-oxybenzotriazole) -N, N, N ', N ' -tetramethyluronium hexafluorophosphate (0.289g,0.76mmol), N, N ' -diisopropylethylamine (0.42ml,2.5mmol) were dissolved in 10ml N, N-dimethylformamide and the reaction was stirred at room temperature for 8.5H. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of gray solid, performing vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 162mg of gray solid, wherein the yield is 51.1 percent, and the melting point is 249-.
1H NMR(400MHz,DMSO-d6)δ13.06(s,1H),9.31(s,1H),8.37(d,J＝8.0Hz,1H),8.05(s,1H),7.76(s,1H),7.54–7.29(m,8H),4.98(s,2H),4.47–4.42(m,2H),3.97(s,3H),3.10–3.05(m,2H),1.97–1.90(m,2H).
HRMS calcd.For C25H26N7O5(M+H)+504.19899,found 504.19855.
Example 12
(3- (5-carbamoyl-7-methoxy-2- (1-methyl-1H-imidazole-5-carboxamido) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.25g,0.63mmol), 1-methyl-1H-imidazole-5-carboxylic acid (0.122g,0.76mmol), 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.96g,0.76mmol), N, N-diisopropylethylamine (0.42ml,2.5mmol) were dissolved in 10ml of N, N-dimethylformamide and reacted for 9H with stirring at room temperature. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of white solid, carrying out vacuum filtration, washing a filter cake by using ether, and drying to obtain 164mg of white solid, wherein the yield is 51.6 percent, and the melting point is 228-.
1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.73(s,1H),7.66(d,J＝8.9Hz,2H),7.38(s,1H),7.37–7.31(m,6H),5.00(s,2H),4.35(t,J＝6.7Hz,2H),3.95(s,6H),3.10–3.06(m,2H),1.93–1.86(m,2H).
HRMS calcd.For C25H28N7O5(M+H)+506.21464,found 506.21301.
Example 13
(3- (5-carbamoyl-7-methoxy-2- (1-methyl-1H-indole-2-carboxamido) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.25g,0.63mmol), 1-methylindole-2-carboxylic acid (0.134g,0.76mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.289g,0.76mmol), N, N-diisopropylethylamine (0.42ml,2.5mmol) were dissolved in 10ml of N, N-dimethylformamide and reacted with stirring at room temperature for 6.5H. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of light pink solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain the light pink solid 240mg with the yield of 68.8 percent and the melting point of 232-.
1H NMR(400MHz,DMSO-d6)δ12.84(s,1H),8.02(s,1H),7.68(s,1H),7.58(d,J＝7.5Hz,1H),7.50(d,J＝8.3Hz,1H),7.40(s,1H),7.35(s,1H),7.31–7.23(m,7H),7.06(t,J＝7.3Hz,1H),4.99(s,2H),4.43(t,J＝6.6Hz,2H),4.18(s,3H),3.97(s,3H),3.14–3.09(m,2H),1.98–1.92(m,2H).
HRMS calcd.For C30H31N6O5(M+H)+555.23504,found 555.23700.
Example 14
(3- (5-carbamoyl-7-methoxy-2- (3-phenylalanylamino) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.25g,0.63mmol), phenylpropionic acid (0.134g,0.76mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.289g,0.76mmol), N, N-diisopropylethylamine (0.42ml,2.5mmol) was dissolved in 10ml N, N-dimethylformamide and reacted for 7H with stirring at room temperature. After the reaction, 30ml of saturated ammonium chloride solution is added, a large amount of white solid is separated out, the pressure reduction and the suction filtration are carried out, the filter cake is washed by ethyl ether and dried to obtain 189mg of white solid, the yield is 56.8 percent, the melting point is 245-
1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),7.96(s,1H),7.77(s,1H),7.37–7.24(m,13H),5.00(s,2H),4.10(t,J＝9.1Hz,2H),3.91(s,3H),2.95–2.91(m,4H),2.75(t,J＝7.2Hz,2H),1.82–1.71(m,2H).
HRMS calcd.For C29H32N5O5(M+H)+530.23980,found 530.23920.
Example 15
(3- (5-carbamoyl-7-methoxy-2- (1-methyl-1H-pyrrole-2-carboxamido) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.25g,0.63mmol), 1-methyl-2-pyrrolidinecarboxylic acid (0.96g,0.76mmol), 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.289g,0.76mmol), N, N-diisopropylethylamine (0.42ml,2.5mmol) were dissolved in 10ml of N, N-dimethylformamide and reacted for 9H with stirring at room temperature. After the reaction, 30ml of saturated ammonium chloride solution is added, a large amount of white solid is separated out, the pressure reduction and the suction filtration are carried out, the filter cake is washed by ether and dried to obtain 164mg of white solid, the yield is 32.6 percent, and the melting point is 232 ℃ and 233 ℃.
1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),7.98(s,1H),7.62(s,1H),7.37–7.30(m,8H),6.95(s,1H),6.90(s,1H),5.96(s,1H),4.99(s,2H),4.33(t,J＝6.8Hz,2H),3.97(s,3H),3.94(s,3H),3.08–3.04(m,2H),1.92–1.85(m,2H).
HRMS calcd.For C26H29N6O5(M+H)+505.21939,found 505.21945.
Example 16
(3- (5-carbamoyl-7-methoxy-2- (1-methylpyrrolidine-2-carboxamido) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.25g,0.63mmol), 1-methyl-2-pyrrolidinecarboxylic acid (0.1g,0.76mmol), 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.289g,0.76mmol), N, N-diisopropylethylamine (0.42ml,2.5mmol) were dissolved in 10ml of N, N-dimethylformamide and reacted for 9H with stirring at room temperature. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of white solid, carrying out vacuum filtration, washing a filter cake by using ether, and drying to obtain 195mg of white solid, wherein the yield is 60.6%, and the melting point is 141-.
1H NMR(400MHz,Methanol-d4)δ7.65(s,1H),7.38–7.34(m,4H),7.32–7.28(m,2H),5.07(s,2H),4.44(t,J＝6.4Hz,2H),3.98(s,3H),3.74–3.61(m,1H),3.16(q,J＝6.9,6.2Hz,2H),3.06–2.96(m,1H),2.92–2.88(m,3H),2.60–2.44(m,1H),2.27–2.12(m,1H),2.03–1.93(m,3H),1.35–1.22(m,2H).
HRMS calcd.For C26H33N6O5(M+H)+509.25069,found 509.25061.
Example 17
(3- (5-carbamoyl-7-methoxy-2- (1-methylpiperidine-4-carboxamido) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.25g,0.63mmol), 1-methyl-piperidine-4-carboxylic acid (0.109g,0.76mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.289g,0.76mmol), N, N-diisopropylethylamine (0.42ml,2.5mmol) were dissolved in 10ml N, N-dimethylformamide and the reaction was stirred at room temperature for 5.5H. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of light brown solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 107mg of light brown solid, wherein the yield is 32.4%, and the melting point is 101-102 ℃.
1H NMR(400MHz,Methanol-d4)δ7.41–7.21(m,7H),5.05(s,2H),4.46–4.40(m,2H),3.97(s,3H),3.54–3.32(m,2H),3.24–3.00(m,3H),2.89–2.82(m,1H),2.77(s,3H),2.73–2.59(m,1H),2.21–2.12(m,4H),2.00–1.94(m,2H).
HRMS calcd.For C27H35N6O5(M+H)+523.26634,found 523.26660.
Example 18
(4- (5-carbamoyl-7-methoxy-2- (2-pyridylamido) -1H-benzo [ d ] imidazol-1-yl) butyl) carbamate tert-butyl ester
(1) Preparation of tert-butyl (4- ((4-carbamoyl-2-methoxy-6-nitrophenyl) amino) butyl) carbamate
4-chloro-3-methoxy-5-nitrobenzamide (1g,4mmol), N-t-butoxycarbonyl-1, 4-butanediamine (1.7mL,8mmol), and potassium carbonate (1.66g, 12mmol) were dissolved in 30mL of N-methylpyrrolidone and reacted at 100 ℃ for 4.5 hours in a flask. Cooling the reaction to room temperature, adding saturated ammonium chloride solution to quench the reaction, separating out a large amount of orange solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 1.4g of orange solid, wherein the yield is 91.6 percent, and the melting point is 204-.
1H NMR(400MHz,DMSO-d6)δ8.19(d,J＝1.9Hz,1H),8.00(s,1H),7.69(t,J＝5.9Hz,1H),7.54(d,J＝1.8Hz,1H),7.30(s,1H),6.79(t,J＝5.5Hz,1H),3.88(s,3H),3.48–3.43(m,2H),2.92–2.87(m,2H),1.53–1.46(m,2H),1.41–1.34(m,11H).
MS(ESI)m/z 383.1(M+H)+.
(2) Preparation of tert-butyl (4- ((2-amino-4-carbamoyl-6-methoxyphenyl) amino) butyl) carbamate
Tert-butyl (4- ((4-carbamoyl-2-methoxy-6-nitrophenyl) amino) butyl) carbamate (1.3g,3.4mmol) was dissolved in 30ml of methanol, Pd/C (0.13g, 10%) was added, hydrogen was passed in, and the reaction was carried out at 25 ℃ for 6 hours. Filtering with diatomite to remove Pd/C, concentrating the reaction solution, and performing column chromatography separation, wherein an eluent is dichloromethane: methanol 10:1, 0.81g of white solid was obtained in 67.6% yield, melting point 134-.
1H NMR(400MHz,DMSO-d6)δ7.60(s,1H),6.96(s,1H),6.85(d,J＝1.9Hz,1H),6.78(d,J＝1.9Hz,1H),4.64(s,2H),3.75(s,3H),2.92–2.86(m,4H),1.41–1.38(m,2H),1.36(s,9H).
MS(ESI)m/z 353.2(M+H)+.
(3) Preparation of tert-butyl (4- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) butyl) carbamate
Tert-butyl (4- ((2-amino-4-carbamoyl-6-methoxyphenyl) amino) butyl) carbamate (1.7g,5mmol), cyanogen bromide (0.62g,5.8mmol) were dissolved in 30ml methanol and heated to 60 ℃ under argon for 5 h. Cooling the reaction to room temperature, adding saturated potassium carbonate solution to adjust the pH value to 7-8, separating out a large amount of white solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 1.56g of white solid, wherein the yield is 82.5%, and the melting point is 211-.1H NMR(400MHz,DMSO-d6)δ12.85(s,1H),8.60(s,2H),8.08(s,1H),7.50(d,J＝1.3Hz,1H),7.45(d,J＝1.3Hz,1H),6.83(t,J＝5.5Hz,1H),4.21(t,J＝7.2Hz,2H),3.97(s,3H),2.95–2.91(m,2H),1.70–1.63(m,2H),1.45–1.40(m,2H),1.35(s,9H).
MS(ESI)m/z 378.2(M+H)+.
(4) Preparation of the title Compound
Tert-butyl (4- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) butyl) carbamate (0.3g,0.8mmol), pyridine-2-carboxylic acid (0.119g,0.95mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.363g,0.95mmol), N, N-diisopropylethylamine (0.53ml,3.18mmol) were dissolved in 10ml of N, N-dimethylformamide and the reaction was stirred at room temperature for 3.5H. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of light yellow solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 114mg of light yellow solid, wherein the yield is 29.6%, and the melting point is 205-. . .
1H NMR(400MHz,DMSO-d6)δ8.76–8.75(m,1H),8.23(br.s,1H),8.11–7.96(m,2H),7.79(s,1H),7.68(s,1H),7.39(s,1H),7.35–7.30(m,1H),6.76(s,1H),4.40–4.20(m,2H),3.99(s,3H),3.01–2.74(m,2H),1.81–1.61(m,2H),1.37–1.27(m,11H).
HRMS calcd.For C24H31N6O5(M+H)+483.23504,found 483.23636.
Example 19
(4- (5-carbamoyl-7-methoxy-2- (pyridazin-3-ylamino) -1H-benzo [ d ] imidazol-1-yl) butyl) carbamic acid tert-butyl ester
(1) Preparation of the title Compound
Tert-butyl (4- (2-amino-5-carbamoyl-7-methoxy-1H-benzo [ d ] imidazol-1-yl) butyl) carbamate (0.3g,0.8mmol), pyridazine-3-carboxylic acid (0.119g,0.95mmol), 2- (7-oxybenzotriazole) -N, N, N ', N ' -tetramethyluronium hexafluorophosphate (0.363g,0.95mmol), N, N ' -diisopropylethylamine (0.53ml,3.18mmol) were dissolved in 10ml N, N-dimethylformamide and the reaction was stirred at room temperature for 3.5H. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of gray solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 156mg of gray solid, wherein the yield is 40.4%, and the melting point is 244-.
1H NMR(400MHz,DMSO-d6)δ13.06(s,1H),9.32(s,1H),8.39–8.37(m,1H),8.02(s,1H),7.81(br.s,1H),7.75(s,1H),7.42(s,1H),7.37(s,1H),6.76(s,1H),4.46–4.37(m,2H),4.00(s,3H),2.99–2.83(m,2H),1.81–1.67(m,2H),1.46–1.35(m,2H),1.31(s,9H).
HRMS calcd.For C23H30N7O5(M+H)+484.23029,found 484.23108.
Example 20
(3- (5-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-amido) -7- (3-methoxypropoxy) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of 4-chloro-3-hydroxy-5-nitrobenzamide
4-chloro-3-methoxy-5-nitrobenzamide (0.5g,2mmol) and 20ml of dichloromethane were added in turn to a bottle, and 1M boron tribromide/dichloromethane solution (9ml, 9mmol) was slowly added dropwise, and the reaction was carried out under argon atmosphere at room temperature for 12 h. Pouring the reaction solution into ice water, separating out a large amount of white solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 0.296g of white solid, wherein the yield is 68.1 percent, and the melting point is 205-.
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),8.17(s,1H),7.92(s,1H),7.71(s,1H),7.65(s,1H).
MS(ESI)m/z 217.0(M+H)+.
(2) Preparation of 4-chloro-3- (3-methoxypropoxy) -5-nitrobenzamide
4-chloro-3-hydroxy-5-nitrobenzamide (1g,5mmol), 3-bromopropylmethyl ether (0.63ml,5.5mmol), potassium carbonate (0.84g,6mmol) were dissolved in 20ml of N, N-dimethylformamide and reacted at 60 ℃ for 4h under argon. After the reaction, 30ml of saturated ammonium chloride solution was added, the mixture was extracted three times with dichloromethane, washed 2 times with distilled water, washed 1 time with saturated sodium chloride solution, and dried over sodium sulfate. Concentrating, separating by column chromatography, and eluting with dichloromethane: methanol 20:1, 1.21g of pale yellow solid was obtained, yield 84%, melting point 128-.
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.05(d,J＝1.8Hz,1H),7.90(d,J＝1.8Hz,1H),7.77(s,1H),7.23(s,1H),4.29(t,J＝6.3Hz,2H),3.51(t,J＝6.2Hz,2H),3.26(s,3H),2.08–1.98(m,2H).
MS(ESI)m/z 289.0(M+H)+.
(3) Preparation of benzyl (3- ((4-carbamoyl-2- (3-methoxypropoxy) -6-nitrophenyl) amino) propyl) carbamate
4-chloro-3- (3-methoxypropoxy) -5-nitrobenzamide (0.1g,0.35mmol), benzyl N- (3-aminopropyl) carbamate (0.13ml,0.7mmol), N, N-diisopropylethylamine (0.17ml, 1.1mmol) was dissolved in 20ml of ethanol and reacted at 120 ℃ for 36 hours under argon protection. Cooling the reaction to room temperature, adding saturated ammonium chloride solution to quench the reaction, separating out a large amount of orange solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 0.13g of orange solid, wherein the yield is 80.7 percent, and the melting point is 126-.
1H NMR(400MHz,DMSO-d6)δ8.20(d,J＝1.9Hz,1H),8.01(s,1H),7.76(t,J＝5.8Hz,1H),7.54(d,J＝1.4Hz,1H),7.39–7.26(m,7H),4.99(s,2H),4.10(t,J＝6.3Hz,2H),3.57–3.51(m,2H),3.49(t,J＝6.2Hz,2H),3.25(s,3H),3.08–2.99(m,2H),2.08–1.98(m,2H),1.72–1.62(m,2H).
MS(ESI)m/z 461.2(M+H)+.
(4) Preparation of benzyl (3- ((2-amino-4-carbamoyl-6- (3-methoxypropoxy) phenyl) amino) propyl) carbamate
Benzyl (3- ((4-carbamoyl-2- (3-methoxypropoxy) -6-nitrophenyl) amino) propyl) carbamate (0.84g,1.83mmol) was dissolved in 30ml of methanol, zinc powder (1.2g, 18.3mmol) was added, glacial acetic acid (1.1ml, 18.3mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 8 h. Filtering with diatomite to remove zinc powder, concentrating the reaction solution, and adding saturated sodium bicarbonate solution to adjust the pH value to be neutral. The mixture was extracted three times with dichloromethane, washed 2 times with distilled water, 1 time with saturated sodium chloride solution and dried over sodium sulfate. Concentrating, separating by column chromatography, and eluting with dichloromethane: methanol 10:1, 0.4g of white solid is obtained, the yield is 50.8%, the melting point is 101-.
1H NMR(400MHz,DMSO-d6)δ7.61(s,1H),7.39–7.27(m,5H),7.25(t,J＝5.7Hz,1H),6.94(s,1H),6.85(d,J＝1.9Hz,1H),6.77(d,J＝1.9Hz,1H),5.01(s,2H),4.65(s,2H),3.98(t,J＝6.3Hz,2H),3.49(t,J＝6.2Hz,2H),3.24(s,3H),3.12–3.03(m,2H),2.98(t,J＝6.4Hz,2H),2.01–1.91(m,2H),1.58–1.47(m,2H).
MS(ESI)m/z 431.2(M+H)+.
(5) Preparation of benzyl (3- (2-amino-5-carbamoyl-7- (3-methoxypropoxy) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamate
Benzyl (3- ((2-amino-4-carbamoyl-6- (3-methoxypropoxy) phenyl) amino) propyl) carbamate (0.4g,0.93mmol), cyanogen bromide (0.118g,1.2mmol) were dissolved in 20ml methanol and heated to 60 ℃ under argon for reaction for 6 h. Cooling the reaction to room temperature, adding saturated potassium carbonate solution to adjust the pH value to 7-8, separating out a large amount of white solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 0.358g of white solid, wherein the yield is 84.6 percent, and the melting point is 214-.
1H NMR(400MHz,DMSO-d6)δ8.64(s,2H),8.09(s,1H),7.49(s,1H),7.43(s,2H),7.38–7.29(m,6H),5.00(s,2H),4.29–4.18(m,4H),3.48(t,J＝5.9Hz,2H),3.16–3.07(m,2H),2.10–2.00(m,2H),1.93–1.82(m,2H).
MS(ESI)m/z 456.2(M+H)+.
(6) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7- (3-methoxypropoxy) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.3g,0.66mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (0.123g,0.8mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.304g,0.8mmol), N, N-diisopropylethylamine (0.43ml,2.6mmol) was dissolved in 10ml of N, N-dimethylformamide and reacted for 6 hours with stirring at room temperature. After the reaction, 30ml of saturated ammonium chloride solution was added, the mixture was extracted three times with dichloromethane, washed 2 times with distilled water, washed 1 time with saturated sodium chloride solution, and dried over sodium sulfate. Concentrating, performing column chromatography separation, and eluting with dichloromethane: methanol 10:1, 0.270g of light pink solid is obtained, the yield is 69.2%, and the melting point is 145-.
1H NMR(400MHz,DMSO-d6)δ12.86(s,1H),8.03(s,1H),7.67(s,1H),7.40–7.23(m,8H),6.66(s,1H),5.00(s,2H),4.64–4.58(m,2H),4.37(t,J＝7.0Hz,2H),4.23(t,J＝6.3Hz,2H),3.52(t,J＝6.1Hz,2H),3.26(s,3H),3.12–3.07(m,2H),2.13(s,3H),2.10–2.04(m,2H),1.95–1.88(m,2H),1.35(t,J＝7.1Hz,3H).
HRMS calcd.For C30H38N7O6(M+H)+592.28781,found 592.28821.
Example 21
(3- (5-carbamoyl-7- (3-methoxypropoxy) -2- (2-pyridylamido) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7- (3-methoxypropoxy) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.3g,0.66mmol), pyridine-2-carboxylic acid (0.99g,0.8mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.304g,0.8mmol), N, N-diisopropylethylamine (0.43ml,2.6mmol) were dissolved in 10ml N, N-dimethylformamide and the reaction was stirred at room temperature for 9H. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of tan solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 201mg of tan solid, wherein the yield is 54.1%, and the melting point is 134-.
1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.60–8.41(m,1H),8.21(s,1H),8.01–7.71(m,3H),7.42–7.30(m,7H),5.04(s,2H),4.55–4.34(m,2H),4.22–4.18(m2H),3.54(t,J＝6.0Hz,2H),3.32(s,3H),3.05–2.96(m,2H),2.10–2.04(m,2H),1.94–1.85(m,2H).
HRMS calcd.For C29H33N6O6(M+H)+561.24561,found 561.24487.
Example 22
(3- (5-carbamoyl-7- (3-methoxypropoxy) -2- (pyridazin-3-ylamino) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7- (3-methoxypropoxy) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.3g,0.66mmol), pyridazine-3-carboxylic acid (0.99g,0.8mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.304g,0.8mmol), N, N-diisopropylethylamine (0.43ml,2.6mmol) were dissolved in 10ml of N, N-dimethylformamide and reacted for 9H with stirring at room temperature. After the reaction is finished, 30ml of saturated ammonium chloride solution is added, a large amount of light green solid is separated out, the pressure reduction and suction filtration are carried out, the filter cake is washed by ethyl ether and dried to obtain 159mg of light green solid, the yield is 47.9 percent, and the melting point is 175-.
1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.39(d,J＝8.0Hz,1H),7.84(s,1H),7.77(s,1H),7.70–7.53(m,2H),7.39–7.00(m,8H),4.95(s,2H),4.44(t,J＝5.6Hz,2H),4.19(t,J＝5.8Hz,2H),3.54(t,J＝5.9Hz,2H),3.27(s,3H),3.04–3.00(m,2H),2.09–2.03(m,2H),1.92–1.87(m,2H).
HRMS calcd.For C28H32N7O6(M+H)+562.24086,found 562.24164.
Example 23
(3- (5-carbamoyl-7- (3-morpholinopropoxy) -2- (2-pyridylamido) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of 4-chloro-3- (3-morpholinopropoxy) -5-nitrobenzamide
4-chloro-3-hydroxy-5-nitrobenzamide (0.2g,0.93mmol), 3-bromopropylmorpholine (182mg,1.12mmol), potassium carbonate (0.167g,1.2mmol) were dissolved in 100ml of N, N-dimethylformamide and reacted at 70 ℃ for 4h under argon. After the reaction, 30ml of saturated ammonium chloride solution was added, the mixture was extracted three times with dichloromethane, washed 2 times with distilled water, washed 1 time with saturated sodium chloride solution, and dried over sodium sulfate. Concentrating, separating by column chromatography, and eluting with dichloromethane: methanol 20:1, light yellow solid 0.169g, yield 52.9%, melting point 165-.1H NMR(400MHz,DMSO-d6)δ8.29(s,1H),8.04(s,1H),7.87(s,1H),7.78(s,1H),4.39–4.18(m,2H),3.65–3.52(m,4H),2.47–2.42(m,2H),2.38–2.34(m,4H),2.01–1.89(m,2H).
MS(ESI)m/z 344.1(M+H)+.
(2) Preparation of benzyl (3- ((4-carbamoyl-2- (3-morpholinopropoxy) -6-nitrophenyl) amino) propyl) carbamate
4-chloro-3- (3-morpholinopropoxy) -5-nitrobenzamide (0.1g,0.29mmol), benzyl N- (3-aminopropyl) carbamate (0.1ml,0.58mmol), N, N-diisopropylethylamine (0.096ml, 0.58mmol) were dissolved in 20ml of isopropanol and reacted at 120 ℃ under argon for 42 hours. Cooling the reaction to room temperature, adding saturated ammonium chloride solution to quench the reaction, separating out a large amount of brick red solid, carrying out suction filtration under reduced pressure, washing a filter cake with diethyl ether, and drying to obtain red-converted solid with the yield of 75.6 percent and the melting point of 93-94 ℃.
1H NMR(400MHz,Chloroform-d)δ8.21(s,1H),8.13(s,1H),7.41(s,1H),7.31–7.27(m,5H),5.05(s,2H),4.04–3.99(m,2H),3.74–3.65(m,6H),3.30–3.21(m,2H),2.64–2.48(m,6H),2.08–1.98(m,2H),1.84–1.76(m,2H).
MS(ESI)m/z 516.2(M+H)+.
(3) Preparation of benzyl (3- ((2-amino-4-carbamoyl-6- (3-morpholinopropoxy) phenyl) amino) propyl) carbamate
Benzyl (3- ((4-carbamoyl-2- (3-morpholinopropoxy) -6-nitrophenyl) amino) propyl) carbamate (1.3g,4mmol) was dissolved in 30ml of methanol, zinc powder (2.5g, 40mmol) was added, glacial acetic acid (2.3ml, 40mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 8 h. Filtering with diatomite to remove zinc powder, concentrating the reaction solution, and adding saturated sodium bicarbonate solution to adjust the pH value to be neutral. The mixture was extracted three times with dichloromethane, washed 2 times with distilled water, 1 time with saturated sodium chloride solution and dried over sodium sulfate. Concentrating, performing column chromatography separation, and eluting with dichloromethane: methanol 10:1 gave 1.1g of brown oil in 56.7% yield.
1H NMR(500 MHz,Chloroform-d)δ7.34–7.28(m,5H),6.83(s,1H),6.73(s,1H),5.07(s,2H),4.02(t,J＝4.1 Hz,2H),3.71–3.66(m,4H),3.34–3.26(m,2H),3.02(t,J＝6.0 Hz,2H),2.50–2.41(m,6H),2.01–1.91(m,2H),1.69–1.63(m,2H).
MS(ESI)m/z 486.2(M+H)+.
(4) Preparation of benzyl (3- (2-amino-5-carbamoyl-7- (3-morpholinopropoxy) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamate
Benzyl (3- ((2-amino-4-carbamoyl-6- (3-morpholinopropoxy) phenyl) amino) propyl) carbamate (1g,2.1mmol), cyanogen bromide (0.262g,2.5mmol) were dissolved in 30ml methanol and heated to 60 ℃ under argon for 10h reaction. Cooling the reaction to room temperature, adding a saturated potassium carbonate solution to adjust the pH value to 7-8, separating out a large amount of white solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and dryingDrying to obtain 0.801g of white solid with the yield of 75.1 percent and the melting point of 184-185 ℃.1H NMR(400MHz,DMSO-d6)δ7.79(d,J＝6.7Hz,1H),7.39(s,1H),7.37–7.26(m,7H),7.08(s,1H),7.06(s,1H),6.45(s,1H),5.01(s,2H),4.20–4.13(m,2H),4.12–4.08(m,2H),3.59–3.53(m,4H),3.11–3.02(m,2H),2.44(t,J＝6.8Hz,2H),2.39–2.33(m,4H),2.01–1.92(m,2H),1.87–1.76(m,2H).
MS(ESI)m/z 511.2(M+H)+.
(5) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7- (3-morpholinopropoxy) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.3g,0.6mmol), pyridine-2-carboxylic acid (0.88g,0.71mmol), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.27g,0.71mmol), N, N-diisopropylethylamine (0.4ml,2.4mmol) were dissolved in 10ml of N, N-dimethylformamide and reacted for 9 hours with stirring at room temperature. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of white solid, carrying out vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 103mg of white solid, wherein the yield is 57.9 percent, and the melting point is 165-166 ℃.
1H NMR(400MHz,DMSO-d6)δ8.89–8.42(m,1H),8.40–8.13(m,1H),8.06–7.92(m,1H),7.86–7.68(m,1H),7.58–6.95(m,10H),5.01(s,2H),4.56–4.39(m,1H),4.37–4.29(m,1H),4.24–4.15(m,2H),3.63–3.51(m,4H),3.10–2.94(m,2H),2.49–2.44(m,2H),2.41–2.33(m,4H),2.04–1.95(m,2H),1.93–1.87(m,2H).
HRMS calcd.For C32H38N7O6(M+H)+616.28781,found 616.29077.
Example 24
(3- (5-carbamoyl-7- (3-morpholinepropoxy) -2- (pyridazin-3-ylamino) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamic acid benzyl ester
(1) Preparation of the title Compound
Benzyl (3- (2-amino-5-carbamoyl-7- (3-morpholinopropoxy) -1H-benzo [ d ] imidazol-1-yl) propyl) carbamate (0.3g,0.6mmol), pyridazine-3-carboxylic acid (0.89g,0.71mmol), 2- (7-benzotriazol-oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.27g,0.71mmol), N, N-diisopropylethylamine (0.4ml,2.4mmol) were dissolved in 10ml of N, N-dimethylformamide and reacted for 9H with stirring at room temperature. After the reaction is finished, adding 30ml of saturated ammonium chloride solution, separating out a large amount of white solid, carrying out vacuum filtration, washing a filter cake by using ether, and drying to obtain 147mg of white solid, wherein the yield is 59.8 percent, and the melting point is 184-.
1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),9.35(s,1H),8.29(d,J＝8.2Hz,1H),8.01(s,1H),7.78(s,2H),7.53(s,1H),7.38–7.25(m,7H),4.96(s,2H),4.46–4.39(m,2H),4.29–4.23(m,2H),4.01–3.94(m,2H),3.84(t,J＝11.8Hz,2H),3.60–3.53(m,2H),3.20–3.11(m,2H),3.11–3.03(m,2H),2.39–2.29(m,2H),2.01–1.91(m,2H).
HRMS calcd.For C31H37N8O6(M+H)+617.28306,found 617.28357.
Example 25
3- (3- ((tert-Butoxycarbonyl) amino) propyl) -2- (1-ethyl-3-methyl-1H-pyrazol-5-ylamino) -3H-imidazo [4,5-b ] pyridine-6-carboxylic acid methyl ester
(1) Preparation of methyl 6- ((3- ((tert-butoxycarbonyl) amino) propyl) amino) -5-nitronicotinate
Methyl 6-chloro-5-nitronicotinate (2g,9.3mmol), N-tert-butoxycarbonyl-1, 3-propanediamine (3.3g,19mmol), and potassium carbonate (3.8g, 27mmol) were dissolved in 30mL of N-methylpyrrolidone and reacted at 100 ℃ for 3 hours in a flask. The reaction was cooled to room temperature and quenched by addition of saturated ammonium chloride solution. The mixture was extracted three times with dichloromethane, washed 2 times with distilled water, 1 time with saturated sodium chloride solution and dried over sodium sulfate. Concentrating, performing column chromatography separation, and eluting with dichloromethane: methanol 20:1, 2.03g of yellow solid was obtained in 61.. 6% yield, melting point 133-.
1H NMR(400MHz,DMSO-d6)δ9.02(t,J＝5.8Hz,1H),8.89(d,J＝2.1Hz,1H),8.73(d,J＝2.1Hz,1H),6.89(t,J＝5.7Hz,1H),3.85(s,3H),3.68–3.59(m,2H),3.03–2.94(m,2H),1.75–1.64(m,2H),1.37(s,9H).
MS(ESI)m/z 355.1(M+H)+.
(2) Preparation of methyl 5-amino-6- ((3- ((tert-butoxycarbonyl) amino) propyl) amino) nitronicotinate
Methyl 6- ((3- ((tert-butoxycarbonyl) amino) propyl) amino) -5-nitronicotinate (1.0g,2.8mmol) was dissolved in 30ml of methanol, Pd/C (0.1g, 10%) was added, hydrogen was passed through, and the reaction was carried out at 25 ℃ for 6 hours. Filtering with diatomite to remove Pd/C, concentrating the reaction solution, and performing column chromatography separation, wherein an eluent is dichloromethane: methanol 10:1 gave 0.79g of brown oil in 87.1% yield.
1H NMR(400MHz,Chloroform-d)δ8.38(d,J＝1.9Hz,1H),7.35(d,J＝1.9Hz,1H),3.82(s,3H),3.62–3.53(m,2H),3.23–3.15(m,2H),1.80–1.69(m,2H),1.42(s,9H).
MS(ESI)m/z 325.1(M+H)+.
(3) 2-amino-3- (3- ((tert-butoxycarbonyl) amino) propyl) -3H-imidazo [4,5-b ] pyridine-6-carboxylic acid methyl ester
Methyl 5-amino-6- ((3- ((tert-butoxycarbonyl) amino) propyl) amino) nitronicotinate (0.764g,2.36mmol), cyanogen bromide (0.3g,2.83mmol) were dissolved in 15ml of methanol and heated to 60 ℃ under argon for 10 h. And cooling the reaction to room temperature, and adding a saturated potassium carbonate solution to adjust the pH value to 7-8. The mixture was extracted three times with dichloromethane, washed 2 times with distilled water, 1 time with saturated sodium chloride solution and dried over sodium sulfate. Concentrating, performing column chromatography separation, and eluting with dichloromethane: methanol 20:1, 0.413g of white solid was obtained, yield 50.1%, melting point 184-.
1H NMR(400MHz,DMSO-d6)δ8.50(d,J＝1.8Hz,1H),7.81(d,J＝1.8Hz,1H),7.12(s,2H),6.86(t,J＝5.2Hz,1H),4.06(t,J＝7.3Hz,2H),3.84(s,3H),3.01–2.92(m,2H),1.84–1.72(m,2H),1.37(s,9H).
MS(ESI)m/z 350.1(M+H)+.
(4) Preparation of the title Compound
Methyl 2-amino-3- (3- ((tert-butoxycarbonyl) amino) propyl) -3H-imidazo [4,5-b ] pyridine-6-carboxylate (0.25g,0.72mmol), 1-ethyl-3-methyl-1H-pyrazole-5-carboxylate (0.111g,0.86mmol), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (0.327g,0.86mmol), N, N-diisopropylethylamine (0.47ml,2.86mmol) were dissolved in 10ml of N, N-dimethylformamide and reacted for 3.5H with stirring at room temperature. After the reaction, 30ml of saturated ammonium chloride solution was added, the mixture was extracted three times with dichloromethane, washed 2 times with distilled water, washed 1 time with saturated sodium chloride solution, and dried over sodium sulfate. Concentrating, separating by column chromatography, and eluting with dichloromethane: methanol is 20:1, white solid is obtained, 0.297g is obtained, the yield is 85.0 percent, and the melting point is 213-. .
1H NMR(400MHz,DMSO-d6)δ12.90(s,1H),8.79(d,J＝4.0Hz,1H),8.16(s,1H),6.86(t,J＝5.6Hz,1H),6.73(s,1H),4.63–4.58(m,2H),4.20(t,J＝7.1Hz,2H),3.90(s,3H),3.03–2.99(m,2H),2.19(s,3H),1.98–1.91(m,2H),1.40–1.30(m,12H).
HRMS calcd.For C23H32N7O5(M+H)+486.24594,found 486.24338.
Example 26
3- (3- ((tert-butoxycarbonyl) amino) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -3H-imidazo [4,5-b ] pyridine-6-carboxylic acid
(1) Preparation of the title Compound
Methyl 3- (3- ((tert-butoxycarbonyl) amino) propyl) -2- (1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -3H-imidazo [4,5-b ] pyridine-6-carboxylate (0.1g,0.21mmol) was dissolved in 10ml of methanol, 3N lithium hydroxide (0.756ml,0.26mmol) was slowly added, and the reaction was stirred at room temperature for 6H. After the reaction is finished, slowly dropwise adding a glacial acetic acid solution until the glacial acetic acid solution is neutral, evaporating most of the solvent, adding distilled water, performing vacuum filtration, washing a filter cake with diethyl ether, and drying to obtain 0.075g of a white solid, wherein the yield is 75.8 percent, and the melting point is 202-.
1H NMR(400MHz,DMSO-d6)δ12.87(s,1H),8.78(d,J＝1.8Hz,1H),8.17(d,J＝1.7Hz,1H),6.86(t,J＝5.5Hz,1H),6.72(s,1H),4.65–4.56(m,2H),4.21(t,J＝7.1Hz,2H),3.05–2.97(m,2H),2.19(s,3H),1.99–1.89(m,2H),1.38–1.33(m,12H).
HRMS calcd.For C22H30N7O5(M+H)+472.23029,found 472.22864.
Example 27
(3- (6-carbamoyl-2- (1-ethyl-3-methyl-1H-pyrazole-5-amido) -3H-imidazo [4,5-b ] pyridin-3-yl) propyl) carbamic acid tert-butyl ester
(1) Preparation of the title Compound
3- (3- ((tert-butoxycarbonyl) amino) propyl) -2- (1-ethyl-3-methyl-1H-pyrazol-5-ylamino) -3H-imidazo [4,5-b ] pyridine-6-carboxylic acid (0.2g,0.43mmol), ethyl chloroformate (0.045ml,0.47mmol), triethylamine (0.065ml,0.47mmol) were dissolved in 10ml of tetrahydrofuran, and the reaction was stirred at room temperature for 6 hours, followed by addition of a 0.5N ammonia in tetrahydrofuran (1.72ml,0.86 mmol). After the reaction, all the solvent was distilled off, and 30ml of a saturated ammonium chloride solution was added, the mixture was extracted three times with dichloromethane, washed 2 times with distilled water, 1 time with a saturated sodium chloride solution, and dried over sodium sulfate. Concentrating, separating by column chromatography, and eluting with dichloromethane: methanol 20:1, 0.105g of white solid is obtained, yield 51.9%, melting point 121-.
1H NMR(400MHz,Methanol-d4)δ8.78(d,J＝1.6Hz,1H),8.19(d,J＝1.4Hz,1H),6.78(s,1H),4.70(q,J＝7.0Hz,2H),4.37(t,J＝6.9Hz,2H),3.13(t,J＝6.4Hz,2H),2.26(s,3H),2.11–2.04(m,2H),1.47–1.37(m,12H).
HRMS calcd.For C22H31N8O4(M+H)+471.24628,found 471.24619.
Pharmacological experiment
Experimental example 1 agonistic Activity on STING protein
The purpose of the experiment is as follows: a cell screening model is established by THP-1-Dual cells (with STING protein expression) and THP-1-Dual KO-STING cells (without STING protein expression), and the compound is subjected to in vitro STING protein agonistic activity and specificity evaluation.
The experimental method comprises the following steps: the experiment adopts an in-vitro screening system of a 96-well plate, 100,000 THP1-Dual cells are paved in each well, then a compound is added for stimulation for 24 hours, and the concentration gradient of the compound is set at 10-4—10-9M, the final volume per well was 200 uL. After the stimulation is finished, 10uL of supernatant is taken to be added into a white 96-hole enzyme label plate, 50uL of prepared QUANTI-Luc detection reagent is added, and fluorescence detection is carried out by using an EnVision multifunctional enzyme label instrument, wherein the measurement method is an end point detection method: 4 seconds on, 0.1 seconds read. The final reading indicates the amount of secreted luciferase to evaluate the agonistic effect of the compound on the SITNG protein.
The experimental results are as follows: as shown in Table 1, the compound of the invention has higher STING protein agonistic activity and half effective rate EC50All are in mu M grade, and have no inhibitory effect on STING protein (IC)50>100 μ M), no agonistic or inhibitory effect (IC) on cells without STING expression (STING-KO)50>100μM，EC50>100 mu M), which shows that the compound of the invention has the function of specifically exciting STING protein.
TABLE 1 agonistic Activity of the Compounds of the invention against STING proteins
Claims (5)
1. A compound represented by the following or a pharmaceutically acceptable salt thereof:
2. the compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulphate, phosphate, acetate, citrate, malate, fumarate, tartrate or mesylate.
3. A pharmaceutical composition comprising a compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4. Use of a compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with STING protein function.
5. Use of a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of neoplastic or virally-infected disease.
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