HK1141948A - Benzimidazoles and pharmaceutical compositions thereof - Google Patents

Description

Benzimidazole and pharmaceutical composition thereof

Reference to related applications

This application claims priority to U.S. provisional application serial No. 60/912,980, filed on 20/4/2007, which is incorporated herein by reference.

Background

Tuberculosis (TB) is one of the first infections identified. Research has been conducted for over 50 years to control and eliminate this disease. However, eradication of TB remains one of the most prominent challenges for basic and clinical research scientists.

TB was once thought to be controlled, but TB case reports have risen dramatically in the united states early in the nineties of the twentieth century. Although this trend has been reversed in industrialized countries and the number of reported new cases has steadily decreased, TB remains a major public health threat worldwide. Recent statistics from the WHO estimate about eight hundred and forty thousand new cases per year with a global mortality rate of 23% or about two million deaths per year.

Poor chemotherapeutic drugs and inadequate local control programs contribute to the inability to manage TB and lead to the emergence of drug resistant strains of bacteria that cause mycobacterium tuberculosis (Mtb). Investigations between 1996 and 1999 at 58 international sites found abnormally high rates of single and multi-drug resistant strains in estonia, latvia, and russia, and revealed high rates of development of multidrug resistance (MDR-TB) in countries such as china and iran. See Kruuner, A., Silastu, H., Danilovitsh, M., Levina, K., Svenson, S.B., Kallenius, G., and (1998) Drug resistant tubericosis in Estonia, IntJTuberc LungDis 2, 130-3 of Hoffher, S.E. Notably, MDR-TB is more difficult to treat than sensitive TB, which requires the administration of more expensive second-line antibiotics for up to two years. The frequency of resistance to at least one first-line TB drug (isoniazid (INH), Rifampin (RIF), pyrazinamide or ethambutol) is 1.7% in yerba to 36.9% in estonia. The frequency of resistance indicates a global problem that involves not only the spread of Mtb but also treatment.

Finally, it is of crucial importance that TB functions as a major opportunistic pathogen in HIV/AIDS patients. Therefore, there is an urgent need to develop new TB drugs that are effective against sensitive and resistant Mtb strains.

Likewise, new drugs are needed to treat patients infected with francisella tularensis (bacteria causing tularemia). However, tularemia is predominantly endemic in humans, causing lesions and flu-like symptoms. The discovery of a new approach to the treatment of Francisella tularensis is of great importance, since it is one of the most pathogenic microorganisms currently known. Thus, it is currently classified as a class a selective agent by the centers for disease control and prevention due to its potential as a bioterrorism agent.

Disclosure of Invention

The present invention relates to molecules having the structural formula I:

wherein:

R¹represents NH₂、NHR⁶、NR⁹R¹⁰、NR⁶CONR⁹R¹⁰、NR⁶CSNR⁹R¹⁰、OH、OR⁶、SH、SR⁶、CHO、COOR⁶、COR⁶、CH₂OH、CR⁷R⁸OH、CH₂OR⁶、CR⁷R⁸OR⁶、CH₂NH₂、CR⁷R⁸NH₂、CR⁷R⁸NR⁹R¹⁰Alkyl, cycloalkyl, aryl, or halo;

R²and R⁴Independently represents H, alkyl, cycloalkyl, or aryl;

R³represents an alkyl group, a cycloalkyl group, or an aryl group;

R⁵representation H, R⁶、OR⁶、SR⁶、NH₂、NHR⁶Or NR⁹R¹⁰；

X represents O, S, NH, or NR⁶；

R⁶、R⁷、R⁸、R⁹And R¹⁰Independently represents an alkyl group, a cycloalkyl group, an aryl group, or a halogen group;

R²and R³、R⁴And R⁵And R⁹And R¹⁰Independently may be combined to represent a heterocycloalkyl or a heterocycloaryl;

R⁷and R⁸May be combined to represent cycloalkyl;

alkyl groups are branched or unbranched, saturated or unsaturated, and have 1 to 18 carbon atoms in their longest chain;

cycloalkyl groups are carbocyclic or heterocyclic, fused or unfused, non-aromatic ring systems having a total of 5-16 ring members including substituted rings;

the aryl group is a carbocyclic or heterocyclic aryl group;

carbocyclic aryl groups are fused or unfused cyclic systems having a total of 6 to 16 ring members including substituted rings;

the heterocyclic aryl group is a fused or unfused cyclic system having a total of 5 to 16 ring members including substituted rings;

halo (halogen) substituents are fluoro, chloro, or bromo;

each alkyl, cycloalkyl, and aryl independently can be unsubstituted or substituted at any position with one or more substituents;

the alkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Cycloalkyl, or aryl;

cycloalkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, or aryl;

aryl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, aryl, nitro, or carboxyl; and

heterocycloalkyl and heterocycloaryl have at least one heteroatom selected from oxygen, nitrogen and sulfur; and

a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating a patient infected with mycobacterium tuberculosis or francisella tularensis, comprising administering to the patient a compound of formula I or a pharmaceutically acceptable salt thereof.

Detailed Description

The present invention relates to novel benzimidazole derivatives. These benzimidazole derivatives can be used to treat patients infected with mycobacterium tuberculosis or francisella tularensis.

The above molecule has structural formula I:

in this formula, R¹Represents NH₂、NHR⁶、NR⁹R¹⁰、NR⁶CONR⁹R¹⁰、NR⁶CSNR⁹R¹⁰、OH、OR⁶、SH、SR⁶、CHO、COOR⁶、COR⁶、CH₂OH、CR⁷R⁸OH、CH₂OR⁶、CR⁷R⁸OR⁶、CH₂NH₂、CR⁷R⁸NH₂、CR⁷R⁸NR⁹R¹⁰Alkyl, cycloalkyl, aryl, or halo.

R²And R⁴Independent of each otherAnd represents H, alkyl, cycloalkyl, or aryl. For example, R²Can represent ethyl and R⁴May represent H.

R³Represents an alkyl group, a cycloalkyl group, or an aryl group. For example, R may represent tetrahydrofuranyl or ethyl.

In another aspect of the invention, R³Represents COR⁶。

In a preferred embodiment, when R is²When represents H, R³Is not methyl.

R⁵Representation H, R⁶、OR⁶、SR⁶、NH₂、NHR⁶Or NR⁹R¹⁰。R⁶、R⁷、R⁸、R⁹And R¹⁰Independently represent an alkyl group, a cycloalkyl group, an aryl group, or a halogen group. Preferably, R⁶、R⁷、R⁸、R⁹And R¹⁰Independently represents an alkyl group, a cycloalkyl group, or an aryl group. More preferably, R⁶、R⁷、R⁸、R⁹And R¹⁰Independently represent an alkyl group or an aryl group.

R²And R³、R⁴And R⁵And R⁹And R¹⁰Independently may be joined to represent a heterocycloalkyl or a heterocycloaryl ring. For example, R²And R³Can be combined to represent a heterocycloalkyl ring, resulting in the structure:

similarly, R⁴And R⁵May be linked to represent a heterocycloalkyl ring, resulting in the structure:

R⁷and R⁸May be combined to represent cycloalkyl.

Alkyl groups are branched or unbranched, saturated or unsaturated, and have 1 to 18 carbon atoms in their longest chain. Some examples of suitable straight-chain, saturated alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl groups, and dodecyl and hexadecyl groups. Preferred straight chain, saturated alkyl groups include methyl and ethyl.

Some examples of suitable branched, saturated alkyl groups include isopropyl, isobutyl, sec-butyl, tert-butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl (isopentyl), 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl (neopentyl), 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and 2-methyl, 5-ethyldecyl groups. Preferred branched, saturated alkyl groups include isopropyl and tert-butyl.

Some examples of unsaturated alkyl groups include ethenyl, ethynyl, propenyl, propargyl, isopropenyl, butenyl, 1-hexenyl, and 1-octenyl.

Cycloalkyl groups are carbocyclic or heterocyclic, fused or unfused, non-aromatic ring systems having a total of 5-16 ring members including substituted rings. The ring system is monocyclic, bicyclic, tricyclic, or tetracyclic and may be bridged or unbridged.

Some examples of carbocycloalkyl groups include cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of fused carbocycloalkyl groups include indenyl, isoindenyl. The bridging group includes bicyclo [2.2.1] heptane, bicyclo [5.2.0] nonane, and bicyclo [5.2.0] nonane.

Some examples of heterocycloalkyl groups include pyrrolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholino, and oxazolidinyl. Examples of fused heterocycloalkyl groups include benzomorpholino, benzopyrrole, indolinyl, and benzopiperidinyl.

The aryl group may be carbocyclic or heterocyclic.

Carbocyclic aryl groups are fused or unfused cyclic systems having a total of 6 to 16 ring members including substituted rings. A preferred unfused carbocyclic aryl group is phenyl.

Some examples of fused carbocyclic aryl groups include naphthyl, phenanthryl, anthracyl, triphenylenyl, chrysenyl, and pyrenyl.

A heterocyclic aryl group is a fused or unfused cyclic system having a total of 5-16 ring members including substituted rings.

Some examples of non-fused heterocyclic aryl groups include thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. Some examples of fused heterocyclic aryl groups include purinyl, 1, 4-naphthyridinyl, indolyl, benzimidazolyl, 4, 5-phenanthridinyl, benzoxazolyl, isoindolyl, quinolinyl, isoquinolinyl, and benzofuranyl.

Halo substituents are fluoro, chloro, or bromo.

Each alkyl, cycloalkyl, and aryl group independently can be unsubstituted or substituted at any position with one or more substituents. The alkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Cycloalkyl, or aryl. Cycloalkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, or aryl. Aryl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, aryl, nitro, or carboxyl.

Heterocycloalkyl and heterocycloaryl have at least one heteroatom selected from oxygen, nitrogen, and sulfur.

X represents O, S, NH, or NR⁶。R⁶As described above.

In the present invention, various parameters (e.g., R) are defined¹、R²、R³、R⁴X). Within each parameter, more than one element (e.g., chemical moiety) is listed. It is to be understood that the present invention contemplates embodiments wherein each element listed under one parameter can be combined with each other and with each element listed under any other parameter. For example, X is defined above as representing O, S, NH, or NR⁶。R⁵Above is defined as representation H, R⁶、OR⁶、SR⁶、NH²、NHR⁶Or NR⁹R¹⁰. Each element (O, S, NH or NR) of X⁶) Can be bound to R⁵Each element (H, R)⁶、OR⁶、SR⁶、NH₂、NHR⁶Or NR⁹R¹⁰). For example, in one embodiment, X may be O and R⁵May be H. Alternatively, X may be NH and R⁵May be NR⁹R¹⁰And the like. Similarly, the third parameter is R⁴Wherein a member is defined as H, alkyl, cycloalkyl, or aryl. Each of the above embodiments may be combined with R⁴Each element of (1). For example, in which X is O and R⁵In embodiments where R is H⁴May be H (or at R)⁴Any other chemical moiety within the element of (a).

The compounds of the present invention are limited to those that are chemically feasible and stable. Thus, combinations of substituents or variables in the above compounds are permissible only if such combinations result in stable or chemically feasible compounds. A stabilizing compound or chemically feasible compound is one in which the chemical structure does not change significantly when maintained at a temperature of 40 ℃ or less for at least 1 week in the absence of moisture or other chemical reaction conditions.

Pharmaceutically acceptable salts

The invention also relates to pharmaceutically acceptable salts of benzimidazole derivatives. Pharmaceutically acceptable salts include the conventional non-toxic salts of benzimidazole derivatives, as formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, p-toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic acids and the like.

Pharmaceutically acceptable salts of the benzimidazole derivatives of the invention may be synthesized from the compounds of the invention, which contain essential moieties, by conventional chemical methods. In general, salts are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric amount or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.

Synthesis of benzimidazole derivatives

The benzimidazoles of the present invention may be synthesized by methods known in the art. The following scheme represents one mode of synthesis of the compounds of the present invention.

Scheme I shows an example of a synthesis that yields a single compound of the invention or a library of compounds of the invention (library). For example, Polymer Assisted Solution Phase (PASP) synthesis may be used to prepare the compounds of the invention. PASP is a parallel synthesis for the preparation of a trisubstituted benzimidazole (BAZ-1) library using 2, 4-dinitro-5-fluoroaniline (1) as starting material.

Scheme 1

i)R²R³NH, DIPEA; ii) acid chlorides, pyridines; iii) Pd-C/HCOOIMH₄(ii) a iv)6N HCl/dioxane-MeOH; v) (RCO)₂O、RSO₂Cl, RCOCl, or RCON, NH₂-scavengers

The first step involves the nucleophilic substitution of compound 1 with a secondary amine in the presence of N, N-diisopropylethylamine. This reaction yields compound 2 in high yield and purity at room temperature.

Acylation of the free amino group of compound 2 with an acyl or aroyl chloride then occurs. The reaction was carried out under reflux conditions using pyridine as solvent.

Thereafter, HCOO was utilized^-NH₄ ⁺And Pd-C to produce a diamine compound 4. The benzimidazole ring is formed by acid catalyzed dehydration.

The free aromatic amino group of compound 5 was modified in different ways. To at-C (X) -R⁵Positional diversity is introduced, with anhydrides, acid chlorides, sulfonyl chlorides, and isocyanates used as modifiers. Modification of the aromatic amine moiety smoothly occurs in dry dichloromethane and all excess acylating agent is purged through a commercially available aminomethylated polystyrene resin (from nova-biochem) to yield the desired product in 80-95% yield.

Use of benzimidazole derivatives

The invention also relates to methods of treating patients infected with mycobacterium tuberculosis or francisella tularensis. The method comprises administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The methods and compounds of the present invention may be employed alone or in conjunction with other antibacterial agents. Other antibacterial agents include isoniazid, rifampin, pyrazinamide, rifabutin, streptomycin, and ciprofloxacin. The combination of these antibacterial agents and the compounds of the present invention will provide novel formulations for the treatment of tuberculosis, including MDR-TB and XDR-TB, as well as tularemia.

As used herein, an effective amount of a compound of structural formula (I) or a pharmaceutically acceptable salt thereof is any amount effective to treat a patient infected with Mtb or francisella tularensis. The mode of administration and dosage can be determined by one skilled in the art. The effective amount of the compound will depend upon the group of patients (age, sex, weight, etc.), the nature and severity of the condition being treated, the particular compound being administered, and the route of administration. The amounts suitable for administration to humans are routinely determined by physicians and clinicians during clinical trials.

The lowest dose of the compound is the lowest dose at which efficacy is observed. For example, the minimum dose of the compound can be about 0.1 mg/kg/day, about 1 mg/kg/day, or about 3 mg/kg/day.

The maximum dose of the compound is the maximum dose at which efficacy is observed in the patient and side effects are tolerable. For example, the maximum dose of the compound may be about 10 mg/kg/day, about 9 mg/kg/day, or about 8 mg/kg/day.

The benzimidazole derivatives useful in the methods of the invention may be administered by any method known in the art. Some examples of suitable modes of administration include oral and systemic administration. Systemic administration may be enteral or parenteral. Liquid or solid (e.g., tablets, gelatin capsules) dosage forms may be employed.

Parenteral administration of benzimidazole derivatives includes, for example, intravenous, intramuscular, and subcutaneous injections. For example, the compounds can be administered to a patient by sustained release, as is known in the art. Sustained release administration is a method of drug delivery to achieve a certain level of drug over a specific period of time.

Other routes of administration include oral, topical, intrabronchial, or intranasal. For oral administration, liquid or solid dosage forms may be used. Some examples of dosage forms suitable for oral administration include tablets, gelatin capsules, pills, troches, elixirs, suspensions, syrups, and wafers. Intrabronchial administration may include an inhaler spray. For intranasal administration, the compound may be administered by nebulizer or liquid mist.

The compounds may be formulated in a suitable pharmaceutical carrier. In this specification, a pharmaceutical carrier is considered synonymous to a carrier or excipient, as will be clear to a person skilled in the art. Examples of carriers include starch, milk, sugar, certain types of clay, gelatin, stearic acid or its salts, magnesium or calcium stearate, talc, vegetable fats and oils, gums, and glycols.

The compounds may be formulated into compositions comprising one or more of the following ingredients: stabilizers, surfactants, preferably non-ionic surfactants, and optionally salts and/or buffers.

The stabilizer may be, for example, an amino acid, such as glycine; or oligosaccharides such as sucrose, tetrasaccharide, lactose or dextran. Alternatively, the stabilizer may be a sugar alcohol such as mannitol, or a mixture thereof. Preferably, the stabilizer or mixture of stabilizers constitutes about 0.1% to about 10% by weight of the compound.

The surfactant is preferably a nonionic surfactant, such as polysorbate. Some examples of suitable surfactants include tween 20, tween 80; polyethylene glycol or polyoxyethylene polyoxypropylene glycol, such as Pluronic F-68, which is from about 0.001% (w/v) to about 10% (w/v).

The salt or buffer may be any salt or buffer, such as sodium chloride or sodium/potassium phosphate, respectively. Preferably, the buffering agent maintains the pH of the compound formulation in the range of about 5.5 to about 7.5. Salts and/or buffers may also be used to maintain osmolality at a level suitable for administration to a patient. Preferably, the salt or buffer is present in an approximately isotonic concentration, which is about 150mM to about 300 mM.

The compounds may be formulated into compositions, which may additionally comprise one or more conventional additives. Some examples of such additives include solubilizing agents such as glycerol; antioxidants such as benzalkonium chloride (a mixture of quaternary ammonium compounds, known as "quart"), benzyl alcohol, chlorobutanol, or chlorobutanol; anesthetics such as morphine derivatives; or an isotonic agent and the like. As a further precaution against oxidation or other spoilage, the composition may be stored in a bottle sealed with a barrier stopper under nitrogen.

Examples

The following examples are presented for purposes of illustration and to describe the best mode of the invention presently contemplated. The scope of the invention is in no way limited to the embodiments described herein.

Example 1

Synthesis of 6-diethylamino-5- (4-methoxybenzoyl) amino-2- (2-methoxyphenyl) -1H-benzo [ d ] imidazole, which is a key intermediate for the synthesis of compound libraries (the process comprises three steps):

(a) synthesis of 1-amino-3-diethylamino-4, 6-dinitrobenzene:

to 20mL of a solution of 2, 4-dinitro-5-fluoroaniline (1.6g, 8.0mmol) in THF was slowly added a mixture of DIPEA (1.1g, 8.8mmol) and diethylamine (644mg, 8.8mmol) in 5mL THF. The reaction mixture was stirred at room temperature for 1 hour. Water (100mL) was added to give the desired product as a yellow precipitate. The product was collected by filtration and washed with water (200 mL). The filtrate was concentrated to dryness in vacuo to give the desired product (1.8g, 90% yield) as a bright yellow solid:¹H-NMR(300MHz，CDCl₃)δ1.96(t，6H，J＝7.2Hz)，3.24(q，4H，J＝7.2Hz)，6.08(s，1H)，8.75(s，1H)；¹³C NMR(75MHz，CDCl₃)512.1，45.7，102.7，123.3，128.2，131.6，147.8，149.4；ESI MS m/z 255.1[M+H]⁺。

(b) synthesis of 5- (diethylamino) -2, 4-dinitro-1- (2-methoxybenzoyl) aminobenzene:

to 5mL of a pyridine solution of 1-amino-3-diethylamino-4, 6-dinitrobenzene (508mg, 2.0mmol) was added 2-methoxybenzoyl chloride (680mg, 4.0 mmol). After refluxing for 5 hours, 50mL of water was added to the reaction mixture, and then the precipitate was collected by filtration and washed with 200mL of water. Recrystallization from dichloromethane and methanol yielded the desired product (622mg, 80% yield) as a yellow solid:¹H-NMR(300MHz，CDCl₃)δ1.29(t，6H，J＝7.2Hz)，3.39(q，4H，J＝7.2Hz)，4.13(s，3H)，7.07(d，1H，J＝8.1)，7.11(t，1H，J＝9.8Hz)，7.55(t，1H，J＝7.8Hz)，8.23(d，1H，J＝8.1Hz)，8.83(s，1H)，8.98(s，1H)；ESI MS m/z 389.1[M+H]⁺。

(c) synthesis of 5-amino-6-diethylamino-2- (2-methoxyphenyl) -1H-benzo [ d ] imidazole:

to a solution of 5- (diethylamino) -2, 4-dinitro-1- (2-methoxybenzoyl) aminobenzene (388mg, 1.0mmol) in 10mL of 1, 4-dioxane and 10mL of methanol under a nitrogen atmosphere were added ammonium formate (1.5g) and 10% Pd/C (200 mg). The reaction mixture was stirred for 30 minutes. The Pd/C and excess ammonium formate were filtered. Concentrated HCl (10 m)L) the filtrate is added. After heating at 75 ℃ for 18 hours, saturated K is used₂CO₃The solution alkalifies the reaction mixture to pH 8. The reaction mixture was diluted with 200mL ethyl acetate, washed with brine, and then anhydrous MgSO₄And (5) drying. The reaction mixture was filtered and concentrated in vacuo to afford the crude product (280mg, 90% yield). The crude product was then purified by column chromatography on silica gel using EtOAc as eluent to give the desired product (188mg, 61% yield) as a brown solid:¹H-NMR(300MHz，CDCl₃)δ1.01(t，6H，J＝7.2Hz)，3.01(q，4H，J＝7.2Hz)，4.05(s，3H)，6.92(s，1H)，7.03(d，1H，J＝8.1Hz)，7.11(t，1H，J＝8.1Hz)，7.36(t，1H，J＝6.9)，7.41(s，1H)，8.52(d，1H，J＝7.8Hz)；ESI MS m/z 311.2[M+H]⁺。

examples 2 to 7

The following key intermediates were prepared and characterized in the same manner as in example 1.

5-amino-6-diethylamino-2- (cyclohexyl) -1H-benzo [ d ] -imidazole:

brown solid:¹H-NMR(300MHz，CDCl₃)δ0.95(t，6H，J＝7.2Hz)，1.2-2.2(m，10H)，2.82(m，1H)，2.92(q，4H，J＝7.2Hz)，6.90(s，1H)，7.33(s，1H)；ESI MS m/z 287.1[M+H]⁺。

5-amino-6-diethylamino-2- (4-fluorophenyl) -1H-benzo [ d ] -imidazole:

brown solid:¹H-NMR(300MHz，CDCl₃)δ0.94(t，6H，J＝7.2Hz)，2.91(q，4H，J＝7.2Hz)，6.80(s，1H)，7.02(t，2H，J＝8.7Hz)，7.27(s，1H)，7.98(ddd，2H，J＝1.8，5.4，8.7Hz)；ESI MS m/z 299.1[M+H]⁺。

5-amino-6-diethylamino-2- (phenyl) -1H-benzo [ d ] -imidazole:

a brown solid;¹H-NMR(300MHz，CDCl₃)δ0.92(t，6H，J＝7.2Hz)，2.92(q，4H，J＝7.2Hz)，6.85(s，1H)，7.32(s，1H)，7.41(m，3H)，8.01(dd，2H，J＝1.8，8.4Hz)；ESI MS m/z 281.1[M+H]⁺。

5-amino-6-diethylamino-2- (4-methylphenyl) -1H-benzo [ d ] -imidazole:

a brown solid;¹H-NMR(300MHz，CDCl₃)δ0.91(t，6H，J＝7.2Hz)，2.90(q，4H，J＝7.2Hz)，2.33(s，3H)，6.79(s，1H)，7.13(d，2H，J＝7.8Hz)，7.32(s，1H)，7.99(d，2H，J＝7.8Hz)；ESI MS m/z 295.1[M+H]⁺。

5-amino-6-diethylamino-2- (4-methoxyphenyl) -1H-benzo [ d ] -imidazole:

a brown solid;¹H-NMR(300MHz，CDCl₃)δ0.93(t，6H，J＝7.2Hz)，2.92(q，4H，J＝7.2Hz)，4.03(s，3H)，6.73(s，1H)，6.75(d，2H，J＝8.4Hz)，7.10(d，2H，J＝8.4Hz)7.16(s，1H)；ESI MS m/z 311.1[M+H]⁺。

5-amino-6-diethylamino-2- (1-naphthyl) -1H-benzo [ d ] -imidazole:

a brown solid;¹H-NMR(300MHz，CDCl₃)δ0.91(t，6H，J＝7.2Hz)，2.92(q，4H，J＝7.2Hz)，6.65(s，1H)，7.10(s，1H)，7.35(t，1H，J＝7.5Hz)，7.44(t，2H，J＝4.2Hz)，7.67(d，1H，J＝6.3)，7.83(m，2H)，8.64(m，1H)；ESI MS m/z 349.2[M+H]⁺。

example 8

Synthesis of 6-diethylamino-5- (4-methoxybenzoyl) amino-2- (2-methoxyphenyl) -1H-benzo [ d ] imidazole:

to 5-amino-6-diethylamino-2- (2-methoxyphenyl) -1H-benzo [ d]To a solution of imidazole (200mg, 0.64mmol) in methylene chloride (5mL) was added 2-methoxybenzoyl chloride (112mg, 0.64mmol) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and then purified by column chromatography on silica gel using hexane/EtOAc (4/1) as eluent to give the desired product (210mg, 78%) as a white powder:¹H-NMR(300MHz，CDCl₃)δ1.00(t，6H，J＝7.2Hz)，3.05(q，4H，J＝7.2Hz)，3.86(s，3H)，4.04(s，3H)，6.85(d，2H，J＝9Hz)，7.03(d，1H，J＝8.7Hz)，7.13(t，1H，J＝7.2Hz)，7.39(t，1H，J＝7.2Hz)，7.66(s，1H)，7.91(d，2H，J＝9Hz)，8.88(s，1H)；¹³C NMR(75MHz，CDCl₃)δ12.9，50.4，55.3，55.7，111.4，113.8，117.9，121.5，127.8，128.6，129.6，130.8，132.8，135.8，149.9，156.6，162.1，164.1；ESI MS m/z 445.4[M+H]⁺。

example 9

Synthesis of 6-diethylamino-5- (4-chlorobenzoyl) amino-2- (2-methoxyphenyl) -1H-benzo [ d ] imidazole:

5-amino-6-diethylamino-2- (2-methoxyphenyl) -1H-benzo [ d ] in the same manner as described above]-imidazole (187mg, 0.6mmol) was reacted with 4-chlorobenzoyl chloride (105mg, 0.6mmol) to give the desired product (216mg, 80% yield) as a pale yellow powder:¹H-NMR(300MHz，CDCl₃)δ0.99(t，6H，J＝7.2Hz)，3.05(q，4H，J＝7.2Hz)，4.07(s，3H)，7.05(d，1H，J＝8.4Hz)，7.11(t，1H，J＝7.8Hz)，7.41(t，1H，J＝7.8Hz)，7.47(d，2H，J＝8.4Hz)，7.67(s，1H)，7.88(d，2H，J＝8.4Hz)，8.55(d，1H，J＝6.9Hz)，8.86(s，1H)；¹³CNMR(75MHz，CDCl₃)δ13.1，50.6，55.9，111.5，117.7，121.7，128.3，129.0，129.8，131.1，132.5，133.9，136.0，137.7，150.2，156.7，163.4；ESI MS m/z 449.2[M+H]⁺。

example 10

Synthesis of 6-diethylamino-5- (benzoyl) amino-2- (cyclohexyl) -1H-benzo [ d ] -imidazole:

5-amino-6-diethyl ester in the same manner as described aboveAmino-2- (cyclohexyl) -1H-benzo [ d]-imidazole (27mg, 0.1mmol) was reacted with benzoyl chloride (11mg, 0.1mmol) to give the desired product (27mg, 74% yield) as a white powder:¹H-NMR(300MHz，CDCl₃)δ0.98(t，6H，J＝7.2Hz)，1.16(m，3H)，1.57-1.70(m，5H)，1.98(m，2H)，2.87(m，1H)，3.03(q，4H，J＝7.2Hz)，7.57(m，3H)，7.57(s，1H)，8.00(dd，2H，J＝1.8，8.4Hz)，8.96(s，1H)；ESI MSm/z 391.0[M+H]⁺。

example 11

Synthesis of 6-diethylamino-5- (4-methoxybenzoyl) amino-2- (cyclohexyl) -1H-benzo [ d ] imidazole:

5-amino-6-diethylamino-2- (cyclohexyl) -1H-benzo [ d ] in the same manner as described above]-imidazole (28mg, 0.1mmol) was reacted with 4-methoxybenzoyl chloride (17mg, 0.1mmol) to give the desired product (33mg, yield 79%) as a white powder:¹H-NMR(300MHz，CDCl₃)δ0.97(t，6H，J＝7.2Hz)，1.16(m，3H)，1.57-1.70(m，5H)，1.98(m，2H)，2.87(m，1H)，3.01(q，4H，J＝7.2Hz)，7.05(d，2H，J＝8.7Hz)，7.57(s，1H)，7.96(d，2H，J＝8.7Hz)，8.94(s，1H)；ESI MS m/z 421.0[M+H]⁺。

example 12

Synthesis of 7-amino-5- (methoxycarbonyl) amino-2- (4-bromophenyl) -1H-benzo [ d ] -imidazole (this procedure comprises three steps):

(a) synthesis of 4-amino-3, 5-dinitro-1- (methoxycarbonyl) aminobenzene:

a suspension of 4-amino-3, 5-dinitrobenzamide (543mg, 2.4mmol) in 4M HCl (20mL) was refluxed overnight. The reaction mixture was cooled and the precipitated solid was filtered to give 4-amino-3, 5-dinitrobenzoic acid as a yellow solid:¹H-NMR(300MHz，DMSOd₆) δ 8.80(s, 2H). The 4-amino-3, 5-dinitrobenzoic acid thus obtained was dissolved in SOCl₂(4mL) and refluxed overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove excess SOCl₂. The crude product was immediately dissolved in acetone (2.4mL) in an ice bath. To this solution was added NaN dropwise in ice water (0.88mL)₃(0.29g, 3.84 mmol). The mixture was stirred at 0 ℃ for 20 minutes until a solid precipitated. After dilution with ice water (12mL), CH₂Cl₂(6mL) the reaction mixture was extracted 2 times with MgSO 0₄Dried for 1 hour and then filtered. The filtrate was concentrated on a rotary evaporator (below room temperature) and the residue was dissolved in toluene (15 mL). After refluxing for 2 hours, the reaction mixture was cooled to room temperature, then MeOH (10mL) was added. After stirring at room temperature overnight, the reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel (hexane/EtOAc ═ 1/1) to give 4-amino-3, 5-dinitro-1- (methoxycarbonyl) aminobenzene as a bright red solid (292mg, 45% yield):¹H-NMR(300MHz，CDCl₃)δ3.73(s，3H)，6.60(s，1H)，8.30(s，2H)，8.64(s，2H)；ESI MS m/z 256.9[M+H]⁺。

(b) synthesis of 7-amino-5- (methoxycarbonyl) amino-2- (4-bromophenyl) -1H-benzo [ d ] imidazole:

to a suspension of 4-amino-3, 5-dinitro-1- (methoxycarbonyl) aminobenzene (311mg, 1.2mmol) in ethanol (24mL) under nitrogen was added ammonium formate (1.8g) and 10% Pd/C (120 mg). In thatThe mixture was stirred at room temperature overnight. The Pd/C and excess ammonium formate were filtered off. The filtrate was treated with 4-bromobenzaldehyde (715mg, 0.84mmol) as an adduct of sodium bisulfite at 0 ℃. After stirring the solution at room temperature under nitrogen for 12-16 hours, the micro-insolubles were removed by filtration and the filtrate was concentrated with a rotary evaporator until approximately 60-70% of the solvent was removed. To the residue was added an equal volume of ethyl acetate, and the mixture was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and then concentrated in vacuo to give the desired product (610mg, 48% yield) as a brown powder:¹H-NMR(300MHz，CD₃OD)δ3.73(s，3H)，6.53(s，1H)，7.16(s，1H)，7.64(dd，2H，J＝6.6，1.8Hz)，7.88(dd，2H，J＝6.6，1.8Hz)；ESI MS m/z 361.0[M+H]⁺。

(c) synthesis of 7-acetylamino-5- (methoxycarbonyl) amino-2- (4-bromophenyl) -1H-benzo [ d ] imidazole:

to 7-amino-5- (methoxycarbonyl) amino-2- (4-bromophenyl) -1H-benzo [ d]To a solution of imidazole (60mg, 0.17mmol) in dichloromethane (5mL) was added acetic anhydride (18mg, 0.17mmol), and the solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel using hexane/EtOAc (4/1) as eluent to give the desired product (55mg, 80%) as a pale yellow powder:¹H-NMR(300MHz，CD₃OD)δ2.24(s，3H)，3.74(s，3H)，7.65(m，3H)，7.67(bs，1H)，7.90(m，2H)；ESI MS m/z 403.0[M+H]⁺。

example 13

Procedure for determining the Minimum Inhibitory Concentration (MIC):use of previously reported [ R.A.Slayden and C.E.Barry, III. "The role of KasA and KasB in thebiosynthesis of meromycolic acids and isoniazid resistance inMycobacterium tuberculosis″，Tuberculosis(Edinb)82：149-60(2002)]MIC values were determined by the microplate dilution method.

The bacteria were cultured in liquid medium to an optical density of about 0.4 (at 600 nm). Bacterial cultures were then prepared for testing by dilution 1: 100 in liquid medium. A total of 50. mu.L of each culture was added to each well of a 96-well plate. 60 μ M of the analogue was prepared in 100% DMSO. The compound stock was diluted 1: 2 in liquid medium and then dispensed in plates as 2-fold serial dilutions to reach a concentration range of 200-0.2mg/mL in a total final volume of 100. mu.L. Plates were incubated at 37 ℃ and assessed by optical density and using a flip-plate reading method for the presence of bacterial growth or non-growth. MIC99 was determined as the lowest concentration of compound that inhibited bacterial growth. The reported MIC values represent measurements obtained in triplicate.

A list of active compounds is included in the appendix.

Examples 14 to 16

The following key intermediates were prepared and characterized in the same manner as in example 1 (a).

1-amino-2, 4-dinitro-5-morpholinobenzene:

the yield is 92%;¹HNMR(400MHz，CDCl₃)δ8.92(s，1H)6.12(s，1H)，3.86(t，4H，J＝6.2Hz)，3.12(t，4H，J＝6.2Hz)；ESI MS m/z 269.2[M+H]⁺。

1-amino-2, 4-dinitro-5-piperidinylbenzene:

the yield is 94%;¹HNMR(300MHz，CDCl₃)δ8.84(s，1H)6.43(bs，2H)，3.09(t，4H，J＝5Hz)，1.71(m，4H)；ESI MS m/z 267.2[M+H]⁺。

1-amino-2, 4-dinitro-5- (4-tert-butoxycarbonylpiperazino) benzene:

the yield is 94%;¹HNMR(400MHz，CDCl₃)δ8.91(s，1H)6.16(s，1H)，3.61(t，4H，J＝5Hz)，3.09(t，4H，J＝4.8Hz)，1.47(s，9H)；ESIMS m/z 368.3[M+H]⁺。

examples 17 to 29

The following key intermediates were prepared and characterized in the same manner as in example 1 (b).

1-cyclohexanecarbonylamino-5-diethylamino-2, 4-dinitrobenzene:

the yield is 88%;¹HNMR(300MHz，CDCl₃)δ8.76(s，1H)，8.65(s，1H)，3.36(q，4H，J＝10.8Hz)，2.38-1.30(m，11H)，1.26(t，6H，J＝7.2Hz)；ESI MS m/z 365.4[M+H]⁺。

1- (4-methylbenzoyl) amino-5-diethylamino-2, 4-dinitrobenzene:

the yield is 67%;¹HNMR(300MHz，CDCl₃)δ8.8(d，2H，J＝5.8Hz)，7.87(d，2H，J＝4Hz)，7.33(d，2H，J＝4Hz)，3.4(q，4H，J＝10.6Hz)，2.43(s，3H)，1.29(t，6H，J＝7.2Hz)；ESI MS m/z 373.3[M+H]⁺。

1- (4-methoxybenzoyl) amino-5-diethylamino-2, 4-dinitrobenzene:

the yield is 85%;¹HNMR(300MHz，CDCl₃)δ11.79(s，1H)，8.82(d，2H，J＝2.1Hz)，7.96(d，2H，J＝4.5Hz)，7.03(d，2H，J＝4.3Hz)，3.39(s，3H)，3.41(q，4H，J＝10.6Hz)，1.30(t，6H，J＝6.9Hz)；ESI MSm/z 389.3[M+H]⁺。

1- (4-tert-butylbenzoyl) amino-5-diethylamino-2, 4-dinitrobenzene:

the yield is 78%;¹HNMR(300MHz，CDCl₃)δ8.84(s，1H)，8.82(s，1H)，7.94(d，2H，J＝4.3Hz)，7.56(d，2H，J＝4.2Hz)，3.41(q，4H，J＝10.6Hz)，1.37(s，9H)，1.30(t，6H，J＝7.2Hz)；ESI MS m/z 415.4[M+H]⁺。

1- (4-fluorobenzoyl) amino-5-diethylamino-2, 4-dinitrobenzene:

the yield is 79%;¹HNMR(300MHz，CDCl₃)δ11.84(s，1H)，8.81(s，1H)，8.8(s，1H)，8.02(d，2H，J＝7.2Hz)，7.22(d，2H，J＝5.2Hz)，3.41(q，4H，J＝10.6Hz)，1.30(t，6H，J＝7.2Hz)；ESI MS m/z 377.3[M+H]⁺。

1-benzoylamino-5-diethylamino-2, 4-dinitrobenzene:

the yield is 80%;¹HNMR(300MHz，CDCl₃)δ11.87(s，1H)，8.84(s，1H)，8.82(s，1H)，8.0(d，2H，J＝4.8Hz)，7.63-7.55(m，3H)，3.41(q，4H，J＝10.6Hz)，1.31(t，6H，J＝7.2Hz)；ESI MS m/z 359.3[M+H]⁺。

1-cyclohexanecarbonylamino-5-morpholino-2, 4-dinitrobenzene:

the yield is 90%;¹HNMR(400MHz，CDCl₃)δ10.92(s，1H)，8.87(s，1H)，8.64(s，1H)，3.83(t，4H，J＝4.8Hz)，3.28(t，4H，J＝4.6Hz)，2.38(m，1H)，2.03-1.26(m，11H)；ESI MS m/z 379.3[M+H]⁺。

1- (4-methylbenzoyl-5-morpholino-2, 4-dinitrobenzene:

the yield is 87%;¹HNMR(400MHz，CDCl₃)δ11.80(s，1H)，8.95(s，1H)，8.83(s，1H)，7.88(d，2H，J＝4.2Hz)，7.36(d，2H，J＝4Hz)，3.88(t，4H，J＝4.6Hz)，3.34(t，4H，J＝4.6Hz)，2.46(s，3H)；ESI MS m/z387.3[M+H]⁺。

1- (4-tert-butylbenzoyl) amino-5-morpholino-2, 4-dinitrobenzene:

the yield is 75%;¹HNMR(400MHz，CDCl₃)δ11.81(s，1H)，8.95(s，1H)，8.84(s，1H)，7.92(d，2H，J＝4.2Hz)，7.57(d，2H，J＝4.2Hz)，3.88(t，4H，J＝4.6Hz)，3.34(t，4H，J＝4.6Hz)，1.37(s，9H)；ESI MS m/z429.4[M+H]⁺。

1-cyclohexanecarbonylamino-2, 4-dinitro-5- (4-tert-butoxycarbonylpiperazin-1-yl) benzene:

the yield is 70%;¹HNMR(400MHz，CDCl₃)δ10.92(s，1H)，8.90(s，1H)，8.67(s，1H)，3.62(t，4H，J＝5.2Hz)，3.28(t，4H，J＝5.2Hz)，2.38(m，1H)，2.03-1.26(m，11H)；ESI MS m/z 478.5[M+H]⁺。

1-cyclohexanecarbonylamino-2, 4-dinitro-5- (piperidin-1-yl) benzene:

the yield is 80%;¹HNMR(300MHz，CDCl₃)δ10.95(s，1H)，8.85(s，1H)，8.63(s，1H)，3.27(t，4H，J＝4.9Hz)，2.38(m，1H)，2.03-1.26(m，16H)；ESI MS m/z 377.4[M+H]⁺。

1- (4-methoxybenzoyl) amino-2, 4-dinitro-5- (piperidin-1-yl) benzene:

the yield is 85%;¹HNMR(300MHz，CDCl₃)δ11.69(s，1H)，8.90(s，1H)，8.79(s，1H)，7.95(d，2H，J＝4.5Hz)，7.03(d，2H，J＝4.3Hz)，3.90(s，3H)，3.32(t，4H，J＝4.95Hz)，1.75(m，6H)；ESI MS m/z 401.3[M+H]⁺。

1-benzoylamino-2, 4-dinitro-5- (piperidin-1-yl) benzene:

the yield is 83%;¹HNMR(300MHz，CDCl₃)δ11.87(s，1H)，8.91(s，1H)，8.80(s，1H)，7.98(d，2H，J＝4.8Hz)，7.66-7.55(m，3H)，3.33(t，4H，J＝4.9Hz)，1.76(m，6H)；ESI MS m/z 371.3[M+H]⁺。

examples 30 to 34

The following key intermediates were prepared and characterized in the same manner as in example 1 (c).

5-amino-2-cyclohexyl-6-diethylaminobenzo [ d ] imidazole:

the yield is 55%;¹HNMR(300MHz，CDCl₃)δ7.31(s，1H)，6.9(s，1H)，2.92(m，4H，J＝10.8Hz)，2.04(m，2H)，1.68(m，5H)，1.26(m，4H)，0.95(t，6H，J＝6.9Hz)；ESI MS m/z 287.4[M+H]⁺。

5-amino-6-diethylamino-2- (4-methylphenyl) -1H-benzo [ d ] imidazole:

the yield is 46%;¹HNMR(400MHz，CDCl₃)δ7.95(d，J＝4.2Hz，2H)，7.21(s，1H)，7.12(d，2H，J＝4Hz)，6.77(s，1H)，2.84(q，4H，J＝10.6Hz)，2.3(s，3H)，0.90(t，6H，J＝7Hz)；ESI MS m/z 295.3[M+H]⁺。

5-amino-6-diethylamino-2- (2-methoxyphenyl) -1H-benzo [ d ] imidazole:

the yield is 52%;¹HNMR(400MHz，CDCl₃)δ8.48(dd，1H)，7.37-7.29(m，2H)，7.48(t，1H，J＝8Hz)，6.97(d，1H，J＝4.2Hz)，6.88(s，1H)，3.96(s，3H)，2.96(q，4H，J＝10.6Hz)，0.97(t，6H，J＝7Hz)；ESI MSm/z 311.3[M+H]⁺。

5-amino-6-diethylamino-2- (4-tert-butylphenyl) -1H-benzo [ d ] imidazole:

the yield is 50%;¹HNMR(400MHz，CDCl₃)δ8.01(d，2H，J＝2.5Hz)，7.35(d，2H，J＝2.5Hz)，7.29(s，1H)，6.78(s，1H)，2.86(q，4H，J＝10.6Hz)，1.27(s，9H)，0.91(t，6H，J＝7Hz)；ESI MS m/z 337.4[M+H]⁺。

5-amino-2-cyclohexyl-6- (piperidin-1-yl) -1H-benzo [ d ] imidazole:

the yield is 66%;¹HNMR(300MHz，CDCl₃)δ7.23(s，1H)，6.81(s，1H)，2.81(t，4H，J＝4.9Hz)，2.04(m，1H)，1.78-1.23(m，16H)；ESIMS m/z 299.4[M+H]⁺。

examples 35 to 48

The following key intermediates were prepared and characterized in the same manner as in examples 9-11.

2-cyclohexyl-6-diethylamino-5- (4-methoxybenzoyl) amino-1H- [ d ] benzimidazole:

the yield is 78%;¹HNMR(300MHz，CDCl₃)δ10.31(s，1H)，8.94(s，1H)，7.95(d，2H，J＝4.35Hz)，7.57(s，1H)，7.05(d，2H，J＝4.35Hz)，3.9(s，3H)，3.0(m，4H)，2.1(s，1H)，1.98(m，2H)，1.58(m，5H)，1.26(m，3H)，0.97(t，6H，J＝7.2Hz)；ESI MS m/z 421.5[M+H]⁺。

5-benzoylamino-2-cyclohexyl-6-diethylamino-1H-benzo [ d ] imidazole:

the yield is 74%;¹HNMR(300MHz，CDCl₃)δ10.3(s，1H)，8.96(s，1H)，7.98(m，2H)，7.57(m，4H)，3.03(m，4H，J＝10.65Hz)，1.98(m，2H)，1.65(m，5H)，1.16(m，4H)，.97(m，6H，J＝7.2Hz)；ESI MS m/z391.5[M+H]⁺。

2-cyclohexyl-6-diethylamino-5- (4-methylbenzoyl) amino-1H-benzo [ d ] imidazole:

the yield is 65%;¹HNMR(300MHz，CDCl₃)δ10.31(s，1H)，8.91(s，1H)，7.87(d，2H，J＝4.5Hz)，7.59(s，1H)，7.34(d，2H，J＝4.2Hz)，3.02(m，4H，J＝10.8Hz)，2.45(s，3H)，2.01(m，2H)，1.69(m，5H)，1.2(m，4H)，0.97(m，6H，J＝7Hz)ESI MS m/z 405.5[M+H]⁺。

5- (4-chlorobenzoyl) amino-2-cyclohexyl-6-diethylamino-1H-benzo [ d ] imidazole:

the yield is 64%;¹HNMR(300MHz，CDCl₃)δ10.26(s，1H)，8.77(s，1H)，7.88(d，2H，J＝3.45Hz)，7.60(s，1H)，7.50(d，2H，J＝4.2Hz)，3.02(m，4H，J＝10.65Hz)，2.11(m，2H)，1.84-1.25(m，9H)，0.97(t，6H，J＝7.2Hz)；ESI MS m/z 425[M+H]⁺。

5-benzyloxycarbonylamino-2-cyclohexyl-6-diethylamino-1H-benzo [ d ] imidazole:

the yield is 61%;¹HNMR(300MHz，CDCl₃)δ8.61(s，1H)，8.25(s，1H)，7.45-7.35(m，5H)，5.22(s，2H)，2.91(m，4H，J＝10.65Hz)，2.11(m，2H)，1.84-1.62(m，5H)，1.38(m，4H)，0.90(t，6H，J＝7.2Hz)；ESI MS m/z 421.5[M+H]⁺。

2-cyclohexyl-6-diethylamino-5-propoxycarbonylamino-1H-benzo [ d ] imidazole:

the yield is 63%;¹HNMR(300MHz，CDCl₃)δ8.51(s，1H)，8.23(s，1H)，7.47(s，1H)，4.14(t，2H，J＝6.75Hz)，2.92(m，4H，J＝10.8Hz)，2.10(m，2H)，1.87-1.60(m，7H)，1.40-1.25(m，4H)，0.98(t，3H，J＝6.15Hz)，0.93(t，6H，J＝7.05Hz)ESI MS m/z 373.5[M+H]⁺。

5-butoxycarbonylamino-2-cyclohexyl-6-diethylamino-1H-benzo [ d ] imidazole:

the yield is 51%;¹HNMR(300MHz，CDCl₃)δ8.50(s，1H)，8.22(s，1H)，7.48(s，1H)，4.18(t，J＝6.75Hz，2H)，2.92(m，J＝10.5Hz，4H)，2.10(m，2H)，1.87-1.60(m，7H)，1.40-1.39(m，6H)，0.96(t，J＝7.5Hz，3H)，0.92(t，J＝7.2Hz，6H)；ESI MS m/z 387.5[M+H]⁺。

5- (but-3-enyloxycarbonyl) amino-2-cyclohexyl-6-diethylamino-1H-benzo [ d ] imidazole:

the yield is 51%;¹HNMR(300MHz，CDCl₃)δ8.51(s，1H)，8.23(s，1H)，7.48(s，1H)，5.84(m，1H)，5.11(m，2H)，4.23(t，2H，J＝6.9Hz)，2.92(m，4H，J＝10.5Hz)，2.47(t，2H，J＝4.65Hz)，2.10(m，2H)，1.82-1.60(m，5H)，1.40-1.32(m，4H)，0.91(t，6H，J＝7.05Hz)；ESIMS m/z 385.2[M+H]⁺。

5- (4-tert-butylbenzoylamino) -2-cyclohexyl-6-diethylamino-1H-benzo [ d ] imidazole:

the yield is 48%;¹HNMR(400MHz，CDCl₃)δ10.41(s，1H)，9.02(s，1H)，7.93(d，2H，J＝4.2Hz)，7.57(d，3H，J＝4.2Hz)，3.02(q，4H，J＝10.6Hz)，2.68(m，1H)，1.92(m，2H)，1.67-1.53(m，5H)，1.38(s，9H)，1.24(s，2H)，1.26(m，3H)，0.97(t，6H，J＝7Hz)；ESI MS m/z 2447.6[M+H]⁺。

2-cyclohexyl-5-cyclopentanecarbonylamino-6-diethylamino-1H-benzo [ d ] imidazole:

the yield is 74%;¹HNMR(400MHz，CDCl₃)δ9.41(s，1H)，8.65(s，1H)，7.50(s，1H)，2.93(q，4H，J＝10.6Hz)，2.81(m，2H)，2.07-1.67(m，15H)，1.31(m，3H)，0.92(t，6H，J＝7Hz)；ESI MS m/z 383.5[M+H]⁺。

2-cyclohexyl-6-diethylamino-5- (3-phenylpropionyl) amino-1H-benzo [ d ] imidazole:

the yield is 55%;¹HNMR(400MHz，CDCl₃)δ9.33(s，1H)，8.69(s，1H)，7.49(s，1H)，7.59(s，1H)，7.27-7.18(m，5H)，3.11(t，2H，J＝7.6Hz)，2.86(q，3H，J＝10.6Hz)，2.76(t，2H，J＝7.6Hz)，2.08(m，2H)，1.8-1.6(m，4H)，1.35-1.23(m，5H)，0.83(t，6H，J＝7Hz)；ESI MSm/z 419.5[M+H]⁺。

2-cyclohexyl-6-diethylamino-5-pentanoylamino-1H-benzo [ d ] imidazole:

the yield is 60%;¹HNMR(3\400MHz，CDCl₃)δ9.45(s，1H)，8.73(s，1H)，7.51(s，1H)，2.94(q，4H，J＝10.9Hz)，2.84(m，1H)，2.49(t，2H，J＝7.6Hz)，2.10(m，2H)，1.84-1.65(m，7H)，1.48-1.25(m，5H)，0.96(t，3H，J＝7.4Hz)，0.92(t，6H，J＝7.2Hz)；ESI MS m/z 371.5[M+H]⁺。

5-butyrylamino-2-cyclohexyl-6-diethylamino-1H-benzo [ d ] imidazole:

the yield is 75%;¹HNMR(400MHz，CDCl₃)δ9.45(s，1H)，8.73(s，1H)，7.52(s，1H)，2.94(q，4H，J＝10.8Hz)，2.84(m，1H)，2.45(t，2H，J＝7.6Hz)，2.10(m，2H)，1.84-1.65(m，7H)，1.48-1.25(m，5H)，1.06(t，3H，J＝7.4Hz)，0.92(t，6H，J＝7.2Hz)；ESI MS m/z 357.5[M+H]⁺。

2-cyclohexyl-6-diethylamino-5- (prop-2-enyloxycarbonyl) amino-1H-benzo [ d ] imidazole:

the yield is 51%;¹HNMR(300MHz，CDCl₃)δ8.51(s，1H)，8.23(s，1H)，7.48(s，1H)，5.84(m，1H)，5.11(m，2H)，4.23(t，2H，J＝6.9Hz)，2.92(q，4H，J＝10.5Hz)，2.47(t，2H，J＝4.65Hz)，2.10(m，2H)，1.82-1.6(m，5H)，1.40-1.32(m，4H)，0.91(t，6H，J＝7.05Hz)；ESIMS m/z 371.4[M+H]⁺。

examples 49 to 54

The following key intermediates 49 to 54 were prepared and characterized in the same manner as 7-amino-5- (methoxycarbonyl) amino-2- (4-bromophenyl) -1H-benzo [ d ] imidazole in example 12 (b).

7-amino-5-ethoxycarbonylamino-2- (furan-2-yl) -1H-benzo [ d ] imidazole:

the yield is 55%;¹H-NMR(300MHz，CD₃OD)δ1.29(t，3H，J＝9Hz)，4.16(dd，2H，J＝14.1，7.2Hz)，6.51(s，1H)，6.61(m，1H)，7.05(m，1H)，7.13(s，1H)，7.67(m，1H)；ESI MS m/z 287.0[M+H]⁺。

7-amino-5-methoxycarbonylamino-2- (4-methoxycarbonylphenyl) -1H-benzo [ d ] imidazole:

the yield is 57%;¹H-NMR(300MHz，CD₃OD)δ3.73(s，3H)，3.93(s，3H)，6.52(s，1H)，7.19(s，1H)，8.12(s，4H)；ESI MS m/z 341.0[M+H]⁺。

7-amino-5-ethoxycarbonylamino-2-phenyl-1H-benzo [ d ] imidazole:

the yield is 54%;¹H-NMR(300MHz，CD₃OD)δ1.30(t，3H，J＝6.9Hz)，4.16(dd，2H，J＝14.4，7.2Hz)，6.51(s，1H)，7.18(s，1H)，7.44(m，3H)，8.01(m，2H)；ESI MS m/z 297.1[M+H]⁺。

7-amino-2- (2, 4-dimethoxyphenyl) -5-methoxycarbonylamino-1H-benzo [ d ] imidazole:

the yield is 53 percent;¹H-NMR(300MHz，CD₃OD)δ3.72(s，3H)，3.85(s，3H)，3.99(s，3H)，6.51(s，1H)，6.66(m，2H)，7.17(bs，1H)，8.06(d，1H，J＝9.3Hz)；ESI MS m/z 343.0[M+H]⁺。

7-amino-2- (3-fluorophenyl) -5-methoxycarbonylamino-1H-benzo [ d ] imidazole:

the yield is 50%;¹H-NMR(300MHz，CD₃OD)δ3.72(s，3H)，6.51(s，1H)，7.17(m，2H)，7.50(m，1H)，7.78(m，2H)；ESI MS m/z 301.1[M+H]⁺。

7-amino-5-ethoxycarbonylamino-2- (phenylamino) -1H-benzo [ d ] imidazole:

the yield is 52%;¹H-NMR(300MHz，CD₃OD)δ1.30(t，3H，J＝7.2Hz)，4.14(dd，2H，J＝14.1，7.2Hz)，6.48(s，1H)，6.95(m，1H)，7.27(t，2H)，7.43(m，2H)；ESI MS m/z 311.9[M+H]⁺。

examples 55 to 56

The following key intermediates 55 and 56 were prepared and characterized in the same manner as 7-acetylamino-5- (methoxycarbonyl) amino-2- (4-bromophenyl) -1H-benzo [ d ] imidazole in example 12 (c).

7-acetylamino-5-ethoxycarbonylamino-2-phenyl-1H-benzo [ d ] imidazole:

the yield is 85%;¹H-NMR(300MHz，CD₃OD)δ1.30(t，3H，J＝7.2Hz)，2.32(s，3H)，4.24(dd，2H，J＝14.4，7.2Hz)，7.58(m，3H)，7.77(bs，1H)，7.85(bs，1H)，8.10(m，2H)；ESI MS m/z 339.1[M+H]⁺。

7-acetylamino-2- (3-fluorophenyl) -5-methoxycarbonylamino-1H-benzo [ d ] imidazole:

the yield is 83%;¹H-NMR(300MHz，CD₃OD)δ2.25(s，3H)，3.74(s，3H)，6.51(s，1H)，7.22(m，1H)，7.52(m，1H)，7.78(m，5H)；ESI MSm/z 343.1[M+H]⁺。

appendix

Active benzimidazole derivatives

Claims (22)

1. A molecule having the structural formula I

Wherein:

R¹represents NH₂、NHR⁶、NR⁹R¹⁰、NR⁶CONR⁹R¹⁰、NR⁶CSNR⁹R¹⁰、OH、OR⁶、SH、SR⁶、CHO、COOR⁶、COR⁶、CH₂OH、CR⁷R⁸OH、CH₂OR⁶、CR⁷R⁸OR⁶、CH₂NH₂、CR⁷R⁸NH₂、CR⁷R⁸NR⁹R¹⁰Alkyl, cycloalkyl, aryl, or halo;

R²and R⁴Independently represents H, alkyl, cycloalkyl, or aryl;

R³represents an alkyl group, a cycloalkyl group, or an aryl group;

R⁵representation H, R⁶、OR⁶、SR⁶、NH₂、NHR⁶Or NR⁹R¹⁰；

X represents O, S, NH, or NR⁶；

R⁶、R⁷、R⁸、R⁹And R¹⁰Independently represents an alkyl group, a cycloalkyl group, an aryl group, or a halogen group;

R²and R³、R⁴And R⁵And R⁹And R¹⁰Independently may be combined to represent a heterocycloalkyl or a heterocycloaryl;

R⁷and R⁸May be combined to represent cycloalkyl;

alkyl groups are branched or unbranched, saturated or unsaturated, and have 1 to 18 carbon atoms in their longest chain;

cycloalkyl groups are carbocyclic or heterocyclic, fused or unfused, non-aromatic ring systems having a total of 5-16 ring members including substituted rings;

the aryl group is a carbocyclic or heterocyclic aryl group;

carbocyclic aryl groups are fused or unfused ring systems having a total of 6 to 16 ring members including substituted rings;

a heterocyclic aryl group is a fused or unfused cyclic system having a total of 5-16 ring members including a substituted ring;

halo substituents are fluoro, chloro, or bromo;

each alkyl, cycloalkyl, and aryl group can independently be unsubstituted or substituted at any position with one or more substituents;

the alkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Cycloalkyl, or aryl;

cycloalkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, or aryl;

aryl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, aryl, nitro, or carboxyl; and

heterocycloalkyl and heterocycloaryl have at least one heteroatom selected from oxygen, nitrogen and sulfur; and

a pharmaceutically acceptable salt thereof.

2. The molecule of claim 1, wherein:

R¹represents cycloalkyl or aryl;

R²and R³Independently represent a C1-C4 alkyl group.

3. The molecule of claim 2, wherein:

R⁴is H; and

x is O.

4. The molecule of claim 2, wherein:

R¹to represent

R²And R³Represents an ethyl group;

R⁴represents H;

R⁵to represent

And

x represents O.

5. The molecule of claim 2, wherein:

R¹to represent

R²And R³Represents an ethyl group;

R⁴represents H;

R⁵to represent

And

x represents O.

6. The molecule of claim 5, wherein:

R¹to represent

R²And R³Represents an ethyl group;

R⁴represents H;

R⁵to represent

And

x represents O.

7. The molecule of claim 5, wherein:

R¹to represent

R²And R³Represents an ethyl group;

R⁴represents H;

R⁵to represent

And

x represents O.

8. The molecule of claim 5, wherein:

R¹to represent

R²And R³Represents an ethyl group;

R⁴represents H;

R⁵to represent

And

x represents O.

9. The molecule of claim 5, wherein:

R¹to represent

R²And R³Represents an ethyl group;

R⁴represents H;

R⁵to represent

And

x represents O.

10. The molecule of claim 5, wherein:

R¹to represent

R²And R³Represents an ethyl group;

R⁴represents H;

R⁵to represent

And

x represents O.

11. The molecule of claim 5, wherein:

R¹to represent

R²And R³Represents an ethyl group;

R⁴represents H;

R⁵to represent

And

x represents O.

12. The molecule of claim 5, wherein:

R¹to represent

R²And R³Represents an ethyl group;

R⁴represents H;

R⁵to represent

And

x represents O.

13. The molecule of claim 1, wherein:

when R is²When represents H, R³Is not methyl.

14. A method for treating a patient infected with Mycobacterium tuberculosis, the method comprising

Comprising administering to said patient a compound of structural formula I:

wherein:

R¹represents NH₂、NHR⁶、NR⁹R¹⁰、NR⁶CONR⁹R¹⁰、NR⁶CSNR⁹R¹⁰、OH、OR⁶、SH、SR⁶、CHO、COOR⁶、COR⁶、CH₂OH、CR⁷R⁸OH、CH₂OR⁶、CR⁷R⁸OR⁶、CH₂NH₂、CR⁷R⁸NH₂、CR⁷R⁸NR⁹R¹⁰Alkyl, cycloalkyl, aryl, or halo;

R²and R⁴Independently represents H, alkyl, cycloalkyl, or aryl;

R³represents an alkyl group, a cycloalkyl group, or an aryl group;

R⁵representation H, R⁶、OR⁶、SR⁶、NH²、NHR⁶Or NR⁹R¹⁰；

X represents O, S, NH, or NR⁶；

R⁶、R⁷、R⁸、R⁹And R¹⁰Independently represents an alkyl group, a cycloalkyl group, an aryl group, or a halogen group;

R²and R³、R⁴And R⁵And R⁹And R¹⁰Independently may be combined to represent a heterocycloalkyl or a heterocycloaryl;

R⁷and R⁸May be combined to represent cycloalkyl;

alkyl groups are branched or unbranched, saturated or unsaturated, and have 1 to 18 carbon atoms in their longest chain;

cycloalkyl groups are carbocyclic or heterocyclic, fused or unfused, non-aromatic ring systems having a total of 5-16 ring members including substituted rings;

the aryl group is a carbocyclic or heterocyclic aryl group;

carbocyclic aryl groups are fused or unfused ring systems having a total of 6 to 16 ring members including substituted rings;

the heterocyclic aryl group is a fused or unfused cyclic system having a total of 5 to 16 ring members including a substituted ring;

halo substituents are fluoro, chloro, or bromo;

each alkyl, cycloalkyl, and aryl independently can be unsubstituted or substituted at any position with one or more substituents;

the alkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Cycloalkyl, or aryl;

cycloalkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, or aryl;

aryl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, aryl, nitro, or carboxyl; and

heterocycloalkyl and heterocycloaryl have at least one heteroatom selected from oxygen, nitrogen and sulfur; and

a pharmaceutically acceptable salt thereof.

15. A method for treating a patient infected with Francisella tularensis comprising administering to the patient a compound of formula I

Wherein:

R¹represents NH₂、NHR⁶、NR⁹R¹⁰、NR⁶CONR⁹R¹⁰、NR⁶CSNR⁹R¹⁰、OH、OR⁶、SH、SR⁶、CHO、COOR⁶、COR⁶、CH₂OH、CR⁷R⁸OH、CH₂OR⁶、CR⁷R⁸OR⁶、CH₂NH₂、CR⁷R⁸NH₂、CR⁷R⁸NR⁹R¹⁰Alkyl, cycloalkyl, aryl, or halo;

R²and R⁴Independently represents H, alkyl, cycloalkyl, or aryl;

R³represents an alkyl group, a cycloalkyl group, or an aryl group;

R⁵representation H, R⁶、OR⁶、SR⁶、NH₂、NHR⁶Or NR⁹R¹⁰；

X represents O, S, NH, or NR⁶；

R⁶、R⁷、R⁸、R⁹And R¹⁰Independently represents an alkyl group, a cycloalkyl group, an aryl group, or a halogen group;

R²and R³、R⁴And R⁵And R⁹And R¹⁰Independently may be combined to represent a heterocycloalkyl or a heterocycloaryl;

R⁷and R⁸May be combined to represent cycloalkyl;

alkyl groups are branched or unbranched, saturated or unsaturated, and have 1 to 18 carbon atoms in their longest chain;

cycloalkyl groups are carbocyclic or heterocyclic, fused or unfused, non-aromatic ring systems having a total of 5-16 ring members including substituted rings;

the aryl group is a carbocyclic or heterocyclic aryl group;

carbocyclic aryl groups are fused or unfused ring systems having a total of 6 to 16 ring members including substituted rings;

the heterocyclic aryl group is a fused or unfused cyclic system having a total of 5 to 16 ring members including a substituted ring;

halo substituents are fluoro, chloro, or bromo;

each alkyl, cycloalkyl, and aryl group can independently be unsubstituted or substituted at any position with one or more substituents;

the alkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Cycloalkyl, or aryl;

cycloalkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, or aryl;

aryl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, aryl, nitro, or carboxyl; and

heterocycloalkyl and heterocycloaryl have at least one heteroatom selected from oxygen, nitrogen and sulfur; and

a pharmaceutically acceptable salt thereof.

16. The molecule of claim 1, wherein:

R⁶、R⁷、R⁸、R⁹and R¹⁰Independently represents an alkyl group, a cycloalkyl group, or an aryl group.

17. The molecule of claim 1, wherein:

R⁶、R⁷、R⁸、R⁹and R¹⁰Independently represent an alkyl group or an aryl group.

18. A molecule according to claim 14, wherein:

R⁶、R⁷、R⁸、R⁹and R¹⁰Independently represents an alkyl group, a cycloalkyl group, or an aryl group.

19. A molecule according to claim 15, wherein:

R⁶、R⁷、R⁸、R⁹and R¹⁰Independently represents an alkyl group, a cycloalkyl group, or an aryl group.

20. A molecule of formula I

Wherein:

R¹represents NH₂、NHR⁶、NR⁹R¹⁰、NR⁶CONR⁹R¹⁰、NR⁶CSNR⁹R¹⁰、OH、OR⁶、SH、SR⁶、CHO、COOR⁶、COR⁶、CH₂OH、CR⁷R⁸OH、CH₂OR⁶、CR⁷R⁸OR⁶、CH₂NH₂、CR⁷R⁸NH₂、CR⁷R⁸NR⁹R¹⁰Alkyl, cycloalkyl, aryl, or halo;

R²and R⁴Independently represents H, alkyl, cycloalkyl, or aryl;

R³represents alkyl, cycloalkyl, aryl, or COR⁶；

R⁵Representation H, R⁶、OR⁶、SR⁶、NH₂、NHR⁶Or NR⁹R¹⁰；

X represents O, S, NH, or NR⁶；

R⁶、R⁷、R⁸、R⁹And R¹⁰Independent earth surfaceRepresents an alkyl group, a cycloalkyl group, or an aryl group;

R²and R³、R⁴And R⁵And R⁹And R¹⁰Independently may be combined to represent a heterocycloalkyl or a heterocycloaryl;

R⁷and R⁸May be combined to represent cycloalkyl;

alkyl groups are branched or unbranched, saturated or unsaturated, and have 1 to 18 carbon atoms in their longest chain;

cycloalkyl groups are carbocyclic or heterocyclic, fused or unfused, non-aromatic ring systems having a total of 5-16 ring members including substituted rings;

the aryl group is a carbocyclic or heterocyclic aryl group;

carbocyclic aryl groups are fused or unfused ring systems having a total of 6 to 16 ring members including substituted rings;

the heterocyclic aryl group is a fused or unfused cyclic system having a total of 5 to 16 ring members including a substituted ring;

halo substituents are fluoro, chloro, or bromo;

each alkyl, cycloalkyl, and aryl group can independently be unsubstituted or substituted at any position with one or more substituents;

the alkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Cycloalkyl, or aryl;

cycloalkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, or aryl;

aryl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, aryl, nitro, or carboxyl; and

heterocycloalkyl and heterocycloaryl have at least one heteroatom selected from oxygen, nitrogen and sulfur; and

a pharmaceutically acceptable salt thereof.

21. A method for treating a patient infected with Mycobacterium tuberculosis, the method comprising administering to the patient a compound of formula I

Wherein:

R¹represents NH₂、NHR⁶、NR⁹R¹⁰、NR⁶CONR⁹R¹⁰、NR⁶CSNR⁹R¹⁰、OH、OR⁶、SH、SR⁶、CHO、COOR⁶、COR⁶、CH₂OH、CR⁷R⁸OH、CH₂OR⁶、CR⁷R⁸OR⁶、CH₂NH₂、CR⁷R⁸NH₂、CR⁷R⁸NR⁹R¹⁰Alkyl, cycloalkyl, aryl, or halo;

R²and R⁴Independently represents H, alkyl, cycloalkyl, or aryl;

R³represents alkyl, cycloalkyl, aryl, or COR⁶；

R⁵Representation H, R⁶、OR⁶、SR⁶、NH₂、NHR⁶Or NR⁹R¹⁰；

X represents O, S, NH, or NR⁶；

R⁶、R⁷、R⁸、R⁹And R¹⁰Independently represent an alkyl group, a cycloalkyl group, or an aryl group;

R²and R³、R⁴And R⁵And R⁹And R¹⁰Independently may be joined to represent heterocycloalkyl or heterocycloaryl;

R⁷and R⁸May be combined to represent cycloalkyl;

alkyl groups are branched or unbranched, saturated or unsaturated, and have 1 to 18 carbon atoms in their longest chain;

cycloalkyl groups are carbocyclic or heterocyclic, fused or unfused, non-aromatic ring systems having a total of 5-16 ring members including substituted rings;

the aryl group is a carbocyclic or heterocyclic aryl group;

carbocyclic aryl groups are fused or unfused ring systems having a total of 6 to 16 ring members including substituted rings;

the heterocyclic aryl group is a fused or unfused cyclic system having a total of 5 to 16 ring members including a substituted ring;

halo substituents are fluoro, chloro, or bromo;

each alkyl, cycloalkyl, and aryl independently can be unsubstituted or substituted at any position with one or more substituents;

the alkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Cycloalkyl, or aryl;

cycloalkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, or aryl;

aryl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, aryl, nitro, or carboxyl; and

heterocycloalkyl and heterocycloaryl have at least one heteroatom selected from oxygen, nitrogen and sulfur; and

a pharmaceutically acceptable salt thereof.

22. A method for treating a patient infected with Francisella tularensis comprising administering to the patient a compound of formula I

Wherein:

R¹represents NH₂、NHR⁶、NR⁹R¹⁰、NR⁶CONR⁹R¹⁰、NR⁶CSNR⁹R¹⁰、OH、OR⁶、SH、SR⁶、CHO、COOR⁶、COR⁶、CH₂OH、CR⁷R⁸OH、CH₂OR⁶、CR⁷R⁸OR⁶、CH₂NH₂、CR⁷R⁸NH₂、CR⁷R⁸NR⁹R¹⁰Alkyl, cycloalkyl, aryl, or halo;

R²and R⁴Independently represents H, alkyl, cycloalkyl, or aryl;

R³represents alkyl, cycloalkyl, aryl, or COR⁶；

R⁵Representation H, R⁶、OR⁶、SR⁶、NH₂、NHR⁶Or NR⁹R¹⁰；

X represents O, S, NH, or NR⁶；

R⁶、R⁷、R⁸、R⁹And R¹⁰Independently represent an alkyl group, a cycloalkyl group, or an aryl group;

R²and R³、R⁴And R⁵And R⁹And R¹⁰Independently may be combined to represent a heterocycloalkyl or a heterocycloaryl;

R⁷and R⁸May be combined to represent cycloalkyl;

alkyl groups are branched or unbranched, saturated or unsaturated, and have 1 to 18 carbon atoms in their longest chain;

cycloalkyl groups are carbocyclic or heterocyclic, fused or unfused, non-aromatic ring systems having a total of 5-16 ring members including substituted rings;

the aryl group is a carbocyclic or heterocyclic aryl group;

carbocyclic aryl groups are fused or unfused ring systems having a total of 6 to 16 ring members including substituted rings;

the heterocyclic aryl group is a fused or unfused cyclic system having a total of 5 to 16 ring members including a substituted ring;

halo substituents are fluoro, chloro, or bromo;

each alkyl, cycloalkyl, and aryl group can independently be unsubstituted or substituted at any position with one or more substituents;

the alkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Cycloalkyl, or aryl;

cycloalkyl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, or aryl;

aryl substituents being halo, hydroxy, OR⁶、SR⁶、NH₂、NHR⁶、NR⁹R¹⁰Alkyl, cycloalkyl, aryl, nitro, or carboxyl; and

heterocycloalkyl and heterocycloaryl have at least one heteroatom selected from oxygen, nitrogen and sulfur; and

a pharmaceutically acceptable salt thereof.