Patent Grant
9845330
This application is a 35 U.S.C. 371 national stage filing and claims priority to International Application No. PCT/IN2014/000202 filed on Mar. 31, 2016, entitled “6-NITRO-2,3-DIHYDROIMIDAZO[2,1-b]OXAZOLES AND A PROCESS FOR THE PREPARATION THEREOF,” which claims the benefit of Indian Patent Application No. 2954/DEL/2013 filed on Oct. 4, 2013, each of which are hereby incorporated herein by reference in their entirety.
The present invention relates to the compounds of 6-nitro-2,3-dihydronitroimidazooxazoles scaffolds that have been designed, synthesized and their biological evaluation result for anti-tuberculosis are presented. The field of invention relates to novel compounds of general formula 1, their method of preparations, and their use as drugs for treatment of tuberculosis either alone or in combination with other anti-tubercular treatments.
Tuberculosis remains a leading infectious cause of death worldwide and infects about one-third of the world's population. The existing TB treatment needs a cocktail of three or four different drugs (first-line drug regimen such as isoniazide, pyrazinamide, and rifampin and several second line drug regimen including ethionamide, para-aminosalicylic acid, kanamycin, amikacin, capreomycin, ciprofloxacin, streptomycin, etc.) and is exceedingly lengthy therapy which has lead to the emergence of multidrug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB), which has further complicated the world situation [BemerMelchior, P.; Bryskier, A.; Drugeon, H. B. J. Antimicrob. Chemother. 2000, 46, 571; Abubaker, J.; Schraufnagel, D. J. Am. Med. Assoc. 2000, 283, 54; Dye. C.; Scheele, S.; Dolin, P.; Pathania, V.; Raviglione, M. C. J. Am. Med. Assoc. 1999, 282, 677]. The World Health Organization (WHO) has estimated that if the present conditions remain unchanged, more than 30 million lives will be claimed by TB between 2000 and 2020. TB has also been declared as a global health emergency because of the increase in secondary infections and/or coinfection in cancer and immunocompromised patients (such as those infected with human immunodeficiency virus). Therefore, the current situation necessitates the development of new and potent anti-tuberculosis agents with low toxicity profiles which are effective against both drug-susceptible and drug-resistant strains of M. tuberculosis along with being capable of shortening the current duration of therapy and can be used in conjunction with drugs used for treatment of secondary infections such as cancer and HIV. After four decades, US-FDA recently approved TMC-207 {bedaquiline, a diarylquinone derivative developed by Johnson & Johnson (J&J)}, first drug against MDR-TB which works by inhibiting ATP-synthase and approval of TMC-207 is being seen as a starting point for a new era of TB treatment [Edney, Anna (Dec. 31, 2012). “J&J Sirturo Wins FDA Approval to Treat Drug-Resistant TB”. Bloomberg. Retrieved 2013-01-01].
In the last decade, nitroimidazole skelton (A,
In present invention, new generation anti-TB molecules based on 6-nitro-2,3-dihydronitroimidazooxazoles as inherent component with triazoles, tetrazoles, isoxazoles, urea and sulphonamide functionalities are designed that may fulfill the challenges of anti-tuberculosis drug discovery such as good stability under various conditions, high oral bioavailability, good elimination half-life, free from genotoxicity/mutagenicity and hERG liabilities and absence of drug-drug interactions which is critical in combination treatments.
The main object of the present invention is to provide newer generation triazoles, tetrazoles, isoxazoles, urea and sulphonamide functionalities containing 6-nitro-2,3-dihydronitroimidazooxazoles agents for treatment of tuberculosis.
Still another object of the present invention is to provide a process for the preparation of triazoles, tetrazoles, isoxazoles, urea and sulphonamide functionalities containing 6-nitro-2,3-dihydronitroimidazooxazoles.
Yet another object of the present invention is to provide the combination therapy for the treatment of tuberculosis.
Still another object of the present invention is to provide treatment against multi-drug resistant (MDR) and extensive drug resistant (XDR) tuberculosis.
Accordingly the present invention relates to a compound of general formula 1 or pharmaceutically acceptable salts thereof
wherein
wherein,
In an embodiment of the present invention, the compound of general formula 1 is selected from the group consisting of compound of formula I and formula II;
wherein
is selected from the group consisting of formula IIa, IIb and IIc;
wherein,
In still another embodiment of the present invention, the compound of formula I is selected from the group consisting of formula IA, IB and IC,
wherein
In yet another embodiment of the present invention, the compound of formula II is selected from the group consisting of compound of formula IIA, IIB and IIC,
wherein
In still another embodiment of the present invention, the compounds of general formula 1 are selected from the group consisting of:
In yet another embodiment of the present invention, the compound of general formula 1 is useful in treatment of tuberculosis.
In still another embodiment of the present invention, the compound of general formula 1 exhibits an in vitro anti-tuberculosis activity against H37Rv Mycobacterium tuberculosis, MDR (resistant to isoniazid and rifampicin) with MIC values in the range of 0.06 to 32 μg/ml.
In yet another embodiment of present invention, the compound of general formula 1 exhibits an in vitro anti-tuberculosis activity against XDR Mycobacterium tuberculosis (resistant to isoniazid, rifampicin, amikacin and moxifloxacin) with MIC values in the range of 0.12 to 32 μg/ml.
In still another embodiment of the present invention, the compound of general formula 1 does not exhibit any cytotoxicity up to 40 μg/ml in macrophage J774 cells line and exhibits safety index more than 10.
In yet another embodiment of the present invention, the compound of general formula 1 shows promising pharmacokinetic properties in mouse model with Cmax of 1 to 5 μg/ml and AUC0-24 of 10 to 50 μg hr/ml at oral dose of 5 mg/kg.
In still another embodiment of the present invention, the compound of general formula 1 exhibits synergistic and additive effect with known anti-tubercular drugs in combination studies.
An embodiment of the present invention provides a process for the preparation of a compound of general formula 1 comprising the steps:
reacting an epoxide (compound 9)
with a substituted phenol selected from the group consisting of compounds of formula 13(a-p), 16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f), 36(a-d), 41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j) in an organic solvent selected from the group consisting of N,N-dimethylformamide, DCM, acetonitrile, THF and acetone in presence of a base selected from the group consisting of sodium hydride, cesium carbonate, potassium carbonate and potassium bicarbonate at a temperature in the range of −20° C. to 10° C. and stirring for a period ranging between 1 to 24 hrs at a temperature in the range of 50° C. to 80° C. to obtain the compound of general formula 1.
In yet another embodiment of the present invention, the pharmaceutically acceptable salts are salts of an acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfonic acid and isoethonic acid and salts of a base selected from the group consisting of potassium carbonate, sodium hydroxide, potassium hydroxide, ammonia, triethylamine and triethanolamine.
In still another embodiment of the present invention, the process for the preparation of the salt of compound of general formula 1 comprising the steps:
An embodiment of the present invention provides a pharmaceutical composition for treatment of tuberculosis comprising an effective amount of a compound of general formula 1 or a combination of a compound of general formula 1 and an anti-tubercular drug, optionally along with pharmaceutically acceptable diluents, excipients or carriers.
In still another embodiment of the present invention, the ratio of compound of formula 1 and an anti-tubercular drug in the pharmaceutical composition is in the range of 0.1% to 50% by weight.
In yet another embodiment of the present invention, the anti-tubercular drug used in the pharmaceutical composition is selected from the group consisting of ethambutal, INH, rifampicin, pyrazinamide, streptomycin, capreomycin, viomycin, enviomycin, kanamycin, amikacin, ethionamide, prothionamide, p-amino salicylic acid, closerine, ciprofloxacin, levoflaxacin and moxiflaxacin.
An embodiment of the present invention provides a method of treating tuberculosis comprising administering to a subject, an effective amount of a compound of general formula 1 or a combination of a compound of general formula 1 and an anti-tubercular drug, optionally along with pharmaceutically acceptable diluents, excipients or carriers.
In an embodiment of the present invention, there is provided a method for treating tuberculosis, wherein the subject is a human.
In another embodiment of the present invention, there is provided a method for treating tuberculosis, wherein the anti-tubercular drug used in combination with the compound of formula 1 is selected from the group consisting of ethambutal, INH, rifampicin, pyrazinamide, streptomycin, capreomycin, viomycin, enviomycin, kanamycin, amikacin, ethionamide, prothionamide, p-amino salicylic acid, closerine, ciprofloxacin, levoflaxacin and moxiflaxacin.
Table 1 shows the structure of representative compounds IA1-IA16 belonging to formula IA and synthesized as per scheme 5 provided in
Table 2 shows the structure of representative compounds IA17-IA24 belonging to formula IA and synthesized as per scheme 5 provided in
Table 3 shows the structure of representative compounds IA25-IA42 belonging to formula IA and synthesized as per scheme 9 provided in
Table 4 shows the structure of representative compounds IB1-IB10 belonging to formula IB and synthesized as per scheme 11 and scheme 13 provided in
Table 5 shows the structure of representative compounds IC1-IC22 belonging to formula IC and synthesized as per scheme 15 and scheme 17 provided in
Table 6 shows the structure of representative compounds IIA1-IIA10 belonging to formula IIA and synthesized as per scheme 19 provided in
Table 7 shows the structure of representative compounds IIB1-IIB6 belonging to formula JIB and synthesized as per scheme 21 provided in
Table 8 shows the structure of representative compounds IIC1-IIC10 belonging to formula IIC and synthesized as per scheme 23 provided in
Table 9 shows the physico-chemical properties, anti-tuberculosis activity and cytotoxicity of representative compound shown in tables 1 to 8.
Table 10 shows the combination studies results of OPC-67683 and selected compounds of general formula 1 (IA25 and IIA3) with rifampicine, INH and ethambutol against M. tuberculosis H37Rv.
Table 11 shows the In vivo pharmacokinetic properties of OPC-67683, and selected compounds of general formula 1 (IA25, IA33, IC13 and IC14).
H.R.: Heterocyclic Ring
The present invention relates to new generation of triazoles, tetrazoles, isoxazoles, urea and sulphonamide functionalities containing 6-nitro-2,3-dihydronitroimidazooxazoles agents, their method of preparation, and their use as drugs for treatment of tuberculosis either alone or in combination with other anti-tubercular agents.
The present invention describes a compound having a general formula 1
wherein
The compound of general formula 1 is selected from the group consisting of compound of formula I and formula II,
wherein
is selected from the group consisting of formula Ia, Ib and Ic;
is selected from the group consisting of formula IIa, IIb and IIc;
wherein,
In another aspect of the present invention, a preferred subclass of compound of general formula 1 is selected from the group consisting of compound of formula IA, IB and IC;
wherein
In another aspect of the present invention, another preferred subclass of compound of general formula 1 is selected from the group consisting of compound of formula IIA, IIB and IIC;
wherein
The compound of general formula 1 is useful in treatment of tuberculosis.
The compound of general formula 1 exhibits potent minimum inhibitory concentration (MIC) against H37Rv Mycobacterium tuberculosis, MDR-TB (resistant to isoniazid and rifampicin) in the range of 0.06 to 32 μg/ml.
The compound of general formula 1 exhibits MIC against XDR Mycobacterium tuberculosis (resistant to isoniazid, rifampicin, amikacin and moxifloxacin) in the range of 0.12 to 32 μg/ml.
The compound of general formula 1 does not exhibit any cytotoxicity up to 40 μg/ml in macrophage J774 cells line and exhibits safety index more than 10.
The compound of general formula 1, wherein one of the representing compound exhibits promising and better pharmacokinetic properties in mouse model with Cmax of 1 to 5 μg/ml and AUC0-24 of 10 to 50 μg*hr/ml at an oral dose of 5 mg/kg.
The compounds of general formula 1 exhibit synergistic and additive effects with other known anti-tubercular drugs such as rafamicin, isoniazid and ethambutol in combination studies.
The compound of formula IA of general formula 1 is prepared by reacting an epoxide (compound 9) with a substituted phenol selected from the group consisting of compounds of formula 13(a-p), 16(a-d), 19(a-d), 23(a-h), 24(a-f) and 25 (a-d) in an organic solvent selected from the group consisting of N,N-dimethylformamide, DCM, acetonitrile, THF and acetone in presence of a base selected from the group consisting of cesium carbonate, potassium carbonate, potassium bicarbonate and sodium hydride at a temperature in the range of −20° C. to 10° C. and stirring for 1 to 24 hrs at a temperature in the range of 50° C. to 80° C.
The compound of formula IB of general formula 1 is prepared by reacting the epoxide (compound 9) with a substituted phenol selected from the group consisting of compounds of formula 30(a-f) and 36(a-d) in an organic solvent selected from the group consisting of DCM, acetonitrile, THF, acetoneand N, N-dimethylformamide in presence of a base selected from the group consisting of cesium carbonate, potassium carbonate, potassium bicarbonate and sodium hydride at a temperature in the range of −20° C. to 10° C. and stirring for 1 to 24 hrs at a temperature in the range of 50° C. to 80° C.
The compound of formula IC of general formula 1 is prepared by reacting an epoxide (compound 9) with a substituted phenol selected from the group consisting of compounds of formula 41(a-l) and 42(a-j) in an organic solvent selected from the group consisting of DCM, acetonitrile, THF, acetone and N, N-dimethylformamide in presence of a base selected from the group consisting of cesium carbonate, potassium carbonate, potassium bicarbonate and sodium hydride at a temperature in the range of −20° C. to 10° C. and stirring for 1 to 24 hrs at a temperature in the range of 50° C. to 80° C.
The compound of formula IIA of general formula 1 is prepared by reacting an epoxide (compound 9) with a substituted phenol selected from the group consisting of compounds of formula 45(a-j) in an organic solvent selected from the group consisting of DCM, acetonitrile, THF, acetone and N,N-dimethylformamide in presence of a base selected from the group consisting of cesium carbonate, potassium carbonate, potassium bicarbonate and sodium hydride at a temperature in the range of −20° C. to 10° C. and stirring for 1 to 24 hrs at a temperature in the range of 50° C. to 80° C.
The compound of formula IIB of general formula 1 is prepared by reacting an epoxide (compound 9) with a substituted phenol selected from the group consisting of compounds of formula 49(a-f) in an organic solvent selected from the group consisting of DCM, acetonitrile, THF, acetone and N,N-dimethylformamide in presence of a base selected from the group consisting of cesium carbonate, potassium carbonate, potassium bicarbonate and sodium hydride at a temperature in the range of −20° C. to 10° C. and stirring for 1 to 24 hrs at a temperature in the range of 50° C. to 80° C.
The compound of formula IIC of general formula 1 is prepared by reacting an epoxide (compound 9) with a substituted phenol selected from the group consisting of compounds of formula 53(a-j) in an organic solvent selected from the group consisting of DCM, acetonitrile, THF, acetone and N,N-dimethylformamide in presence of a base selected from the group consisting of cesium carbonate, potassium carbonate, potassium bicarbonate and sodium hydride at a temperature in the range of −20° C. to 10° C. and stirring for 1 to 24 hrs at a temperature in the range of 50° C. to 80° C.
The compounds of the present invention, combination thereof, isomers, and physiologically functionally salt derivatives are useful for treatment of Mycobacterium tuberculosis infection.
In the present invention, the pharmaceutically acceptable salts are salts of an acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfonic acid and isoethonic acid or salts of a base selected from the group consisting of potassium carbonate, sodium hydroxide, potassium hydroxide, ammonia, triethylamine and triethanolamine.
The most preferred compounds of formula I and II of general formula 1 are:
The following examples are given by way of illustrating the present invention and should not be construed to limit the scope of the invention:
Fragment A (compound 9) was successfully synthesized from a starting material 4-nitroimidiazole 1 as shown in scheme 1 (provided in
Triazolyl based fragment B, that is compounds 13(a-p), 16(a-d), 19(a-d), 23(a-h), 24(a-f) and 25 (a-d) were synthesized by following method reported in the literature (Boechat, N.; Ferreira, V. F.; Ferreira, S. B.; Ferreira, M. L. G.; Silva, F. C.; Bastos, M. M.; Costa, M. S.; Lourenc-o, M. C. S.; Pinto, A. C.; Krettli, A. U.; Aguiar, A. C.; Teixeira, B. M.; Silva, N. V.; Martins, P. R. C.; Bezerra, F. A. F. M.; Camilo, A. L. S.; Silva, G. P.; Costa, C. C. P.; J. Med. Chem. 2011, 54, 5988-5999) as shown in the scheme 2 (provided in
First uridyl based fragment C, that is compound 45(a-j) was synthesized from commercially available starting materials by following the method reported in literature (Valgeirsson, J.; Nielsen, E.; Peters, D.; Varming, T.; Mathiesen, C.; Kristensen, A. S.; Madsen, U.; J. Med. Chem. 2003, 46, 5835) as shown in scheme 18 (provided in
General Procedure for the Preparation of Compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
To a mixture of compound 9 (0.127 g, 0.586 mmol) and a compound selected from the group consisting of compounds 13(a-p), 16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f), 36(a-d), 41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j) (0.468 mmol) in N,N-dimethylformamide (3 mL), 60% sodium hydride (0.022 g, 0.562 mmol) was added at 0° C. portionwise to obtain a mixture. After the mixture was stirred at 50° C. for 12 hrs under a nitrogen atmosphere, the mixture was cooled in an ice bath and carefully quenched with ethyl acetate (2.3 mL) and ice water (0.5 mL). The thus-obtained mixture was poured into water (30 mL) and extracted with ethylacetate, washed twice with brine solution and dried under vacuum to obtain a crude product. This crude product was purified by silica gel column chromatography using a dichloromethane and ethyl acetate mixture as solvent to obtain compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6) and (IIC1-10).
General Procedure for the Preparation of Compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
To a mixture of compound 9 (0.127 g, 0.586 mmol) and a compound selected from the group consisting of compounds 13(a-p), 16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30 (a-f), 36(a-d), 41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j) (0.468 mmol) in N,N-dimethylformamide (3 mL), cesium carbonate (0.562 mmol) was added at 0° C. portionwise to obtain a mixture. After the mixture was stirred at 80° C. for 12 hrs under a nitrogen atmosphere, the mixture was cooled in an ice bath. The mixture was then poured into ice water (30 mL) and extracted with ethylacetate, washed twice with brine solution and dried under vacuum to obtain a crude product. This crude product was purified by silica gel column chromatography using a dichloromethane and ethyl acetate mixture as solvent to obtain compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6) and (IIC1-10).
General Procedure for the Preparation of Compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
To a mixture of compound 9 (0.127 g, 0.586 mmol) and a compound selected from the group consisting of compounds 13(a-p), 16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f), 36(a-d), 41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j) (0.468 mmol) in THF (3 mL), 60% sodium hydride (0.022 g, 0.562 mmol) was added at 0° C. portionwise to obtain a mixture. After the mixture was stirred at 80° C. for 24 hrs under a nitrogen atmosphere, the mixture was cooled in an ice bath and carefully quenched with ethyl acetate (2.3 mL) and ice water (0.5 mL). The thus-obtained mixture was poured into water (30 mL) and extracted with ethylacetate, washed twice with brine solution and dried under vacuum to obtain a crude product. This crude product was purified by silica gel column chromatography using a dichloromethane and ethyl acetate mixture as solvent to obtain compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10).
General Procedure for the Preparation of Compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
To a mixture of compound 9 (0.127 g, 0.586 mmol) and a compound selected from the group consisting of compounds 13(a-p), 16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f), 36(a-d), 41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j) (0.468 mmol) in ACN (3 mL), potassium carbonate (0.562 mmol) was added at 0° C. portionwise to obtain a mixture. After the mixture was stirred at 80° C. for 24 hrs under a nitrogen atmosphere, the mixture was cooled in an ice bath. The mixture was poured into water (30 mL) and extracted with ethylacetate, washed twice with brine solution and dried under vacuum to obtain a crude product. This crude product was purified by silica gel column chromatography using a dichloromethane and ethyl acetate mixture as solvent to obtain compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10).
General Procedure for the Preparation of Compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
To a mixture of compound 9 (0.127 g, 0.586 mmol) and a compound selected from the group consisting of compounds 13(a-p), 16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f), 36(a-d), 41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j) (0.468 mmol) in ACN (3 mL), cesium carbonate (0.562 mmol) was added at 0° C. portionwise to obtain a mixture. After the mixture was stirred at 80° C. for 24 hrs under a nitrogen atmosphere, the mixture was cooled in an ice bath. The mixture was poured into water (30 mL) and extracted with ethylacetate, washed twice with brine solution and dried under vacuum to obtain a crude product. This crude product was purified by silica gel column chromatography using a dichloromethane and ethyl acetate mixture as solvent to obtain compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10).
General Procedure for the Preparation of Compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
To a mixture of compound 9 (0.127 g, 0.586 mmol) and a compound selected from the group consisting of compounds 13(a-p), 16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f), 36(a-d), 41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j) (0.468 mmol) in Acetone (3 mL), potassium carbonate (0.562 mmol) was added at 0° C. portionwise to obtain a mixture. After the mixture was stirred at 60° C. for 18 hrs under a nitrogen atmosphere, the mixture was cooled in an ice bath. The mixture was poured into water (30 mL) and extracted with ethylacetate, washed twice with brine solution and dried under vacuum to obtain a crude product. This crude product was purified by silica gel column chromatography using a dichloromethane and ethyl acetate mixture as solvent to obtain compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10).
General Procedure for the Preparation of Compounds (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10)
To a mixture of compound 9 (0.127 g, 0.586 mmol) and a compound selected from the group consisting of compounds 13(a-p), 16(a-d), 19(a-d), 23 (a-h), 24(a-f), 25(a-d), 30(a-f), 36(a-d), 41(a-l), 42(a-j), 45(a-j), 49(a-f) and 53(a-j)(0.468 mmol) in DCM (5 mL), 60% sodium hydride (0.022 g, 0.562 mmol) was added at 0° C. portionwise to obtain a mixture. After the mixture was stirred at 40° C. for 24 hrs under a nitrogen atmosphere, the mixture was cooled in an ice bath and carefully quenched with ethyl acetate (2.3 mL) and ice water (0.5 mL). The thus-obtained mixture was poured into water (30 mL) and extracted with ethylacetate, washed twice with brine solution and dried under vacuum to obtain a crude product. This crude product was purified by silica gel column chromatography using a dichloromethane and ethyl acetate mixture as solvent to obtain (IA1-42), (IB1-10), (IC1-22), (IIA1-10), (IIB1-6), (IIC1-10).
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ1.86 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.5 Hz), 7.41 (m, 1H), 7.45 (d, 2H, J=7.5 Hz), 7.51 (m, 2H), 7.79 (m, 2H), 8.08 (s, 1H), 9.08 (s, 1H); MS (ESI+): m\z 418.14.
TLC (DCM: EtOAc 1:9): Rf=0.32; 1H NMR (400 MHz, Acetone d6): δ1.25 (t, 3H, J=8), 1.86 (s, 3H), 2.60 (m, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.5 Hz), 7.35 (d, 1H, J=7.8), 7.45 (d, 2H, J=7.5 Hz), 7.74 (d, 2H, J=7.8), 8.09 (s, 1H), 9.10 (s, 1H); MS (ESI+): m\z 446.17.
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ1.86 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.97 (d, 2H, J=7.6 Hz), 7.30 (m, 2H), 7.45 (d, 2H, J=7.6 Hz), 8.08 (s, 1H), 8.15 (m, 2H), 9.10 (s, 1H); MS (ESI+): m\z 436.13.
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ1.86 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz), 7.28 (m, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.49 (m, 1H), 7.71-7.77 (m, 2H), 8.08 (s, 1H), 9.10 (s, 1H); MS (ESI+): m\z 436.13.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.86 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.99 (d, 2H, J=7.6 Hz), 7.05 (d, 2H, J=7.8 Hz), 7.45 (d, 2H, J=7.6 Hz), 7.55 (d, 2H, J=7.8 Hz), 8.08 (s, 1H), 8.96 (s, 1H); MS (ESI+): m\z 502.12.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.86 (s, 3H), 4.41 (d, 1H, J=10.8 Hz), 4.52 (dd, 2H, J=21.1, 10.6 Hz), 4.70 (d, 1H, J=10.8 Hz), 6.97 (d, 2H, J=7.6 Hz), 7.45 (d, 2H, J=7.6 Hz), 7.68 (d, 2H, J=7.9 Hz), 7.72 (d, 2H, J=7.9 Hz), 8.08 (s, 1H), 9.10 (s, 1H); MS (ESI+): m\z 486.13.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.80 (s, 3H), 4.45 (d, 1H, J=10.8 Hz), 4.56 (dd, 2H, J=21.1, 10.6 Hz), 4.72 (d, 1H, J=10.8 Hz), 6.79 (m, 1H), 6.95 (d, 2H, J=7.6 Hz), 7.07 (m, 2H, J=7.9 Hz), 7.45 (d, 2H, J=7.6 Hz), 7.75 (d, 2H, J=7.9 Hz), 8.08 (s, 1H), 9.09 (s, 1H); MS (ESI+): m\z 454.12.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ 1.86 (s, 3H), 2.15 (s, 3H), 4.45 (d, 1H, J=10.8 Hz), 4.56 (dd, 2H, J=21.1, 10.6 Hz), 4.72 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz), 7.30 (d, 2H, J=7.8 Hz), 7.45 (d, 2H, J=7.6 Hz), 7.78 (d, 2H, J=7.8 Hz), 8.15 (s, 1H), 8.99 (s, 1H); MS (ESI+): m\z 432.12.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.35 (d, 6H, J=8.5 Hz), 1.86 (s, 3H), 2.15 (m, 1H, J=8.5 Hz), 4.45 (d, 1H, J=10.8 Hz), 4.56 (dd, 2H, J=21.1, 10.6 Hz), 4.72 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz), 7.30 (d, 2H, J=7.8 Hz), 7.45 (d, 2H, J=7.6 Hz), 7.78 (d, 2H, J=7.8 Hz), 8.15 (s, 1H), 8.99 (s, 1H); MS (ESI+): m\z 460.19.
(R)-2-{4-[4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl]phenoxymethyl}-2,3-dihydro-2-methyl-6-nitroimidazo[2,1-b]oxazole (compound IA10, Table 1,
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ1.85 (s, 3H), 4.45 (d, 1H, J=10.8 Hz), 4.56 (dd, 2H, J=21.1, 10.6 Hz), 4.72 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz), 7.20 (m, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.49-7.52 (m, 3H), 8.15 (s, 1H), 9.01 (s, 1H); MS (ESI+): m\z 436.13.
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ1.85 (s, 3H), 4.15 (s, 3H), 4.45 (d, 1H, J=10.8 Hz), 4.56 (dd, 2H, J=21.1, 10.6 Hz), 4.72 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz), 7.09 (d, 2H, J=7.75 Hz), 7.45 (d, 2H, J=7.6 Hz), 7.68 (d, 2H, J=7.75 Hz), 8.15 (s, 1H), 8.89 (s, 1H); MS (ESI+): m\z 448.15.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.86 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz), 7.20 (m, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.45-7.50 (m, 3H), 8.15 (s, 1H), 8.92 (s, 1H); MS (ESI+): m\z 502.12.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.88 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz), 7.40 (m, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.47-7.50 (m, 3H), 8.10 (s, 1H), 9.10 (s, 1H); MS (ESI+): m\z 486.13.
TLC (DCM: EtOAc 1:9): Rf=0.20; 1H NMR (400 MHz, Acetone d6): δ 1.89 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz), 7.36 (m, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.85 (m, 1H), 8.10 (s, 1H), 8.40 (m, 1H), 8.65 (m, 1H), 9.01 (s, 1H); MS (ESI+): m\z 419.13.
TLC (DCM: EtOAc 1:9): Rf=0.45; 1H NMR (400 MHz, Acetone d6): δ 0.91 (m, 3H), 1.15 (m, 2H), 1.21 (m, 4H), 1.89 (s, 3H), 2.25 (t, 2H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz), 7.45 (d, 2H, J=7.6 Hz), 7.62 (s, 1H), 7.95 (s, 1H); MS (ESI+): m\z 412.19.
TLC (DCM: EtOAc 1:9): Rf=0.50; 1H NMR (400 MHz, Acetone d6): δ 1.09 (m, 3H), 1.15 (m, 2H), 1.21-1.24 (m, 8H), 1.89 (s, 3H), 2.25 (t, 2H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz), 7.45 (d, 2H, J=7.6 Hz), 7.60 (s, 1H), 7.95 (s, 1H); MS (ESI+): m\z 440.22.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ1.89 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.91 (s, 1H), 6.95 (m, 1H), 7.18 (m, 1H), 7.20 (m, 1H), 7.30 (d, 2H, J=7.6 Hz), 8.15 (d, 2H, J=7.6 Hz), 8.18 (s, 1H), 8.98 (s, 1H); MS (ESI+): m\z 436.13.
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ1.89 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.91 (s, 1H), 6.95 (m, 1H), 7.18 (m, 1H), 7.20 (m, 1H), 7.45 (d, 2H, J=7.6 Hz), 8.11 (d, 2H, J=7.6 Hz), 8.15 (s, 1H), 9.08 (s, 1H); MS (ESI+): m\z 486.13.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.89 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.91 (s, 1H), 6.95 (m, 1H), 7.18 (m, 1H), 7.20 (m, 1H), 7.35 (d, 2H, J=7.6 Hz), 7.82 (d, 2H, J=7.6 Hz), 8.05 (s, 1H), 8.89 (s, 1H); MS (ESI+): m\z 502.12.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.89 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.91 (s, 1H), 6.95 (m, 1H), 7.18 (m, 1H), 7.20 (m, 1H), 7.25 (m, 2H, J=7.9 Hz), 7.45 (d, 2H, J=7.6 Hz), 7.75 (d, 2H, J=7.9 Hz), 8.05 (s, 1H), 8.93 (s, 1H); LC MS (ESI+): m\z 454.12.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ 1.79 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (m, 1H), 7.14 (m, 1H), 7.28 (m, 1H), 7.45 (m, 1H), 7.48 (d, 2H, J=7.6 Hz), 8.05 (d, 2H, J=7.6 Hz), 8.12 (s, 1H), 8.98 (s, 1H); MS (ESI+): m\z 436.13.
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ 1.87. (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (m, 1H), 7.14 (m, 1H), 7.28 (m, 1H), 7.45 (m, 1H), 7.68 (d, 2H, J=7.6 Hz), 8.05 (d, 2H, J=7.6 Hz), 8.12 (s, 1H), 9.08 (s, 1H); MS (ESI+): m\z 486.13.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.85 (s, 3H), 4.37 (d, 1H, J=10.8 Hz), 4.52 (dd, 2H, J=21.1, 10.6 Hz), 4.66 (d, 1H, J=10.8 Hz), 6.97 (m, 1H), 7.14 (m, 1H), 7.28 (m, 1H), 7.45 (m, 1H), 7.34 (d, 2H, J=7.6 Hz), 7.85 (d, 2H, J=7.6 Hz), 8.02 (s, 1H), 8.87 (s, 1H); MS (ESI+): m\z 502.12.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.89 (s, 3H), 4.35 (d, 1H, J=10.8 Hz), 4.49 (dd, 2H, J=21.1, 10.6 Hz), 4.66 (d, 1H, J=10.8 Hz), 6.74 (s, 1H), 6.95 (m, 1H), 7.07 (d, 1H, J=8.05 Hz), 7.14 (m, 1H), 7.20 (m, 1H), 7.45 (m, 2H), 7.75 (d, 2H, J=8.05 Hz), 8.05 (s, 1H), 8.90 (s, 1H); MS (ESI+): m\z 454.12.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 1.82 (s, 3H), 4.09 (d, 1H, J=10.3 Hz), 4.16 (d, 1H, J=10.2 Hz), 4.32 (d, 1H, J=10.3 Hz), 4.53 (d, 1H, J=10.2 Hz), 5.28 (s, 2H), 7.00 (m, 4H), 7.17 (d, 2H, J=8.7 Hz), 7.58 (s, 1H), 7.66 (d, 2H, J=9.0 Hz), 7.99 (s, 1H); MS (ESI+): m\z 532.13.
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, CDCl3): δ 1.82 (s, 3H), 4.09 (d, 1H, J=10.2 Hz), 4.16 (d, 1H, J=10.1 Hz), 4.31 (d, 1H, J=10.1 Hz), 4.53 (d, 1H, J=10.3 Hz), 5.25 (s, 2H), 6.94-7.02 (m, 6H), 7.59 (s, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.98 (s, 1H); MS (ESI+): m\z 466.14.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 1.82 (s, 3H), 4.09 (d, 1H, J=10.2 Hz), 4.16 (d, 1H, J=10.2 Hz), 4.31 (d, 1H, J=10.2 Hz), 4.52 (d, 1H, J=10.2 Hz), 5.33 (s, 2H), 6.99 (d, 2H, J=9.0 Hz), 7.10 (d, 2H, J=8.5 Hz), 7.57 (d, 2H, J=7.0 Hz), 7.35 (s, 1H), 7.66 (d, 2H, J=9.0 Hz), 7.99 (s, 1H); MS (ESI+): m\z 516.14.
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, CDCl3): δ 1.82 (s, 3H), 4.09 (d, 1H, J=11.4 Hz), 4.16 (d, 1H, J=11.1 Hz), 4.31 (d, 1H, J=10.1 Hz), 4.53 (d, 1H, J=10.3 Hz), 5.36 (s, 2H), 6.96-6.92 (m, 1H), 6.99 (d, 2H, J=9.0 Hz), 7.09-7.13 (m, 2H), 7.16 (t, 1H, J=7.9 Hz), 7.59 (s, 1H), 7.66 (d, 2H, J=8.1 Hz), 8.03 (s, 1H); MS (ESI+): m\z 466.14.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, CDCl3): δ 1.82 (s, 3H), 2.29 (s, 3H), 4.09 (d, 1H, J=10.3 Hz), 4.16 (d, 1H, J=10.2 Hz), 4.32 (d, 1H, J=10.3 Hz), 4.53 (d, 1H, J=10.2 Hz), 5.25 (s, 2H), 6.92 (d, 2H, J=8.5 Hz), 6.98 (d, 2H, J=8.9 Hz), 7.14 (d, 2H, J=8.5 Hz), 7.58 (s, 1H), 7.65 (d, 2H, J=8.9 Hz), 7.98 (s, 1H); MS (ESI+): m\z 462.17.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, CDCl3): δ 1.21 (d, 6H, J=8.82 Hz), 1.81 (s, 3H), 2.12 (m, 1H, J=8.82 Hz), 4.09 (d, 1H, J=10.3 Hz), 4.16 (d, 1H, J=10.2 Hz), 4.32 (d, 1H, J=10.3 Hz), 4.53 (d, 1H, J=10.2 Hz), 5.22 (s, 2H), 6.92 (d, 2H, J=8.6 Hz), 6.98 (d, 2H, J=8.8 Hz), 7.17 (d, 2H, J=8.6 Hz), 7.58 (s, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.98 (s, 1H); MS (ESI+): m\z 490.20.
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, CDCl3): δ 1.21 (t, 3H, J=7.6 Hz), 1.83 (s, 3H), 2.60 (m, 2H, J=7.6 Hz), 4.09 (d, 1H, J=10.3 Hz), 4.15 (d, 1H, J=10.1 Hz), 4.31 (d, 1H, J=10.1 Hz), 4.53 (d, 1H, J=10.3 Hz), 5.27 (s, 2H), 6.94 (d, 2H, J=8.5 Hz), 6.98 (d, 2H, J=9.0 Hz), 7.14 (d, 2H, J=8.5 Hz), 7.58 (s, 1H), 7.65 (d, 2H, J=9.0 Hz), 7.98 (s, 1H); MS (ESI+): m\z 476.18.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 0.81 (t, 3H, J=8.85 Hz), 1.21 (d, 2H, J=8.95 Hz), 1.58-1.51 (m, 3H, J=8.85 Hz), 1.82 (s, 3H), 2.61 (m, 1H, J=8.95 Hz), 4.09 (d, 1H, J=10.3 Hz), 4.16 (d, 1H, J=10.2 Hz), 4.32 (d, 1H, J=10.3 Hz), 4.53 (d, 1H, J=10.2 Hz), 5.23 (s, 2H), 6.96 (m, 4H), 7.12 (d, 2H, J=8.6 Hz), 7.58 (s, 1H), 7.65 (d, 2H, J=8.7 Hz), 7.98 (s, 1H); MS (ESI+): m\z 504.21.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 1.81 (s, 3H), 4.08 (d, 1H, J=10.2 Hz), 4.18 (d, 1H, J=10.2 Hz), 4.34 (d, 1H, J=10.3 Hz), 4.51 (d, 1H, J=10.2 Hz), 5.28 (s, 2H), 6.93 (m, 1H), 7.02 (d, 2H, J=9.1 Hz), 7.17 (d, 2H, J=8.9 Hz), 7.34 (m, 2H), 7.44 (m, 1H), 7.57 (s, 1H), 8.05 (s, 1H); MS (ESI+): m\z 532.13.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, CDCl3): δ 1.81 (s, 3H), 4.08 (d, 1H, J=10.2 Hz), 4.18 (d, 1H, J=10.2 Hz), 4.34 (d, 1H, J=10.3 Hz), 4.51 (d, 1H, J=10.2 Hz), 5.25 (s, 2H), 6.90-7.03 (m, 5H), 7.33 (m, 2H), 7.43 (m, 1H), 7.57 (s, 1H), 8.04 (s, 1H); MS (ESI+): m\z 466.14.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 1.82 (s, 3H), 4.09 (d, 1H, J=10.2 Hz), 4.19 (d, 1H, J=10.2 Hz), 4.36 (d, 1H, J=10.3 Hz), 4.53 (d, 1H, J=10.2 Hz), 5.29 (s, 2H), 6.93 (m, 1H), 7.02 (d, 2H, J=9.1 Hz), 7.17 (d, 2H, J=8.9 Hz), 7.34 (m, 2H), 7.44 (m, 1H), 7.85 (s; 1H), 8.15 (s, 1H); MS (ESI+): m\z 516.14.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, CDCl3): δ 1.82 (s, 3H), 4.09 (d, 1H, J=10.2 Hz), 4.19 (d, 1H, J=10.2 Hz), 4.36 (d, 1H, J=10.3 Hz), 4.53 (d, 1H, J=10.2 Hz), 5.29 (s, 2H), 6.93 (m, 1H), 7.05-7.15 (m, 3H), 7.22-7.27 (m, 4H), 7.59 (s, 1H), 8.05 (s, 1H); MS (ESI+): m\z 466.14.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, CDCl3): δ 1.82 (s, 3H), 2.12 (s, 3H), 4.07 (d, 1H, J=10.2 Hz), 4.16 (d, 1H, J=10.2 Hz), 4.34 (d, 1H, J=10.3 Hz), 4.51 (d, 1H, J=10.2 Hz), 5.25 (s, 2H), 6.93 (m, 1H), 7.05-7.15 (m, 3H), 7.22-7.27 (m, 4H), 7.60 (s, 1H), 8.05 (s, 1H); MS (ESI+): m\z 462.17.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 1.21 (d, 6H, J=8.82 Hz), 1.82 (s, 3H), 2.15 (s, 3H), 4.07 (d, 1H, J=10.2 Hz), 4.16 (d, 1H, J=10.2 Hz), 4.34 (d, 1H, J=10.3 Hz), 4.51 (d, 1H, J=10.2 Hz), 5.25 (s, 2H), 6.97 (m, 1H), 7.09-7.18 (m, 3H), 7.22-7.27 (m, 4H), 7.71 (s, 1H), 8.05 (s, 1H); MS (ESI+): m\z 462.17.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 1.67 (s, 3H), 3.87 (d, 1H, J=10.2 Hz), 4.09 (d, 1H, J=10.3 Hz), 4.34 (d, 1H, J=10.2 Hz), 4.38 (d, 1H, J=10.3 Hz), 5.16 (m, 2H), 7.03 (d, 2H, J=9.2 Hz), 7.09 (d, 1H, J=8.0 Hz), 7.18 (m, 3H), 7.45 (s, 1H), 7.49 (m, 2H), 7.73 (s, 1H), 8.05 (s, 1H); MS (ESI+): m\z 532.13.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, CDCl3): δ 1.67 (s, 3H), 3.88 (d, 1H, J=10.2 Hz), 4.09 (d, 1H, J=10.3 Hz), 4.36 (d, 1H, J=10.2 Hz), 4.39 (d, 1H, J=10.3 Hz), 5.19 (m, 2H), 7.03 (d, 2H, J=9.2 Hz), 7.09 (d, 1H, J=8.0 Hz), 7.18 (m, 3H), 7.47 (s, 1H), 7.51 (m, 2H), 7.73 (s, 1H), 8.06 (s, 1H); MS (ESI+): m\z 466.14.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 1.71 (s, 3H), 3.89 (d, 1H, J=10.2 Hz), 4.09 (d, 1H, J=10.3 Hz), 4.34 (d, 1H, J=10.2 Hz), 4.38 (d, 1H, J=10.3 Hz), 5.16 (m, 2H), 7.03 (d, 2H, J=9.2 Hz), 7.12 (d, 1H, J=8.0 Hz), 7.19 (m, 3H), 7.47 (s, 1H), 7.59 (m, 2H), 7.85 (s, 1H), 8.10 (s, 1H); MS (ESI+): m\z 516.43.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, CDCl3): δ 1.67 (s, 3H), 3.88 (d, 1H, J=10.2 Hz), 4.09 (d, 1H, J=10.3 Hz), 4.36 (d, 1H, J=10.2 Hz), 4.39 (d, 1H, J=10.3 Hz), 5.19 (m, 2H), 7.03 (m, 1H), 7.09 (d, 1H, J=8.0 Hz), 7.18 (m, 3H), 7.28 (m, 3H) 7.47 (s, 1H), 7.77 (s, 1H), 8.08 (s, 1H); MS (ESI+): m\z 466.14.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ 1.83 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.5 Hz), 7.41 (m, 1H), 7.45 (d, 2H, J=7.5 Hz), 7.51 (m, 2H), 7.79 (m, 2H), 9.08 (s, 1H); MS (ESI+): m\z 419.13.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.81 (s, 3H), 4.37 (d, 1H, J=10.8 Hz), 4.48 (dd, 2H, J=21.1, 10.6 Hz), 4.65 (d, 1H, J=10.8 Hz), 6.98 (d, 2H, J=7.8 Hz), 7.05 (d, 2H, J=8.12 Hz), 7.51 (d, 2H, J=7.8 Hz), 7.97 (d, 2H, J=8.12 Hz), 9.05 (s, 1H); MS (ESI+): m\z 503.12.
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ1.83 (s, 3H), 2.30 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.49 (dd, 2H, J=21.1, 10.6 Hz), 4.66 (d, 1H, J=10.8 Hz), 6.99 (d, 2H, J=7.8 Hz), 7.29 (d, 2H, J=8.05 Hz), 7.51 (d, 2H, J=7.8 Hz), 9.07 (s, 1H); MS (ESI+): m\z 433.15.
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ1.83 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.48 (dd, 2H, J=21.1, 10.6 Hz), 4.65 (d, 1H, J=10.8 Hz), 6.98 (d, 2H, J=7.8 Hz), 7.05 (d, 2H, J=8.12 Hz), 7.51 (d, 2H, J=7.8 Hz), 7.97 (m, 2H), 9.05 (s, 1H); MS (ESI+): m\z 437.12.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.81 (s, 3H), 4.37 (d, 1H, J=10.8 Hz), 4.48 (dd, 2H, J=21.1, 10.6 Hz), 4.65 (d, 1H, J=10.8 Hz), 6.99 (d, 2H, J=7.91 Hz), 7.53 (d, 2H, J=7.91 Hz), 7.68 (d, 2H, J=7.5 Hz), 8.37 (d, 2H, J=7.5 Hz), 9.05 (s, 1H); MS (ESI+): m\z 487.12.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.21 (t, 3H, J=8.85 Hz), 1.83 (s, 3H), 2.28 (m, 2H), 4.39 (d, 1H, J=10.8 Hz), 4.49 (dd, 2H, J=21.1, 10.6 Hz), 4.66 (d, 1H, J=10.8 Hz), 6.99 (d, 2H, J=7.8 Hz), 7.29 (d, 2H, J=8.05 Hz), 7.51 (d, 2H, J=7.8 Hz), 9.07 (s, 1H); MS (ESI+): m\z 444.17.
TLC (DCM: EtOAc 2:8): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ 1.83 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.48 (dd, 2H, J=21.1, 10.6 Hz), 4.65 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.18 Hz), 7.07 (d, 2H, J=7.82 Hz), 7.25 (d, 2H, J=7.82 Hz), 7.45 (d, 2H, J=7.18 Hz), 8.90 (s, 1H); MS (ESI+): m\z 453.12.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.85 (s, 3H), 4.39 (d, 1H, J=10.8 Hz), 4.48 (dd, 2H, J=21.1, 10.6 Hz), 4.65 (d, 1H, J=10.8 Hz), 6.90 (d, 2H, J=7.10 Hz), 7.14 (d, 2H, J=7.53 Hz), 7.45 (d, 2H, J=7.53 Hz), 7.48 (d, 2H, J=7.10 Hz), 8.90 (s, 1H); MS (ESI+): m\z 503.12.
TLC (DCM: EtOAc 2:8): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ 1.83 (s, 3H), 2.30 (s, 3H), 4.36 (d, 1H, J=10.8 Hz), 4.47 (dd, 2H, J=21.1, 10.6 Hz), 4.62 (d, 1H, J=10.8 Hz), 6.93 (d, 2H, J=7.10 Hz), 7.06 (d, 2H, J=7.35 Hz), 7.09 (d, 2H, J=7.35 Hz), 7.48 (d, 2H, J=7.10 Hz), 8.88 (s, 1H); MS (ESI+): m\z 449.14.
TLC (DCM: EtOAc 2:8): Rf=0.42; 1H NMR (400 MHz, Acetone d6): δ 1.82 (s, 3H), 4.35 (d, 1H, J=10.8 Hz), 4.43 (dd, 2H, J=21.1, 10.6 Hz), 4.62 (d, 1H, J=10.8 Hz), 6.82 (d, 2H, J=7.65 Hz), 6.99 (d, 2H, J=7.10 Hz), 7.13 (d, 2H, J=7.65 Hz), 7.51 (d, 2H, J=7.10 Hz), 8.85 (s, 1H); MS (ESI+): m\z 519.11.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ1.82 (s, 3H), 4.07 (d, 1H, J=10.2 Hz), 4.16 (d, 1H, J=10.0 Hz), 4.31 (d, 1H, J=10.0 Hz), 4.52 (d, 1H, J=10.2 Hz), 6.78 (s, 1H), 6.95 (d, 2H, J=8.8 Hz), 7.46-7.51 (m, 3H), 7.58 (s, 1H), 7.83 (m, 4H); MS (ESI+): m\z 418.13
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ1.21 (m, 3H), 1.84 (s, 3H), 2.40 (m, 2H), 4.36 (d, 1H, J=10.8 Hz), 4.44 (d, 1H, J=10.6 Hz), 4.48 (d, 1H, J=10.8 Hz), 4.66 (d, 1H, J=10.6 Hz), 7.09 (d, 2H, J=8.9 Hz), 7.24 (s, 1H), 7.37 (d, 2H, J=8.5 Hz), 7.80 (d, 2H, J=8.5 Hz), 7.88 (d, 2H, J=8.9 Hz), 7.90 (s, 1H); MS (ESI+): m\z 446.46.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.78 (s, 3H), 4.30 (d, 1H, J=10.8 Hz), 4.38 (d, 1H, J=10.6 Hz), 4.42 (d, 1H, J=10.8 Hz), 4.60 (d, 1H, J=10.6 Hz), 7.03 (d, 2H, J=8.9 Hz), 7.18 (m, 1H), 7.19-7.29 (d, 2H, J=8.5 Hz), 7.86 (d, 2H, J=4.7 Hz), 7.89 (s, 1H), 8.03 (m, 1H); MS (ESI+): m\z 454.14.
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ1.80 (s, 3H), 4.32 (d, 1H, J=10.8 Hz), 4.40 (d, 1H, J=10.6 Hz), 4.45 (d, 1H, J=10.8 Hz), 4.62 (d, 1H, J=10.6 Hz), 7.05 (d, 2H, J=8.9 Hz), 7.19-7.29 (d, 2H, J=8.5 Hz), 7.86 (m, 3H), 7.83 (s, 1H), 7.98 (m, 1H); MS (ESI+): m\z 436.12.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.89 (s, 3H), 4.38 (d, 1H, J=10.8 Hz), 4.47 (d, 1H, J=10.6 Hz), 4.49 (d, 1H, J=10.8 Hz), 4.68 (d, 1H, J=10.6 Hz), 7.09 (d, 2H, J=8.9 Hz), 7.26 (s, 1H), 7.39 (d, 2H, J=8.5 Hz), 7.83 (d, 2H, J=8.5 Hz), 7.89, (d, 2H, J=8.9 Hz), 7.92 (s, 1H); MS (ESI+): m\z 486.12.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ1.84 (s, 3H), 2.40 (s, 2H), 4.36 (d, 1H, J=10.8 Hz), 4.44 (d, 1H, J=10.6 Hz), 4.48 (d, 1H, J=10.8 Hz), 4.66 (d, 1H, J=10.6 Hz), 7.09 (d, 2H, J=8.9 Hz), 7.24 (s, 1H), 7.37 (d, 2H, J=8.5 Hz), 7.80 (d, 2H, J=8.5 Hz), 7.88 (d, 2H, J=8.9 Hz), 7.90 (s, 1H); MS (ESI+): m\z 432.14.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ 1.85 (s, 3H), 3.89 (s, 3H), 4.38 (d, 1H, J=10.8 Hz), 4.44 (d, 1H, J=10.6 Hz), 4.48 (d, 1H, J=10.8 Hz), 4.66 (d, 1H, J=10.6 Hz), 7.10 (m, 4H), 7.17 (s, 1H), 7.88 (m, 4H), 8.02 (s, 1H); MS (ESI+): m\z 448.14.
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ 1.80 (s, 3H), 4.32 (d, 1H, J=10.8 Hz), 4.40 (d, 1H, J=10.6 Hz), 4.45 (d, 1H, J=10.8 Hz), 4.62 (d, 1H, J=10.6 Hz), 7.05 (d, 2H, J=8.9 Hz), 7.17 (s, 1H), 7.19-7.29 (d, 2H, J=8.5 Hz), 7.86 (m, 2H), 7.83 (s, 1H), 7.98 (m, 2H); MS (ESI+): m\z 436.12.
TLC (DCM: EtOAc 1:9): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ 1.82 (s, 3H), 4.34 (d, 1H, J=10.8 Hz), 4.43 (d, 1H, J=10.6 Hz), 4.47 (d, 1H, J=10.8 Hz), 4.64 (d, 1H, J=10.6 Hz), 7.12 (d, 2H, J=8.9 Hz), 7.19 (s, 1H), 7.29 (d, 2H, J=8.5 Hz), 7.86 (m, 3H), 7.89 (s, 1H), 8.40 (m, 1H); MS (ESI+): m\z 419.12.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.83 (s, 3H), 4.33 (d, 1H, J=10.8 Hz), 4.42 (d, 1H, J=10.6 Hz), 4.44 (d, 1H, J=10.8 Hz), 4.64 (d, 1H, J=10.6 Hz), 7.05 (d, 2H, J=8.9 Hz), 7.22 (s, 1H), 7.32 (d, 2H, J=8.5 Hz), 7.80 (d, 2H, J=8.5 Hz), 7.85 (d, 2H, J=8.9 Hz), 7.90 (s, 1H); MS (ESI+): m\z 502.12.
TLC (DCM: EtOAc 1:9): Rf=0.45; 1H NMR (400 MHz, Acetone d6): δ0.91 (m, 3H), 1.15 (m, 2H), 1.21 (m, 4H), 1.89 (s, 3H), 2.25 (t, 2H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.95 (d, 2H, J=7.6 Hz), 7.05 (s, 1H), 7.25 (d, 2H, J=7.6 Hz), 7.85 (s, 1H); MS (ESI+): m\z 412.19.
TLC (DCM: EtOAc 1:9): Rf=0.45; 1H NMR (400 MHz, Acetone d6): δ0.91 (m, 3H), 1.15 (m, 2H), 1.21-1.24 (m, 8H), 1.89 (s, 3H), 2.25 (t, 2H), 4.39 (d, 1H, J=10.8 Hz), 4.50 (dd, 2H, J=21.1, 10.6 Hz), 4.69 (d, 1H, J=10.8 Hz), 6.96 (d, 2H, J=7.6 Hz), 7.07 (s, 1H), 7.26 (d, 2H, J=7.6 Hz), 7.83 (s, 1H); MS (ESI+): m\z 440.21.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 1.81 (s, 3H), 4.06 (d, 1H, J=10.2 Hz), 4.14 (d, 1H, J=10.1 Hz), 4.29 (d, 1H, J=10.1 Hz), 4.51 (d, 1H, J=10.2 Hz), 5.18 (s, 2H), 6.60 (s, 1H), 6.92 (d, 2H, J=8.9 Hz), 6.98 (d, 2H, J=9.2 Hz), 7.18 (d, 2H, J=9.2 Hz), 7.56 (s, 1H), 7.74 (d, 2H, J=8.9 Hz); MS (ESI+): m\z 532.12.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, CDCl3): δ 1.81 (s, 3H), 4.06 (d, 1H, J=10.2 Hz), 4.14 (d, 1H, J=10.1 Hz), 4.29 (d, 1H, J=10.1 Hz), 4.51 (d, 1H, J=10.2 Hz), 5.16 (s, 2H), 6.58 (s, 1H), 6.90-6.95 (m, 4H), 7.01 (m, 2H), 7.57 (s, 1H), 7.74 (d, 2H, J=8.8 Hz); MS (ESI+): m\z 466.13.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 1.81 (s, 3H), 4.06 (d, 1H, J=10.2 Hz), 4.14 (d, 1H, J=10.1 Hz), 4.29 (d, 1H, J=10.1 Hz), 4.51 (d, 1H, J=10.2 Hz), 5.24 (s, 2H), 6.61 (s, 1H), 6.92 (d, 2H, J=8.9 Hz), 7.06 (d, 2H, J=8.6 Hz), 7.57 (s, 1H), 7.59 (d, 2H, J=8.6 Hz), 7.75 (d, 2H, J=8.9 Hz); MS (ESI+): m\z 516.13.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, CDCl3): δ 1.81 (s, 3H), 4.06 (d, 1H, J=10.2 Hz), 4.14 (d, 1H, J=10.1 Hz), 4.29 (d, 1H, J=10.1 Hz), 4.51 (d, 1H, J=10.2 Hz), 5.26 (s, 2H), 6.63 (s, 1H), 6.92 (d, 2H, J=8.8 Hz), 6.98 (m, 1H), 7.02-7.09 (m, 2H), 7.12 (m, 1H), 7.57 (s, 1H), 7.75 (d, 2H, J=8.8 Hz); MS (ESI+): m\z 466.13.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, CDCl3): δ 1.83 (s, 3H), 2.32 (s, 3H), 4.08 (d, 1H, J=10.3 Hz), 4.15 (d, 1H, J=10.1 Hz), 4.31 (d, 1H, J=10.1 Hz), 4.53 (d, 1H, J=10.3 Hz), 5.19 (s, 2H), 6.60 (s, 1H), 6.92 (m, 4H), 7.13 (d, 2H, J=7.8 Hz), 7.59 (s, 1H), 7.76 (d, 2H, J=8.8 Hz); MS (ESI+): m\z 462.15.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 1.25 (d, 6H, J=6.9 Hz), 1.83 (s, 3H), 2.89 (m, 1H), 4.09 (d, 1H, J=10.3 Hz), 4.15 (d, 1H, J=10.1 Hz), 4.30 (d, 1H, J=10.1 Hz), 4.53 (d, 1H, J=10.3 Hz), 5.18 (s, 2H), 6.61 (s, 1H), 6.93 (m, 4H), 7.19 (d, 2H, J=8.0 Hz), 7.58 (s, 1H), 7.75 (d, 2H, J=7.7 Hz); MS (ESI+): m\z 490.19.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 1.23 (m, 3H), 1.83 (s, 3H), 2.85 (m, 2H), 4.09 (d, 1H, J=10.3 Hz), 4.15 (d, 1H, J=10.1 Hz), 4.30 (d, 1H, J=10.1 Hz), 4.53 (d, 1H, J=10.3 Hz), 5.18 (s, 2H), 6.61 (s, 1H), 6.93 (m, 4H), 7.19 (d, 2H, J=8.0 Hz), 7.58 (s, 1H), 7.75 (d, 2H, J=7.7 Hz); MS (ESI+): m\z 476.17.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 1.11 (m, 3H), 1.22 (m, 3H), 1.28 (m, 2H), 1.82 (s, 3H), 2.89 (m, 1H), 4.09 (d, 1H, J=10.3 Hz), 4.15 (d, 1H, J=10.1 Hz), 4.30 (d, 1H, J=10.1 Hz), 4.53 (d, 1H, J=10.3 Hz), 5.18 (s, 2H), 6.61 (s, 1H), 6.93 (m, 4H), 7.19 (d, 2H, J=8.0 Hz), 7.58 (s, 1H), 7.75 (d, 2H, J=7.7 Hz); MS (ESI+): m\z 504.20.
TLC (DCM: EtOAc 1:9): Rf=0.30; 1H NMR (400 MHz, CDCl3): δ 1.81 (s, 3H), 4.06 (d, 1H, J=10.2 Hz), 4.14 (d, 1H, J=10.1 Hz), 4.29 (d, 1H, J=10.1 Hz), 4.51 (d, 1H, J=10.2 Hz), 5.26 (s, 2H), 6.78 (s, 1H), 6.95 (d, 2H, J=8.8 Hz), 7.51-7.46 (m, 3H), 7.58 (s, 1H), 7.83 (m, 4H); MS (ESI+): m\z 448.14.
TLC (DCM: EtOAc 1:9): Rf=0.40; 1H NMR (400 MHz, CDCl3): δ 1.81 (s, 3H), 4.06 (d, 1H, J=10.2 Hz), 4.14 (d, 1H, J=10.1 Hz), 4.29 (d, 1H, J=10.1 Hz), 4.51 (d, 1H, J=10.2 Hz), 5.26 (s, 2H), 6.63 (s, 1H), 6.92 (d, 2H, J=8.8 Hz), 7.02-7.09 (m, 2H), 7.57 (s, 1H), 7.75 (d, 2H, J=8.8 Hz), 7.89 (m, 1H); MS (ESI+): m\z 484.12.
TLC (DCM: EtOAc 2:8): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ1.80 (s, 3H), 4.32 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 6.87 (d, 2H, J=9.0 Hz), 7.23 (d, 2H, J=8.4 Hz), 7.44 (d, 2H, J=9.1 Hz), 7.68 (m, 2H), 7.90 (s, 1H), 8.11 (s, 1H), 8.34 (s, 1H); MS (ESI+): m\z 493.12.
(R)-1-(4-ethylphenyl)-3-{4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)methoxyphenyl}urea (compound IIA2, Table 6,
TLC (DCM: EtOAc 2:8): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ 1.21 (t, 3H, J=8.85 Hz), 1.80 (s, 3H), 2.28 (m, 2H, J=8.85 Hz), 4.30 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 6.87 (d, 2H, J=9.0 Hz), 7.23 (d, 2H, J=8.4 Hz), 7.44 (d, 2H, J=9.1 Hz), 7.64 (d, 2H, J=9.1 Hz), 7.90 (s, 1H), 8.11 (s, 1H), 8.34 (s, 1H); MS (ESI+): m\z 437.17.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.81 (s, 3H), 4.34 (m, 3H), 4.65 (d, 1H, J=10.8 Hz), 6.89 (d, 2H, J=9.0 Hz), 7.25 (d, 2H, J=8.4 Hz), 7.45 (d, 2H, J=9.1 Hz), 7.68 (d, 2H, J=9.1 Hz), 7.90 (s, 1H), 8.11 (s, 1H), 8.34 (s, 1H); MS (ESI+): m\z 477.13.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.81 (s, 3H), 2.38 (s, 3H), 4.32 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 6.85 (d, 2H, J=9.0 Hz), 7.25 (d, 2H, J=8.4 Hz), 7.47 (d, 2H, J=9.1 Hz), 7.65 (d, 2H, J=9.1 Hz), 7.90 (s, 1H), 8.10 (s, 1H), 8.32 (s, 1H); MS (ESI+): m\z 423.15.
TLC (DCM: EtOAc 2:8): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ1.82 (s, 3H), 3.76 (s, 3H), 4.33 (m, 3H), 4.62 (d, 1H, J=10.7 Hz), 6.86 (m, 4H), 7.44 (m, 4H), 7.91 (s, 1H), 8.03 (s, 2H; MS (ESI+): m\z 439.15.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.80 (s, 3H), 4.32 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 6.87 (d, 2H, J=9.0 Hz), 7.23 (d, 2H, J=8.4 Hz), 7.44 (d, 2H, J=9.1 Hz), 7.64 (d, 2H, J=9.1 Hz), 7.90 (s, 1H), 8.11 (s, 1H), 8.34 (s, 1H); MS (ESI+): m\z 493.12.
TLC (DCM: EtOAc 2:8): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ 1.80 (s, 3H), 3.73 (s, 3H), 4.33 (m, 3H), 4.60 (d, 1H, J=10.7 Hz), 6.83 (m, 4H), 7.40 (m, 4H), 7.89 (s, 1H), 8.00 (s, 2H; MS (ESI+): m\z 455.13.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.80 (s, 3H), 4.32 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 6.87 (d, 2H, J=9.0 Hz), 7.23 (d, 2H, J=8.4 Hz), 7.44 (d, 2H, J=9.1 Hz), 7.64 (d, 2H, J=9.1 Hz), 7.90 (s, 1H), 8.11 (s, 1H), 8.34 (s, 1H); MS (ESI+): m\z 509.10.
TLC (DCM: EtOAc 2:8): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ1.80 (s, 3H), 4.30 (m, 3H), 4.60 (d, 1H, J=10.8 Hz), 6.85 (d, 2H, J=9.0 Hz), 7.22 (d, 2H, J=8.4 Hz), 7.42 (d, 2H, J=9.1 Hz), 7.65 (m, 2H), 7.90 (s, 1H), 8.10 (s, 1H), 8.32 (s, 1H); MS (ESI+): m\z 443.11.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.81 (s, 3H), 4.34 (m, 3H), 4.65 (d, 1H, J=10.8 Hz), 6.89 (d, 2H, J=9.0 Hz), 7.25 (d, 2H, J=8.4 Hz), 7.45 (d, 2H, J=9.1 Hz), 7.68 (d, 2H, J=9.1 Hz), 7.90 (s, 1H), 8.11 (s, 1H), 8.34 (s, 1H); MS (ESI+): m\z 493.10.
TLC (DCM: EtOAc 2:8): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ1.80 (s, 3H), 2.38 (s, 3H), 4.01 (brs, 1H), 4.32 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 6.98 (d, 2H, J=7.85 Hz), 7.02 (d, 2H, J=7.85 Hz), 7.12 (d, 2H, J=7.25 Hz), 7.64 (d, 2H, J=7.25 Hz), 7.90 (s, 1H); MS (ESI+): m\z 444.11.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.81 (s, 3H), 4.03 (brs, 1H), 4.33 (m, 3H), 4.64 (d, 1H, J=10.8 Hz), 6.94 (d, 2H, J=7.45 Hz), 7.12 (d, 2H, J=7.05 Hz), 7.64 (d, 2H, J=7.05 Hz), 7.89 (s, 1H); MS (ESI+): m\z 514.08.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.83 (s, 3H), 4.05 (brs, 1H), 4.35 (m, 3H), 4.65 (d, 1H, J=10.8 Hz), 6.98 (d, 2H, J=7.05 Hz), 7.12 (d, 2H, J=7.26 Hz), 7.30 (d, 2H, J=7.05 Hz), 7.64 (d, 2H, J=7.26 Hz), 7.91 (s, 1H); MS (ESI+): m\z 498.08.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.80 (s, 3H), 3.20 (s, 3H), 4.32 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 6.78-6.92 (m, 5H), 7.02 (d, 2H, J=7.25 Hz), 7.64 (d, 2H, J=7.25 Hz), 7.85 (s, 1H); MS (ESI+): m\z 444.11.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.80 (s, 3H), 2.34 (s, 3H), 3.20 (s, 3H), 4.33 (m, 3H), 4.63 (d, 1H, J=10.8 Hz), 6.98 (d, 2H, J=7.85 Hz), 7.02 (d, 2H, J=7.85 Hz), 7.12 (d, 2H, J=7.25 Hz), 7.64 (d, 2H, J=7.25 Hz), 7.90 (s, 1H); MS (ESI+): m\z 458.13.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.83 (s, 3.20 (s, 3H), 4.35 (m, 3H), 4.65 (d, 1H, J=10.8 Hz), 6.98 (d, 2H, J=7.05 Hz), 7.12 (d, 2H, J=7.26 Hz), 7.30 (d, 2H, J=7.05 Hz), 7.64 (d, 2H, J=7.26 Hz), 7.91 (s, 1H); MS (ESI+): m\z 512.10.
TLC (DCM: EtOAc 2:8): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ 1.81 (s, 3H), 3.19 (s, 8H), 4.32 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 7.01 (m, 2H), 7.05-7.24 (m, 3H), 7.12 (d, 2H, J=7.05 Hz), 7.64 (d, 2H, J=7.05 Hz), 7.89 (s, 1H); MS (ESI+): m\z 499.15.
TLC (DCM: EtOAc 2:8): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ 1.82 (s, 3H), 3.21 (s, 8H), 4.33 (m, 3H), 4.63 (d, 1H, J=10.8 Hz), 6.94 (d, 2H, J=7.15 Hz), 7.12 (d, 2H, J=7.05 Hz), 7.25 (m, 2H), 7.64 (d, 2H, J=7.05 Hz), 7.91 (s, 1H); MS (ESI+): m\z 517.14.
TLC (DCM: EtOAc 2:8): Rf=0.35; 1H NMR (400 MHz, Acetone d6): δ1.81 (s, 3H), 3.20 (s, 8H), 4.31 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 6.94-7.12 (m, 3H), 7.21 (d, 2H, J=7.05 Hz), 7.35 (m, 1H), 7.64 (d, 2H, J=7.05 Hz), 7.90 (s, 1H); MS (ESI+): m\z 533.11.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.81 (s, 3H), 3.19 (s, 8H), 4.31 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 6.94 (d, 2H, J=7.15 Hz), 7.01 (d, 2H, J=7.05 Hz), 7.25 (d, 2H, J=7.15 Hz), 7.64 (d, 2H, J=7.05 Hz), 7.89 (s, 1H); MS (ESI+): m\z 583.13.
TLC (DCM: EtOAc 2:8): Rf=0.20; 1H NMR (400 MHz, Acetone d6): δ1.29 (m, 3H), 1.80 (s, 3H), 3.25 (s, 8H), 4.13 (m, 2H), 4.31 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 7.12 (d, 2H, J=7.15 Hz), 7.64 (d, 2H, J=7.15 Hz), 7.95 (s, 1H); MS (ESI+): m\z 495.14.
TLC (DCM: EtOAc 2:8): Rf=0.20; 1H NMR (400 MHz, Acetone d6): δ1.81 (s, 3H), 3.19 (s, 8H), 4.31 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 6.94 (m, 3H), 7.01 (d, 2H, J=7.05 Hz), 7.30 (m, 2H), 7.64 (d, 2H, J=7.05 Hz), 7.91 (s, 1H); MS (ESI+): m\z 527.15.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.53 (m, 211), 1.59 (m, 4H), 1.80 (s, 3H), 3.07 (m, 4H), 4.31 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 7.12 (d, 2H, J=7.15 Hz), 7.64 (d, 2H, J=7.15 Hz), 7.95 (s, 1H); MS (ESI+): m\z 422.13.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ1.59 (m, 4H), 1.80 (s, 3H), 2.59 (m, 1H), 3.17 (m, 4H), 4.31 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 6.95-7.05 (m, 5H), 7.12 (d, 2H, J=7.15 Hz), 7.64 (d, 2H, J=7.15 Hz), 7.93 (s, 1H); MS (ESI+): m\z 498.16.
TLC (DCM: EtOAc 2:8): Rf=0.40; 1H NMR (400 MHz, Acetone d6): δ 1.92 (m, 4H), 1.80 (s, 3H), 3.07 (m, 4H), 4.31 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 7.12 (d, 2H, J=7.15 Hz), 7.64 (d, 2H, J=7.15 Hz), 7.95 (s, 1H); MS (ESI+): m\z 408.11.
TLC (DCM: EtOAc 2:8): Rf=0.30; 1H NMR (400 MHz, Acetone d6): δ 1.80 (s, 3H), 2.96 (m, 4H), 3.67 (m, 4H), 4.31 (m, 3H), 4.62 (d, 1H, J=10.8 Hz), 7.14 (d, 2H, J=7.15 Hz), 7.65 (d, 2H, J=7.15 Hz), 7.99 (s, 1H); MS (ESI+): m\z 424.11.
Table 1 shows the structure of representative compounds IA1-IA16 belonging to formula IA and synthesized as per scheme 5 provided in
Table 2 shows the structure of representative compounds IA17-IA24 belonging to formula IA and synthesized as per scheme 5 provided in
Table 3 shows the structure of representative compounds IA25-IA42 belonging to formula IA and synthesized as per scheme 9 provided in
Table 4 shows the structure of representative compounds IB1-IB10 belonging to formula IB and synthesized as per scheme 11 and scheme 13 provided in
Table 5 shows the structure of representative compounds IC1-IC22 belonging to formula IC and synthesized as per scheme 15 and scheme 17 provided in
Table 6 shows the structure of representative compounds IIA1-IIA10 belonging to formula IIA and synthesized as per scheme 19 provided in
Table 7 shows the structure of representative compounds IIB1-IIB6 belonging to formula IIB and synthesized as per scheme 21 provided in
Table 8 shows the structure of representative compounds IIC1-IIC10 belonging to formula IIC and synthesized as per scheme 23 provided in
The physiochemical properties (log P0/w, log S, log Khsa) of the compounds IA1 to IIC10 were evaluated by using the schrodinger software. The detailed results were shown in Table 9.
MIC Determination:
MIC was determined by broth dilution method against M. tuberculosis H37Rv (ATCC 27294; American Type Culture Collection, Manassas, Va.), M. tuberculosis MDR (resistant to isoniazid and rifampicin) and M. tuberculosis XDR (resistant to isoniazid, rifampicin, amikacin and moxifloxacin). The bacterial strains were grown for 10 to 15 days in Middlebrook 7H9 broth (Difco Laboratories, Detroit, Mich.) supplemented with 0.5% (v/v) glycerol, 0.25% (v/v) Tween 80 (Himedia, Mumbai India), and 10% ADC (albumin dextrose catalase; Becton Dickinson, Sparks, Md.) under shaking conditions at 37° C. in 5% CO2 to facilitate exponential-phase growth of the organism. Bacterial suspension was prepared by suspending M. tuberculosis growth in normal saline containing 0.5% tween 80 and turbidity was adjusted to 1 McFarland standard which is equivalent to 1.5×107 CFU/ml. The 2-fold serial dilutions of compounds IA1 to IIC10 were prepared in Middle brook 7H9 (Difco laboratories) for M. tuberculosis in 100 □l per well in 96-well U bottom microtitre plates (Tarson, Mumbai, India). The above-mentioned bacterial suspension was further diluted in the growth media and 100 □l volume of this diluted inoculum was added to each well of the plate resulting in the final inoculum of 5×105 CFU/ml in the well and the final concentrations of compound IA1 to IIC10 ranged from 0.015 to 32 μg/ml. The plates were incubated at 37° C. for 3-weeks in 5% CO2. The plates were read visually and the minimum concentration of the compound showing no turbidity was recorded as MIC.
Results:
Triazolyl containing 6-nitro-2,3-dihydroimidazo[2,1-b]-oxazole compounds IA1-IA42, were screened against both sensitive H37Rv as well as multi- and extensive-drug resistant strains of M. tuberculosis, wherein 12 compounds IA3, IA5, IA11, IA12, IA25, IA26, IA27, IA28, IA31, IA32, IA33 and IA34 showed MIC value of <1.0 μg/ml (results provided in Table 9). Two compounds IA25 and IA33 showed very potent MIC of 0.12 μg/ml against sensitive and resistant strains of M. tuberculosis. Tetrazolyl containing 6-nitro-2,3-dihydroimidazo[2,1-b]-oxazole compounds IB1-IB10 showed MIC of 1 to 4.0 μg/ml against H37Rv, MDR and XDR M. tuberculosis. Isoxazolyl containing 6-nitro-2,3-dihydroimidazo[2,1-b]-oxazole compounds IC1-IC22 were also screened against both sensitive H37Rv as well as multi- and extensive-drug resistant strains of M. tuberculosis, wherein 11 compounds IC1, IC3, IC7, IC10, IC13, IC14, IC15, IC16, IC17, IC18 and IC22 showed potent MIC value of <1.0 μg/ml. Among these compounds, three compounds IC1, IC13 and IC14 showed MIC value of 0.06, 0.12 and 0.06 μg/ml respectively against H37Rv M. Tuberculosis. Uridyl containing 6-nitro-2,3-dihydro imidazo[2,1-b]-oxazole compounds IIA1-IIA10 were also synthesized and screened against sensitive H37Rv as well as multi- and extensive-drug resistant strains of M. tuberculosis, wherein 4 compounds IIA2, IIA3, IIA4 and IIA6 showed MIC value of <1.0 μg/ml against H37Rv, MDR and XDR M. tuberculosis. Sulphanamidyl containing 6-nitro-2,3-dihydroimidazo[2,1-b]-oxazole compounds IIB1-IIB6 and IIC1-IIC10 were also synthesized and screened, wherein two compounds IIC8 and IIC10 showed MIC of 0.5 μg/ml against sensitive and resistant strains of M. tuberculosis. From these medicinal chemistry program, several new generation nitroimidazole based compounds were identified which possessed potent MIC against sensitive as well as resistant strain of M. tuberculosis
Cell Culture:
The study was carried out using macrophage J774 cells line (ATCC-USA). Cells were grown in Rosewell Park Memorial Institute Medium (RPMI) containing 10% fetal calf serum (FCS) and supplemented with 75 mg/liter penicillin, 100 mg/liter streptomycin, 110 mg/liter Sodium pyruvate, 2.38 gm/liter HEPES, 0.05 mM 2 β-mercaptoethanol, and 2 gm/liter NaHCO3, in a humidified atmosphere in 5% CO2 at 37° C., and were sub-cultured at 1:4 ratio once a week.
Cell Treatment:
Cells were plated at a density of 3×104 cells/cm2 and maintained in culture medium for 12 hours. Cells were seeded onto 96-well flat bottom plates and FCS was reduced to 5% for the experiment. Stock solutions of compounds IA1 to IIC10 were prepared fresh to avoid oxidation. Cells were incubated with the compounds (40 μg/ml) for 24 hrs.
Cytotoxicity Assays:
After the completion of incubation, the medium was removed and cell viability was evaluated by assaying for the ability of functional mitochondria to catalyze the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to form formazan salt by mitochondrial dehydrogenases, and determined by Elisa reader at 450 nm (Multiskan Spectrum; Thermo Electron Corporation, USA). Percentage cytotoxicity was calculated with respect to the untreated cells.
Results:
Compounds IA1 to IIC10 were not toxic up to 40 μg/ml concentration and the cytotoxicity assay results are shown in Table 9.
Table 9 shows the physico-chemical properties, Anti-tuberculosis activity and cytotoxicity of representative compound shown in tables 1 to 8.
Compounds were administered orally to mice (Balb/c mice) at a dose of 5 mg/kg as a suspension in 0.5% CMC and Tween 80. Samples were derived from plasma at different time points i.e. 0.16 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h, which were then analysed by LC-MS/MS to generate the required pharmacokinetic parameters.
Result:
Four compounds IA25, IA33, IC13 and IC14 were studied for the pharmacokinetic properties along with OPC-67683 (clinical candidate of Otsuka). Two compounds IA25 (Cmax 1023 nM and AUC 13960.67 nM*hr), IC13 (Cmax 2533.81 nM and AUC 33679 nM*hr) showed improved pharmacokinetic properties compared to OPC-67683 (Cmax 668 nM and AUC 9322.33 nM*hr). The detailed pharmacokinetic properties for the four compounds are shown in Table 11.
The efficacy of compounds IA25 and IIA3 (conc range 4 μg/ml to 0.007 μg/ml) in combination with currently used anti-TB drugs such as rifampicin, isoniazid and ethambutol (each drug tested at conc range 4 μg/ml to 0.007 mg/ml), wherein the ratio of drugs was ranging between 0.1% to 50%, was determined in vitro using checkerboard method. The checkerboard procedure was performed based on the MIC values by the broth microdilution method. The checkerboard method was performed in 96 well U bottom microtitre plates. 100 microliters of 4× concentration of drug was added to first column of the plate. 50 microliters from first column was transferred to second column and was serially diluted in horizontal manner upto column 10 of the plate. Seven dilutions of 4× concentration of compound were prepared in eppendorfs and fifty microliters of each concentration was added vertically starting from eleventh column of row eight to row second of the plate. First row of the plate served as drug control. 100 microliters of 1:10 diluted of 1 Mc Farland inoculum was added to each well of the plate. Plates were then incubated at 37° C. for 14 days. MIC of drug alone and in presence of compound and vice versa was observed visually. The level of synergy was determined by calculating the fractional inhibitory concentration (FIC) index based on the following formula: FIC of drug A=MIC of drug A in combination/MIC of drug A alone; FIC of drug B=MIC of drug B in combination/MIC of drug B alone; and FIC index=FIC of drug A+FIC of drug B. Results of FIC index were interpreted as follows: ≦0.5: synergy, >0.5 to 0.75: partial synergy, >0.75 to 1.0: additive effect, >1.0 to 4.0: indifference, and >4.0: antagonism. The FIC index value for each concentration of two-drug combination was calculated and the minimum value was adopted.
Result:
The efficacy of compound IA25 in combination with known anti tuberculosis drugs has shown additive effect with rifampicin, synergistic effect with isoniazid and additive effect with ehambutol. Similarly compound IIA3 in combination with known anti tuberculosis drugs has shown synergistic effect with rifampicin, additive effect with isoniazid and additive effect with ehambutol and the detailed results of combination studies given in Table 10.
Compounds of formula I and II of general formula 1 have shown potent MIC against H37Rv TB as well MDR-TB and XDR-TB.
Compounds of the general formula 1 exhibit promising pharmaco-kinetics properties with acceptable Cmax and AUC.
Compounds of the formula I and II of general formula 1 shows synergistic as well as additive affect in combination studies with other first line anti-TB agents such as isoniazid, rifampicine and ethambutol.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2954/DEL/2013 | Oct 2013 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IN2014/000202 | 3/31/2014 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2015/049693 | 4/9/2015 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 7262212 | Tsubouchi | Aug 2007 | B2 |
| 7666864 | Ding | Feb 2010 | B2 |
| 8163753 | Tsubouchi | Apr 2012 | B2 |
| Number | Date | Country |
|---|---|---|
| 2007013477 | Feb 2007 | WO |
| Entry |
|---|
| Nagarajan, Kuppuswamy et al., “Nitroimidazoles XXI** 2,3-dihydro-6-nitroimidazo [2,1-b] oxaoles with antitubercular activity”, Eur. J. Med. Chem. 1989, 24, 63. |
| Ashtekar, D. R. et al., “In Vitro and In Vivo Activities of the Nitroimidazole CGI 17341 against Mycobacterium tuberculosis,” Antimicrobial Agents and Chemotherapy,1993, 37, 183. |
| Dye, Christopher et al., “Global Burden of Tuberculosis Estimated Incidence, Prevalence, and Mortality by Country,” American Medical Association, 1999, 282, 677. |
| Stover, Kendall et al., “A Small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis,” Nature, 2000,405, 962. |
| Bemer-Melchior, Pascale et al., “Comparison of the in vitro activites of rifapentine and rifampicin against Mycobacterium tuberculosis complex,” Journal of Antimicrobial Chemotherapy, 2000, 46, 571. |
| Sasaki, Hirofumi et al., “Synthesis and Antituberculosis Activity of a Novel Series of Optically Active 6-Nitro-2,3-dihydroimidazo [2,1-b] oxazoles,” J. Med. Chem. 2006, 49, 7854. |
| Edney, Anna, “J&J Sirturo Winds FDA Approval to Treat Drug-Resistatn TB,” Bloomberg, 2013. |
| Number | Date | Country | |
|---|---|---|---|
| 20160244462 A1 | Aug 2016 | US |
