7H-pyrrolo [3, 2-f] quinazoline derivative and anti-infection application thereof

Abstract

The invention belongs to the technical field of anti-infection drugs, and discloses a 7H-pyrrolo [3, 2-f] quinazoline derivative and anti-infection application thereof. In particular to a 1, 3-diamino-7H-pyrrole [3, 2-f] quinazoline heterocyclic compound, a preparation method of the compound and application of the compound in preparation of anti-infective drugs. The compound contains an aromatic fused ring structure, is connected with a 1, 3-diamino-7H-pyrrole [3, 2-f] quinazoline skeleton through different carbon chains, has better antibacterial activity compared with the existing dihydrofolate reductase inhibitor, and can be used as an anti-infection drug.

Description

Technical Field

[0001] The invention belongs to the technical field of anti-infective drugs, and relates to a 1,3-diamino-7H-pyrrole [3,2-f] quinazoline heterocyclic compound, a method for preparing the compound, and use of the compound as an anti-infective drug. Background Art

[0002] Dihydrofolate reductase (DHFR) is a type of oxidoreductase that uses nicotinamide adenine dinucleotide phosphate (NADPH) to reduce dihydrofolate (DHF) to produce tetrahydrofolate (THF). In prokaryotes and eukaryotes, this 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-infection and anti-tumor drugs, and several different types of drugs have been widely used in clinical practice.

[0003]

[0004] The structures of the anti-infective DHFR inhibitors currently used in clinical practice have certain similarities, and the binding site of DHFR has a conserved domain. Most of the anti-infective DHFR inhibitors used in clinical practice have a 2,4-diaminopyrimidine structure as the skeleton structure (such as trimethoprim and pyrimethamine). With the widespread clinical application of DHFR inhibitors, drug resistance problems of varying degrees have emerged in both the anti-tumor field and the anti-infective field (Malaria journal, 9 (2010) 247. Stem cells, 14 (1996) 5-9.). Compared with trimethoprim, the new drug elaprilin has overcome some drug resistance problems and exhibited stronger antibacterial activity. It has now entered the new drug application stage (NAD).

[0005] 1,3-diamino-7H-pyrrole [3,2-f] quinazoline heterocyclic compounds are a class of dihydrofolate reductase inhibitors with non-classical structures, first reported in a 1978 patent (US4208520 A). In subsequent studies, it was found that the derivatives of this structure have clinical application value for anti-infection (CN 106632350, CN107536835 and WO2022006432). Compared with the classical dihydrofolate reductase inhibitors, its structure is more rigid and has stronger permeability to bacteria, so that the compound can better exert its active effect. The present invention provides a new class of 1,3-diamino-7H-pyrrole [3,2-f] quinazoline derivatives (structure as Formula I). ​​The present invention has the following advantages over the prior art: the compounds provided by the present invention are all new compounds reported for the first time, and some compounds have better antibacterial activity and a wider antibacterial spectrum than IRS-16 and trimethoprim. Summary of the invention:

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

[0007] This discovery provides the following technical solutions:

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

[0009]

[0010] in,

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

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

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

[0014] Fragment A is connected to fragment B via a carbon-carbon bond or a carbon-nitrogen bond;

[0015] The A fragment or the B fragment may have 0-1 substituents, wherein the substituents X and Y are selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, urea, methoxy, halogen, cyano, methyl, and ethyl, and the substitution position is selected from any position on the fragment;

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

[0017] When the A fragment is an alkyne and the B fragment is a benzene ring, the B fragment must have a substituent, and the substituent Y is selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, urea, methoxy, halogen, cyano, methyl, and 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 core and can be connected to any position on the A fragment.

[0019] More preferably, a class of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline heterocyclic compound derivatives or pharmaceutically acceptable salts thereof are shown in formula (Ia):

[0020]

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

[0022] More preferably, a class of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline heterocyclic compound derivatives or pharmaceutically acceptable salts thereof are shown in formula (Ib):

[0023]

[0024] The invention is 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 may have 0-1 substituents, and the substituents X and Y are selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, urea, methoxy, halogen atom, cyano, methyl, ethyl, and the substitution position is selected from any position on the fragment; when the A fragment is an alkyne, the B fragment must have a substituent, and the substituent Y is selected from carboxyl, carboxymethyl ester , carboxyethyl ester, aminomethyl, amino, amidino, urea, methoxy, halogen atom, cyano, methyl, ethyl, and the substitution position is selected from any position on the benzene ring; when fragment A is a benzene ring, fragment A or fragment B must have a substituent, and the substituent X / Y is selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, urea, 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 mother core can be connected to any position on fragment A.

[0025] More preferably, a class of 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline heterocyclic compound derivatives or pharmaceutically acceptable salts thereof are shown in formula (Ic):

[0026]

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

[0028] Preferably, the 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivative provided by the present invention is:

[0029]

[0030]

[0031] The second aspect of the technical solution of the present invention provides a method for preparing the above-mentioned 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivative, comprising the following steps:

[0032] (1) The starting material 5-nitroindole is subjected to a catalytic reduction reaction under Pd / C conditions to obtain an intermediate having a structure shown in formula (II):

[0033]

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

[0035]

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

[0037]

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

[0039] The reaction in step (1) uses methanol as solvent and reacts for 12-16 hours under the conditions of 10% Pd / C and pressurized hydrogen;

[0040] In the reaction of step (2) and step (3), the intermediate (II) is first dissolved in 2M hydrochloric acid ethyl acetate, stirred at room temperature for 45 minutes, and then the solvent is removed under reduced pressure to prepare the corresponding hydrochloride. Then, the hydrochloride is redissolved in N,N-dimethylformamide, sodium dicyanamide is added, and heated at 110°C for 8 hours, wherein the molar ratio of the intermediate (II) to ethyl acetate hydrochloride to sodium dicyanamide is 1:1.2-1.5:2-3;

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

[0042] In step (5), the reaction uses N,N-dimethylformamide as a solvent, adds sodium hydride and a chloromethyl or bromomethyl compound, and reacts with the intermediate (IV) at room temperature for 6-8 hours to obtain the target compound (I), which can be purified by rapid column chromatography. The molar ratio of the sodium hydride to the chloromethyl or bromomethyl compound to the intermediate (IV) is 1-2:1-2:1. The synthetic route is shown in the following formula:

[0043]

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

[0045] The fourth aspect of the technical solution of the present invention provides the use of the 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivative or a pharmaceutically acceptable salt thereof described in the first aspect in the preparation of an anti-infective disease drug.

[0046] The infectious disease is selected from the group consisting of infections caused by Staphylococcus aureus, drug-resistant Staphylococcus aureus, Escherichia coli and Bacillus baumannii, or infectious diseases caused by multidrug-resistant bacteria.

[0047] Beneficial technical effects:

[0048] In terms of anti-infection applications, the present invention provides the use of 1,3-diamino-7H-pyrrole[3,2-f]quinazoline derivatives as antibacterial drugs. Preferably, the antibacterial use is mainly for strains such as Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis or Enterococcus faecium represented by Gram-positive bacteria, and strains such as Escherichia coli and Acinetobacter baumannii represented by Gram-negative bacteria. 1,3-diamino-7H-pyrrole[3,2-f]quinazoline derivatives have significant inhibitory activity against the above strains, and are superior to the listed drug TMP dihydrofolate reductase inhibitor. DETAILED DESCRIPTION

[0049] The present invention is further described below in conjunction with examples, but the embodiments of the present invention are not limited thereto. The following synthesis method of compounds 1-21:

[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. The mixture was stirred under pressurized hydrogen for 12 h, filtered, the filtrate was collected, and the solvent was removed under reduced pressure to obtain a light yellow transparent oily intermediate II with a yield of 90%. Intermediate II, ESI-MS (m / z): 133.31 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.56 (s, 1H), 7.20–7.00 (m, 2H), 6.69 (d, J = 2.1Hz, 1H), 6.49 (dd, J = 8.6, 2.1Hz, 1H), 6.13 (t, J = 2.5Hz, 1H), 4.47 (s, 2H).

[0052] Preparation of intermediate III:

[0053] 1.8g (13.6mmol) of intermediate II was dissolved in 16.4ml 1M hydrochloric acid ethyl acetate solution, added and stirred at room temperature for 45min. The solvent was removed under reduced pressure, redissolved in 10ml N,N-dimethylformamide solvent, 3.0g (34.0mmol) of sodium dicyanamide was added, heated at 110℃ for 8h, cooled to room temperature, and quenched by adding 50mL of water. Extraction was performed with ethyl acetate (3×50ml), and the organic phase was washed with saturated NaCl solution, combined, dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification was then performed using a flash column chromatography system, and the eluent ratio was dichloromethane: methanol = 98:2 to obtain a red-black oily intermediate (III), with a yield of 87%. Intermediate III, ESI-MS (m / z): 200.42 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 8.86 (s, 1H), 7.46 (d, J = 2.0Hz, 1H), 7.34 (dd, J=6.0, 3.1Hz, 2H), 6.94 (dd, J=8.6, 2.0Hz, 1H), 6.74 (s, 2H), 6.40 (t, J=2.6Hz, 1H).

[0054] Preparation of Intermediate IV:

[0055] Intermediate III 1g (5.0mmol) was dissolved in 6mL ethylene glycol dimethyl ether solvent, nitrogen protection, 3.05ml (24mmol) of boron trifluoride ether solution was added at 0°C, and stirred at 85°C for 12h. Cooled to room temperature, 6ml of water was added to quench the reaction, and the organic solvent was removed under reduced pressure. Extraction was performed with n-butanol (3×6ml), the organic phases were combined, the solvent was removed under reduced pressure, the crude product was redissolved with dichloromethane, and the above crude product was purified by flash column chromatography system (dichloromethane: methanol = 10:1 as eluent) to obtain black solid intermediate IV with a yield of 51-56%. Intermediate IV, ESI-MS (m / z): 200.13 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ11.68(s,1H),7.76(d,J=8.5Hz,1H),7.54(s,1H),7.29(s,2H),7.14(s,1H),7.09(d,J=8.7Hz,1H),6.33(s,2H).

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

[0057] 50 mg (0.25 mmol) of intermediate IV was dissolved in 2 mL of N,N-dimethylformamide solvent, and 13 mg (0.33 mmol) of 60% sodium hydride was added under nitrogen protection, and stirred at room temperature for 30 min, and 92 mg (0.30 mmol) of 4-(bromomethyl)-(1,1-biphenyl)-4-carboxylic acid methyl ester 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 ethyl acetate or n-butanol (3×5 ml) was used for extraction, and the organic phases were combined and washed with saturated brine. The organic phase was freed of solvent under reduced pressure, and the crude product was purified by flash column chromatography (dichloromethane: methanol = 95:5 as eluent) to obtain a light yellow solid compound. The above product was redissolved in 2 ml of a methanol: water (1:1) mixed solvent, 40 mg (1 mmol) of sodium hydroxide was added, stirred at 50°C for 4 h, cooled to room temperature, the organic solvent was removed under reduced pressure, the pH value was adjusted to 2-3, cooled at 0°C, a solid was precipitated, and filtered to obtain a yellow-brown solid compound 1, with a total yield of 64%. ESI-MS (m / z): 410.62 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ10.93(s,1H),8.00(d,J=8.2Hz,5H),7.84(s,1H),7 .69–7.63(m,6H),7.31(d,J=8.3Hz,3H),7.25(d,J=8.8Hz,1H),5.61(s,2H).

[0058] Example 2: Preparation of Compound 2 (1,3-diamino-7-(5-phenylcyclopyrimidine-2-methyl)-7H-pyrrole[3,2-f]quinazoline) Intermediate IV 50 mg (0.25 mmol) was dissolved in 2 mL N,N-dimethylformamide solvent, nitrogen protection, 13 mg (0.33 mmol) 60% sodium hydride was added, stirred at room temperature for 30 min, 2-(bromomethyl)-5-phenylcyclopyrimidine 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, and ethyl acetate or n-butanol (3×5 ml) was used for extraction operation, the organic phases were combined, and the organic phases were washed with saturated brine. The organic phase was freed from the solvent under reduced pressure, and the crude product was purified using 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 (500MHz, DMSO-d6) δ8.87(d,J=4.9Hz,2H),8.32(d,J=8.0Hz,2H),7.83(d,J=8.9Hz,1H),7.73(d,J=3.1Hz,1H),7.41(t,J= 4.9Hz,1H),7.31(d,J=8.0Hz,2H),7.20(d,J=3.2Hz,1H),7.18–7.11(m,2H),7.09(d,J=8.9Hz,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] 50mg (0.25mmol) of intermediate IV was dissolved in 2mL of N,N-dimethylformamide solvent, and nitrogen was protected. 13mg (0.33mmol) of 60% sodium hydride was added, and the mixture was stirred at room temperature for 30min. 143mg (0.30mmol) of 2-(bromomethyl)-4'-(di(tert-butoxycarbonyl)aminomethyl)-1,1'-biphenyl was added, and the mixture was reacted at room temperature for 5h. 3ml of water was added to quench the reaction, and ethyl acetate or n-butanol (3×5ml) was used for extraction. The organic phases were combined and washed with saturated brine. The organic phase was desolventized under reduced pressure, and the crude product was purified by a flash column chromatography system (dichloromethane: methanol = 95:5 as the eluent) to obtain a yellow-brown solid compound. 2.5ml of 4M hydrochloric acid-1,4-dioxane solution was added to the above yellow-brown solid compound, and the mixture was stirred at room temperature for 4h. 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(500MHz,DMSO-d6)δ7.78(d,J=9.0Hz,1H),7.65(s,1H),7.57(s,4H),7.41(s,1H),7.28(dd,J=21.5,7.5H z,3H),7.11(s,1H),7.04(d,J=8.9Hz,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 ring-4-methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0062] The reaction procedure was as in Example 2, and the starting materials were intermediate IV (50 mg, 0.25 mmol) and 2-(4-(bromomethyl)phenyl ring)pyrimidine 75 mg (0.30 mmol). The yield was 68%, white solid. ESI-MS (m / z): 368.41 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.87(d,J=4.9Hz,2H),8.32(d,J=8.0Hz,2H),7.83(d,J=8.9Hz,1H),7.73(d,J=3.1Hz,1H),7.41(t,J= 4.9Hz, 1H), 7.31 (d, J = 8.0Hz, 2H), 7.20 (d, J = 3.2Hz, 1H), 7.18–7.11 (m, 2H), 7.09 (d, J = 8.9Hz, 1H), 6.23 (s, 2H), 5.62 (s, 2H).

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

[0064] The reaction procedure was as in Example 2, and the starting materials were intermediate IV (50 mg, 0.25 mmol) and 4-(4-(bromomethyl)phenyl ring)pyridine 75 mg (0.30 mmol). The yield was 75%, yellow-brown solid. ESI-MS (m / z): 367.60 [M+H] + . 1 HNMR (500MHz, DMSO-d6) δ8.60(d,J=5.3Hz,2H),7.79(d,J=9.1Hz,1H),7.74(d,J=8.0Hz,2H),7.69(d,J=3.1Hz,1H),7.65(d ,J=5.3Hz,2H),7.31(d,J=8.0Hz,2H),7.14(d,J=3.1Hz,1H),7.05(d,J=9.0Hz,1H),6.85(s,2H),5.87(s,2H),5.58(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 procedure was as in Example 2, and the starting materials were intermediate IV (50 mg, 0.25 mmol) and 4-(bromomethyl)-3-methyl-1,1'-biphenyl 78 mg (0.30 mmol). The yield was 78%, yellow-brown solid. ESI-MS (m / z): 380.43 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.01(d,J=8.8Hz,1H),7.76(d,J=3.1Hz,1H),7.61(d,J=7.6Hz,2H),7.54(s,1H),7.43( t,J=6.6Hz,5H),7.33(t,J=7.5Hz,2H),7.23(d,J=8.9Hz,1H),6.51(d,J=8.0Hz,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 procedure was as in Example 1, and the starting materials were intermediate IV (50 mg, 0.25 mmol) and 5-(1-bromoethyl)-3-carboxymethyl ester-1,1'-biphenyl 96 mg (0.30 mmol). The yield was 33%, dark brown solid. ESI-MS (m / z): 424.67 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ13.12(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=7.4Hz,3H),7.38(q,J=7.2,6.0Hz,3H),6.39(s,3H),6.14(d,J=7.2Hz,2H),1.44(d,J=7.0Hz,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 procedure was as in Example 2, and the starting materials were intermediate IV (50 mg, 0.25 mmol) and 4-(bromomethyl)-2'-cyano-1,1'-biphenyl 86 mg (0.30 mmol). The yield was 69%, white solid. ESI-MS (m / z):391.44 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ7.91(d,J=7.7Hz,1H),7.80(d,J=9.0Hz,1H),7.75(t,J=7.7Hz,1H),7.67(d,J=3.1Hz,1H),7.56(dd,J=7.8,3.5H z, 2H), 7.52 (d, J = 8.0Hz, 2H), 7.31 (d, J = 7.9Hz, 2H), 7.13 (d, J = 3.1Hz, 1H), 7.06 (d, J = 9.0Hz, 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 as in Example 2, and the starting materials were intermediate IV (50 mg, 0.25 mmol) and 4-(bromomethyl)-4'-cyano-1,1'-biphenyl 86 mg (0.30 mmol). The yield was 72%, white solid. ESI-MS (m / z): 391.58 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ7.88(d,J=8.1Hz,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 = 3.2Hz, 1H), 7.06 (dd, J = 9.0, 3.7Hz, 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 as in Example 2, and the starting materials were intermediate IV (50 mg, 0.25 mmol) and 4-(bromomethyl)-4'-guanidino-1,1'-biphenyl 91 mg (0.30 mmol). The yield was 35%, yellow-brown solid. ESI-MS (m / z): 423.52 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.99(s,1H),10.19(d,J=5.3Hz,1H),8.92(s,1H),8.14(d,J=8.9Hz,1H),7.97(d,J=3.0Hz,1H),7 .75(s,1H),7.65(dd,J=32.4,7.9Hz,8H),7.42(d,J=3.1Hz,1H),7.30(t,J=8.2Hz,3H),7.24(d,J=8.8Hz,1H),5.64(s,2H).

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

[0076] The reaction procedure was as in Example 2, and the starting materials were intermediate IV (50 mg, 0.25 mmol) and 4-cyclohexyl-bromomethylbenzene 76 mg (0.30 mmol). The yield was 79%, white solid. ESI-MS (m / z): 372.67 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ7.75(d,J=9.0Hz,1H),7.60(d,J=3.0Hz,1H),7.17–7.07(m,5H),7.03(d,J=9 .0Hz,1H),6.70(s,2H),5.72(s,2H),5.44(s,2H),1.70(dt,J=24.8,11.7Hz,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 procedure was as in Example 2, and the starting materials were intermediate IV (50 mg, 0.25 mmol) and 4-(bromomethyl)-3-chloro-1,1'-biphenyl 84 mg (0.30 mmol). The yield was 72%, white solid. ESI-MS (m / z): 400.49 [M+H] + .

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

[0080] The reaction procedure was as in Example 2, and the starting materials were intermediate IV (50 mg, 0.25 mmol) and 4-(bromomethyl)-4'-amidino-1,1'-biphenyl 87 mg (0.30 mmol). The yield was 52%, yellow-brown solid. ESI-MS (m / z): 408.66 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ7.16(d,J=9.3Hz,1H),7.04(t,J=6.0Hz,4H),6.96(s,1H),6.85( d, J=7.9Hz, 2H), 6.49 (d, J=7.8Hz, 2H), 6.40 (s, 1H), 6.36 (d, J=8.8Hz, 1H), 4.83 (s, 2H).

[0081] Example 14: Preparation of Compound 14 (1,3-diamino-7-(1-(4-carboxyphenyl ring)-ethynyl-2-methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0082] The reaction procedure was as in Example 1, and the starting materials were intermediate IV (50 mg, 0.25 mmol) and 1-(4-carboxymethyl ester benzene ring)-3-chloro-1-propyne 76 mg (0.30 mmol). The yield was 52%, yellow-brown solid. ESI-MS (m / z): 358.55 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.04(d,J=8.8Hz,1H),7.90(d,J=8.1Hz,2H),7.69(d,J=3.1Hz,1H),7.63(s ,1H),7.56(s,1H),7.47(d,J=7.7Hz,2H),7.25(d,J=9.1Hz,1H),7.20(d,J=3.3Hz,1H),5.49(s,2H).

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

[0084] 50 mg (0.25 mmol) of intermediate IV was dissolved in 2 mL of N,N-dimethylformamide solvent, and 13 mg (0.33 mmol) of 60% sodium hydride was added under nitrogen protection, and stirred at room temperature for 30 min, and 36 mg (0.30 mmol) of 3-bromopropyne 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 ethyl acetate or n-butanol (3×5 ml) was used for extraction, and the organic phases were combined and washed with saturated brine. The organic phase was freed of solvent under reduced pressure, and the crude product was purified by flash column chromatography (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, and 4-azido-1,1'-biphenyl (1 equivalent), cuprous iodide (0.1 equivalent), N,N-diisopropylethylamine (2 equivalents) were added, stirred at 100°C for 3h, cooled to room temperature, and 10 ml of water was added to precipitate a solid, which was filtered to obtain a dark brown solid compound 18 with a total yield of 38%. ESI-MS (m / z): 433.23 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ8.81(s,1H),7.86(d,J=41.9Hz,5H),7.62(d,J=57.7Hz,4H),7.40(d,J=42.5Hz,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-naphthalene)-triazole 4-methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0086] The reaction procedure was as in Example 18, and the reaction materials were intermediate IV (50 mg, 0.25 mmol), 3-bromopropyne 36 mg (0.30 mmol) and 2-naphthalene azide (0.25 mmol). The yield was 42%, black solid. ESI-MS (m / z): 407.52 [M+H] + , 1 H NMR(500MHz,DMSO-d6)δ8.90(s,1H),8.43(s,1H),8.13(d,J=9.0Hz,1H),8.08–7.99 (m,3H),7.96(s,1H),7.62(q,J=8.1Hz,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-triazole 4-methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0088] The reaction procedure was as in Example 18, and the reaction materials were intermediate IV (50 mg, 0.25 mmol), 3-bromopropyne 36 mg (0.30 mmol) and 2-azidobenzene (0.25 mmol). The yield was 54%, black solid. ESI-MS (m / z): 357.54 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ8.79(s,1H),8.14(s,1H),7.90(d,J=50.9Hz,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-carboxylphenyl ring)-triazole 4-methyl)-7H-pyrrolo[3,2-f]quinazoline)

[0090] The reaction procedure was as described in Example 18. The reaction materials were intermediate IV (50 mg, 0.25 mmol), 3-bromopropyne 36 mg (0.30 mmol) and 2-azido-3-benzoic acid (0.25 mmol). The yield was 27%, black solid. ESI-MS (m / z): 401.22 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.02(s,1H),8.97(s,1H),8.36(s,1H),8.26(d,J=8.8Hz,1H),8.10(d,J=8.0Hz,1H),8.03(s ,1H),7.89(d,J=3.1Hz,1H),7.84(s,1H),7.72(s,1H),7.54(s,2H),7.37(d,J=3.6Hz,1H),7.31(s,2H),5.74(s,2H).

[0091] Pharmacological experiments

[0092] Unless otherwise specified, the experimental materials, reagents, operations and methods used in the following active examples can be obtained from commercial channels or can be easily known or prepared based on existing technologies.

[0093] Experimental example: In vitro antibacterial experiment

[0094] Experimental methods

[0095] The in vitro antibacterial activity of the compounds against sensitive / resistant strains was evaluated by the broth microdilution method (refer to CLSI 27th edition). The in vitro antibacterial activity of the compounds against different strains was tested. The specific operation steps were as follows: the drug stock solution was diluted twice with CAMH medium in a 96-well plate to a series of required concentration gradients (volume 50ul), and then 50μl of bacterial solution (4-5×10 5 CFU / ml) was added to the above series of two-fold dilutions of drug-containing CAMH broth culture medium. In the experiment, control wells without bacteria, without drugs, and quality control bacteria were set up at the same time. The 96-well plate was placed at a constant temperature of 37°C 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 in the well and whether there were colonies deposited at the bottom of the well were observed with the naked eye. When the test results of the quality control strains were within the quality control range, the test results were interpreted. The minimum concentration of the drug contained in the sterile growth well is the MIC value (Minimal Inhibitory Concentration).

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

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

[0098]

[0099]

[0100] NT not tested.

Claims

1. A 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivative or a pharmaceutically acceptable salt thereof as represented by formula (I), in, R is selected from H, CH3, C2H5; The A fragment is selected from a benzene ring, pyridine, pyrimidine, alkyne, alkene, and triazole; The B fragment is selected from a benzene ring, a 3 to 6 carbon ring alkyl group, a pyridine, a pyrimidine, and a naphthyl group; Fragment A is connected to fragment B via a carbon-carbon bond or a carbon-nitrogen bond; The A fragment or the B fragment may have 0-1 substituents, wherein the substituents X and Y are independently selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, urea, methoxy, halogen, cyano, methyl, and ethyl, and the substitution position is selected from any position on the fragment; When both fragment A and fragment B are benzene rings, fragment A or fragment B must have a substituent, and the substituent X and Y are selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, urea, methoxy, halogen, cyano, methyl, and ethyl, and the substitution position is selected from any position on the benzene ring; When the A fragment is an alkyne and the B fragment is a benzene ring, the B fragment must have a substituent, and the substituent Y is selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, urea, methoxy, halogen, cyano, methyl, and ethyl, and the substitution position is selected from any position on the benzene ring; n is selected from 0 and 1, and the quinazoline core can be connected to any position on the A fragment.

2. The 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline heterocyclic compound according to claim 1 or a pharmaceutically acceptable salt thereof, as shown in formula (Ia): Features: in, R is H; Fragment A is a benzene ring; The B fragment is selected from 3 to 6 carbocyclic alkyl groups, benzene rings, pyridine, and pyrimidine; Fragment A is connected to fragment B via a carbon-carbon bond; The A fragment or the B fragment may have 0-1 substituents, wherein the substituents X and Y are independently selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, urea, methoxy, halogen, cyano, methyl, and ethyl, and the substitution position is selected from any position on the fragment; When the B fragment is a benzene ring, the A fragment or the B fragment must have a substituent, and the substituent X and Y are selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, urea, methoxy, halogen, cyano, methyl, and ethyl, and the substitution position is selected from any position on the fragment; n is 0, and the quinazoline core can be connected to any position on the A fragment.

3. The 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, as shown in formula (Ib): Features: R is H; The A fragment is selected from a benzene ring, pyridine, pyrimidine, triazole, alkyne, alkene; The B fragment is a benzene ring; Fragment A is connected to fragment B via a carbon-carbon bond; The A fragment or the B fragment may have 0-1 substituents, wherein the substituents X and Y are independently selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, urea, methoxy, halogen, cyano, methyl, and ethyl, and the substitution position is selected from any position on the fragment; When the A fragment is an alkyne, its B fragment must have a substituent, and its substituent Y is selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, urea, methoxy, halogen, cyano, methyl, and 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, and the substituent X / Y is selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, urea, methoxy, halogen atom, cyano, methyl, ethyl, and the substitution position is selected from any position on the fragment; n is 0, and the quinazoline core can be connected to any position on the A fragment.

4. The 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline heterocyclic compound or a pharmaceutically acceptable salt thereof according to claim 1, as shown in formula (Ic): Features: R is H; The A fragment is selected from a benzene ring, pyridine, and pyrimidine; The B fragment is selected from a benzene ring, a 3 to 6 carbon ring alkyl group, a pyridine, a pyrimidine, and a naphthyl group; Fragment A is connected to fragment B via a carbon-carbon bond or a carbon-nitrogen bond; The A fragment or the B fragment may have 0-1 substituents, wherein the substituents X and Y are independently selected from carboxyl, carboxymethyl ester, carboxyethyl ester, aminomethyl, amino, amidino, urea, methoxy, halogen, cyano, methyl, and ethyl, and the substitution position is selected from any position on the fragment; Fragment A and fragment B cannot be benzene rings at the same time. n is 0, and the quinazoline core can be connected to any position on the A fragment.

5. The 1,4-dicarbonylthiourea compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: The compound is selected from the following group:

6. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier or excipient.

7. Use of the 1,3-diamino-7H-pyrrolo[3,2-f]quinazoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of an anti-infective disease drug.

8. The use according to claim 7, characterized in that The infectious disease is selected from the group consisting of infections caused by Staphylococcus aureus, drug-resistant Staphylococcus aureus, Escherichia coli and Bacillus baumannii, or infectious diseases caused by multidrug-resistant bacteria.

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