DESC:Related Application
This application is related to and takes priority from the Indian application no. 201941010942 filed on 20th March 2019 and is incorporated herein in its entirety.

Field of Invention
The present invention is related to novel compounds of benzimidazole derivatives as anti-tubercular agents.

Background
Tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide, despite having an effective and economical quadruple drug therapy regimen, put in place 40 years ago (Raviglione, M. et al. Lancet 379, 1902-1913 (2012); World Health Organization. Global Tuberculosis Report (2012)). It is gratifying to see US Food and Drug Administration (FDA)'s recent accelerated approval of Janssen's Sirturo (bedaquiline) for multidrug-resistant tuberculosis (MDR-TB), putting an end to four-decade-long lull for a new TB drug with novel mechanism of action (Cohen, J. Science 339, 130-131 (2013)). However, the impact of Sirturo on disease landscape and patient's lives needs to be seen; in the context of associated safety risks and the burden of post marketing studies.
The nitro-benzothiazinones (BTZs) and related compounds are known to inhibit decaprenylphosphoryl-ß-D-ribose2'-epimerasel (DprE1) involved in the conversion of decaprenylphosphoryl-ß-D-ribose (DPR) to decaprenylphosphoryl-ß-D-arabinofuranose (DPA), a precursor of mycobacterial cell wall arabinan (Trefzer, et al J. Am. Chem. Soc. 132, 1366313665). This reaction is catalysed by a heteromeric enzyme decaprenyl-phospho-ribose 2'epimerase (DprE), which occurs via a sequential oxidation-reduction mechanism involving an intermediate (decaprenylphosphoryl-2-keto-ß-D-erythro-pentofuranose, DPX). This enzyme is composed of two proteins encoded by the dprE1 and dprE2 genes. DprE1 enzyme is the FAD containing oxidoreductase, while DprE2 is the NADH-dependent reductase (Mikusova, et al. J. Bacteriol. 187. 8020-8025 (2005); Makarov, V. et als Science 324, 801-804 (2009)).
The identification of BTZ043 as a covalent inhibitor of DprEl with potent antimycobacterial activity confirms the validity of this target for a novel TB therapy (Science 324, 801-804 (2009)). However, it remains to be understood whether non-nitro inhibitors of DprE1 will lead to efficacy in vivo. Additionally, it needs to be evaluated whether nanomolar cellular activity is adequate for in vivo efficacy. Greater understanding in relation to these aspects of DprE1 inhibition will significantly influence future TB drug discovery efforts directed at this target. Thus, a need exists in the art for additional compounds that target DprE1.
Brief Description of Drawings
Figure 1. Bactericidal activity and intracellular efficacy of compound 1 (Example 1)
Figure 2A. In vivo efficacy of compound 1 (Example 1) following multiple oral dose administration in Mtb infected male Balb/C mice at 10 and 30 mg/kg.
Figures 2 B and C provides efficacy of compound 1 (Example 1) in chronic TB infection model in BALB/c mice.

Description of the Invention
The invention provides, a compound of formula (I):

wherein
R1 is selected from a group consisting of hydrogen, fluorine, bromine, -OCH3, cyclopropyl and methyl;
R2 is hydrogen, methyl, alkyl or cycloalkyl;
R3 is hydrogen, methyl, alkyl or cycloalkyl;
R4 is hydrogen, methyl, alkyl or cycloalkyl;
X is N, N-R5 or C-R5;
R5 is selected from a group consisting of hydrogen, Methyl, -CHF2, haloalkyl and haloalkoxy;
Y is selected from C-H, COR6 , -C-N(CH3)2 or C=O;
R6 is selected from a group consisting of hydrogen, Methyl, -CHF2, -OCH2CF3, haloalkyl and haloalkoxy;
R7 is selected from a group consisting of hydrogen, fluorine, -CH3, -OH, -CHF2, -CF3, -CH(F)CH3, -CH2CF3, haloalkyl and haloalkoxy;
n is 1 or 2;
ora pharmaceutically acceptable salt thereof.

Unless specified otherwise, these terms have the following meanings. “Alkyl” means a straight or branched alkyl group composed of 1 to 6 carbons. “Cycloalky” means a monocyclic ring system composed of 3 to 7 carbons. “Halo” includes fluoro, chloro, bromo, and Iodo. “Haloalkyl” and “Haloalkoxy” include all halogenated isomers from monohalo or perhalo.
In one aspect, the invention provides, at least in part, a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluents
In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of tuberculosis or Mycobacterium infection.
In yet another aspect, the invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of tuberculosis or a Mycobacteriuminfection.
The invention also provides a method of treating tuberculosis or a Mycobacterium infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In some aspects, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of tuberculosis or a Mycobacterium infection.
In some aspects, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the inhibition of DprE1.
In some aspects, the invention provides a compound of formula (I) for use in the manufacture of a medicament for inhibition of DprE1.
In some aspects, the invention provides a method of inhibiting DprE1 comprising administering to a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In some aspects, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for inhibiting DprE1.
The compounds of formula I are exemplified in Table 1.
Table 1: Examples
Example No. Structure Example No. Structure Example No. Structure Example No. Structure
1
4
7 10

2 5
8 11
3 6 9 12

The IUPAC names of the compounds 1-12 of the invention are provided below:
Example No. IUPAC Name
1 N-(2-fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-benzo[d]imidazole-4-carboxamide
2 N-(2-fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-benzo[d]imidazole-4-carboxamide
3 1-((6-(difluoromethoxy)-5-methylpyrimidin-4-yl)methyl)-N-(2-fluoroethyl)-6-methyl-1H-benzo[d]imidazole-4-carboxamide
4 1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-(2-fluoroethyl)-1H-benzo[d]imidazole-4-carboxamide
5 N-(2,2-difluoroethyl)-1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-1H-benzo[d]imidazole-4-carboxamide
6 N-(2-fluoroethyl)-6-methoxy-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-benzo[d]imidazole-4-carboxamide
7 N-(2,2-difluoroethyl)-1-((6-(difluoromethoxy)-5-methylpyrimidin-4-yl)methyl)-6-methoxy-1H-benzo[d]imidazole-4-carboxamide
8 1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-(2-fluoroethyl)-6-methoxy-1H-benzo[d]imidazole-4-carboxamide
9 N-(2,2-difluoroethyl)-1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-6-methoxy-1H-benzo[d]imidazole-4-carboxamide
10 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-N-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-4-carboxamide
11 6-methoxy-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-N-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-4-carboxamide
12 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-N-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-4-carboxamide

Methods of Use
In some aspects, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of tuberculosis or a Mycobacteriuminfection.
In some aspects, the invention provides a compound of formula (I) in the manufacture of a medicament for use in the treatment of tuberculosis or a Mycobacteriuminfection.
In some aspects, the invention provides a method of treating tuberculosis or a Mycobacteriuminfection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The language “therapeutically effective amount” includes an amount of the co-crystals described herein that will elicit the biological or medical response of a subject, for example, the reduction or inhibition of enzyme or protein activity related to a Mycobacteriuminfection or tuberculosis, amelioration of symptoms of a Mycobacteriuminfection or tuberculosis, or the slowing or delaying of progression of a Mycobacteriuminfection or tuberculosis. In some embodiments, the language “therapeutically effective amount” includes the amount of a co-crystal described herein, that when administered to a subject, is effective to at least partially alleviate, inhibit, and/or ameliorate a Mycobacteriuminfection or tuberculosis, and/or reduce or inhibit the bacterial growth, replication or bacterial load of Mycobacteriumin a subject.
The term “subject” includes warm blooded mammals, for example, primates, cows, sheep, dogs, cats, rabbits, rats, voles, seals and mice. In some embodiments, the subject is a primate, for example, a human. In some embodiments, the subject is suffering from a Mycobacteriuminfection or tuberculosis. In some embodiments, the subject is in need of treatment (e.g., the subject would benefit biologically or medically from treatment).
The language “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.
The language “treat,” “treating” and “treatment” includes the reduction or inhibition of enzyme or protein activity related to a Mycobacteriuminfection or tuberculosis in a subject, amelioration of one or more symptoms of a Mycobacterium infection or tuberculosis in a subject, or the slowing or delaying of progression of a Mycobacteriuminfection or tuberculosis in a subject. The language “treat,” “treating” and “treatment” also includes the reduction or inhibition of the bacterial growth, replication or a reduction or inhibition of the bacterial load of Mycobacteriumin a subject.
The language “Mycobacterium infection” includes infections caused by one or more of the species of the Mycobacterium tuberculosis complex, e.g., Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium microti or Mycobacterium pinnipedii. In some embodiments, the Mycobacterium infection is a Mycobacterium tuberculosis infection.
The term “tuberculosis” refers to the disease caused by an infection in a subject of one or more species of the Mycobacteriumtuberculosis complex. The term “tuberculosis” includes latent tuberculosis (LTBI), non-drug resistant tuberculosis, multiple drug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XRD-TB). The language “latent tuberculosis” includes an infection of a subject caused by one or more species of Mycobacteriumtuberculosis complex but where the subject does not necessarily exhibit symptoms a tuberculosis disease. The language “non-drug resistant tuberculosis” includes tuberculosis caused by an infection by one or more species of the Mycobacterium tuberculosis complex that exhibits no antibacterial resistance to standard tuberculosis therapy. The language “multiple drug resistant tuberculosis (MDR-TB)” includes tuberculosis caused by an infection by of one or more species of the Mycobacteriumtuberculosis complex that is resistant to rifampicin and isoniazid. The language “extensively drug resistant tuberculosis (XRD-TB)” includes tuberculosis caused by an infection by one or more species of the Mycobacteriumtuberculosis complex that is resistant to rifampicin and isoniazid, as well as any member of the quinolone family, and is also resistant to at least one of kanamycin, capreomycin and amikacin. In some embodiments, the tuberculosis infection is acute. In some embodiments, the tuberculosis infection is chronic.
In some aspects, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for inhibiting DprE1.
In some aspects, the invention provides a compound of formula (I) in the manufacture of a medicament for use in inhibiting DprE1.
In some aspects, the invention provides a method of inhibiting DprE1comprising contacting a cell with a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Combinations
The compounds described herein may be applied as a sole therapy or may involve one or more other substances and/or treatments. Such co-treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination. Suitable classes and substances include one or more antibacterial agents useful in the treatment of Mycobacterium infections and/or tuberculosis, such as, for example, rifampicin, isoniazid, pyrizinamide, ethambutol, quinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin and gatifloxacin), aminoglycosides (e.g., streptomycin, kanamycin, and amikacin), polypeptides (e.g., capreomycin, viomycin and enviomycin), rifabutin, clarithromycin, linezolid, thioacetazone, thioridazine, arginine, vitamin D and R207910.

All anhydrous solvents, reagent grade solvents for chromatography and starting materials were purchased from either Sigma Aldrich Chemical Co. or Fisher Scientific. Water was distilled and purified through a Milli-Q water system (Millipore Corp., Bedford, MA). General methods of purification of compounds involved the use of silica cartridges purchased from Grace Purification systems. The reactions were monitored by TLC on precoated Merck 60 F254 silica gel plates and visualized using UV light (254 nm). All compounds were analyzed for purity by HPLC and characterized by 1H NMR using Bruker 300 MHz NMR and/or Bruker 400 MHz NMR spectrometers. Chemical shifts are reported in ppm (d) relative to the residual solvent peak in the corresponding spectra; chloroform d 7.26, methanol d 3.31, DMSO-d6 d 2.50 and coupling constants (J) are reported in hertz (Hz) (where, s = singlet, bs = broad singlet, d = doublet, dd = doublet of doublet, bd = broad doublet, ddd = double doublet of doublet, t = triplet, tt = triplet of triplet, q = quartet, m = multiplet) and analyzed using ACD NMR data processing software. Mass spectra values are reported as m/z.
All reactions were conducted under Nitrogen unless otherwise noted. Solvents were removed in vacuo on a rotary evaporator.

Abbreviations: NMP = N-methyl Pyrrolidine; HCl = hydrochloric acid; DMF = N,N-dimethylformamide; NaH = sodium hydride. EI = electrospray ionization; HRMS = high resolution mass spectrometry.

Compounds having the general Formula (I) can be prepared by the following one or more of the synthetic Schemes. The variables in the schemes are meant only to illustrate how to make some of the compounds of this invention.
The synthesis of benzimidazole analogues is outlined in Schemes 1-3. Synthesis is initiated with the commercially available starting material, A. Benzimidazole scaffold can be obtained using formic acid and iron to yield B which is further alkylated with benzyl halide in the presence of suitable base such as cesium carbonate to give compound C. Suitable aryl halides are either commercially available or can be readily obtained from the corresponding readily available starting materials by methods known to one skilled in the art.
Further hydrolysis of C to acid D followed by amide coupling results final compounds. To introduce 6-methoxy functionality on benzimidazole core, the syntheses is started with the acetylation of 2-amino-5-methoxybenzoic acid (G) to give intermediate H, which is subsequently hydrolyzed to yield N-acetyl benzoic acid I. Nitration of I using nitronium tetrafluoroborate yields intermediate J, which is further deprotected under acidic condition to obtain K. Reduction followed by cyclization can yield benzimidazole core Lwhich on esterification gives intermediate M. Similar to Scheme 1, intermediate M is also used to obtain final compounds.
Analysis of the compounds of the invention was carried out by reverse phase analytical HPLC.
Scheme 1

Intermediate B: Methyl 2-amino-3-nitrobenzoate A (1 mmol), ammonium chloride (15 mmol) and iron (10 mmol) were taken in IPA (5 ml) and formic acid (5 mL). The reaction mixture was stirred at 80 °C for 2h. The reaction mixture was diluted with 2-PrOH (20 mL) and filtered to remove insoluble material. The filtrate was concentrated to dryness, and the resulting residue partitioned between CH2Cl2 (50 mL) and (10 mL) sat. aq NaHCO3. The aqueous layer was extracted with additional CH2Cl2 (5 × 30 mL). The combined organic extracts were dried over sodium sulphate, filtered, and concentrated to yield the pure solid of Intermediate B.

Intermediate C:A solution ofIntermediate B (1 mmol)in DMF (5 mL) and was added cesium carbonate (3 mmol). The mixture was stirred for 10 minutes at rt and then 4-(chloromethyl)-X-5-methylpyrimidine (1.50 mmol) was added followed by addition of sodium iodide (1.50 mmol). The resulting mixture was stirred at rtfor 5h. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with water. The organic layer was dried over sodium sulphate, filtered and concentrated to provide residue. The crude was taken in minimum amount of methanol and excess of water to precipitate solid, which was filtered and dried under high vacuum to afford a solid of Intermediate C.

Intermediate D: To a solution of Intermediate C (1 mmol) in MeOH (5 mL) was added 5M solution of lithium hydroxide and thereaction mixture was heated to 60°C for 2h. The reaction mixture was cooled to ambient temperature and concentrated in vacuoto provideresidue, which was acidified with 2N HCl to precipitate solid. Solid was filtered and dried under high vacuum to afford a solid of IntermediateD.

Scheme 2

Methyl 2-amino-5-bromo-3-nitrobenzoate (E):To a solution of methyl 2-amino-3-nitrobenzoate (2 g, 10.20 mmol) in 20 mL of acetic acid, a solution of bromine (0.52 mL, 10.20 mmol) in 20mL of acetic acid was added drop wise over 5 minutes. The mixture was stirred at rt for 30 minutes and poured into ice and yellow precipitate was collected by filtration and dried to afford a yellow solid of compound E (2.65 g, 90% yield). ES+MS m/z: 273(M+1).

Methyl 2-amino-5-methyl-3-nitrobenzoate (F): A solution of compound E (2 g, 7.27 mmol) in 1,4-dioxane (80 mL), were added 2M potassium carbonate (3.01 g, 21.81 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.51 g, 0.73 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.37 g, 10.91 mmol). The resulting mixture was stirred at 110°C for overnight. The reaction mixture was concentrated to dryness to get solid. The solid was taken in ethyl acetate (200 mL) and washed with water. The organic layer was dried over sodium sulphate to obtain gummy liquid. The crude was purified by flash chromatography eluting with 0-50% EtOAc:Hexaneto afford compound Fas a pale yellow solid (1.25 g, 80% yield).ES+MS m/z: 211(M+1).

Scheme 3

6-Methoxy-2-methyl-4H-benzo[d][1,3]oxazin-4-one (H):2-Amino-5-methoxybenzoic acid (5 g, 29.91 mmol) and acetic anhydride (56.4 mL, 598.22 mmol) were taken and stirred at rt for overnight. The reaction mixture was concentrated to providecompound H as a solid (5.72 g, 90% yield). ES+MS m/z:192 (M-1).

2-Acetamido-5-methoxybenzoic acid (I):Asuspension compound H (5.72 g, 29.92 mmol) in water (150 mL) was heated to 85 °C. After 3h the LCMS indicated complete conversion to the product. The reaction mixture was cooled to rt and the solid was filtered, washed with water thoroughly and dried under high vacuum to provide compound Ias a pale red solid (5.51 g,80% yield). ES+MS m/z: 208.26 (M-1).

2-Acetamido-5-methoxy-3-nitrobenzoic acid (J):Nitronium tetrafluoroborate (3.49 g, 26.29 mmol) was dissolved in acetonitrile (30 mL) was added drop wise to an ice cold solution of compoundI (5.5 g, 26.29 mmol) in acetonitrile (70 mL), the reaction mixture was stirred for 30 minutes and then poured onto ice to precipitate solid. The solid was collected by filtration and dried to providecompound Jas a pale yellow solid (5.68 g, 80% yield). ES+MS m/z:253 (M-1).

2-Amino-5-methoxy-3-nitrobenzoic acid (K):A solution of compound J (5.68 g, 22.34 mmol) in MeOH (50 mL), and then 6N HCl (100 mL, 3.93 mmol) was added and the mixture was heated to 85 °C for overnight. The reaction mixture was cooled to rt and concentrated to dryness to get orange solid compound K (4.74 g, 90% yield). ES+MS m/z:213 (M+1).

6-Methoxy-1H-benzo[d]imidazole-4-carboxylic acid (L):A suspension of compound K (4.74 g, 22.34 mmol), iron (18.72 g, 335.13 mmol) and ammonium chloride (23.90 g, 446.83 mmol) were taken in IPA( 240 mL) and formic acid (240 mL) and the mixture was stirred at 80 °C for 2h. The reaction cooled and diluted withIPA (300 mL) and filtered to remove insoluble materials. The filtrate was concentrated to dryness to providecompound L as a brown solid (4.29 g, 90% yield). ES+MS m/z: 193 (M+1).

Methyl 6-methoxy-1H-benzo[d]imidazole-4-carboxylate (M):Compound L (4.29 g, 22.32 mmol) was taken in MeOH (200 mL), cooled to 0oC and sulfuric acid (23.80 mL, 446.48 mmol) was added slowly and the reaction mixture was refluxed for overnight. The reaction mixture was cooled to rtand concentrated to provide thick solution which was acidified with sat. sodium bicarbonate. Then the aqueous layer was extracted with DCM, dried over sodium sulphate and concentrated to obtain compound Mas a solid (2.85 g, 60%). ES+MS m/z: 207 (M+1).
The Examples provided herein better describe the invention. However, these examples are for illustrative purposes and are not construed to be limiting.
Example 1.
All anhydrous solvents, reagent grade solvents for chromatography and starting materials were purchasedfrom either Sigma Aldrich Chemical Co. or Fisher Scientific. Water was distilled and purified through aMilli-Q water system (Millipore Corp., Bedford, MA). General methods of purification of compoundsinvolved the use of silica cartridges purchased from Grace Purification systems. The reactions weremonitored by TLC on precoated Merck 60 F254 silica gel plates and visualized using UV light (254 nm).
All compounds were analyzed for purity by HPLC and characterized by 1H NMR using Bruker 300 MHzNMR and/or Bruker 400 MHz NMR spectrometers. Chemical shifts are reported in ppm (d) relative to theresidual solvent peak in the corresponding spectra; chloroform d 7.26, methanol d 3.31, DMSO d 3.33 andcoupling constants (J) are reported in hertz (Hz) (where s = singlet, bs = broad singlet, d = doublet, dd =double doublet, bd = broad doublet, ddd = double doublet of doublet, t = triplet, tt – triple triplet, q = quartet,m = multiplet) and analyzed using ACD NMR data processing software. Mass spectra values are reportedas m/z. All reactions were conducted under Nitrogen unless otherwise noted. Solvents were removed invacuo on a rotary evaporator. All final compounds for biological testing were purified by reverse phaseHPLC with >95% purity [Shimadzu HPLC instrument with a Hamilton reversed phase column (HxSil, C18,3µm, 2.1 mm × 50 mm (H2)). Eluent A: 5% CH3CN in H2O, eluent B: 90% CH3CN in H2O. A flow rate of0.2 mL/min was used with UV detection at 254 and 214 nm]Abbreviations: NMP = N-methyl Pyrrolidine; HCl = hydrochloric acid; DMF = N,N-dimethylformamide;NaH = sodium hydride. EI = electrospray ionization; HRMS = high resolution mass spectrometry.

N-(2-fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-benzo[d]imidazole-4-
carboxamide (1)
ES+MS m/z: 344
1H NMR (300 MHz, DMSO-d6) d ppm: 2.28 (s, 3 H) 3.69 - 3.86 (m, 2 H) 3.94 (s, 3 H) 4.54 (t, J=4.99 Hz,1 H) 4.70 (t, J=4.90 Hz, 1 H) 5.76 (s, 2 H) 7.34 (t, J=7.82 Hz, 1 H) 7.69 (dd, J=8.10, 0.94 Hz, 1 H) 7.90(dd, J=7.54, 0.94 Hz, 1 H) 8.41 (s, 1 H) 8.56 (s, 1 H) 10.02 (t, J=5.75 Hz, 1 H)
HRMS (M+H) calculated for C17H18FN5O2: 344.1517, observed: 344.15164.

N-(2-fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-
b]pyridine-3-carboxamide (2)
ES+MS m/z: 358
1H NMR (300 MHz, DMSO-d6) d ppm: 2.24 (s, 3 H) 2.40 (s, 3 H) 3.62 - 3.80 (m, 2 H) 3.93 (s, 3 H) 4.49(t, J=4.99 Hz, 1 H) 4.65 (t, J=4.99 Hz, 1 H) 5.64 (s, 2 H) 7.76 (s, 1 H) 8.16 (s, 1 H) 8.32 - 8.43 (m, 2 H)8.88 (t, J=5.75 Hz, 1 H)
HRMS (M+H) calculated for C18H20FN5O2: 358.16735, observed: 358.16814.

1-((6-(difluoromethoxy)-5-methylpyrimidin-4-yl)methyl)-N-(2-fluoroethyl)-6-methyl-1Hbenzo[
d]imidazole-4-carboxamide (3)
ES+MS m/z: 394
1H NMR (300 MHz, DMSO-d6) d ppm: 2.34 (s, 3 H) 2.43(s, 3h) 3.72 (d, J=5.09 Hz, 1 H) 3.81 (d, J=5.27Hz, 1 H) 4.53 (t, J=4.99 Hz, 1 H) 4.69 (t, J=4.99 Hz, 1 H) 5.82 (s, 2 H) 7.50 – 8.04 (m, 3 H) 8.44 (s, 1 H)8.53 (s, 1 H) 9.96 (t, J=5.11 Hz, 1 H)
HRMS (M+H) calculated for C18H18F3N5O2: 394.1485, observed: 394.14969.

1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-(2-fluoroethyl)-6-methyl-1Hbenzo[
d]imidazole-4-carboxamide (4)
ES+MS m/z: 371
1H NMR (300 MHz, DMSO-d6) d ppm: 2.27 - 2.35 (m, 3 H) 2.40 - 2.47 (m, 3 H) 2.96 (s, 6 H) 3.31 (s, 1H) 3.68 - 3.85 (m, 2 H) 4.53 (t, J=4.90 Hz, 1 H) 4.69 (t, J=4.90 Hz, 1 H) 5.61 (s, 2 H) 7.49 (s, 1 H) 7.73 (s,1 H) 8.22 (s, 1 H) 8.43 (s, 1 H) 9.99 (t, J=5.65 Hz, 1 H)
HRMS (M+H) calculated for C19H23FN6O: 371.19898, observed: 371.19908.

N-(2,2-difluoroethyl)-1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-6-methyl-1Hbenzo[
d]imidazole-4-carboxamide (5)
ES+MS m/z: 389
1H NMR (300 MHz, DMSO-d6) d ppm: 2.31 (s, 3 H) 2.44 (s, 3 H) 2.97 (s, 6 H) 3.92 (tdd, 2 H) 5.62 (s, 2H) 6.05-6.42 (tt, 8 Hz, 1 H) 7.52 (s, 1 H) 7.74 (s, 1 H) 8.22 (s, 1 H) 8.45 (s, 1 H) 10.03 (t, J=5.93 Hz, 1 H)HRMS (M+H) calculated for C19H22F2N6O: 389.18956, observed: 389.19021.

N-(2-fluoroethyl)-6-methoxy-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-benzo[d]imidazole-
4-carboxamide (6)
ES+MS m/z: 374
1H NMR (300 MHz, DMSO-d6) d ppm: 2.26 (s, 3 H) 3.70 - 3.84 (m, 5 H) 3.94 (s, 3 H) 4.53 (t, J=4.90 Hz,1 H) 4.69 (t, J=4.99 Hz, 1 H) 5.71(s, 2 H) 7.30 (d, J=2.45 Hz, 1 H) 7.47 (d, J=2.45 Hz, 1 H) 8.40 (s, 1 H)8.43 (s, 1 H) 9.98 (t, J=5.11 Hz, 1 H).
HRMS (M+H) calculated for C18H20FN5O3: 374.16226, observed: 374.1628.

N-(2,2-difluoroethyl)-1-((6-(difluoromethoxy)-5-methylpyrimidin-4-yl)methyl)-6-methoxy-1Hbenzo[
d]imidazole-4-carboxamide (7)
ES+MS m/z: 428
1H NMR (300 MHz, DMSO-d6) d ppm: 2.34 (s, 3 H) 3.79 (s, 3 H) 3.82 - 4.04 (m, 2 H) 5.82 (s, 2 H) 6.06-6.44 (tt, 1 H) 7.35 (d, J=2.45 Hz, 1 H) 7.49 (d, J=2.45 Hz, 1 H) 7.57- 8.04 (s, 1 H) 8.41 (s, 1 H) 8.54 (s, 1H) 10.02 (t, J=6.03 Hz, 1 H)
HRMS (M+H) calculated for C18H17F4N5O3: 428.134, observed: 428.1348.

1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-(2-fluoroethyl)-6-methoxy-1Hbenzo[
d]imidazole-4-carboxamide (8)
ES+MS m/z: 387
1H NMR (300 MHz, DMSO-d6) d ppm: 2.31 (s, 3 H) 2.96 (s, 6 H) 3.70 - 3.86 (m, 5 H) 4.53 (t, J=4.99 Hz,1 H) 4.69 (t, J=4.90 Hz, 1 H) 5.60 (s, 2 H) 7.29 (d, J=2.45 Hz, 1 H) 7.48 (d, J=2.45 Hz, 1 H) 8.25 (s, 1 H)8.37 (s, 1 H) 9.99 (t, J=5.65 Hz, 1 H).
HRMS (M+H) calculated for C19H23FN6O2: 387.19389, observed: 387.19438.

N-(2,2-difluoroethyl)-1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-6-methoxy-1Hbenzo[
d]imidazole-4-carboxamide (9)
ES+MS m/z: 405
1H NMR (300 MHz, DMSO-d6) d ppm: 2.31 (s, 3 H) 2.97 (s, 6 H) 3.8 (s, 3 H) 3.92 (tdd, 2 H) 5.61 (s, 2 H)6.05-6.43 (tt, J=3.58 Hz, 1 H) 7.32 (d, J=2.45 Hz, 1 H) 7.48 (d, J=2.45 Hz, 1 H) 8.24 (s, 1 H) 8.39 (s, 1 H)10.03 (t, J=5.93 Hz, 1 H).
HRMS (M+H) calculated for C19H22F2N6O2: 405.18447, observed: 405.18462.

1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-N-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-4-carboxamide(10)
ES+MS m/z: 379
1H NMR (300 MHz, DMSO-d6) d ppm: 2.29 (s, 3 H) 3.72 - 3.86 (m, 2 H) 3.95 (s, 3 H), 5.78 (s, 2 H) 7.37 (t, J=7.82 Hz, 1 H) 7.61 (dd, J=8.10, 0.94 Hz, 1 H) 7.92 (dd, J=7.54, 0.94 Hz, 1 H) 8.42 (s, 1 H) 8.58 (s, 1 H) 10.02 (t, J=5.75 Hz, 1 H)
HRMS (M+H) calculated for C17H16F3N5O2: 379.12561, observed: 379.12591
6-methoxy-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-N-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-4-carboxamide (11)
ES+MS m/z: 409
1H NMR (300 MHz, DMSO-d6) d ppm: 2.26 (s, 3 H) 3.72 - 3.85 (m, 2 H), 3.80 (s, 3H), 3.94 (s, 3 H), 5.75 (s, 2 H), 7.63 (d, J=0.94 Hz, 1 H) 7.95 (d, J=0.94 Hz, 1 H) 8.44 (s, 1 H) 8.54 (s, 1 H) 10.04 (t, J=5.75 Hz, 1 H)
HRMS (M+H) calculated for C18H18F3N5O3: 409.13617, observed: 409.13645.
1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-N-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-4-carboxamide (12)
ES+MS m/z: 4393
1H NMR (300 MHz, DMSO-d6) d ppm: 2.27 (s, 3 H), 2.36 (s, 3h), 3.74 - 3.87 (m, 2 H), 3.80 (s, 3H), 3.93 (s, 3 H), 5.74 (s, 2 H), 7.66 (d, J=0.94 Hz, 1 H) 7.95 (d, J=0.94 Hz, 1 H) 8.46 (s, 1 H) 8.51 (s, 1 H) 10.07 (t, J=5.75 Hz, 1 H)
HRMS (M+H) calculated for C18H18F3N5O2: 393.14126, observed: 393.14145.

Example 2. Biological assays
Biological assay protocols for MIC determination, cytotoxicity, mutant generation, resistance frequency, whole genome sequencing, DprE1 construct & protein purification, DprE1 enzyme assay & IC50 measurement, pharmacokinetics (PK) of benzimidazole compound, in vivo efficacy study, solubility assay, plasma protein binding assay, metabolic stability assay (microsomal CL and hepatocyte CL), logD, and hERG assay were performed as described in Reference J. Med. Chem. 2013, 56, 23, 9701-9708.
Results of MIC of compounds 1-12 (Example 1-12) of the invention are provided in Table 2.
Table 2: Minimum inhibitory concentration (MIC) against Mycobacterium tuberculosis (Mtb)strain-H37rv and enzymatic inhibition of Mtb DprE1 (IC50)
Example No. MIC (µM) IC50 (µM)
1 1.56 0.034
2 0.78 0.008
3 <0.39 0.016
4 <0.39 0.009
5 <0.39 0.004
6 <0.39 0.006
7 <0.39 0.005
8 <0.39 0.016
9 <0.39 0.009
10 <1.32 not tested
11 <1.22 not tested
12 <1.27 not tested

Bactericidal activity and intracellular efficacy (as provided in the reference) of compound 1 (Example 1) are provided in Figure 1.
DMPK results and safety properties of compounds 1 and 8 (Examples 1 and 8) are provided in Table 3.
Table 3: DMPK and safety properties Examples 1 and 8

In vivo efficacy of compound 1 (Example 1) following multiple oral dose administration in Mtb infected male Balb/C mice at 10 and 30 mg/kg is provided in Figure 2A. Figures 2 B and C provides the efficacy of compound 1 (Example 1) in chronic TB infection model in BALB/c mice.
,CLAIMS:Claims
We Claim:
1. A compound of formula (I):

wherein
R1 is selected from a group consisting of hydrogen, fluorine, bromine, -OCH3, cyclopropyl and methyl;
R2 is hydrogen, methyl, alkyl or cycloalkyl;
R3 is hydrogen, methyl, alkyl or cycloalkyl;
R4 is hydrogen, methyl, alkyl or cycloalkyl;
X is N, N-R5 or C-R5;
R5 is selected from a group consisting of hydrogen, Methyl, -CHF2, haloalkyl and haloalkoxy;
Y is selected from C-H, COR6 , -C-N(CH3)2 or C=O;
R6 is selected from a group consisting of hydrogen, Methyl, -CHF2, -OCH2CF3, haloalkyl and haloalkoxy;
R7 is selected from a group consisting of hydrogen, fluorine, -CH3, -OH, -CHF2, -CF3, -CH(F)CH3, -CH2CF3, haloalkyl and haloalkoxy;
n is 1 or 2;or a pharmaceutically acceptable salt thereof.

2. The compound of formula I, wherein the said compounds are selected from the group consisting of:
(1) N-(2-fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-benzo[d]imidazole-4-carboxamide;
(2) N-(2-fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-benzo[d]imidazole-4-carboxamide;
(3) 1-((6-(difluoromethoxy)-5-methylpyrimidin-4-yl)methyl)-N-(2-fluoroethyl)-6-methyl-1H-benzo[d]imidazole-4-carboxamide;
(4) 1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-(2-fluoroethyl)-1H-benzo[d]imidazole-4-carboxamide;
(5) N-(2,2-difluoroethyl)-1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-1H-benzo[d]imidazole-4-carboxamide;
(6) N-(2-fluoroethyl)-6-methoxy-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-benzo[d]imidazole-4-carboxamide;
(7) N-(2,2-difluoroethyl)-1-((6-(difluoromethoxy)-5-methylpyrimidin-4-yl)methyl)-6-methoxy-1H-benzo[d]imidazole-4-carboxamide;
(8) 1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-N-(2-fluoroethyl)-6-methoxy-1H-benzo[d]imidazole-4-carboxamide;
(9) N-(2,2-difluoroethyl)-1-((6-(dimethylamino)-5-methylpyrimidin-4-yl)methyl)-6-methoxy-1H-benzo[d]imidazole-4-carboxamide;
(10) 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-N-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-4-carboxamide;
(11) 6-methoxy-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-N-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-4-carboxamide; and
(12) 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-N-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-4-carboxamide; or a pharmaceutically acceptable salt thereof.
3. A pharmaceutical composition comprising the compound as claimed in claim 1 or 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
4. A pharmaceutical composition comprising the compound as claimed in claim 1 or 2 or a pharmaceutically acceptable salt thereof,for use in the treatment of tuberculosis or a Mycobacterium infection.
5. A method of treating tuberculosis or a Mycobacterium infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising the compound as claimed in claim 1 or 2 or a pharmaceutically acceptable salt thereof,for use in the inhibition of DprE1.
7. A compound as claimed in claim 1 or 2for use in the manufacture of a medicament inhibiting DprE1.
8. A method of inhibiting DprEl comprising administering to a therapeutically effective amount of a compound as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof.