7h-pyrrolo[3,2-f]quinazoline derivatives and their anti-infective use

Abstract

The application belongs to the technical field of anti-infective drugs, and discloses 7H-pyrrolo[3,2-f]quinazoline derivatives and anti-infective applications thereof. Specifically, it relates to 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline heterocyclic compounds, a preparation method of the compounds and the use of the compounds in the preparation of anti-infective drugs. The compounds contain an aromatic fused ring structure, and are connected to the 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline skeleton through different carbon chains. Compared with existing dihydrofolate reductase inhibitors, the compounds have better antibacterial activity and can be used as anti-infective drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of anti-infective drugs, and relates to 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline heterocyclic compounds, a preparation method of the compounds and use of the compounds as anti-infective drugs. BACKGROUND

[0002] Dihydrofolate reductase (DHFR) is a class of oxidoreductases that reduces dihydrofolate (DHF) to produce tetrahydrofolate (THF) using nicotinamide adenine dinucleotide phosphate (NADPH). In prokaryotes and eukaryotes, the enzyme has very important biological functions and is a key protein in folate metabolism. If the catalytic reduction activity of DHFR is selectively inhibited, the reduction of DHF to THF can be directly blocked, thereby affecting DNA synthesis and ultimately leading to cell (bacterial) death. Therefore, DHFR has been used as an important target for anti-infective and antitumor drugs, and several different types of drugs have been widely used in clinical practice.

[0003]

[0004] The anti-infective DHFR inhibitors currently used in clinical practice have certain structural similarities, and the binding site of DHFR has a conserved domain. The anti-infective DHFR inhibitors used in clinical practice mostly have a 2,4-diaminopyrimidine structure as the backbone structure (such as trimethoprim and ethyl pyrimidine). With the wide application of DHFR inhibitors in clinical practice, different degrees of drug resistance have appeared in both the antitumor field and the anti-infective field (Malaria journal, 9 (2010) 247. Stem cells, 14 (1996) 5-9.). Compared with trimethoprim, the new drug Iraplirine overcomes some drug resistance problems and shows stronger antibacterial activity, and has entered the new drug application stage (NAD).

[0005] 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline heterocyclic compounds are a class of non-classical structure dihydrofolate reductase inhibitors, first reported in the patent (US4208520 A) in 1978, and it was found in subsequent studies that derivatives of this structure have clinical application value for anti-infection (CN 106632350, CN 107536835 and WO2022006432). Compared with the classic dihydrofolate reductase inhibitors, the structure is more rigid, and the permeability to bacteria is stronger, so that the compound can better exert active effect. The present application provides a new type of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivative (structure as formula I). Compared with the prior art, the present application has the following advantages: the compounds provided by the present application are all new compounds reported for the first time, and some compounds have better antibacterial activity and wider antibacterial spectrum than IRS-16 and methicillin. SUMMARY

[0006] The purpose of the present application is to provide a class of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivatives with strong biological activity, a compound preparation method and its use as an anti-infective drug.

[0007] The present application provides the following technical solutions:

[0008] The first aspect of the technical scheme of the present application provides a class of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivatives, which has a compound as shown in formula (I):

[0009]

[0010] Among them,

[0011] R is selected from H, CH3, C2H5;

[0012] The A fragment is selected from a benzene ring, pyridine, pyrimidine, alkyne, alkene, triazole;

[0013] The B fragment is selected from a benzene ring, a 3 to 6 carbon ring alkyl group, pyridine, pyrimidine, naphthyl;

[0014] The A fragment and the B fragment are connected by a carbon-carbon bond or a carbon-nitrogen bond;

[0015] There can be 0-1 substituents on the A fragment or the B fragment, and the substituents X and Y are selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, ureido, methoxy, halogen atom, cyano, methyl, ethyl, and the substitution position is selected from any position on the fragment;

[0016] When the A segment is a benzene ring and the B segment is also a benzene ring, the A segment or the B segment must have a substituent, the substituent X, Y is selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, ureido, methoxy, halogen atom, cyano, methyl, ethyl, and the substitution position is selected from any position on the benzene ring;

[0017] When the A segment is an alkyne and the B segment is a benzene ring, the B segment must have a substituent, the substituent Y is selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, ureido, methoxy, halogen atom, cyano, methyl, ethyl, and the substitution position is selected from any position on the benzene ring;

[0018] n is selected from 0, 1, 7H-pyrrolo[3,2-f]quinazoline nucleus can be connected to any position on the A segment.

[0019] More preferably, a class of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline heterocyclic compound derivatives or its pharmaceutically acceptable salt, as shown in formula (I-a):

[0020]

[0021] characterized in that R is H; the A segment is a benzene ring; the B segment is selected from 3 to 6 carbon ring alkyl, benzene ring, pyridine, pyrimidine; the A segment and the B segment are connected by a carbon-carbon bond; there can be 0-1 substituents on the A segment or the B segment, the substituent X, Y is selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, ureido, methoxy, halogen atom, cyano, methyl, ethyl, and the substitution position is selected from any position on the segment; when the B segment is a benzene ring, the A segment or the B segment must have a substituent, the substituent X, Y is selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, ureido, methoxy, halogen atom, cyano, methyl, ethyl, and the substitution position is selected from any position on the segment; n is 0, 7H-pyrrolo[3,2-f]quinazoline nucleus can be connected to any position on the A segment.

[0022] More preferably, a class of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline heterocyclic compound derivatives or its pharmaceutically acceptable salt, as shown in formula (I-b):

[0023]

[0024] characterized in that R is H; the A fragment is selected from a benzene ring, pyridine, pyrimidine, triazole, alkyne, olefin; the B fragment is a benzene ring; the A fragment and the B fragment are connected by a carbon-carbon bond; the A fragment or the B fragment can have 0-1 substituent, the substituent X, Y is selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, ureido, methoxy, halogen atom, cyano, methyl, ethyl, and the substitution position is selected from any position on the fragment; when the A fragment is alkyne, the B fragment must have a substituent, the substituent Y is selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, ureido, methoxy, halogen atom, cyano, methyl, ethyl, and the substitution position is selected from any position on the benzene ring; when the A fragment is a benzene ring, the A fragment or the B fragment must have a substituent, the substituent X / Y is selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, ureido, methoxy, halogen atom, cyano, methyl, ethyl, and the substitution position is selected from any position on the fragment; n is 0, and the 7H-pyrrolo[3,2-f]quinazoline nucleus can be connected to any position on the A fragment.

[0025] More preferably, the present application provides a 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline heterocyclic compound derivative or a pharmaceutically acceptable salt thereof, as shown in the formula (I-c):

[0026]

[0027] characterized in that R is H; the A fragment is selected from a benzene ring, pyridine, pyrimidine; the B fragment is selected from a benzene ring, 3 to 6 carbon ring alkyl, pyridine, pyrimidine, naphthyl; the A fragment and the B fragment are connected by a carbon-carbon bond or a carbon-nitrogen bond; the A fragment or the B fragment can have 0-1 substituent, the substituent X, Y is selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, ureido, methoxy, halogen atom, cyano, methyl, ethyl, and the substitution position is selected from any position on the fragment; the A fragment and the B fragment cannot be benzene rings at the same time. n is 0, and the 7H-pyrrolo[3,2-f]quinazoline nucleus can be connected to any position on the A fragment.

[0028] Preferably, the present application provides a 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivative:

[0029]

[0030]

[0031] The second aspect of the technical scheme of the present application provides a preparation method of the above-mentioned 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivative, comprising the following operation steps:

[0032] (1) The starting material 5-nitroindole is catalytically reduced under Pd / C conditions to obtain an intermediate with the structure shown in formula (II):

[0033]

[0034] The intermediate (II) is used as a raw material, and is reacted with hydrochloric acid to form a salt, and then reacted with sodium dicyanamide to obtain an intermediate with the structure shown in formula (III):

[0035]

[0036] The intermediate (III) is used as a raw material, and is subjected to ring closure under the condition of boron trifluoride ether solution to obtain an intermediate with the structure shown in formula (IV):

[0037]

[0038] (2) The intermediate (IV) is used as a raw material, and is reacted with a bromomethyl or chloromethyl compound to obtain a 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivative with the structure shown in formula (I);

[0039] The reaction in step (1) is carried out in methanol as a solvent under the condition of 10% Pd / C and pressurized hydrogen for 12-16 h;

[0040] The reactions in steps (2) and (3) are first to dissolve the intermediate (II) in 2M hydrochloric acid ethyl acetate, stir at room temperature for 45 min, then remove the solvent under reduced pressure to prepare the corresponding hydrochloride salt. Then, the hydrochloride salt is dissolved in N,N-dimethylformamide, sodium dicyanamide is added, and heated at 110°C for 8 h. The molar ratio of the intermediate (II) to hydrochloric acid ethyl acetate to sodium dicyanamide is 1:1.2-1.5:2-3;

[0041] The reaction in step (4) is carried out in ethylene glycol dimethyl ether as a solvent, and boron trifluoride ether solution is added to the intermediate (III) at 0°C, and the reaction is carried out at room temperature for 8-10 h. The molar ratio of the intermediate (III) to boron trifluoride ether is 1:4-5;

[0042] The reaction in step (5) is carried out in N,N-dimethylformamide as a solvent, and sodium hydride and a chloromethyl or bromomethyl compound are added, and the reaction is carried out at room temperature for 6-8 h to obtain the target compound formula (I), which can be purified by flash column chromatography. The molar ratio of sodium hydride to the chloromethyl or bromomethyl compound to the intermediate (IV) is 1-2:1-2:1. The synthesis route is shown in the following formula:

[0043]

[0044] The third aspect of the technical scheme of the present application provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises the 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivative or the pharmaceutically acceptable salt thereof according to the first aspect and a pharmaceutically acceptable carrier or excipient.

[0045] The fourth aspect of the technical scheme of the present application provides the use of the 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivative or the pharmaceutically acceptable salt thereof according to the first aspect in the preparation of an anti-infectious disease drug.

[0046] The infectious disease is selected from the group consisting of infections of Staphylococcus aureus, drug-resistant Staphylococcus aureus, Escherichia coli and Baumanii, or an infectious disease caused by a multi-drug resistant pathogenic bacterium.

[0047] Beneficial technical effects:

[0048] In the application of resisting infection, the present application provides the use of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivatives as antibacterial drugs. As preferred, the antibacterial use is mainly for strains of Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis or Enterococcus faecium, etc. as representatives of Gram-positive bacteria, and strains of Escherichia coli and Baumanii as representatives of Gram-negative bacteria. The 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivatives have significant inhibitory activity on the above strains, and are superior to the marketed drug TMP dihydrofolate reductase inhibitor. DETAILED DESCRIPTION

[0049] The present application will be further described below in combination with examples, but the embodiments of the present application are not limited thereto. The following compound 1-21 synthesis method:

[0050] Preparation of intermediate II:

[0051] 5-nitroindole (30.8 mmol) was dissolved in 45 mL of methanol solution, and 0.5 g of 10% Pd / C was added. After stirring this mixture under pressurized hydrogen for 12 h, filtration was performed, the filtrate was collected, and the solvent was removed under reduced pressure to obtain intermediate II in the form of a light yellow transparent oil with a yield of 90. Intermediate II, ESI-MS (m / z): 133.31 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.20-7.00 (m, 2H), 6.69 (d, J = 2.1 Hz, 1H), 6.49 (dd, J = 8.6, 2.1 Hz, 1H), 6.13 (t, J = 2.5 Hz, 1H), 4.47 (s, 2H).

[0052] Preparation of intermediate III:

[0053] Intermediate II 1.8g (13.6mmol) was dissolved in 16.4ml 1M hydrochloric acid in ethyl acetate solution, stirred at room temperature for 45min. The solvent was removed under reduced pressure, redissolved in 10ml N,N-dimethylformamide solvent, added 3.0g (34.0mmol) sodium dicyanamide, heated at 110°C for 8h, cooled to room temperature, added 50mL water to quench. Extraction was performed with ethyl acetate (3x50ml), and the organic phase was washed with saturated NaCl solution, the organic phase was combined and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification was performed again using a flash column chromatography system, with a ratio of dichloromethane:methanol = 98:2 as eluent, to obtain red-black oily intermediate (III), yield: 87%. Intermediate III, ESI-MS (m / z): 200.42 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.86 (s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 6.0, 3.1 Hz, 2H), 6.94 (dd, J = 8.6, 2.0 Hz, 1H), 6.74 (s, 2H), 6.40 (t, J = 2.6 Hz, 1H).

[0054] Preparation of Intermediate IV:

[0055] Intermediate III 1g (5.0mmol) was dissolved in 6mL ethylene glycol dimethyl ether solvent, protected by nitrogen, added 3.05ml (24mmol) boron trifluoride ether solution at 0°C, stirred at 85°C for 12h. Cooled to room temperature, added 6ml water to quench the reaction, and the organic solvent was removed under reduced pressure. Extraction was performed with n-butanol (3x6ml), the organic phase was combined, and the solvent was removed under reduced pressure. The crude product was redissolved in dichloromethane, and the above crude product was purified using a flash column chromatography system (dichloromethane:methanol = 10:1 as eluent) to obtain black solid intermediate IV, yield 51-56%. Intermediate IV, ESI-MS (m / z): 200.13 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.54 (s, 1H), 7.29 (s, 2H), 7.14 (s, 1H), 7.09 (d, J = 8.7 Hz, 1H), 6.33 (s, 2H).

[0056] Example 1: Preparation of compound 1 (1,3-diamino-7-(4'-carboxy-(1,1'-biphenyl)-4- methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0057] Intermediate IV 50 mg (0.25 mmol) was dissolved in 2 mL of N,N-dimethylformamide solvent, protected by nitrogen, 13 mg (0.33 mmol) of 60% sodium hydride was added, stirred at room temperature for 30 min, 4-(bromomethyl)-(1,1-biphenyl)-4-carboxylic acid methyl ester 92 mg (0.30 mmol) was added, and the reaction was carried out at room temperature for 5 h. 3 ml of water was added to quench the reaction, extraction was carried out with ethyl acetate or n-butanol (3x5 ml), the organic phase was combined, and the organic phase was washed with saturated brine. The organic phase was removed under reduced pressure to remove the solvent, and the crude product was purified by a flash column chromatography system (dichloromethane:methanol=95:5 as eluent) to obtain a light yellow solid compound. The above product was redissolved in 2 ml of a mixture of methanol:water (1:1), 40 mg (1 mmol) of sodium hydroxide was added, and stirred at 50°C for 4 h. After cooling to room temperature, the organic solvent was removed under reduced pressure, the pH value was adjusted to 2-3, and cooled at 0°C. A solid was precipitated, filtered, and a yellow-brown solid compound 1 was obtained, with a total yield of 64%. ESI-MS (m / z): 410.62 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.00 (d, J = 8.2 Hz, 5H), 7.84 (s, 1H), 7.69 - 7.63 (m, 6H), 7.31 (d, J = 8.3 Hz, 3H), 7.25 (d, J = 8.8 Hz, 1H), 5.61 (s, 2H).

[0058] Example 2: Preparation of compound 2 (1,3-diamino-7-(5-phenylpyrimidin-2-ylmethyl)-7H-pyrrolo[3,2-f]quinazoline) Intermediate IV 50 mg (0.25 mmol) was dissolved in 2 mL of N,N-dimethylformamide solvent, protected by nitrogen, 13 mg (0.33 mmol) of 60% sodium hydride was added, stirred at room temperature for 30 min, 2-(bromomethyl)-5-phenylpyrimidine 75 mg (0.30 mmol) was added, and the reaction was carried out at room temperature for 5 h. 3 ml of water was added to quench the reaction, extraction was carried out with ethyl acetate or n-butanol (3x5 ml), the organic phase was combined, and the organic phase was washed with saturated brine. The organic phase was removed under reduced pressure to remove the solvent, and the crude product was purified by a flash column chromatography system (dichloromethane:methanol=95:5 as eluent) to obtain a light yellow solid compound 2, with a yield of 75%. ESI-MS (m / z): 368.41 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 8.87 (d, J = 4.9 Hz, 2H), 8.32 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 3.1 Hz, 1H), 7.41 (t, J = 4.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 3.2 Hz, 1H), 7.18 - 7.11 (m, 2H), 7.09 (d, J = 8.9 Hz, 1H), 6.23 (s, 2H), 5.62 (s, 2H).

[0059] Example 3: Preparation of compound 3 (1,3-diamino-7-(4'-aminomethyl-1,1'-biphenyl-4- methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0060] Intermediate IV 50 mg (0.25 mmol) was dissolved in 2 mL of N,N-dimethylformamide solvent, protected by nitrogen, 13 mg (0.33 mmol) of 60% sodium hydride was added, stirred at room temperature for 30 min, 2-(bromomethyl)-4'-(bis(tert- butyloxycarbonyl)aminomethyl)-1,1'-biphenyl 143 mg (0.30 mmol) was added, and the reaction was carried out at room temperature for 5 h. 3 ml of water was added to quench the reaction, and extraction was carried out with ethyl acetate or n-butanol (3 x 5 ml), and the organic phase was combined and washed with saturated brine. The organic phase was removed under reduced pressure, and the crude product was purified using a flash column chromatography system (dichloromethane:methanol = 95:5 as eluent) to obtain a yellow-brown solid compound. 2.5 ml of 4M hydrochloric acid-1,4 dioxane solution was added to the above yellow-brown solid compound, stirred at room temperature for 4 h, and the solvent was removed under reduced pressure to obtain a yellow-brown solid, with a yield of 46%. ESI-MS (m / z): 395.70 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.78 (d, J = 9.0 Hz, 1H), 7.65 (s, 1H), 7.57 (s, 4H), 7.41 (s, 1H), 7.28 (dd, J = 21.5, 7.5 Hz, 3H), 7.11 (s, 1H), 7.04 (d, J = 8.9 Hz, 1H), 6.74 (s, 2H), 5.82 (s, 2H), 5.54 (s, 2H), 4.15 (s, 1H), 3.82 (s, 1H).

[0061] Example 4: Preparation of compound 4 (1,3-diamino-7-(4-(2-pyrimidine)-phenyl-4- methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0062] The reaction was operated according to the procedure of Example 2, starting from intermediate IV (50 mg, 0.25 mmol), 2-(4-(bromomethyl)phenyl)cyclopyrimidine 75 mg (0.30 mmol). Yield 68%, white solid. ESI-MS (m / z): 368.41 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.87 (d, J = 4.9 Hz, 2H), 8.32 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 3.1 Hz, 1H), 7.41 (t, J = 4.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 3.2 Hz, 1H), 7.18 - 7.11 (m, 2H), 7.09 (d, J = 8.9 Hz, 1H), 6.23 (s, 2H), 5.62 (s, 2H).

[0063] Example 5: Preparation of compound 5 (1,3-diamino-7-(4-(4-pyridinyl)- phenyl-4-methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0064] The reaction was operated according to the procedure of Example 2, starting from intermediate IV (50 mg, 0.25 mmol), 2-(4-(bromomethyl)phenyl)cyclopyrimidine 75 mg (0.30 mmol). Yield 68%, white solid. ESI-MS (m / z): 367.60 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.87 (d, J = 4.9 Hz, 2H), 8.32 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.9 Hz, 1H), 7.73 (d, J = 3.1 Hz, 1H), 7.41 (t, J = 4.9 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 3.2 Hz, 1H), 7.18 - 7.11 (m, 2H), 7.09 (d, J = 8.9 Hz, 1H), 6.23 (s, 2H), 5.62 (s, 2H).

[0065] Example 6: Preparation of compound 6 (1,3-diamino-7-(3-methyl-(1,1'- biphenyl)-4-methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0066] The reaction was operated according to the procedure of Example 2, starting from intermediate IV (50 mg, 0.25 mmol), 4-(bromomethyl)-3-methyl-1,1'-biphenyl 78 mg (0.30 mmol). Yield 78%, tan solid. ESI-MS (m / z): 380.43 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.01 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 3.1 Hz, 1H), 7.61 (d, J = 7.6 Hz, 2H), 7.54 (s, 1H), 7.43 (t, J = 6.6 Hz, 5H), 7.33 (t, J = 7.5 Hz, 2H), 7.23 (d, J = 8.9 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 5.63 (s, 2H), 2.41 (s, 3H).

[0067] Example 7: Preparation of compound 7 (1,3-diamino-7-(3-carboxy-(1,1'- biphenyl)-4-(1-ethyl))-7H-pyrrolo[3,2-f]quinazoline)

[0068] The reaction was operated according to the procedure of Example 1, starting from intermediate IV (50 mg, 0.25 mmol), 5-(1-bromoethyl)-3-carboxymethyl-1,1'- biphenyl 96 mg (0.30 mmol). Yield 33%, tan solid. ESI-MS (m / z): 424.67 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 13.12 (s, 1H), 11.28 (s, 1H), 8.05 (s, 1H), 7.82 (s, 1H), 7.54 - 7.50 (m, 2H), 7.49 (s, 2H), 7.44 (t, J = 7.4 Hz, 3H), 7.38 (q, J = 7.2, 6.0 Hz, 3H), 6.39 (s, 3H), 6.14 (d, J = 7.2 Hz, 2H), 1.44 (d, J = 7.0 Hz, 3H).

[0069] Example 8: Preparation of compound 8 (1,3-diamino-7-(2'-cyano-(1,1'- biphenyl)-4-methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0070] The reaction was operated according to the procedure of Example 2, starting from intermediate IV (50 mg, 0.25 mmol), 4-(bromomethyl)-2'-cyano-1,1'-biphenyl 86 mg (0.30 mmol). Yield 69%, white solid. ESI-MS (m / z):391.44 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.91 (d, J = 7.7 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.67 (d, J = 3.1 Hz, 1H), 7.56 (dd, J = 7.8, 3.5 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 3.1 Hz, 1H), 7.06 (d, J = 9.0 Hz, 1H), 6.70 (s, 2H), 5.71 (s, 2H), 5.60 (s, 2H).

[0071] Example 9: Preparation of compound 9 (1,3-diamino-7-(4'-cyano-(1,1'-biphenyl)-4- methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0072] The reaction procedure was according to Example 2, starting from intermediate IV (50 mg, 0.25 mmol), 4-(bromomethyl)-4'-cyano-1,1'-biphenyl 86 mg (0.30 mmol). Yield 72%, white solid. ESI-MS (m / z): [M+H] 406.0. 391.58 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.88 (d, J = 8.1 Hz, 2H), 7.85 - 7.77 (m, 3H), 7.70 - 7.64 (m, 3H), 7.30 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 3.2 Hz, 1H), 7.06 (dd, J = 9.0, 3.7 Hz, 1H), 6.84 (s, 2H), 5.85 (s, 2H), 5.57 (s, 2H).

[0073] Example 10: Preparation of compound 10 (1,3-diamino-7-(4'-guanidino-(1,1'-biphenyl)-4- methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0074] The reaction procedure was according to Example 2, starting from intermediate IV (50 mg, 0.25 mmol), 4-(bromomethyl)-4'-guanidino-1,1'-biphenyl 91 mg (0.30 mmol). Yield 35%, yellow-brown solid. ESI-MS (m / z): [M+H] 406.0. 423.52 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 12.99 (s, 1H), 10.19 (d, J = 5.3 Hz, 1H), 8.92 (s, 1H), 8.14 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 3.0 Hz, 1H), 7.75 (s, 1H), 7.65 (dd, J = 32.4, 7.9 Hz, 8H), 7.42 (d, J = 3.1 Hz, 1H), 7.30 (t, J = 8.2 Hz, 3H), 7.24 (d, J = 8.8 Hz, 1H), 5.64 (s, 2H).

[0075] Example 11: Preparation of compound 11 (1,3-diamino-7-(4-cyclohexyl-phenyl- methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0076] The reaction was performed according to the procedure described in example 2, starting from intermediate IV (50 mg, 0.25 mmol), 4-cyclohexyl-bromomethylbenzene 76 mg (0.30 mmol). The yield was 79% as a white solid. ESI-MS (m / z): 372.67 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.75 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 3.0 Hz, 1H), 7.17 - 7.07 (m, 5H), 7.03 (d, J = 9.0 Hz, 1H), 6.70 (s, 2H), 5.72 (s, 2H), 5.44 (s, 2H), 1.70 (dt, J = 24.8, 11.7 Hz, 6H), 1.45 - 1.08 (m, 6H).

[0077] Example 12: Preparation of compound 12 (1,3-diamino-7-(3-chloro-(1,1'- biphenyl)-4-methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0078] The reaction was performed according to the procedure described in example 2, starting from intermediate IV (50 mg, 0.25 mmol), 4-(bromomethyl)-3-chloro-1,1'- biphenyl 84 mg (0.30 mmol). The yield was 72% as a white solid. ESI-MS (m / z): 400.49 [M+H] + .

[0079] Example 13: Preparation of compound 13 (1,3-diamino-7-(4'-carbamimidoyl- (1,1'-biphenyl)-4-methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0080] The reaction was performed according to the procedure described in example 2, using intermediate IV (50 mg, 0.25 mmol) and 4-(bromomethyl)-4'-cyanophenylboronic acid 87 mg (0.30 mmol) as starting materials. The yield was 52% as a yellow-brown solid. ESI-MS (m / z): 408.66 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 7.16 (d, J = 9.3 Hz, 1H), 7.04 (t, J = 6.0 Hz, 4H), 6.96 (s, 1H), 6.85 (d, J = 7.9 Hz, 2H), 6.49 (d, J = 7.8 Hz, 2H), 6.40 (s, 1H), 6.36 (d, J = 8.8 Hz, 1H), 4.83 (s, 2H).

[0081] Example 14: Preparation of compound 14 (1,3-diamino-7-(1-(4- carboxyphenyl)-ethyn-2-yl)-7H-pyrrolo[3,2-f]quinazoline)

[0082] The reaction was performed according to the procedure described in example 1, using intermediate IV (50 mg, 0.25 mmol) and 1-(4-carboxyphenyl)-3-chloro-1- propyn-76 mg (0.30 mmol) as starting materials. The yield was 52% as a yellow-brown solid. ESI-MS (m / z): 358.55 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.04 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 3.1 Hz, 1H), 7.63 (s, 1H), 7.56 (s, 1H), 7.47 (d, J = 7.7 Hz, 2H), 7.25 (d, J = 9.1 Hz, 1H), 7.20 (d, J = 3.3 Hz, 1H), 5.49 (s, 2H).

[0083] Example 15: Preparation of compound 15 (1,3-diamino-7-(1-(4-(1,1'- biphenyl))-triazol-4-yl)-7H-pyrrolo[3,2-f]quinazoline)

[0084] Intermediate IV 50 mg (0.25 mmol) was dissolved in 2 mL of N,N- dimethylformamide solvent, protected by nitrogen, 13 mg (0.33 mmol) of 60% sodium hydride was added, stirred at room temperature for 30 min, 3-bromopropyne 36 mg (0.30 mmol) was added, and the reaction was carried out at room temperature for 5 h. 3 mL of water was added to quench the reaction, and extraction was carried out with ethyl acetate or n-butanol (3 x 5 mL), and the organic phase was combined and washed with saturated brine. The organic phase was removed under reduced pressure to remove the solvent, and the crude product was purified by a flash column chromatography system (dichloromethane:methanol = 95:5 as eluent) to obtain a yellow-brown solid compound. The above product was redissolved in 2 mL of N,N-dimethylformamide solvent, 4-azido-1,1'-biphenyl (1 equivalent), cuprous iodide (0.1 equivalent), N,N-diisopropyl ethylamine (2 equivalents) were added, stirred at 100°C for 3 h, cooled to room temperature, 10 mL of water was added, and a solid was precipitated, filtered, and a black-brown solid compound 18 was obtained, with a total yield of 38%. ESI-MS (m / z): 433.23 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.86 (d, J = 41.9 Hz, 5H), 7.62 (d, J = 57.7 Hz, 4H), 7.40 (d, J = 42.5 Hz, 4H), 7.04 (s, 2H), 6.66 (s, 2H), 5.60 (s, 2H).

[0085] Example 16: Preparation of compound 16 (1,3-diamino-7-(1-(2-naphthalenyl)- triazol-4-yl)-7H-pyrrolo[3,2-f]quinazoline)

[0086] The reaction was carried out according to the procedure of Example 18, and the reaction material was intermediate IV (50 mg, 0.25 mmol), 3-bromopropyne 36 mg (0.30 mmol), and 2-azidonaphthalene (0.25 mmol). The yield was 42%, and the product was a black solid. ESI-MS (m / z): 407.52 [M+H] + , 1 H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.43 (s, 1H), 8.13 (d, J = 9.0 Hz, 1H), 8.08 - 7.99 (m, 3H), 7.96 (s, 1H), 7.62 (q, J = 8.1 Hz, 3H), 7.09 (s, 2H), 6.66 (s, 2H), 5.67 (s, 2H).

[0087] Example 17: Preparation of compound 17 (1,3-diamino-7-(1-phenyl- triazol-4-ylmethyl)-7H-pyrrolo[3,2-f]quinazoline)

[0088] The reaction was operated according to the procedure of Example 18, with intermediate IV (50 mg, 0.25 mmol), 3-bromopropyne 36 mg (0.30 mmol) and 2-azido-benzoic acid (0.25 mmol). The yield was 27% as black solid. ESI-MS (m / z): 357.54 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.14 (s, 1H), 7.90 (d, J = 50.9 Hz, 3H), 7.59 (s, 3H), 7.46 (s, 3H), 7.26 (s, 1H), 7.07 (s, 1H), 6.65 (s, 1H), 5.64 (s, 2H).

[0089] Example 18: Preparation of compound 18 (1,3-diamino-7-(1-(3- carboxyphenyl)-triazol-4-ylmethyl)-7H-pyrrolo[3,2-f]quinazoline)

[0090] The reaction was operated according to the procedure of Example 18, with intermediate IV (50 mg, 0.25 mmol), 3-bromopropyne 36 mg (0.30 mmol) and 2-azido-benzoic acid (0.25 mmol). The yield was 27% as black solid. ESI-MS (m / z): 401.22 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.97 (s, 1H), 8.36 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.89 (d, J = 3.1 Hz, 1H), 7.84 (s, 1H), 7.72 (s, 1H), 7.54 (s, 2H), 7.37 (d, J = 3.6 Hz, 1H), 7.31 (s, 2H), 5.74 (s, 2H).

[0091] Pharmacological experiments

[0092] Unless otherwise indicated, the experimental materials, reagents, procedures and methods used in the following active examples can be obtained from commercial sources or readily known or prepared based on the prior art.

[0093] Experimental example: In vitro antibacterial experiment

[0094] Experimental method

[0095] The in vitro antibacterial activity of the compounds on sensitive / drug-resistant strains was evaluated by microdilution method (referring to CLSI 27th edition). The in vitro antibacterial activity of the compounds on different strains was tested according to the following steps: the drug stock solution was diluted into a series of required concentration gradients (50ul in volume) in a 96-well plate using CAMH medium, 50ul of bacterial solution (4-5x10 5 CFU / ml) was added into the above series of drug-containing CAMH broth, and no bacteria, no drug and quality control bacteria control wells were set in the experiment. The 96-well plate was placed at 37℃ for constant temperature standing and culture for 16-18 hours. When reading the results, the 96-well plate was placed in a well-lit place, and the turbidity of the broth and whether there were colonies deposited at the bottom of the well were observed with the naked eye. When the experimental results of the quality control strain met the quality control range, the experimental results were judged. The minimum concentration of the drug contained in the sterile growth well was the MIC value (Minimal Inhibitory Concentration).

[0096] The strains used in the experiment were Staphylococcus aureus ATCC29213, methicillin-resistant Staphylococcus aureus ATCC43300, epidermis Staphylococcus ATCC12228, Acinetobacter baumannii ATCC19606, Enterococcus faecalis ATCC29212, and Escherichia coli ATCC25922. The following table is the in vitro MIC test results.

[0097] Table 1: In vitro antibacterial activity results of the compounds

[0098]

[0099]

[0100] NT not tested.

Claims

1. A 1,3-diamino-7H-pyrrole[3,2-f]quinazoline derivative or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are selected from the following group: 。 2. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the 1,3-diamino-7H-pyrrole[3,2-f]quinazoline derivative of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

3. The use of the 1,3-diamino-7H-pyrrole[3,2-f]quinazoline derivative of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-infective medicament.

4. The application according to claim 3, characterized in that, The infectious diseases mentioned are selected from infections caused by Staphylococcus aureus, drug-resistant Staphylococcus aureus, Escherichia coli and Baumannii, or multidrug-resistant bacteria.

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