Compounds for treating bacterial infections and enhancing antibiotics

Abstract

The present invention relates to compounds for treating bacterial infections and enhancing antibiotics. Provided herein are compounds and methods for treating bacterial infections caused by, for example, gram-positive bacteria, gram-negative bacteria, and / or mycobacteria. Also provided herein are compounds and methods for enhancing the effect of an antibiotic in the treatment of a bacterial infection. Also provided are pharmaceutical compositions comprising the compounds as described herein.

Description

[0001] This application is a divisional application of the invention patent application with application date of December 18, 2020, application number 202080088030.6, and invention name “Compounds for treating bacterial infections and enhancing antibiotics”.

[0002] Cross-reference to priority application

[0003] This application claims priority to U.S. Provisional Application No. 62 / 950,852, filed on December 19, 2019, which is incorporated herein by reference in its entirety. Technical Field

[0004] The present invention provides compounds useful for treating medical conditions caused by bacteria or as potentiators of antibiotics for treating medical conditions caused by bacteria. Background Art

[0005] Despite the overall success of antibiotics in reducing the impact of infectious diseases in the modern world, their easy availability has led to overuse, which has led to the development of bacterial resistance. Antibiotic resistance is on the rise worldwide, leading the World Health Organization to classify antibiotic resistance as “no longer a serious threat predicted for the future” (“Antimicrobial resistance: global report on surveillance 2014,” World Health Organization, April 2014). Antibiotic resistance is associated with inappropriate antibiotic prescribing, inappropriate dosing, and missed doses. In the United States, approximately 2.8 million people become infected with antibiotic-resistant bacteria each year, and approximately 35,000 die as a result (“Antibiotic / Antimicrobial Resistance (AR / AMR)” Centers for Disease Control and Prevention, https: / / www.cdc.gov / drugresistance / ). Some bacteria are naturally resistant to certain types of antibiotics, while others may acquire resistance through genetic mutations or horizontal gene transfer from species that are already resistant. Bacteria can reduce the effectiveness of antibiotics by altering or inactivating the drug, changing the target or binding site, altering the metabolic pathways that propagate the drug's effects, or reducing the drug's accumulation within the cell by decreasing drug permeability or increasing efflux. Certain bacteria, commonly known as "superbugs," may eventually become resistant to multiple types of antibiotics, necessitating higher doses of alternative drugs that are often more costly and toxic.

[0006] Several preventive measures have been proposed to slow the development of bacterial resistance to currently available antibiotics. Proper antibiotic stewardship and improved hygiene have provided significant progress in preventing future resistance. Nevertheless, new therapies are necessary to treat infections caused by currently resistant strains of bacteria. From the 1950s to the 1970s was the peak of antibiotic discovery, but since then, no new classes of antibiotics have been discovered, and the development of new antibiotics in existing classes has been minimal. Alternative strategies, such as the development of bacterial vaccines and phage therapy, have not yet achieved the necessary success for widespread use.

[0007] In the 1920s, researchers discovered that the antidiabetic drug Synthalin had therapeutic activity against Trypanosoma brucei infection in mice. Among a series of subsequently developed analogs, pentamidine was found to be effective against T. rhodesiense infection in mice (Yorke W. "Recent work on the chemotherapy of protozoal infections", Trans. R., Soc. Trop. Med. Hyg. 1940, 33: 463). It was not until the 1960s that pentamidine began to be used on a limited basis to treat protozoan infections, and it was not until the 1980s that pentamidine was more widely used to treat Pneumocystis pneumonia in immunocompromised individuals (such as AIDS patients) (Sands et al., "Pentamidine: A Review", Reviews of Infectious Diseases 1985, 7 (5): 625-634). In recent years, pentamidine has regained interest as a possible therapeutic agent for the treatment of antibiotic-resistant bacterial infections. For example, pentamidine has been shown to enhance the sensitivity of resistant bacteria to colistin, one of the last-resort antibiotics (Stokes et al. "Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance", Nat. Microbiol. 2017, 2: 17028; Bean et al. "Pentamidine: a drug to consider re-purposing in the targeted treatment of multi-drug resistant bacterial infections?" J. Lab. Precis. Med. 2017, 2: 49).

[0008]

[0009] The use of amidine compounds in biological applications is described in the following: Geratz et al. "Novel Bis (benzamidino) Compounds with an Aromatic Central Link. Inhibitors of Thrombin, Pancreatic Kallikrein, Trypsin, and Complement" J. Med. Chem. 1976, 19 (5): 634; Parrish et al. "Structure-Activity Relationships for the Inhibition of Acrosin by Benzamidine Derivati ​​ves" J. Med. Chem. 1978, 21 (11) 1132; Patrick et al. "Synthesis and an tiprotozoal activities of dicationic bis (phenoxymethyl) benzenes, bis (phenoxymethyl) naphthalenes, and bis (benzyoxy) naphthalenes" Eur. J. Med. Chem.2009, 44:3543; Giordani et al., “Green Fluorescent Diamidine as Diagnostic Probes for Trypanosomes,” Antimicrobial Agents and Chemotherapy 2014, 58:1793; Munde et al., “The Unusual Monomer Recognition of Guanine-Containing Mixed Sequence DNA by a Dithiophene Heterocyclic Diamidine,” Biochemistry 2014, 53:1218; Araf et al., “Novel linear triaryl guanidines, N-substituted guanidines and potential prodrugs as antiprotozoal agents,” European Journal of Medicinal Chemistry, 2008, 43:2901; Stephens et al., “Diguanidino and ‘Reversed’ Diamidino 2,5-Diarylfurans as Antimicrobial Agents,” J. Med. Chem, 2001, 44:1741; Munde et al., “Structure-dependent inhibition of the ETS-family transcription factor PU.1 by novel heterocyclic diamidines,” Nucleic Acids Research, 2014, 42:1379; Gonzalez, et al., “Synthesis and antiparasitic evaluation of bis-2,5-[4-guanidinophenyl] thiophenes,” Eur J Med Chem, 2007, 42:552; and Wang et al., “Evaluation of the Influence of Compound Structure on Stacked-Dimer Formation in the DNA Minor Groove,” Biochemistry, 2001, 40, 2511.

[0010] The University of North Carolina describes the use of amidine compounds to inhibit RSV-induced cell fusion in U.S. Pat. No. 4,619,942, entitled "Inhibition of Respiratory Syncytial Virus-Induced Cell Fusion by Amidino Compounds."

[0011] Eisai Co., Ltd., in U.S. Patent No. 4,034,010, entitled "Bis-(Meta-Amidinophenoxy)-Compounds and Pharmacologically Acceptable Acid Addition Salts Thereof," describes the use of amidine compounds as antifungal, antibacterial, and antitrichomonal therapeutic agents.

[0012] Berlex Laboratories describes the use of amidine compounds as anticoagulants in International Patent Application Publication No. WO96 / 28427, entitled “Benzamidine Derivatives Their Preparation and Their Use as Anti-Coagulants”; International Patent Application Publication No. WO97 / 29067, entitled “Benzamidine Derivatives Substituted by Amino Acid and Hydroxy Acid Derivatives and Their Use as Anti-Coagulants”; and International Patent Application Publication No. WO00 / 31068, entitled “Polyhydroxylated Heterocyclic Derivatives as Anticoagulants”.

[0013] The use of amidine compounds in the treatment of amyloidosis and microbial infections is jointly disclosed by the Georgia State University Research Foundation, Inc. and the University of North Carolina in International Patent Application Publication No. WO2003 / 103598 entitled "Amidine Derivatives for Treating Amyloidosis" and International Patent Application Publication No. WO2005 / 033065 entitled "Novel Amidine Compounds for Treating Microbial Infections". The use of compounds for treating microbial infections including protozoa is disclosed in WO 2005 / 086808 and WO 2005 / 040132. Bichalcophene as an antiprotozoal agent is also described in US2006 / 0293540 assigned to the University of North Carolina and the Georgia State University Research Foundation, Inc.

[0014] The Georgia State University Research Foundation and Albert Einstein College of Medicine, Inc. disclosed in WO 2017 / 223260 the use of amidine and diamidine compounds for inhibiting PU.1 and treating conditions associated with abnormal PU.1 levels.

[0015] The Georgia State University Research Foundation and the Ohio Innovation Foundation disclosed the use of amidine compounds for treating fungal infections in WO 2018 / 045106, and compounds for treating parasitic organisms in WO 2018 / 045104.

[0016] The Georgia State University Research Foundation, Inc. also discloses the use of amidine compounds as DNA targeting agents in US 2010 / 0249175, and compounds for use against protozoa in WO 2009 / 051796 and WO 2005 / 086754.

[0017] Neurochem Corporation describes the use of amidine compounds in the treatment of amyloidosis in International Patent Application Publication No. WO03 / 017994, entitled "Amidine Derivatives for Treating Amyloidosis".

[0018] Altana Pharma AG describes compounds including amidine derivatives as tryptase inhibitors in US Pat. No. 9,960,588, entitled "Tryptase Inhibitors."

[0019] Mpex Pharmaceuticals describes the use of amidine compounds as bacterial efflux inhibitors in International Patent Application Publication No. WO2005 / 089738, entitled "Use and Administration of Bacterial Efflux Inhibitors". Bostian et al. also describe similar uses of amidine compounds as bacterial efflux inhibitors in the treatment of eye and ear infections in U.S. Patent Application Publication No. US2008 / 0132457, entitled "Bacterial Efflux Inhibitors for the Treatment of Ophthalmic and Otic Infections".

[0020] The University of Cincinnati describes the use of amidine compounds for treating pneumonia in International Patent Application Publication No. WO2006 / 021833, entitled "Bisbenzamidines for the Treatment of Pneumonia." Xavier University of Louisiana describes the use of amidine compounds for treating trypanosomiasis in International Patent Application Publication No. WO2008 / 090831, entitled "Bisbenzamidines and Bisbenzamidoximes for the Treatment of Human African Trypanosomiasis."

[0021] The University of Oregon, in International Patent Application Publication No. WO 2009 / 105691, entitled "Use of Pentamidine and Related Compounds," describes the use of pentamidine and related compounds in the treatment of myotonic dystrophy.

[0022] Orion Corporation describes the use of amidine compounds as protease inhibitors in International Patent Application Publication No. WO 2010 / 133748 entitled "Protease Inhibitors".

[0023] There remains a need to develop new therapeutic agents and pharmaceutical compositions and their use for treating bacterial infections, including therapeutic agents that enhance the effectiveness of antibiotics against bacterial strains, including bacterial strains that are resistant to certain antibiotics. Summary of the invention

[0024] The present invention provides compounds and methods for treating bacterial infections and for enhancing the therapeutic effect of antibiotics in treating bacterial infections, the method comprising administering an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. The bacterial infection may be caused by gram-positive bacteria, gram-negative bacteria and / or antibiotic-resistant bacteria. In one embodiment, the bacterial infection is caused by mycobacteria.

[0025] In one aspect, the present invention is a compound of Formula I or a pharmaceutically acceptable salt thereof:

[0026]

[0027] in:

[0028] m and o are independently selected from 0, 1, 2 or 3;

[0029] n is 0, 1, 2, 3 or 4;

[0030] X 1 O, S or NR 4 ;

[0031] X 3 In each occurrence, independently selected from C(R 3 )2. O, S and NR 4 The group composed of;

[0032] X 4 Selected independently from CR at each occurrence 3 and N;

[0033] X 5 C(R 3 )2. O or S;

[0034] R is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3)2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano;

[0035] R 1 and R 2 At each occurrence, independently selected from the group consisting of:

[0036]

[0037] R 3 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, carbocycle, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryl, heterocyclyl, -COOR, -C(O)R, fluorine, chlorine, bromine, and iodine; and

[0038] R 4 and R 5 is independently selected at each occurrence from the group consisting of hydrogen and C1-C6 alkyl.

[0039] In one aspect, a method for treating a bacterial infection in a host, typically a human, is provided, the method comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

[0040] In one aspect, a method for enhancing the therapeutic effect of a bacterial infection in a host, typically a human, is provided, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, in combination with an antibiotic.

[0041] Also provided are pharmaceutical compositions comprising an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier, alone or in combination with an effective amount of an additional antibiotic.

[0042] In another aspect, a method for treating a bacterial infection is provided, comprising administering to a host in need thereof an effective amount of a compound of Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof:

[0043]

[0044] in

[0045] L 1 Selected from

[0046] L 2 Selected from

[0047] v and w are independently selected from 0, 1, 2, 3 and 4;

[0048] R is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano;

[0049] X 6 , X 7 , X 8 and X 9 independently selected from O, S, NH and Se;

[0050] X 10 Selected from Se, S or NH;

[0051] R 6 and R 7 At each occurrence, independently selected from the group consisting of:

[0052]

[0053] X3 , X 4 , R 4 and R 5 As defined herein.

[0054] In some embodiments of Formula II, Formula III, Formula IV and / or Formula V, X 10 Not S.

[0055] In some embodiments of Formula II, Formula III, Formula IV and / or Formula V, X 10 Not NH.

[0056] In some embodiments of Formula II, Formula III, Formula IV and / or Formula V, L 2 no

[0057]

[0058] In some embodiments of Formula II, Formula III, Formula IV and / or Formula V, X 6 , X 7 , X 8 and X 9 One or more of is not NH.

[0059] In another aspect, a method for treating a bacterial infection is provided, the method comprising administering an effective amount of Compound A, Compound B or Compound C to a host in need thereof.

[0060]

[0061] or a pharmaceutically acceptable salt thereof.

[0062] In certain embodiments, the compounds of Formula I, Formula II, Formula III, Formula IV, or Formula V, or pharmaceutically acceptable salts thereof, can be used to enhance the effectiveness of antibiotics in treating bacterial infections.

[0063] In certain embodiments, Compound A, Compound B or Compound C or a pharmaceutically acceptable salt thereof can be used to enhance the effect of antibiotics in treating bacterial infections.

[0064] In certain embodiments, the bacterial infection is caused by Gram-positive bacteria.

[0065] In certain embodiments, the bacterial infection is caused by a Gram-negative bacteria.

[0066] In certain embodiments, the bacterial infection is caused by mycobacteria.

[0067] In another aspect, a method for treating a Gram-positive or Gram-negative bacterial infection is provided, the method comprising administering an effective amount of a compound of formula VI:

[0068]

[0069] or a pharmaceutically acceptable salt thereof,

[0070] in

[0071] R 9 and R 12 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano; and

[0072] R 10 and R 11 independently selected at each occurrence from the group consisting of hydroxy, C1-C6 alkanoyl, carbocycle, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -C(O)R, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, bromine, iodine, thiol and cyano.

[0073] In another aspect, a method for treating a Gram-positive bacterial or Gram-negative bacterial infection is provided, the method comprising administering to a host in need thereof an effective amount of Compound D or Compound E:

[0074]

[0075] or a pharmaceutically acceptable salt thereof.

[0076] In some cases, the compound used to treat a bacterial infection is not Compound D or Compound E.

[0077] In one aspect, the present invention is a compound selected from Compound F to Compound L or a pharmaceutically acceptable salt thereof:

[0078]

[0079]

[0080] Also provided is a pharmaceutical composition comprising an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI or a compound selected from Compound A to Compound L or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier in combination with an effective amount of an additional antibiotic. In one embodiment, the pharmaceutical composition is suitable for topical application, such as a cream or ointment. The topical composition may include any one or more carriers that do not react adversely with the active agent and achieve the desired effect.

[0081] In another aspect, provided herein is a compound of Formula VII or a pharmaceutically acceptable salt thereof:

[0082]

[0083] in:

[0084] m and n are independently selected from 1, 2, 3 or 4;

[0085] p is 0, 1, 2 or 3;

[0086] q and t are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 at each occurrence;

[0087] L 3 and L 4 Each independently is C(R 3 )2. O or S;

[0088] R is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano;

[0089] R 3 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, carbocycle, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryl, heterocyclyl, -COOR, -C(O)R, fluorine, chlorine, bromine, and iodine;

[0090] R 13 and R 14 At each occurrence, independently selected from the group consisting of:

[0091] and –C(R 3 ) o NR 4 R 5 ,

[0092] Where R 4 and R 5 is independently selected at each occurrence from the group consisting of hydrogen and C1-C6 alkyl, and o is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0093] X 11 and X 12 Each independently selected from C(R 3 )2, O, NH or S;

[0094] Y 1 and Y 2 Each independently selected from C(R 3)2, O, NH or S; and

[0095] Z is CR 3 or N.

[0096] Optionally, R 4 and R 5 For hydrogen.

[0097] Optionally, X 11 and X 12 In some cases, X 11 and X 12 Selected from the group consisting of O, CH2 and S.

[0098] Optionally, Y 1 and Y 2 In some cases, Y 1 and Y 2 Selected from the group consisting of O and CH2.

[0099] Optionally, each R is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and fluorine.

[0100] Optionally, the compound has the following structure:

[0101]

[0102] In another aspect, a method for treating a bacterial infection is provided, the method comprising administering a compound of formula VII or a pharmaceutically acceptable salt thereof. A method for enhancing the effect of antibiotic therapy during the treatment of a bacterial infection is also provided, the method comprising administering a compound of formula VII or a pharmaceutically acceptable salt thereof. In some cases, the bacterial infection is caused by gram-positive bacteria. In other cases, the bacterial infection is caused by gram-negative bacteria. Optionally, the bacterial infection is caused by mycobacteria.

[0103] In another aspect, provided herein is a compound of Formula VIII or a pharmaceutically acceptable salt thereof:

[0104]

[0105] in:

[0106] m and n are independently selected from 1, 2, 3 or 4;

[0107] p is 0, 1, 2 or 3;

[0108] q and t are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 at each occurrence;

[0109] L 3 and L4 Each independently is C(R 3 )2. O or S;

[0110] R is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano;

[0111] R 3 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, carbocycle, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryl, heterocyclyl, -COOR, -C(O)R, fluorine, chlorine, bromine, and iodine;

[0112] R 13 and R 14 At each occurrence, independently selected from the group consisting of:

[0113] and –C(R 3 ) o NR 4 R 5 ,

[0114] Where R 4 and R 5 is independently selected at each occurrence from the group consisting of hydrogen and C1-C6 alkyl, and o is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0115] X 11 and X 12 Each independently selected from C(R 3 )2, O, NH or S;

[0116] Y 1 and Y 2 Each independently selected from C(R 3 )2, O, NH or S; and

[0117] Z is CR 3 or N.

[0118] Optionally, R 4 and R 5 For hydrogen.

[0119] Optionally, X 11 and X 12 In some cases, X 11 and X 12 Selected from the group consisting of O, CH2 and S.

[0120] Optionally, Y 1 and Y 2 In some cases, Y 1 and Y 2 Selected from the group consisting of O and CH2.

[0121] Optionally, each R is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and fluorine.

[0122] Optionally, the compound has the following structure:

[0123]

[0124] In another aspect, a method for treating a bacterial infection is provided, the method comprising administering a compound of formula VIII or a pharmaceutically acceptable salt thereof. A method for enhancing the effect of antibiotic therapy during the treatment of a bacterial infection is also provided, the method comprising administering a compound of formula VIII or a pharmaceutically acceptable salt thereof. In some cases, the bacterial infection is caused by gram-positive bacteria. In other cases, the bacterial infection is caused by gram-negative bacteria. Optionally, the bacterial infection is caused by mycobacteria.

[0125] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula VII or Formula VIII, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

[0126] The present invention also provides a topical composition for treating acne vulgaris, the composition containing an effective amount of a compound selected from Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII or Formula VIII, or a compound selected from Compound A to Compound L, or a pharmaceutically acceptable salt thereof, alone or in combination with an effective amount of an antibiotic. The compounds used in the topical compositions and methods provided herein have an antimicrobial effect that helps alleviate the symptoms of acne vulgaris and treats potential overgrowth of acne-causing bacteria (e.g., Propionibacterium acnes or Staphylococcus epidermidis).

[0127] The present invention also provides treatment options that may supplement or replace currently available treatment options in the treatment of this highly common skin condition.

[0128] For example, topical carriers can be water-based or anhydrous. Water-based topical compositions are well known and are further described below. Anhydrous pharmaceutically acceptable topical materials are also well known and include silicone-based oils, aliphatic-based compositions, oleaginous materials, jellies, mineral oils, dimethicone and other substantially anhydrous lipophilic carriers.

[0129] The active compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII or Formula VIII or a compound selected from Compound A-Compound L can be provided in a topical formulation in any amount to achieve the desired effect. In certain non-limiting examples, the weight percentage of the active compound in the topical formulation is from about 0.1% to about 50%, or from about 0.1% to about 40%, or from about 1% to about 30%, or from about 2%, 3%, 4% or 5% to about 20%, or between about 5% to about 10%.

[0130] Examples include at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, or 15% by weight. In one embodiment, the topical formulation contains a compound of Formula I, II, III, IV, V, VI, VII, or VIII, or a compound selected from Compound A to Compound L, or a pharmaceutically acceptable salt thereof, in combination with an additional active agent, such as benzoyl peroxide, a retinoid, azelaic acid, an antibiotic, or salicylic acid, as long as the additional active agent does not adversely affect the active agent.

[0131] In one embodiment, at least one hydrogen in the compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII or formula VIII is replaced by deuterium. On the one hand, the deuterium is located at the position of metabolism. In one embodiment, at least one hydrogen in compound A-compound L is replaced by deuterium. On the one hand, the deuterium is located at the position of metabolism.

[0132] Therefore, the present invention includes at least the following features:

[0133] (a) a compound of formula I or a pharmaceutically acceptable salt thereof;

[0134] (b) a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier;

[0135] (c) a method for treating bacterial infection, comprising administering a compound or a pharmaceutically acceptable salt of Formula I, Formula II, Formula III, Formula IV or Formula V to a host in need thereof;

[0136] (d) a method for treating bacterial infection, comprising administering to a host in need thereof a compound or a pharmaceutically acceptable salt of Formula I, Formula II, Formula III, Formula IV or Formula V in combination with an effective amount of an antibiotic;

[0137] (e) a method for enhancing the effect of an antibiotic in treating a bacterial infection, the method comprising administering to a host in need thereof an antibiotic in combination with a compound of Formula I, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof;

[0138] (f) The method of (c), (d) or (e), wherein the bacterial infection is caused by Gram-positive bacteria;

[0139] (g) The method of (c), (d) or (e), wherein the bacterial infection is caused by Gram-negative bacteria;

[0140] (h) The method of (c), (d) or (e), wherein the bacterial infection is caused by mycobacteria;

[0141] (i) a method for treating acne vulgaris, comprising administering to a host in need thereof a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or a pharmaceutically acceptable salt thereof, alone or in combination with an antibiotic;

[0142] (j) The method as described in (i), wherein acne vulgaris is caused by the bacteria Propionibacterium acnes or Staphylococcus epidermidis;

[0143] (k) a compound of Formula I, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection in a host in need thereof;

[0144] (l) a compound of Formula I, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof in combination with an effective amount of an antibiotic for use in treating a bacterial infection in a host in need thereof;

[0145] (m) a compound of Formula I, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof, which is used to enhance the effect of antibiotics in treating bacterial infections;

[0146] (n) The compound as described in (k), (l) or (m), wherein the bacterial infection is caused by Gram-positive bacterial infection;

[0147] (o) The compound as described in (k), (l) or (m), wherein the bacterial infection is caused by Gram-negative bacterial infection;

[0148] (p) The compound of (k), (l) or (m), wherein the bacterial infection is caused by mycobacteria;

[0149] (q) a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or a pharmaceutically acceptable salt thereof, for use in treating acne vulgaris in a host in need thereof;

[0150] (r) The compound as described in (q), wherein the acne vulgaris is caused by the bacteria Propionibacterium acnes or Staphylococcus epidermidis;

[0151] (s) Use of a compound of Formula I, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a bacterial infection in a host in need thereof;

[0152] (t) Use of a compound of Formula I, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt thereof in combination with an effective amount of an antibiotic in the manufacture of a medicament for treating a bacterial infection in a host in need thereof;

[0153] (u) use of a compound of Formula I, Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for enhancing the effect of an antibiotic in treating a bacterial infection in a host in need thereof;

[0154] (v) The use according to (s), (t) or (u), wherein the bacterial infection is caused by a Gram-positive bacterial infection;

[0155] (w) The use as described in (s), (t) or (u), wherein the bacterial infection is caused by Gram-negative bacterial infection;

[0156] (x) The use according to (s), (t) or (u), wherein the bacterial infection is caused by mycobacteria;

[0157] (y) use of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating acne vulgaris in a host in need thereof;

[0158] (z) The use as described in (y), wherein the acne vulgaris is caused by the bacteria Propionibacterium acnes or Staphylococcus epidermidis;

[0159] (aa) a method for treating a bacterial infection, comprising administering to a host in need thereof a compound selected from Compound A, Compound B, Compound C, or Compound F to Compound L or a pharmaceutically acceptable salt thereof;

[0160] (bb) a method for treating bacterial infection, comprising administering to a host in need thereof a compound or a pharmaceutically acceptable salt selected from Compound A, Compound B, Compound C or Compound F to Compound L in combination with an effective amount of an antibiotic;

[0161] (cc) a method for enhancing the effect of an antibiotic in treating a bacterial infection, the method comprising administering to a host in need thereof an antibiotic in combination with a compound selected from Compound A, Compound B, Compound C, or Compound F to Compound L, or a pharmaceutically acceptable salt thereof;

[0162] (dd) The method of (aa), (bb) or (cc), wherein the bacterial infection is caused by a Gram-positive bacterial infection;

[0163] (ee) The method of (aa), (bb) or (cc), wherein the bacterial infection is caused by a Gram-negative bacterial infection; The method of (aa), (bb) or (cc), wherein the bacterial infection is caused by a mycobacterium;

[0164] (ff) a method for treating acne vulgaris, comprising administering to a host in need thereof a compound selected from Compound A, Compound B, Compound C or Compound F-Compound L, or a pharmaceutically acceptable salt thereof, alone or in combination with an antibiotic;

[0165] (gg) The method of (ff), wherein the acne vulgaris is caused by the bacteria Propionibacterium acnes or Staphylococcus epidermidis;

[0166] (hh) a method for treating Gram-positive or Gram-negative bacterial infection, the method comprising administering a compound of Formula VI or a pharmaceutically acceptable salt thereof to a host in need thereof;

[0167] (ii) a method for treating Gram-positive or Gram-negative bacterial infection, the method comprising administering to a host in need thereof a compound of formula VI or a pharmaceutically acceptable salt thereof in combination with an effective amount of an antibiotic;

[0168] (jj) a method for enhancing the effect of an antibiotic in treating a Gram-positive or Gram-negative bacterial infection, the method comprising administering to a host in need thereof an antibiotic in combination with a compound of Formula VI or a pharmaceutically acceptable salt thereof;

[0169] (kk) a method for treating Gram-positive bacteria or Gram-negative bacteria infection, the method comprising administering Compound D or Compound E or a pharmaceutically acceptable salt thereof to a host in need thereof;

[0170] (ll) a method for treating Gram-positive or Gram-negative bacterial infection, the method comprising administering to a host in need thereof a compound or a pharmaceutically acceptable salt selected from Compound D or Compound E in combination with an effective amount of an antibiotic;

[0171] (mm) a method for enhancing the effect of an antibiotic in treating a Gram-positive or Gram-negative bacterial infection, the method comprising administering to a host in need thereof an antibiotic in combination with a compound selected from Compound D or Compound E or a pharmaceutically acceptable salt thereof;

[0172] (nn) a pharmaceutical composition comprising an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, in combination with an effective amount of an antibiotic;

[0173] (oo) a topical formulation for treating acne, comprising an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, or a pharmaceutically acceptable salt thereof, in a topically acceptable carrier;

[0174] (pp) a pharmaceutical composition comprising an effective amount of a compound selected from Compound A, Compound B, Compound C or Compound F to Compound L, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, in combination with an effective amount of an antibiotic;

[0175] (qq) a topical formulation for treating acne, comprising an effective amount of a compound selected from Compound A, Compound B, Compound C, or Compound F-Compound L, or a pharmaceutically acceptable salt thereof, in a topically acceptable carrier;

[0176] (rr) a compound of Formula VII or Formula VIII or a pharmaceutically acceptable salt thereof;

[0177] (ss) a pharmaceutical composition comprising a compound of Formula VII or Formula VIII or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier;

[0178] (tt) a method for treating a bacterial infection, comprising administering a compound of Formula VII or Formula VIII or a pharmaceutically acceptable salt thereof to a host in need thereof;

[0179] (uu) a method for treating a bacterial infection, the method comprising administering to a host in need thereof a compound or a pharmaceutically acceptable salt of Formula VII or Formula VIII in combination with an effective amount of an antibiotic;

[0180] (vv) a method for enhancing the effect of an antibiotic in treating a bacterial infection, the method comprising administering to a host in need thereof an antibiotic in combination with a compound of Formula VII or Formula VIII or a pharmaceutically acceptable salt thereof;

[0181] (ww) The method of (tt), (uu) or (vv), wherein the bacterial infection is caused by a Gram-positive bacterial infection;

[0182] (xx) The method of (tt), (uu) or (vv), wherein the bacterial infection is caused by a Gram-negative bacterial infection;

[0183] (yy) The method of (tt), (uu) or (vv), wherein the bacterial infection is caused by mycobacteria;

[0184] (zz) A process for preparing a therapeutic product containing an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII or Formula VIII, or a pharmaceutically acceptable salt thereof, alone or in combination with an effective amount of an antibiotic.

[0185] The details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0186] Figure 1 shows that MD-124 enhances the sensitivity of Gram-negative bacteria to various existing antibiotics. Figure (A) is the structure of MD-124. Figure (B) shows that 5μg / ml of MD-124 enhances the sensitivity of Escherichia coli (E. coli) to rifampicin (Rif). Values ​​are mean ± SD. n = 3. Figure (C) demonstrates that 5μg / ml of MD-124 itself does not show a bacterial growth inhibitory effect. Values ​​are mean ± SD. n = 3. Figure (D) shows the results of a checkerboard assay of MD-124 (0 to 100μg / ml) and rifampicin on Escherichia coli. Figure (E) shows the results of a checkerboard assay of MD-124 (0 to 10μg / ml) and rifampicin on Escherichia coli. Figure (F) is a chart showing that MD-124 enhances the sensitivity of various Gram-negative bacterial strains to rifampicin (Rif). Sensitization factor = MIC of rifampicin alone / MIC of rifampicin in the presence of MD-124. Figure (G) is a chart showing a comparison of bacterial sensitivity of Escherichia coli to rifampicin activity between MD-124, pentamidine and PMBN. Figure (H) shows that 5 μg / ml MD-124 can enhance the sensitivity of Escherichia coli to a wide range of existing antibiotics. All results represent 3 replicates.

[0187] Figure 2 shows the results of the MD-124 resistance frequency study. Figure (A) shows the resistance frequency of Escherichia coli to clindamycin (4 times, 6 times and 7 times the MIC) and Escherichia coli to the clindamycin / MD-124 combination. Figure (B) shows the resistance frequency of Escherichia coli to trovafloxacin (2 times, 3 times and 4 times the MIC) and Escherichia coli to the trovafloxacin / MD-124 combination. Figure (C) shows the resistance frequency of Escherichia coli to novobiocin (4 times, 5 times and 6 times the MIC) and Escherichia coli to the novobiocin / MD-124 combination. The blue asterisks in Figures (A), (B) and (C) indicate the resistance frequency of Escherichia coli from 3×10 9 No resistant colonies were observed in CFU. Values ​​are mean ± SD. n = 3. ***: P < 0.001.

[0188] Figure 3 depicts the results of a mechanistic study that revealed that MD-100 and MD-124 enhance the sensitivity of Escherichia coli by disrupting the outer membrane and increasing antibiotic absorption. Figure (A) shows the proposed sensitization mechanism of MD-124 and MD-100. Figure (B) is a graph depicting the impaired ability of MD-124 in enhancing the sensitivity of the mutant outer membrane "leaky" Escherichia coli strain NR698 to clarithromycin. Values ​​are mean ± SD. n = 3. Figure (C) shows that bacterial sensitizers can promote the lysis of Escherichia coli by lysozyme. Escherichia coli stock solutions were incubated with 50 μg / ml lysozyme at room temperature for 10 minutes in the presence and absence of various bacterial sensitizers, and then the OD was recorded. 600 . Poly B and penta are abbreviations for polymyxin B and pentamidine, respectively. The Escherichia coli stock solution was also incubated with various bacterial sensitizers at the same concentration in the absence of lysozyme as a control. The values ​​are mean ± SD. n = 3. ***: P < 0.001 compared with the vehicle group. Figure (D) shows the correlation between the outer membrane destruction ability and bacterial sensitization activity of various bacterial sensitizers. Figure (E) shows the HPLC results of O-methylnobiocin concentration in Escherichia coli in the presence (a) and absence (b) of 25 μg / ml of MD-100.

[0189] Figure 4 shows a molecular mechanism study of bacterial sensitizers. Figure (A) shows that LPS can reduce the sensitizing ability of MD-124 in a concentration-dependent manner. Escherichia coli was treated with 10 μM MD-124 (about 5 μg / ml) in combination with rifampicin with various concentrations of LPS (from 0 to 40 μM) at 37°C for 20 hours, and then the OD was measured. 600 And the sensitization factor was calculated as mentioned above. Figure (B) shows Mg 2+ The sensitizing ability of MD-124 can be reduced in a concentration-dependent manner. Escherichia coli was treated with 10 μM MD-124 (about 5 μg / ml) and varying concentrations of Mg 2+ (from 0 to 15 mM) at 37 °C for 20 h, then measure OD 600 The sensitization factor under different conditions was calculated. Figure (C) shows the dansyl-PMBN displacement assay. The Escherichia coli stock solution (OD 600=0.3) was added with 10 μM dansyl-PMBN, and the fluorescence intensity was recorded as F1 (Ex = 340 nm; Em = 520 nm), then different concentrations of bacterial sensitizers were added, and the fluorescence intensity was recorded as Fx. The fluorescence intensity of 10 μM dansyl-PMBN in HEPES buffer was recorded as baseline F0. Fluorescence intensity / % = (F1-Fx) / (F1-F0). Values ​​are mean ± SD. n = 3; D) MD-124 enhances the sensitivity of Escherichia coli strains overexpressing mcr-1 to rifampicin. All results were repeated three times.

[0190] Figure 5 shows that MD-124 enhances the sensitivity of wild-type Acinetobacter baumannii (A.baumannii), Klebsiella pneumoniae (K.pneumoniae) and resistant Gram-negative strains to existing antibiotics. Figures (A) and (B) are the results of the chessboard method, which show that MD-124 enhances the sensitivity of Acinetobacter baumannii to rifampicin and neomycin. Figures (C) and (D) are the results of the chessboard method, which show that MD-124 enhances the sensitivity of Klebsiella pneumoniae to rifampicin and clarithromycin. Figure (E) shows that MD-124 enhances the sensitivity of Escherichia coli overexpressing NDM-1 to rifampicin. Figure (F) shows that MD-124 enhances the sensitivity of Escherichia coli overexpressing MCR-1 to rifampicin. All experiments are the results of at least two repetitions.

[0191] Figure 6 shows that MD-124 and antibiotic combinations achieve growth inhibition of Escherichia coli (wild-type and resistant strains) in an ex vivo skin burn infection model. Figure (A) shows that the combination of MD-124 and novobiocin inhibits the growth of wild-type Escherichia coli. The concentrations (w / w) of polymyxin B (poly B), novobiocin (Novo), and MD-124 are 1‰, 4‰, and 1.5‰. The same concentrations of novobiocin and MD-124 were used in the combination group (Novo+MD-124). Figure (B) shows that the combination of MD-124 and clindamycin inhibits the growth of Escherichia coli expressing NDM-1. The concentrations (w / w) of polymyxin B (poly B), clindamycin (Clind), and MD-124 are 1‰, 3‰, and 1.5‰, respectively. The same concentrations of clindamycin and MD-124 were used in the combination group (Clind+MD-124). Values ​​are mean ± SEM. n=5, ***P<0.001 compared with vehicle or antibiotic groups alone. Figure (C) shows that the combination of MD-124 and various polymyxin Bs resulted in inhibition of the growth of mcr-1-positive Escherichia coli in an ex vivo skin burn infection model. The concentrations (w / w) of polymyxin B (poly B) and MD-124 were 3‰ and 1.5‰. The same concentrations of polymyxin B and MD-124 were used in the combination group (Poly B+MD-124). Values ​​are mean ± SEM. n=5, ***P<0.001 compared with antibiotic or MD-124 groups alone.

[0192] Figure 7 shows the results of the molecular mechanism study of bacterial sensitizers. Figure (A) shows that MD-100 failed to enhance the sensitivity of the mutant outer membrane "leaky" Escherichia coli strain NR698. Ery is the abbreviation of erythromycin. 10μg / ml MD-100 enhanced the sensitivity of wild-type Escherichia coli to erythromycin by 32 times (comparison of the "Ery+10μg / ml MD-100 line" with the "Ery alone" line in Figure B, the MIC of erythromycin was 50μg / ml, and the MIC of erythromycin in the presence of 10μg / ml MD-100 was 1.6μg / ml). In the presence or absence of bacterial sensitizers, Escherichia coli NR698 was cultured at 37°C for 24h with various concentrations of antibiotics. Then, the OD 600 Determine the bacterial growth density. Figure (B) shows LPS and high concentration of Mg 2+ E. coli was treated with 10 μg / ml MD-100 and erythromycin in combination at 37°C for 20 h in the presence and absence of 40 μM LPS. 600 Calculate the growth density / % in the presence and absence of 20 mM Mg 2+In the case of Escherichia coli, 10 μg / ml MD-100 and erythromycin were treated at 37°C for 20 h, and then the OD 600 Calculate the growth density / %.

[0193] Figure 8 It was demonstrated that 5 μg / ml MD-124 enhanced the sensitivity of E. coli to polymyxin B. E. coli was cultured with various concentrations of polymyxin B at 37°C for 20 h in the presence or absence of 5 μg / ml MD-124. The OD 600 Determine bacterial growth density.

[0194] Fig. 9 The effect of phosphatidylcholine on the sensitizing activity of MD-124 is shown.

[0195] Figure 10 contains graphs showing that membrane disruptors enhance the susceptibility of B. subtilis (Panel A) and MRSA (Panel B) to rifampicin. Bacteria were cultured with various concentrations of antibiotics at 37°C for 24 hours in the presence or absence of bacterial sensitizers. The OD 600 Bacterial growth density was determined. ***: p < 0.01.

[0196] FIG. 11 contains graphs showing that MD-108 can alter the combination between MRSA and E. coli (Panel A) or MRSA and B. subtilis (Panel B) when the bacterial strains are under the same antibiotic pressure. DETAILED DESCRIPTION

[0197] Compounds and methods for treating bacterial infections and for enhancing the therapeutic effects of antibiotics for treating bacterial infections are described herein. The method comprises administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. The bacterial infection may be caused by gram-positive bacteria, gram-negative bacteria, and / or antibiotic-resistant bacteria. In one embodiment, the bacterial infection is caused by mycobacteria.

[0198] I. Definitions

[0199] The compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0200] The terms "a" and "an" do not represent a limit to quantity, but represent that there is at least one item mentioned. The term "or" means "and / or". Unless otherwise specified herein, the enumeration of numerical ranges is intended only to be used as a shorthand method for individually referring to each individual numerical value falling within the range, and each individual numerical value is incorporated into the patent specification as if it were individually listed herein. The endpoints of all ranges are included in the range and can be independently combined. All methods described herein can be performed in a suitable order, unless otherwise specified herein or clearly contradictory to the context. Unless otherwise stated, the use of examples or exemplary language (e.g., "such as") is merely to better illustrate the present invention, rather than to limit the scope of the present invention.

[0201] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH2 is attached through the carbon of the keto group (C=O).

[0202] "Alkyl" is a branched or straight chain saturated aliphatic hydrocarbon group. In a non-limiting preferred embodiment, the alkyl group generally contains 1 to about 12 carbon atoms, 1 to about 8 carbon atoms, 1 to about 6 carbon atoms, or 1 to about 4 carbon atoms. In certain embodiments, the alkyl group is C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, C1-C7, C1-C8, C1-C9, or C1-C 10 . In one embodiment, the alkyl group contains about 1 to about 50 carbon atoms or about 1 to about 36 carbon atoms. For example, the term C1-C6 alkyl as used herein represents a straight or branched alkyl group with 1, 2, 3, 4, 5 or 6 carbon atoms, and means that each of these is described as an independent substance. For example, the term C1-C4 alkyl as used herein represents a straight or branched alkyl group with 1, 2, 3 or 4 carbon atoms, and means that each of these is described as an independent substance. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, sec-pentyl, 3-pentyl, active pentyl, neopentyl, n-hexyl, sec-hexyl, tert-hexyl, isohexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane. In some embodiments, the alkyl group is optionally substituted as defined herein.

[0203] In one embodiment, "alkyl" is C1-C 10 alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl or C1-C2 alkyl.

[0204] When using terms that include "alk", it should be understood that "cycloalkyl" or "carbocycle" can be considered part of this definition unless the context clearly excludes it. For example and without limitation, the terms alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkenyloxy, haloalkyl, etc. can all be considered to include cyclic forms of alkyl unless the context clearly excludes it.

[0205] For example, a "cycloalkyl" is an alkyl group that forms or contains a ring. When composed of two or more rings, the rings may be joined together in a fused manner. Non-limiting examples of typical cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0206] As used herein, "aryl" refers to a group having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) ("C6-C 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl"; e.g., anthracenyl). "Aryl" also includes ring systems in which an aromatic ring as defined above is fused to one or more cycloalkyl or heterocycloalkyl groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of carbon atoms continues to indicate the number of carbon atoms in the aromatic ring system. The one or more fused cycloalkyl or heterocycloalkyl groups may be a 4- to 7-membered or 5- to 7-membered cycloalkyl or heterocycloalkyl group optionally containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron. In a non-limiting embodiment, the aryl group is pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In some embodiments, the aryl group is optionally substituted as defined herein.

[0207] In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0208] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0209] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a heterocycle, wherein the point of attachment is the aromatic ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the point of attachment of each group is on the aromatic ring.

[0210] For example, is an "aryl" group.

[0211] but, It is a "heterocyclic" group.

[0212] In one embodiment, "aryl" is a 6-carbon aromatic group fused to a cycloalkyl, wherein the point of attachment is the aromatic ring. Non-limiting examples of "aryl" include indane and tetralin, wherein the point of attachment for each group is on the aromatic ring.

[0213] For example, is an "aryl" group.

[0214] but, is a "cycloalkyl" group.

[0215] In one embodiment, "aryl" is "substituted aryl".

[0216] In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0217] Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[0218] In one embodiment, "heteroaryl" is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (ie, pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).

[0219] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0220] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0221] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur.

[0222] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0223] In one embodiment, "heteroaryl" is "substituted heteroaryl".

[0224] "Haloalkyl" refers to a branched or straight chain alkyl group substituted with one or more of the above halogen atoms (up to the maximum permissible number of halogen atoms). Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Perhaloalkyl" refers to an alkyl group in which all hydrogen atoms are substituted with halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0225] In one embodiment, "haloalkyl" is C1-C 10 "Alkoxy" refers to an alkyl group as defined above that is covalently bound by an oxygen bridge (-O-). The example of an alkoxy group includes but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl and 3-methylpentyloxy. "Haloalkoxy" refers to a haloalkyl group as defined herein that is attached by an oxygen bridge (-O-).

[0226] As used herein, the term "active agent" refers to any type of drug, medicine, pharmaceutical, hormone, antibiotic, protein, gene, growth factor, biologically active material, etc., used to treat, control or prevent a disease or medical condition as described herein. The term "active agent" also includes active compounds as described in this application.

[0227] "Dosage form" refers to the unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal administration forms, sublingual administration forms, topical administration forms, gels, mucosal administration forms, etc. "Dosage forms" may also include implants, such as optical implants.

[0228] As used herein, an "effective amount" means an amount that provides a therapeutic or prophylactic benefit.

[0229] "Parenteral" administration of the pharmaceutical compositions includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), intrasternal injection or infusion techniques.

[0230] As used herein, the term "treating" a disease means reducing the frequency or severity of at least one sign or symptom of the disease or condition experienced by a subject (ie, palliative treatment), or reducing the cause or effects of the disease or condition (ie, disease-modifying treatment).

[0231] As used herein, a "pharmaceutical composition" is a composition comprising at least one active agent and at least one other substance, such as a carrier. A "pharmaceutical combination" refers to a combination of at least two active agents that can be combined into a single dosage form, or provided together in separate dosage forms, with instructions for using the active agents together to treat any of the conditions described herein.

[0232] The term "carrier" as applied to the pharmaceutical composition / combination of the present invention refers to a diluent, excipient or vehicle with which the active compound is provided.

[0233] "Pharmaceutically acceptable excipient" means an excipient useful in the preparation of a pharmaceutical composition / combination that is generally safe, non-toxic, and neither biologically nor otherwise unsuitable for administration to a host (usually a human). In one embodiment, an excipient acceptable for veterinary use is used.

[0234] A "patient" or "host" or "subject" is a human or non-human animal in need of treatment or prevention of any of the conditions specifically described herein. Typically, the host is a human. "Host" may alternatively refer to, for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0235] The "therapeutically effective amount" of the pharmaceutical composition / combination of the present invention means an amount that, when administered to a host, is effective in providing therapeutic benefits such as improvement of symptoms or alleviation or reduction of the disease itself.

[0236] The compounds or Compound A-Compound L in any formula described herein may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomers, mixture of diastereomers, tautomers, N-oxides or other isomers (e.g., rotamers), as if each is specifically described unless the context specifically excludes it.

[0237] The present invention includes compounds of formula I, formula II, formula III, formula IV or formula V, which have at least one desired isotope atom substitution, the amount of the atom is higher than the natural abundance of the isotope, i.e. enrichment. The present invention also includes compounds selected from compound A-compound L, which have at least one desired isotope atom substitution, the amount of the atom is higher than the natural abundance of the isotope, i.e. enrichment. Isotopes are atoms with the same atomic number but different mass numbers, i.e. atoms with the same number of protons but different numbers of neutrons.

[0238] Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 Cl and 125 I. In one non-limiting embodiment, isotopically labeled compounds can be used in metabolic studies (using 14 C) Reaction kinetics studies (using e.g. 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), the detection or imaging techniques including drug or substrate tissue distribution determination) or radiotherapy of patients. In particular, 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes or Examples and Preparations described below, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0239] By way of general example and not limitation, isotopes of hydrogen, such as deuterium ( 2 H) and tritium ( 3 H) can be used anywhere in the described structures to achieve the desired result. Alternatively or in addition, isotopes of carbon can be used, such as 13 C and 14 C.

[0240] Isotope substitution, such as deuterium substitution, can be partial or complete.Partial deuterium substitution means that at least one hydrogen is replaced by deuterium.In certain embodiments, the isotope is 90%, 95% or 99% or more enriched at any position of interest of the isotope.In a non-limiting embodiment, deuterium is 90%, 95% or 99% enriched at the desired position.

[0241] In a non-limiting embodiment, the substitution of one or more hydrogen atoms by a deuterium atom may be provided in any of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI. In a non-limiting embodiment, the substitution of one or more hydrogen atoms by a deuterium atom may be provided in a compound selected from Compound A to Compound L. In a non-limiting embodiment, the substitution of one or more hydrogen atoms by a deuterium atom occurs in a compound selected from R, R 1 , R 2 , R 3 , R 4 and R 5 In any of the groups. For example, when any of the groups is or contains (e.g., by substitution) a methyl, ethyl, or methoxy group, the alkyl residue may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In certain other embodiments, when two substituents are combined to form a ring, the unsubstituted carbon may be deuterated.

[0242] The compounds of the present invention can form solvates with solvents. Therefore, in a non-limiting embodiment, the present invention includes solvated forms of the compounds. The term "solvate" refers to a molecular complex of the compounds of the present invention (including its salt) and one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents. Other non-limiting examples of solvents are dimethylacetamide and N-methyl-2-pyrrolidine. The term "hydrate" refers to a molecular complex comprising the compounds of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be isotopically substituted (e.g., D2O, d6-acetone, D6-DMSO). Solvates can be in liquid or solid form.

[0243] As used herein, "pharmaceutically acceptable salts" are derivatives of the disclosed compounds wherein the parent compound is modified by preparing inorganic or organic, non-toxic acid or base addition salts thereof. Salts of the compounds of the invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.

[0244] Generally, such salts can be prepared by reacting the free acid form of these compounds with a suitable alkali (such as hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K) of a stoichiometric amount, or by reacting the reactive free alkali form of these compounds with a suitable acid of a stoichiometric amount. Such reactions are usually carried out in a variety of solvents or solvent mixtures compatible with the compound. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are typical where feasible. The salt of the compounds of this invention further includes a solvate of the compound and a solvate of the compound salt.

[0245] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts and quaternary ammonium salts of the parent compound formed from non-toxic organic acids. For example, conventional non-toxic acid salts include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, esylic, benzenesulfonic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2)n-COOH (wherein n is 0-4), etc., or salts prepared from different acids that produce the same counterion. Additional lists of suitable salts may be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0246] II. Compounds of the Invention

[0247] In one aspect of the present invention, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof:

[0248]

[0249] in:

[0250] m and o are independently selected from 0, 1, 2 or 3;

[0251] n is 0, 1, 2, 3 or 4;

[0252] X 1 O, S or NR 4 ;

[0253] X 3 In each occurrence, independently selected from C(R 3)2. O, S and NR 4 The group composed of;

[0254] X 4 Selected independently from CR at each occurrence 3 and N;

[0255] X 5 C(R 3 )2. O or S;

[0256] R is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano;

[0257] R 1 and R 2 At each occurrence, independently selected from the group consisting of:

[0258]

[0259] R 3 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, carbocycle, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryl, heterocyclyl, -COOR, -C(O)R, fluorine, chlorine, bromine, and iodine; and

[0260] R 4 and R 5is independently selected at each occurrence from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, carbocycle, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclyl, -COOR and -C(O)R.

[0261] In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof is provided, optionally in a pharmaceutically acceptable carrier, thereby forming a pharmaceutical composition;

[0262] In one embodiment of formula I, m is 0. In one embodiment of formula I, m is 1. In one embodiment of formula I, m is 2. In one embodiment of formula I, m is 3.

[0263] In one embodiment of formula I, n is 0. In one embodiment of formula I, n is 1. In one embodiment of formula I, n is 2. In one embodiment of formula I, n is 3. In one embodiment of formula I, n is 4.

[0264] In one embodiment of formula I, o is 0. In one embodiment of formula I, o is 1. In one embodiment of formula I, o is 2. In one embodiment of formula I, o is 3.

[0265] In one embodiment of formula I, p is 0. In one embodiment of formula I, p is 1. In one embodiment of formula I, p is 2.

[0266] In one embodiment of Formula I, X 1 In one embodiment of Formula I, X 1 NR 4 And R 4 In one embodiment of Formula I, X 1 NR 4 And R 4 It is a C1-C6 alkyl group.

[0267] In one embodiment of Formula I, X 2 In one embodiment of Formula I, X 2 is S. In one embodiment of Formula I, X 2 NR 4 And R 4 In one embodiment of Formula I, X 2 NR 4 And R 4 It is a C1-C6 alkyl group.

[0268] In one embodiment of Formula I, X 3 C(R3 )2 and R 3 In one embodiment of Formula I, X 3 is S. In one embodiment of Formula I, X 3 C(R 3 )2 and R 3 is a C1-C6 alkyl group. In one embodiment of Formula I, X 3 C(R 3 )2 and an R 3 is hydrogen and the other R 3 is a C1-C6 alkyl group. In one embodiment of Formula I, X 3 C(R 3 )2 and an R 3 is fluorine, chlorine, bromine, iodine or C1-C6 haloalkyl. 3 In one embodiment of Formula I, X 3 NR 4 And R 4 In one embodiment of Formula I, X 3 NR 4 And R 4 In one embodiment of Formula I, X 4 is N. In one embodiment of Formula I, X 4 CR 3 And R 3 In one embodiment of Formula I, X 4 CR 3 And R 3 is a C1-C6 alkyl group. In one embodiment of Formula I, X 4 C(R 3 )2 and R 3 It is fluorine, chlorine, bromine, iodine or C1-C6 haloalkyl.

[0269] In one embodiment of Formula I, X 5 C(R 3 )2 and R 3 In one embodiment of Formula I, X 5 C(R 3 )2 and R 3 is a C1-C6 alkyl group. In one embodiment of Formula I, X 5 C(R 3 )2 and an R 3 is hydrogen and the other R 3 is alkyl, hydroxy, fluorine, chlorine, bromine, iodine or C1-C6 haloalkyl. 5 is O.

[0270] In one embodiment of formula I, R is hydrogen, fluorine, chlorine, bromine or iodine.

[0271] In one embodiment of Formula I, R 1 for Where R 4 and R 5 are independently hydrogen or C1-C6 alkyl. 1 for Where R 4 and R 5 are independently hydrogen or C1-C6 alkyl.

[0272] In one embodiment of Formula I, R 2 for Where R 4 and R 5 is independently hydrogen or alkyl. 2 for Where R 4 and R 5 are independently hydrogen or C1-C6 alkyl.

[0273] In one embodiment of Formula I, R 1 and R 2 Each Where R 4 and R 5 are independently hydrogen or C1-C6 alkyl. In one embodiment of Formula I, R 1 and R 2 Each Where R 4 and R 5 are independently hydrogen or C1-C6 alkyl.

[0274] In one embodiment of Formula I, Select from the group consisting of:

[0275]

[0276] In one embodiment of Formula I, Select from the group consisting of:

[0277]

[0278] In one embodiment of Formula I, Select from the group consisting of:

[0279]

[0280]

[0281] In one embodiment of Formula I, Select from the group consisting of:

[0282]

[0283] In one embodiment of Formula I, Select from the group consisting of:

[0284]

[0285]

[0286] In certain embodiments, the compound of Formula I is a compound of the formula:

[0287]

[0288]

[0289] In certain embodiments, the compound of Formula I is a compound of the formula:

[0290]

[0291]

[0292] In certain embodiments, the compound of Formula I is a compound of the formula:

[0293]

[0294]

[0295] Non-limiting examples of compounds of Formula I include:

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306] In another aspect, a method for treating a bacterial infection is provided, comprising administering to a host in need thereof an effective amount of a compound of Formula II, Formula III, Formula IV or Formula V, or a pharmaceutically acceptable salt thereof:

[0307]

[0308] in

[0309] L 1 Selected from

[0310] L 2 Selected from

[0311] v and w are independently selected from 0, 1, 2, 3 and 4;

[0312] R is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano;

[0313] X 6 , X 7 , X 8 and X 9 independently selected from O, S, NH or Se;

[0314] X 10 Selected from Se, S or NH;

[0315] R 6 and R 7At each occurrence, independently selected from the group consisting of:

[0316] and

[0317] R, R 1 , R 2 , R 4 and R 5 As defined herein.

[0318] In some embodiments of Formula II, Formula III, Formula IV and / or Formula V, X 10 Not S.

[0319] In some embodiments of Formula II, Formula III, Formula IV and / or Formula V, X 10 Not NH.

[0320] In some embodiments of Formula II, Formula III, Formula IV and / or Formula V, L 2 no

[0321]

[0322] In some embodiments of Formula II, Formula III, Formula IV and / or Formula V, X 6 , X 7 , X 8 and X 9 One or more of is not NH.

[0323] In some embodiments of Formula II, the compound has a chemical structure selected from:

[0324]

[0325]

[0326] Non-limiting examples of compounds of Formula II include:

[0327]

[0328]

[0329] In some embodiments of Formula III, the compound has a chemical structure selected from:

[0330]

[0331]

[0332] Non-limiting examples of compounds of Formula III include:

[0333]

[0334] In some embodiments of Formula IV, the compound has a chemical structure selected from:

[0335]

[0336] Non-limiting examples of compounds of Formula IV include:

[0337]

[0338]

[0339] In some embodiments of Formula V, the compound has a chemical structure selected from:

[0340]

[0341] Non-limiting examples of compounds of Formula V include:

[0342]

[0343]

[0344]

[0345] In another aspect, a method for treating a Gram-positive or Gram-negative bacterial infection is provided, the method comprising administering an effective amount of a compound of formula VI:

[0346]

[0347] or a pharmaceutically acceptable salt thereof.

[0348] in

[0349] R 9 and R 12 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R3)2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3)2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano; and

[0350] R 10 and R 11 independently selected at each occurrence from the group consisting of hydroxy, C1-C6 alkanoyl, carbocycle, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2-, -C(O)R, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, bromine, iodine, thiol and cyano.

[0351] In one embodiment, the compound of formula VI is the following:

[0352]

[0353]

[0354] In one aspect, a compound or a pharmaceutically acceptable salt of Formula VII or Formula VIII is provided:

[0355]

[0356] in:

[0357] m and n are independently selected from 1, 2, 3 or 4;

[0358] p is 0, 1, 2 or 3;

[0359] q and t are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 at each occurrence;

[0360] L 3 and L 4 Each independently is C(R 3 )2. O or S;

[0361] R is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano;

[0362] R 3 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, carbocycle, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryl, heterocyclyl, -COOR, -C(O)R, fluorine, chlorine, bromine, and iodine;

[0363] R 13 and R 14 Independently selected from the group consisting of:

[0364] and –C(R 3 ) o NR 4 R 5 ,

[0365] Where R 4 and R 5 is independently selected at each occurrence from the group consisting of hydrogen and C1-C6 alkyl, and o is 0 to 10 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);

[0366] X 11 and X 12 Each independently selected from C(R 3 )2, O, NH or S, wherein R 3 is independently selected at each occurrence from the group as defined above;

[0367] Y1 and Y 2 Each independently selected from C(R 3 )2, O, NH or S, wherein R 3 is independently selected at each occurrence from the group as defined above; and

[0368] Z is CR 3 or N, where R 3 As defined above.

[0369] In some cases, a compound of Formula VII or Formula VIII, or a pharmaceutically acceptable salt thereof, is provided optionally in a pharmaceutically acceptable carrier to form a pharmaceutical composition.

[0370] In some cases of Formula VII or Formula VIII, R 13 for Where R 4 and R 5 is independently hydrogen or C1-C6 alkyl. In some cases of Formula VII or Formula VIII, R 13 for Where R 4 and R 5 are independently hydrogen or C1-C6 alkyl.

[0371] In some examples of Formula VII or Formula VIII, R 14 for Where R 4 and R 5 In some examples of Formula VII or Formula VIII, R 14 for Where R 4 and R 5 are independently hydrogen or C1-C6 alkyl.

[0372] In some examples of Formula VII or Formula VIII, R 13 and R 14 Each Where R 4 and R 5 are independently hydrogen or C1-C6 alkyl. In some examples of Formula VII or Formula VIII, R 13 and R 14 Each Where R 4 and R 5 is independently hydrogen or C1-C6 alkyl. 4 and R 5 For hydrogen.

[0373] Optionally, X 11 and X 12is selected from the group consisting of O, CH2, and S. In some cases, X 11 and X 12 Same (for example, X 11 and X 12 O, X respectively 11 and X 12 Each is CH2, or X 11 and X 12 Each is S).

[0374] Optionally, Y 1 and Y 2 is selected from the group consisting of O and CH2. 1 and Y 2 Same (for example, Y 1 and Y 2 Each is O or Y 1 and Y 2 Each is CH2).

[0375] In some cases, each R is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and fluorine is C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl.

[0376] In Formula VII, when t is 0, L 3 does not exist and a direct key exists in X 11 and L in the structure 3 Similarly, in Formula VII, when q is 0, L 4 does not exist and a direct key exists in X 12 and L in the structure 4 In some embodiments of Formula VII, t and q are both absent, resulting in a compound having a chemical structure as shown below:

[0377]

[0378] Where m, n, p, R, R 13 , R 14 , X 11 , X 12 , Y 1 , Y 2 and Z are as defined herein for Formula VII.

[0379] In Formula VIII, when t is 0, L 3 does not exist and a direct key exists in X 11 and L in the structure 3 Similarly, in Formula VIII, when q is 0, L 4does not exist and a direct key exists on X 12 and L in the structure 4 In some embodiments of Formula VIII, t and q are both absent, resulting in a compound having a chemical structure as shown below:

[0380]

[0381] Where m, n, p, R, R 13 , R 14 , X 11 , X 12 , Y 1 , Y 2 and Z are as defined herein for Formula VIII.

[0382] In certain aspects, the compound of Formula VII is a compound of the formula:

[0383]

[0384]

[0385]

[0386]

[0387] In certain aspects, the compound of formula VIII is a compound of the formula:

[0388]

[0389] Additional compounds described herein include the following. In some cases, the compounds can be used in methods of treating bacterial infections as described herein.

[0390]

[0391] The compounds of any formula described herein may be in the form of racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides or other isomers (such as rotational isomers), as if each is specifically described, unless the context specifically excludes. Compound A-Compound L may be in the form of racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides or other isomers (such as rotational isomers), as if each is specifically described, unless the context specifically excludes.

[0392] The present invention includes compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII or formula VIII, which have at least one desired isotope atom substitution, the amount of the atom is higher than the natural abundance of the isotope, i.e. enrichment. The present invention also includes compounds selected from compound A-compound L, which have at least one desired isotope atom substitution, the amount of the atom is higher than the natural abundance of the isotope, i.e. enrichment.

[0393] III. Pharmaceutical Compositions

[0394] The active compounds as described herein can be administered to a host (e.g., a human) in need thereof in an effective amount as a pure chemical substance, but are more typically administered as a pharmaceutical composition comprising a pharmaceutically acceptable carrier suitable for the selected mode of delivery. In one embodiment, the present disclosure provides a pharmaceutical composition comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier for any use described herein. The pharmaceutical composition may contain a compound or salt as the sole active agent, or in an alternative embodiment, contain the compound and at least one additional active agent.

[0395] When used to describe the amount of a compound in a method, an effective amount refers to the amount of a compound that achieves a desired pharmacological effect or other biological effect. For example, an effective amount can be a 10% reduction in the symptoms or signs of a disease or condition compared to a control. As used herein, a control refers to an untreated condition (e.g., a subject or cell not treated with the compounds and compositions described herein). Therefore, the reduction can be a reduction of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or any percentage between 10% and 100% compared to a natural or control level. It should be understood that treatment does not necessarily refer to curing or completely ablating a disease, condition, or the symptoms of a disease or condition.

[0396] An effective amount of an active compound as described herein or an active compound as described herein that is administered in combination or alternation with another active agent or administered before another active agent, concomitantly with another active agent, or administered after another active agent can be used in an amount sufficient to (a) inhibit the progression of a bacterial infection; (b) cause regression of a bacterial infection; (c) cause a cure of a bacterial infection; or (d) inhibit or prevent the development of a bacterial infection. For example, an effective amount can be a concentration of the compound at which a reduction in bacterial load is observed (e.g., a reduction of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percentage between 10% and 100% compared to a natural or control level).

[0397] Selected compounds disclosed herein or used as described herein can be administered, for example, orally, topically, parenterally, by inhalation or spray, sublingually, by implants (including ocular implants), transdermally, by buccal administration, rectally, as an ophthalmic solution, by injection (including ocular injection), intravenously, intraaortically, intracranialy, subdermally, intraperitoneally, subcutaneously, nasally, sublingually, intrathecally or rectally, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.

[0398] For ocular delivery, the compounds can be administered as desired, for example, in the form of solutions, suspensions or other formulations, by intravitreal, intrastromal, intracameral, sub-Tenon's, subretinal, retrobulbar, peribulbar, suprachoroidal, subchoroidal, choroidal, conjunctival, subconjunctival, episcleral, peri-ocular, transscleral, retrobulbar, posterior juxtascleral, circumcorneal or lacrimal injection, or across mucus, mucin or mucosal barriers, in an immediate or controlled release manner or via ocular devices, injections or topically applied formulations, such as solutions or suspensions provided as eye drops.

[0399] The exact amount of an active compound or pharmaceutical composition described herein to be delivered to a host in need thereof, typically a human, can be determined at the discretion of the health care provider to achieve the desired clinical benefit.

[0400] In certain embodiments, the pharmaceutical composition is in a dosage form containing from about 0.1 mg to about 1000 mg, from about 10 mg to about 750 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound in a unit dosage form, and optionally containing from about 0.1 mg to about 2000 mg, from about 10 mg to about 750 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent.

[0401] Examples are dosage forms containing at least about 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1250 mg, 1300 mg, 1400 mg, 1500 mg or 1600 mg of active compound, or a pharmaceutically acceptable salt or prodrug thereof. In one embodiment, the dosage form has at least about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 200 mg, 400 mg, 500 mg, 600 mg, 1000 mg, 1200 mg or 1600 mg of active compound or a pharmaceutically acceptable salt thereof. The amount of active compound in the dosage form is calculated without reference to the salt. The dosage form can be administered as needed, for example, once a day (qd), twice a day (bid), three times a day (tid), four times a day (qid), once every other day (Q2d), once every three days (Q3d), or any dosage regimen for providing treatment of the conditions described herein.

[0402] The pharmaceutical composition may, for example, contain an active compound and an additional active agent in a molar ratio to achieve a desired result. For example, the pharmaceutical composition may contain an additional active agent in combination with an active compound described herein or a pharmaceutically acceptable salt thereof in a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1 (additional active agent:active compound). In one embodiment, the additional active agent is an antibiotic.

[0403] The pharmaceutical composition can be formulated into any pharmaceutically useful form, such as in the form of a cream, gel, gel cap, pill, capsule, microparticle, nanoparticle, injection or infusion solution, capsule, tablet, syrup, in the form of an aerosol, transdermal patch, subcutaneous patch, dry powder, inhalation formulation, in the form of a medical device, suppository, buccal or sublingual formulation, parenteral formulation, or ophthalmic solution or suspension. Some dosage forms such as tablets and capsules are subdivided into appropriately sized unit doses containing an appropriate amount of the active ingredient, such as an effective amount to achieve the desired purpose.

[0404] Pharmaceutical compositions suitable for administration as contemplated herein and methods of making such pharmaceutical compositions are known in the art. Examples of known techniques include, for example, U.S. Pat. Nos. 4,983,593, 5,013,557, 5,456,923, 5,576,025, 5,723,269, 5,858,411, 6,254,889, 6,303,148, 6,395,302, 6,497,903, 7,060,296, 7,078,05 7, 7,404,828, 8,202,912, 8,257,741, 8,263,128, 8,337,899, 8,431,159, 9,028,870, 9,060,938, 9,211,261, 9,265,731, 9,358,478, and 9,387,252, which are incorporated herein by reference.

[0405] The pharmaceutical compositions contemplated herein may optionally include a carrier. The carrier must have sufficiently high purity and sufficiently low toxicity to make it suitable for administration to a patient receiving treatment. The carrier may be inert, or it may have its own pharmaceutical benefits. The amount of the carrier used in conjunction with the compound is sufficient to provide material for the actual amount of compound administered per unit dose.

[0406] The types of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, fillers, flavoring agents, glidants, lubricants, pH adjusters, preservatives, stabilizers, surfactants, solubilizers, tableting agents, and wetting agents. Some carriers may be listed in more than one category, for example, vegetable oils may be used as lubricants in some formulations and as diluents in other formulations. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, powdered tragacanth, malt, gelatin; talc and vegetable oils.

[0407] Examples of other base materials, fillers or diluents include lactose, mannitol, xylitol, microcrystalline cellulose, dicalcium phosphate and starch.

[0408] Examples of surfactants include sodium lauryl sulfate and polysorbate 80. Examples of drug complexing agents or solubilizing agents include polyethylene glycol, caffeine, xanthene, gentisic acid, and cyclodextrin.

[0409] Examples of disintegrants include sodium starch gycolate, sodium alginate, sodium carboxymethylcellulose, methylcellulose, colloidal silicon dioxide, and cross-linked sodium carboxymethylcellulose. Examples of binders include methylcellulose, microcrystalline cellulose, starch, and gums such as guar gum and tragacanth.

[0410] Examples of lubricants include magnesium stearate and calcium stearate. Examples of pH adjusters include acids such as citric acid, acetic acid, ascorbic acid, lactic acid, aspartic acid, succinic acid, phosphoric acid, etc.; bases such as sodium acetate, potassium acetate, calcium oxide, magnesium oxide, trisodium phosphate, sodium hydroxide, calcium hydroxide, aluminum hydroxide, etc., and buffers generally comprising a mixture of an acid and a salt of the acid. Optional other active agents may be included in the pharmaceutical composition, which do not substantially interfere with the activity of the compounds of the present invention.

[0411] In certain embodiments, the pharmaceutical composition for administration further comprises a compound or salt as described herein, and optionally comprises one or more of the following: phosphoglycerides; phosphatidylcholine; dipalmitoylphosphatidylcholine (DPPC); dioleylphosphatidylethanolamine (DOPE); dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol esters; diacylglycerols; diacylglycerol succinate; diphosphatidylglycerol (DPPG); hexanedecanol; fatty alcohols, such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; surface-active fatty acids, such as palmitic acid or oleic acid; fatty acids; fatty acid monoglycerides; fatty acid diglycerides; fatty acid amides; sorbitan trioleate Glycocholate; Sorbitan Monolaurate Polysorbate Polysorbate Polysorbate Polysorbate Polysorbate Polyoxyethylene monostearate; surfactin; poloxamer; sorbitan fatty acid esters such as sorbitan trioleate; lecithin; lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin; phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid; cerebrosides; diacetyl phosphate; dipalmitoylphosphatidylglycerol; stearylamine; dodecylamine; hexadecylamine; acetyl palmitate; ricinoleyl glyceride; hexadecyl stearate; isopropyl myristate; tyloxapol; poly(ethylene glycol) 5000-phosphatidylethanolamine; poly(ethylene glycol) 400-monostearate; phospholipids; synthetic and / or natural detergents with high surfactant properties; deoxycholate; cyclodextrins; chaotropic salts salt); ion pairing agents; glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellobiose, mannose, xylose, arabinose, glucuronic acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine and neuraminic acid; pullulan, cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran, glycogen, hydroxyethyl starch, carrageenan, glycon, amylose, chitosan, N,O-carboxymethyl chitosan, algin and alginic acid, starch, chitin, inulin, konjac, glucomannan, psoralen, heparin, hyaluronic acid, curdlan and xanthan gum, mannitol, sorbitol, xylitol, erythritol, maltitol and lactitol, pluronic polymers, poly Ethylene, polycarbonate (e.g., poly(1,3-dioxane-2-one), polyanhydride (e.g., poly(sebacic anhydride)), polypropyl fumarate, polyamide (e.g., polycaprolactam), polyacetal, polyether, polyester (e.g., polylactide, polyglycolide, polylactide-co-glycolide, polycaprolactone, polyhydroxy acid (e.g., poly(β-hydroxyalkanoate)), poly(orthoester), polycyanoacrylate, polyvinyl alcohol, polyurethane, polyphosphazene, polyacrylate, polymethacrylate, polyurea, polystyrene and polyamine, polylysine, polylysine-PEG copolymer and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymer, glyceryl monocapryloyldecanoate, propylene glycol, vitamin E TPGS (also known as d-α-tocopheryl polyethylene glycol 1000 succinate), gelatin, titanium dioxide, polyvinyl pyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), block copolymer of ethylene oxide and propylene oxide (PEO / PPO), polyethylene glycol (PEG), sodium carboxymethylcellulose (NaCMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0412] In some embodiments, the pharmaceutical formulation may include a polymer for controlling the delivery of the compound, including, but not limited to, pluronic polymers, polyesters (e.g., polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone, polyvalerolactone, poly(1,3-dioxane-2-one)); polyanhydrides (e.g., poly(sebacic anhydride)); polyethers (e.g., polyethylene glycol); polyurethanes; polymethacrylates; polyacrylates; and polycyanoacrylates. In some embodiments, the polymer may be modified with polyethylene glycol (PEG), modified with carbohydrates, and / or modified with acyclic polyacetals derived from polysaccharides. See, e.g., Papisov, 2001, ACS Symposium Series, 786:301, which is incorporated herein by reference.

[0413] The compounds of the present invention may be formulated as particles. In one embodiment, the particles are or comprise microparticles. In alternative embodiments, the particles are or comprise nanoparticles.

[0414] Common techniques for preparing particles include, but are not limited to, solvent evaporation, solvent removal, spray drying, phase inversion, coacervation, and low temperature casting. Suitable methods for particle formulation are briefly described below. Pharmaceutically acceptable excipients including pH regulators, disintegrants, preservatives, and antioxidants may optionally be incorporated into the particles during the particle formation process.

[0415] In one embodiment, the particles are obtained by a solvent evaporation method. In this method, a compound as described herein (or a polymer matrix and one or more compounds as described herein) is dissolved in a volatile organic solvent such as dichloromethane. The organic solution containing the compound as described herein is then suspended in an aqueous solution containing a surfactant such as poly(vinyl alcohol). The resulting emulsion is stirred until most of the organic solvent evaporates, leaving solid nanoparticles or microparticles. The resulting nanoparticles or microparticles are washed with water and dried overnight in a freeze dryer. Nanoparticles of different sizes and morphologies can be obtained by this method.

[0416] Pharmaceutical compositions containing unstable polymers, such as certain polyanhydrides, may degrade during the manufacturing process due to the presence of water. For these polymers, the particles can be prepared using methods performed in completely or substantially anhydrous organic solvents.

[0417] Solvent removal can also be used to prepare particles from hydrolytically unstable compounds. In this method, the compound (or polymer matrix and one or more

[0418] In one embodiment, the active compound as described herein is administered to a patient in need thereof in the form of a spray dried dispersion (SDD). In another embodiment, the invention provides a spray dried dispersion (SDD) comprising a compound of the invention and one or more pharmaceutically acceptable excipients as defined herein. In another embodiment, the SDD comprises a compound of the invention and an additional active agent. In a further embodiment, the SDD comprises a compound of the invention, an additional active agent, and one or more pharmaceutically acceptable excipients.

[0419] In another embodiment, any of the spray-dried dispersions described can be coated to form coated tablets. In alternative embodiments, the spray-dried dispersion is formulated into tablets but without coating. Phase inversion methods can be used to form particles from active compounds as described herein. In this method, the compound (or polymer matrix and one or more active compounds) is dissolved in a suitable solvent, and the solution is poured into a strong non-solvent so that the compound spontaneously produces microparticles or nanoparticles under favorable conditions. The method can be used to produce nanoparticles including, for example, a wide range of sizes from nanoparticles to microparticles, usually with a narrow particle size distribution.

[0420] In one embodiment, the polymer particles are between about 0.1 nm and about 10000 nm, between about 1 nm and about 1000 nm, between about 10 nm and 1000 nm, between about 1 nm and 100 nm, between about 1 nm and 10 nm, between about 1 nm and 50 nm, between about 100 nm and 800 nm, between about 400 nm and 600 nm, or about 500 nm. In one embodiment, the microparticles are no more than about 0.1 nm, 0.5 nm, 1.0 nm, 5.0 nm, 10 nm, 25 nm, 50 nm, 75 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 1000 nm, 1250 nm, 1500 nm, 1750 nm, or 2000 nm. In some embodiments, the compounds described herein can be covalently coupled to the polymer used in the nanoparticles (e.g., polystyrene particles, PLGA particles, PLA particles, or other nanoparticles).

[0421] The pharmaceutical composition can be formulated for oral administration. These compositions can contain any amount of active compound to achieve the desired result, such as between 0.1% and 99% by weight (wt.%) of the compound, typically at least about 5% by weight of the compound. Some embodiments contain at least about 10%, 15%, 20%, 25% to about 50%, or about 5% to about 75% by weight of the compound.

[0422] Pharmaceutical compositions suitable for rectal administration are usually presented in the form of unit-dose suppositories. These can be prepared by mixing the active compound with one or more conventional solid carriers, such as cocoa butter, and then shaping the resulting mixture.

[0423] Pharmaceutical compositions suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Useful carriers include vaseline, lanolin, polyethylene glycol, alcohol, transdermal enhancers and combinations of two or more thereof.

[0424] The pharmaceutical composition suitable for transdermal administration can exist in the form of discrete patches, and the patch is suitable for keeping close contact with the epidermis of the receptor for a long time. The pharmaceutical composition suitable for transdermal administration can also be delivered by iontophoresis (for example, referring to Pharmaceutical Research 3 (6): 318 (1986)), and usually takes the form of an optional buffered aqueous solution of the active compound. In one embodiment, a microneedle patch or device is provided for passing or entering biological tissue, particularly skin, by drug delivery. Microneedle patch or device allow drug to be delivered through or enter skin or other tissue barriers at a clinically relevant rate, and the damage, pain or stimulation caused to tissue is minimal or there is no damage, pain or stimulation to tissue.

[0425] Pharmaceutical compositions suitable for pulmonary administration can be delivered by a wide range of passive breath-driven and active power-driven single / multi-dose dry powder inhalers (DPIs). The devices most commonly used for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of suitable pulmonary delivery devices depends on parameters such as the properties of the drug and its formulation, site of action, and the pathophysiology of the lungs.

[0426] Additional non-limiting examples of inhaled drug delivery devices and methods include, for example, US 7,383,837 entitled "Inhalation device" (SmithKline Beecham Corporation); WO / 2006 / 033584 entitled "Powder inhaler" (Glaxo SmithKline Pharmaceuticals SA); WO / 2005 / 044186 entitled "Inhalable pharmaceutical formulations employing desiccating agents and methods of administering the same" (Glaxo Group Ltd and SmithKline Beecham Corporation); US 9,095,670 entitled "Inhalation device and method of dispensing medicament", US 8,205,611 entitled "Dry powder inhaler" (Astrazeneca AB); WO / 2013 / 038170 entitled "Inhaler" (Astrazeneca AB and Astrazeneca UK Ltd.); US / 2014 / 0352690 entitled “Inhalation Device with Feedback System”, US 8,910,625 and US / 2015 / 0165137 entitled “Inhalation Device for Use in Aerosol Therapy” (Vectura GmbH);US 6,948,496 entitled "Inhalers", US / 2005 / 0152849 entitled "Powders comprising anti-adherent materials for use in dry powder inhalers", US 6,582,678, US 8,137,657, US / 2003 / 0202944 and US / 2010 / 0330188 entitled "Carrier particles for use in dry powder inhalers", US 6,221,338 entitled "Method of producing particles for use in dry powder inhalers", US 6,989,155 entitled "Powders", US / 2007 / 0043030 entitled "Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation", US 6,582,678, US 8,137,657, US / 2003 / 0202944 and US / 2010 / 0330188 entitled "Carrier particles for use in dry powder inhalers", US 6,221,338 entitled "Method of producing particles for use in dry powder inhalers", US 6,989,155 entitled "Powders", US / 2007 / 0043030 entitled "Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation", US 7,845,349, US / 2012 / 0114709 and US 8,101,160, entitled “Formulations for Use in Inhaler Devices”, US / 2013 / 0287854, entitled “Compositions and Uses”, US / 2014 / 0037737 and US 8,580,306, entitled “Particles for Use in a Pharmaceutical Composition”, US / 2015 / 0174343, entitled “Mixing Channel for an Inhalation Device”, US 7,744,855 and US / 2010 / 0285142, entitled “Method of making particles for use in a pharmaceutical composition”, US 7,541,022, US / 2009 / 0269412 and US / 2015 / 0050350 (Vectura Limited). ;

[0427] IV. Treatment Methods

[0428] In one embodiment, an effective amount of a compound of Formula I to Formula V, or a pharmaceutically acceptable salt or composition thereof, or a compound of Formula VII or Formula VIII, or a pharmaceutically acceptable salt or composition thereof, is used to treat or prevent a medical condition caused by the presence of bacteria, such as a bacterial infection. Optionally, the compound is MD-124 as described herein. In one embodiment, an effective amount of a compound selected from Compound A, Compound B, or Compound F to Compound L, or a pharmaceutically acceptable salt or composition thereof, is used to treat or prevent a medical condition mediated by the presence of bacteria, such as a bacterial infection. In one embodiment, the compounds of the present invention can be used to treat a condition caused by pathogenic bacteria, typically an infection. In one embodiment, a method is provided, the method comprising administering an effective amount of a compound of Formula I to Formula V, or a pharmaceutically acceptable salt or composition thereof, or a compound of Formula VIII, or a pharmaceutically acceptable salt or composition thereof, to a subject (typically a human) to treat an infection caused by pathogenic bacteria.

[0429] Compounds as described herein are particularly effective in combination with antibiotics because they enhance the antimicrobial effect of antibiotics. In one embodiment, active compounds as described herein or their salts or compositions can be combined with antibiotics or used alternately to enhance the antimicrobial effect of antibiotics. Commonly used antibiotics include clindamycin, erythromycin, metronidazole, sulfacetamide and tetracyclines, such as doxycycline and minocycline. Other representative topical antibiotics include bacitracin, polymyxin b, neomycin, retapaline, mupirocin, praxine, gentamicin, mafenide and ozenoxacin. In one embodiment, active compounds or their salts are combined with antibiotics to be formulated into topical preparations as described herein.

[0430] In one embodiment, the compounds of the present invention can be used to treat conditions caused by gram-positive bacteria, typically infections. In one embodiment, a method is provided, comprising administering an effective amount of a compound of Formula I to Formula VIII or a pharmaceutically acceptable salt or composition thereof to treat an infection caused by gram-positive bacteria. In one embodiment, a method is provided, comprising administering an effective amount of a compound selected from Compound A-Compound L or a pharmaceutically acceptable salt or composition thereof to treat an infection caused by gram-positive bacteria.

[0431] Non-limiting examples of Gram-positive bacteria that can be treated using the compounds of the invention, alone or in combination with another therapeutic agent, include: Actinomyces species, including Actinomyces israelii, Actinomyces naeslundii, Actinomyces viscosus, Actinomyces odontolyticus, and Actinomyces pyogenes; Bacillus species, including Bacillus anthracis, Bacillus cereus, and Bacillus subtilis; Clostridium species, including Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium sordellii, and Clostridium spp. sordellii and Clostridium tetani; Corynebacterium species, including Corynebacterium diphtheriae, Corynebacterium jeikeium, Corynebacterium minutissimum, Corynebacterium mucifaciens, Corynebacteriumpseudotuberculosis, Corynebacterium striatum, Corynebacterium tenuis and Corynebacterium ulcerans; Enterococcus species, including Enterococcus casseliflavus, Enterococcus faecalis, Enterococcus faecium, faecium), Enterococcus raffinosus, and Enterococcus hirae;Leuconostoc species, including Leuconostoc pseudomesenteroides; Micrococcus species, such as Microccocus luteus; Nocardia species, including Nocardia asteroides; Propionibacterium species, including Propionibacterium acnes; Staphylococcus species, including Staphylococcus aureus, Staphylococcus capitis, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus spp. hominis, Staphylococcus lugdunensis, Staphylococcus pasteuri, and Staphylococcus saprophyticus; and Streptococcus species, including Streptococcus agalactiae, Streptococcus anginosus, Streptococcus bovis, Streptococcus dysgalactiae, Streptococcus mitis, Streptococcus mutans, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus sanguinis, Streptococcus suis, and Streptococcus viridans.

[0432] In one embodiment, the compounds of the present invention can be used to treat conditions caused by gram-negative bacteria, typically infections. In one embodiment, a method is provided, comprising administering an effective amount of a compound of Formula I to Formula VIII, or a pharmaceutically acceptable salt or composition thereof, to treat an infection caused by gram-negative bacteria. In one embodiment, a method is provided, comprising administering an effective amount of a compound selected from Compound A-Compound L, or a pharmaceutically acceptable salt or composition thereof, to treat an infection caused by gram-negative bacteria.

[0433] Non-limiting examples of Gram-negative bacteria that can be treated using the compounds of the invention, alone or in combination with another therapeutic agent, include: Acinetobacter species, including Acinetobacter baumannii and Acinetobacter iwoffii; Aeromonas species, including Aeromonas veronii biovarsobria (formerly Aeromonas sobria), Aeromonascaviae, and Aeromonas hydrophila; Alcaligenes / Achromobacter species, including Alcaligenes faecalis and Alcaligenes xylosoxidans; Bacteroides species, including Bacteroides fragilis; fragilis; Bartonella species, including Bartonella bacilliformis, Bartonella clarridgeiae, Bartonella elizabethae, Bartonella henselae, Bartonella koehlerae, Bartonalla naantalienis, Bartonella quintana, Bartonella rochalimae, Bartonella vinsonii, and Bartonella washoensis; Bordetella species, including Bordetella bronchispetica, Bordetella pertussis, and Bordetella parapertussis. parapertussis);Borrelia species, including Borrelia afzelii, Borrelia burgdorferi, Borrelia crocidurae, Borrelia duttoni, Borrelia garinii, Borrelia hermsii, Borrelia hispanica, Borrelia miyamotoi, Borrelia parkeri, Borrelia persica, Borrelia recurrentis, Borrelia turicatae, and Borrelia venezuelensis; Brevundimonas species, including Brevundimonas diminuta and Brevundimonas vesicularis; Brucella species, including Brucella abortus, Brucella canis, Brucella melitensis and Brucella suis; Burkholderia species, including Burkholderia cepacia, Burkholderia mallei and Burkholderia pseudomallei; Campylobacter species, including Campylobacter jejuni, Campylobacter coli, Campylobacter upsaliensis, Campylobacter lari and Campylobacter coli;Chlamydia / Chlamidophila species, including Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamidophila pecorum, and Chlamydia trachomatis; Citrobacter species, including Citrobacter amalonaticus, Citrobacter freundii, Citrobacter koseri, and Citrobacter diversus; Coxiella burnetti; Ehrlichia species, including Ehrlichia canis canis and Ehrlichia chaffeensis; Enterobacter species, including Enterobacter aerogenes and Enterobacter cloacae; Escherichia species, including Escherichia coli; Francisella species, including Francisella novicida, Francisella philomiragia and Francisella tularensis; Haemophilus species, including Haemophilus influenzae and Haemophilus ducreyi; Helicobacter species, including Helicobacter pylori; pylori); Klebsiella species, including Klebsiella granulomatis, Klebsiella oxytoca, and Klebsiella pneumoniae; Leclercia adecarboxylata; Legionella species, including Legionella pneumophila;Leptospira species, including Leptospira interrogans, Leptospira noguchii, Leptospira santarosai, and Leptospira weilii; Listeria species, including Listeria monocytogenes; Moraxella species, including Moraxella catarrhalis, Moraxella lacunata, and Moraxella bovis; Morganella species, including Morganella morganii; Mycoplasma species, including Mycoplasma amphoriforme, Mycoplasma buccale, Mycoplasma faucium, Mycoplasma fermentans, Mycoplasma genitalium, Mycoplasma hominis, Mycoplasma lipophilum, Mycoplasma orale, Mycoplasma penetrans, Mycoplasma mapirum, Mycoplasma pneumoniae, Mycoplasma primatum, Mycoplasma salivarium, Mycoplasma spermatophilum; Neisseria species, including Neisseria meningitidis and Neisseria gonorrhoeae gonorrhoeae); Orientia species, including Orientia tsutsugamushi and Orientia chuto; Pantoea species, including Pantoea agglomerans;Paracoccus species, including Paracoccus yeei; Prevotella species, including Prevotella intermedia and Prevotella melaninogenica; Proteus species, including Proteus mirabilis, Proteus penneri and Proteus vulgaris; Providencia species, including Providencia rettgeri and Providencia stuartii; Pseudomonas species, including Pseudomonas aeruginoas, Pseudomonas oryzae, and Pseudomonas stuartii. oryzihabitans), Pseudomonas plecoglossidica, and Pseudomonas stutzeri; Ralstonia species, including Ralstonia pickettii and Ralstonia insidiosa; Rickettsia species, including Rickettsia africae, Rickettsia akari, Rickettsia australis, Rickettsia conorii, Rickettsia felis, Rickettsia japonica, Rickettsia prowazekii, Rickettsia rickettsii, and rickettsia, Rickettsia sibirica, and Rickettsia typhi; Roseomonas species, including Roseomonas gilardii;Salmonella species, including Salmonella bongori, Salmonella enterica, Salmonella paratyphi, Salmonella typhi, and Salmonella typhimurium; Serratia species, including Serratia marcescens, Serratia liquefaciens, Serratia rubidaea, and Serratia odoriferae; Shigella species, including Shigella dysenteriae and Shigella sonnei sonnei; Sphingomonas species, including Sphingomonas mucosissima and Sphingomonas paucimobilus; Stenotrophomas species, including Stenotrophomas maltophilia; Treponema species, including Treponema carateum, Treponema paraluiscuniculi, and Treponema pallidum; Ureaplasma species, including Ureaplasma urealyticum; Vibrio species, including Vibrio cholera, Vibrio parahaemolyticus, and Vibrio cholerae. parahaemolyticus and Vibrio vulnificus; and Yersinia species, including Yersinia enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis.

[0434] In one embodiment, the compounds of the present invention can be used to treat a condition caused by mycobacteria, typically an infection. In one embodiment, a method is provided, comprising administering an effective amount of a compound of Formula I to Formula V, or a pharmaceutically acceptable salt thereof, or a composition to treat an infection caused by mycobacteria. In one embodiment, a method is provided, comprising administering an effective amount of a compound of Formula VII or Formula VIII, or a pharmaceutically acceptable salt thereof, or a composition to treat an infection caused by mycobacteria. In one embodiment, a method is provided, comprising administering an effective amount of a compound selected from Compound A, Compound B, or Compound F-Compound L, or a pharmaceutically acceptable salt thereof, or a composition to treat an infection caused by mycobacteria.

[0435] Non-limiting examples of mycobacteria that can be treated using the compounds of the invention, alone or in combination with another therapeutic agent, include Mycobacterium abcessus, Mycobacterium africanum, Mycobacterium agri, Mycobacterium aichiense, Mycobacterium alvei, Mycobacterium arabiense, Mycobacterium aromaticivorans, Mycobacterium arosiense, Mycobacterium arupense, Mycobacterium aquaticum, Mycobacterium asiaticum, Mycobacterium aubagnese, Mycobacterium aurum, Mycobacterium australis, Mycobacterium truncatum ... austroafricanum, Mycobacterium avium, Mycobacterium avium paratuberculosis, Mycobacterium avium silvaticum, Mycobacterium aviumhominussuis, Mycobacterium bacteremicum, Mycobacteriumbarrassiae, Mycobacterium boenickei, Mycobacterium bohemicum, Mycobacterium bolletii, Mycobacterium botniense, Mycobacterium bovis, Mycobacterium branderi, Mycobacterium brisbane brisbanense), Mycobacteriumbrumae), Mycobacterium canariasense, Mycobacterium canettii, Mycobacterium caprae, Mycobacterium chimaera, Mycobacterium chelonae, Mycobacterium chitae, Mycobacterium chubuense, Mycobacterium colombiense, Mycobacterium conceptionense, Mycobacterium confluentis, Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium cosmeticum, Mycobacterium diernhoferi, Mycobacterium doricum, Mycobacterium duvalii, Mycobacterium elephantis, Mycobacterium fallax, Mycobacterium farcinogenes, Mycobacterium flavescens, Mycobacterium florentinum, Mycobacterium fortuitum, Mycobacteriumfrederikbergense, Mycobacterium gadium, Mycobacterium gastri, Mycobacterium genavense, Mycobacterium gilvum, Mycobacterium gordonae, Mycobacterium florentinum, haemophilum), Mycobacterium hassiacum, Mycobacterium Heidelbergensisheidelbergense, Mycobacterium heckshornense; Mycobacterium hiberniae, Mycobacterium hodleri, Mycobacterium holsaticum, Mycobacterium houstonense, Mycobacterium icosium assilensis, Mycobacterium immunogenum, Mycobacterium indicus pranii, Mycobacterium intacellulare, Mycobacterium intracellulare, Mycobacterium interjectum, Mycobacterium intermedium, Mycobacterium iranicum, Mycobacterium kansasii kansasii), Mycobacterium komossense, Mycobacterium kubicae, Mycobacterium lentiflavum, Mycobacterium leprae, Mycobacterium lepraemurium, Mycobacterium lepromatosis, Mycobacterium liflandii, Mycobacterium llatzerense, Mycobacterium madagascariense, Mycobacterium mageritense, Mycobacterium malmoense, Mycobacterium marinum, Mycobacterium massiliense、Mycobacterium massilipolynesiensis、Mycobacteriummicroti), Mycobacterium monacense, Mycobacterium montfiorense, Mycobacterium morokaense, Mycobacterium mucogenicum, Mycobacterium mungi, Mycobacterium murale, Mycobacterium nebraskense, Mycobacterium neoaurum, Mycobacterium neworleansense, Mycobacterium nonchromogenicum, Mycobacterium obuense, Mycobacterium orygis, Mycobacterium palustre, Mycobacterium parascofulaceum), Mycobacterium parafortuitum, Mycobacterium eriumperigrinum, Mycobacterium phlei, Mycobacterium eriumphocaicum, Mycobacterium pinnipedii, Mycobacterium porcinum, Mycobacterium pseudoshottsii, Mycobacterium psychotolerans, Mycobacterium pulveris, Mycobacterium pyrenivorans, Mycobacterium saskatchewanense, Mycobacterium sediminis, Mycobacterium senegalense, Mycobacterium septicum septicum), Mycobacterium shimoidei, Mycobacteriumshottsii), Mycobacterium simiae, Mycobacterium smegmatis, Mycobacterium sphagni, Mycobacterium stephanolepidis, Mycobacterium suricattae, Mycobacterium szulgai, Mycobacterium talmoniae, Mycobacterium terrae, Mycobacterium thermoresistibile, Mycobacterium triplex, Mycobacterium triviale, Mycobacterium tuberculosis, Mycobacterium tusciae, Mycobacterium ulcerans ulcerans), Mycobacterium vaccae, Mycobacterium vanbaalenii, Mycobacterium xenopi, and Mycobacterium yongonense.

[0436] In one embodiment, an effective amount of an active compound as described herein, or a pharmaceutically acceptable salt or composition thereof, is used to treat or prevent a medical condition mediated by the presence of antibiotic-resistant bacteria. In one embodiment, the compounds of the invention are useful for treating a condition, typically an infection, caused by pathogenic antibiotic-resistant bacteria.

[0437] In one embodiment, a method is provided, comprising administering an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof or a composition thereof to a subject (typically a human) to treat an infection caused by pathogenic antibiotic-resistant bacteria.

[0438] Non-limiting examples of Gram-positive antibiotic-resistant bacteria include: antibiotic-resistant Clostridium difficile, antibiotic-resistant Streptococcus pneumoniae, clindamycin-resistant Group B Streptococcus, erythromycin-resistant Group A Streptococcus, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA), and vancomycin-resistant Enterococcus (VRE).

[0439] Non-limiting examples of Gram-negative antibiotic-resistant bacteria include: antibiotic-resistant Burkholderia cepacia, carbapenem-resistant Enterobacteriaceae (CRE) enteric bacteria, drug-resistant Campylobacter, drug-resistant non-typhoidal Salmonella, drug-resistant Shigella, multidrug-resistant Acinetobacter, multidrug-resistant Escherichia coli, multidrug-resistant Klebsiella pneumoniae, multidrug-resistant Neisseria gonorrhoeae, and multidrug-resistant Pseudomonas aeruginosa.

[0440] In one embodiment, an effective amount of a compound of Formula I to Formula V or a pharmaceutically acceptable salt thereof or a composition is used to treat or prevent a medical condition mediated by the presence of antibiotic-resistant mycobacteria. Optionally, an effective amount of a compound of Formula VII or Formula VIII or a pharmaceutically acceptable salt thereof or a composition is used to treat or prevent a medical condition mediated by the presence of antibiotic-resistant mycobacteria. In one embodiment, an effective amount of a compound selected from Compound A-Compound L or a pharmaceutically acceptable salt thereof or a composition is used to treat or prevent a medical condition mediated by the presence of antibiotic-resistant mycobacteria. In one embodiment, the compounds of the present invention can be used to treat a condition caused by pathogenic antibiotic-resistant mycobacteria, typically an infection. In one embodiment, a method is provided, the method comprising administering an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof or a composition as described herein to a subject (typically a human) to treat an infection caused by pathogenic antibiotic-resistant mycobacteria. In one embodiment, the antibiotic-resistant mycobacteria are multidrug-resistant mycobacteria tuberculosis (MDR-TB).

[0441] Non-limiting examples of bacterial-mediated conditions that can be treated with the compounds of the invention, alone or in combination with another therapeutic agent, include actinomycosis, anaplasmosis, anthrax, bacillary angiomatosis, actinomycoma, bacterial pneumonia, bacterial vaginosis, bacterial endocarditis, bartonellosis, botulism, Butane fever, brucellosis, bejel, Brucellosis spondylitis, bubonic plague, Buruli ulcer, Bairnsdale ulcer, bacillary dysentery, campylobacteriosis, Carrion's disease, cat scratch disease, cellulitis, chancroid, chlamydia, chlamydial conjunctivitis, clostridial myonecrosis, cholera, Clostridium difficile colitis, diphtheria, diphtheria ulcer, donavanosis, dysentery, erhlichiosis, epidemic typhus, fried rice syndrome, five-day fever, floppy baby syndrome, Far East scarlet-like fever), gas gangrene, glanders, gonorrhea, granuloma inguinale, human necrotizing bacillus disease, hemolytic uremic syndrome, human ewingii ehrlichiosis, human monocytic ehrlichiosis, human granulocytic anaplasmosis, infant botulism, spring fever, Kawasaki disease, Kumasi ulcer, lymphogranuloma venereum, Lemierre's syndrome, Legionnaires' disease, leprosy, leptospirosis, listeriosis, Lyme disease, lymphogranuloma venereum, Malta fever, Mediterranean fever, myonecrosis, mycobacterial ulcer ulcer), mucocutaneous lymphadenopathy, melioidosis, meningococcal disease, murine typhus, mycoplasma pneumonia, mycetoma, neonatal conjunctivitis, nocardiosis, Oroya fever, neonatal ophthalmia, ornithosis, Pontia fever, hepatic purpura, pneumonic plague, postanginal shock including sepsis, pasteurellosis, pelvic inflammatory disease, pertussis, plague, pneumococcal infection, pneumonia, psittacosis, psittacosis, pseudotuberculosis, Q fever, quintan fever, rabbit fever, relapsing fever, rickettsialpox, Rocky Mountain spotted fever, rat-bite fever, Reiter syndrome, rheumatic fever, salmonellosis, scarlet fever, sepsis, septicemic plague, Searls ulcer, shigellosis, chancroid, syphilis, streptobacil fever, scrub typhus, Taiwan acute respiratory factor agent), trench fever, trachoma, tuberculosis, tularemia, typhoid fever, typhus, tetanus, toxic shock syndrome, undulant fever, chancroid, Vibrio parahaemolyticus enteritis, Whitmore's diseasedisease, walking pneumonia, Waterhouse-Friderichsen syndrome, yaws, and yersiniosis.

[0442] In one embodiment, the compounds of the invention can be used to treat inflammatory conditions caused by bacterial infection. Non-limiting examples of such inflammatory conditions include adenitis, appendicitis, arteritis, ascending cholangitis, balanitis, blepharitis, bronchitis, bursitis, cellulitis, cerebral vasculitis, cervicitis, chemosis, cholecystitis, chondritis, chorioamnionitis, colitis, conjunctivitis, constrictive pericarditis, cryptitis, lacrimal gland inflammation, dermatitis, duodenal lymphocytosis, encephalitis, endocarditis, endometritis, endotheliitis, enteritis, enterocolitis, eosinophilic fasciitis, epididymitis, esophagitis, folliculitis, gastritis, gingivitis, glomerulonephritis, glossitis, hepatitis, infectious arthritis, ileitis, intertrigo, keratitis, keratoconjunctivitis, otitis interna abyrithitis), lymphadenitis, mastitis, mastoiditis, myocarditis, myopericarditis, myositis, necrotizing fasciitis, nephritis, omphalitis, oophoritis, ophthalmitis, orchitis, osteitis, osteomyelitis, pancreatitis, pericorectitis, mumps, pericarditis, perichondritis, perifolliculitis, periodontitis, peritonitis, pharyngitis, phlebitis, pleurisy, pneumonia, pneumonitis, proctitis, prostatitis, pulpitis, pyelonephritis, pyomyositis, retinal vasculitis, rheumatic fever, rhinitis, scleritis, salpingitis, sialadenitis, sinusitis, stomatitis, synovitis, sepsis, tenosynovitis, thyroiditis, tonsillitis, tularemia, urethritis, uveitis, vaginitis, vasculitis, and vulvitus.

[0443] V. Combination Therapy

[0444] In one embodiment, the compound of Formula I to Formula VIII, or a pharmaceutically acceptable salt thereof, or composition can be combined or provided in alternation with an effective amount of at least one additional active agent, or provided before, concomitantly with, or after at least one additional active agent, for example to treat a condition listed herein. Non-limiting examples of additional active agents for such combination therapy are provided below.

[0445] Whenever any term is used hereinafter and described generally herein in reference to an active compound as described herein, or a pharmaceutically acceptable salt or composition thereof, it should be understood that the pharmaceutically acceptable salt, prodrug or composition is considered to be included unless otherwise specified or inconsistent with the context.

[0446] In one embodiment, the active compound of Formula I to Formula VIII or a pharmaceutically acceptable salt or composition thereof as described herein may be used in combination or alternation with an antibiotic.

[0447] In one embodiment, a compound selected from Compound A to Compound L or a pharmaceutically acceptable salt or composition thereof as described herein may be used in combination or alternation with an antibiotic.

[0448] In one embodiment, the antibiotic is an aminoglycoside. In one embodiment, the antibiotic is selected from amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin and spectinomycin.

[0449] In one embodiment, the antibiotic is an ansamycin. In one embodiment, the antibiotic is selected from geldanamycin, herbemycin and rifaximin.

[0450] In one embodiment, the antibiotic is a carbapenem. In one embodiment, the antibiotic is selected from ertapenem, doripenem, imipenem, panipenem, biapenem, tebipenem and meropenem.

[0451] In one embodiment, the antibiotic is a cephalosporin. In one embodiment, the antibiotic is selected from cefacetrile, cefadroxil, cephalexin, cefaloglycin, cefuroxime, cefaloglycin, cefalonin, cephalothin, cephapirin, ceftriaxone, cefazolin, cefazolin, cephradine, cefotaxime and cefotaxime. In one embodiment, the antibiotic is selected from cefaclor, cefonicid, cefprozil, cefuroxime, cefazolin, cefmetazole, cefotetan, cefoxitin, loracarbef, cefbuperazone, cefminox, cefoxitin and cefotiam. In one embodiment, the antibiotic is selected from cefcarpine, cefdoxime, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefotaxime, cefovici, cefimizoline, cefpodoxime, cefditoren, ceftamere, ceftibuten, ceftiofur, ceftiolin, cefazolin, ceftriaxone, cefoperazone, ceftazidime and latamoxef. In one embodiment, the antibiotic is selected from cefixime, cefepime, cefuroxime, cefuroxime, ceftriaxone, cefoperazone, ceftazidime and latamoxef. In one embodiment, the antibiotic is selected from cefixime, cefepime, cefuroxime, ceftriaxone, cefoperazone, cefuroxime and fluoxetine. In one embodiment, the antibiotic is selected from ceftobiprole, ceftaroline and ceftolozane.

[0452] In one embodiment, the antibiotic is a glycopeptide. In one embodiment, the antibiotic is selected from teicoplanin, vancomycin, telavancin, dalbavancin, ramoplanin, decaplanin, and oritavancin.

[0453] In one embodiment, the antibiotic is lincosamide. In one embodiment, the antibiotic is selected from lincomycin, clindamycin and pirimicin. In one embodiment, the antibiotic is daptomycin.

[0454] In one embodiment, the antibiotic is a macrolide. In one embodiment, the antibiotic is selected from azithromycin, clarithromycin, erythromycin, fidaxomycin, telithromycin, carbomycin A, josamycin, kitasamycin, midecamycin, oleandomycin, solithromycin, spiramycin, troleandomycin, tylosin and roxithromycin.

[0455] In one embodiment, the antibiotic is a ketolide. In one embodiment, the antibiotic is selected from telithromycin, quiniramicin and solithromycin.

[0456] In one embodiment, the antibiotic is a monobactam.

[0457] In one embodiment, the antibiotic is selected from aztreonam. In one embodiment, the antibiotic is a nitrofuran. In one embodiment, the antibiotic is selected from diruazone, furazolidone, nifuroline, nifuroxide, nifuroquinazole, nifurotoinol, nifurozine, nitrofurazone and nitrofurantoin.

[0458] In one embodiment, the antibiotic is an oxazolidinone. In one embodiment, the antibiotic is selected from linezolid, preszolid, tedizolid, radezolid, torezolid, and cycloserine.

[0459] In one embodiment, the antibiotic is penicillin. In one embodiment, the antibiotic is selected from penicillin G, penicillin K, penicillin N, penicillin O and penicillin V. In one embodiment, the antibiotic is selected from methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin and flucoxacillin. In one embodiment, the antibiotic is selected from ampicillin, amoxicillin, pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin and epicillin. In one embodiment, the antibiotic is selected from carbenicillin, ticarcillin and temocillin. In one embodiment, the antibiotic is selected from mezlocillin and piperacillin. In one embodiment, the antibiotic is selected from clavulanic acid, sulbactam and tazobactam.

[0460] In one embodiment, the antibiotic is a polypeptide antibiotic. In one embodiment, the antibiotic is selected from bacitracin, colistin and polymyxin B.

[0461] In one embodiment, antibiotic is a quinolone or fluoroquinolone antibiotic. In one embodiment, antibiotic is selected from flumequine, oxolinic acid, rosofloxacin, cinoxacin, nalidixic acid and piromidic acid (piromidic acid). In one embodiment, antibiotic is selected from ciprofloxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, ofloxacin, pefloxacin, rufloxacin and enoxacin. In one embodiment, antibiotic is selected from balofloxacin, grefloxacin, levofloxacin, pazufloxacin, sparfloxacin, temafloxacin and tozufloxacin. In one embodiment, antibiotic is selected from clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin, prulifloxacin, besifloxacin, gemifloxacin, trovafloxacin, delafloxacin and ozenoxacin.

[0462] In one embodiment, the antibiotic is a sulfonamide. In one embodiment, the antibiotic is selected from sulfacetamide, sulfadiazine, sulfadimethazine, sulfafurazole, sulfadimethoxine, sulfadoxine, sulfamethoxazole, sulfamoxole, sulfadiazine, sulfadimethoxine, sulfametoxydiazine, sulfadoxine, sulfametopyrazine, terephtyl, mafenide, sulfa, sulfasalazine, sulfisoxazole and sulfonamicochrysoidine.

[0463] In one embodiment, the antibiotic is tetracycline. In one embodiment, the antibiotic is selected from tetracycline, chlortetracycline, oxytetracycline, demethylchlortetracycline, lymecycline, meclocycline, metacycline, minocycline and pyrimethocycline. In one embodiment, the antibiotic is selected from clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine and streptomycin. In another embodiment, the antibiotic is selected from arsphenamide, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, plate mycin, quinupristin, dalfopristin, thiamphenicol, tigecycline and trimethoprim.

[0464] VI. Topical Preparations for the Treatment of Acne Vulgaris

[0465] Acne vulgaris is a skin disease caused in part by an overgrowth of Propionibacterium acnes bacteria and inflammation induced in response to the P. acnes bacteria. Acne is a common skin disease that occurs when hair follicles become clogged with dead skin cells and skin oils. Acne forms due to an increase in sebum production under the influence of androgens, which results in excessive deposition of keratin in the follicles, leading to comedone formation, which results in blockage. The earliest pathological changes involve the formation of microcomedones due to the accumulation of skin cells in the follicles, which mix with the oily sebum to block the follicles, a process further exacerbated by the presence of P. acnes biofilm. If the microcomedones are superficial, the melanin within the plug oxidizes upon exposure to air, forming a blackhead or open comedone. If the microcomedones are located deep within the follicles, whiteheads or closed comedones form.

[0466] Propionibacterium acnes (reclassified as Keratitis acnes in 2016) is a Gram-positive (rod-shaped) bacterium that is associated with acne and belongs to the genus Keratitis and the family Propionibacteriaceae. It is typically slow-growing and a facultative anaerobe, meaning that it tolerates the presence of oxygen but does not use it to grow. While this bacterium is involved in the maintenance of healthy skin, it can also cause many common skin conditions, such as acne vulgaris. The bacterium lives primarily deep in hair follicles and pores, where it uses sebum, cellular debris, and metabolic byproducts of the surrounding skin tissue as a source of energy and nutrients. Increased sebum production or clogged hair follicles can lead to bacterial growth, and this rapid growth can trigger inflammation, which can lead to symptoms of common skin conditions, such as folliculitis and acne vulgaris.

[0467] Although less common, Staphylococcus epidermidis can also cause acne. It is a Gram-positive bacterium belonging to the genus Staphylococcus and family Staphylococcaceae, which is part of the normal human flora, usually the skin flora or mucosal flora. It is a facultative anaerobic bacterium and can therefore grow in the presence or absence of oxygen. It is not usually pathogenic, but in patients with a compromised immune system, the bacteria can cause infection. Staphylococcus epidermidis is able to form biofilms on plastics, and its infections are often associated with catheters or surgical implants.

[0468] The presence of P. acnes induces skin inflammation due to the ability of this bacterium to bind to toll-like receptors (TLRs), particularly TLR2 and TLR4, and to alter the lipid composition of oily sebum by oxidizing squalene. The ensuing inflammatory cascade leads to the formation of inflammatory acne lesions such as papules, pustules or nodules. If the inflammatory reaction is very severe, the hair follicles invade into the dermis and subcutaneous tissue in the form of deep nodules, leading to local tissue destruction and scarring.

[0469] Traditionally, acne has been classified as either non-inflammatory (open / closed comedones) or inflammatory (papules, pustules, or nodules). Increasing evidence suggests that inflammation is present throughout the life cycle of acne lesions, establishing a key role for inflammation in acne pathology. In the earliest stages of acne lesion development, CD3+ T cell, CD4+ T cell, and macrophage populations are elevated, while levels of the pro-inflammatory cytokine interleukin-1 are also upregulated. The onset of inflammatory events has been documented even before acne lesions are clinically detected.

[0470] For people who need to treat acne vulgaris, the active compounds described herein can be administered to people in need as pure chemicals or as topical preparations containing an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. Therefore, in one embodiment, the present disclosure provides a topical preparation for any use described herein, which contains an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, and at least one topically acceptable carrier. The topical preparation can contain the compound or salt as the only active ingredient, or in an alternative embodiment, contains the compound and at least one additional active agent.

[0471] An effective amount of a compound as described herein or a compound as described herein administered in combination or alternating with another active agent or administered before another active agent, concomitantly administered with another active agent, or administered after another active agent can be used in an amount sufficient to (a) inhibit the progression of acne vulgaris; (b) cause acne vulgaris to regress; (c) cause acne vulgaris to heal; or inhibit or prevent the development of acne vulgaris. Therefore, an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof or a composition will provide a sufficient amount of agent when administered to a human, thereby providing the desired benefit.

[0472] Topical preparations are divided into three major categories: solid forms (such as dusting powders); liquid forms (such as lotions and liniments); and semi-liquid forms (such as ointments, pastes, creams and gels). Additives or excipients are used as inactive ingredients in topical preparations for structuring. The main uses of topical preparation additives are to control the degree of absorption of the active compound, maintain viscosity, improve stability and sensory properties, and increase the volume of the preparation. The main goal of topical preparations is to limit the desired effect to the skin or to the skin. Such preparations are preferred because they are protective, emollient, and deliver active agents to exert local activity when applied to the skin or mucous membranes.

[0473] In one embodiment, the topical formulation is a solid formulation, such as a dusting powder. Dusting powder is a finely divided insoluble powder containing ingredients for use on the skin, particularly ingredients for alleviating irritation or absorbing moisture, preventing bacterial growth and providing lubricity. Powder flowability and spreadability are important parameters to consider when manufacturing and evaluating dusting powder formulations. Dusting powders should adhere to the skin, provide good coverage and skin adsorption, should have non-irritating properties, and should protect the skin from drying and irritation. Representative examples of excipients that can be used in dusting powder formulations include, but are not limited to, talc, starch (such as corn starch, wheat starch or potato starch), kaolin, zinc stearate, zinc oxide, aluminum chlorohydrate, aluminum zirconium chlorhydrex, micronized wax, and chlorhexidine (in the form of acetate, gluconate or hydrochloride).

[0474] In one embodiment, the topical formulation is a cream formulation. Cream is a semisolid emulsion formulation applied to the skin or mucous membrane. Creams can be formulated as water-in-oil (w / o) emulsions or oil-in-water (o / w) emulsions. Compared with ointments, water-in-oil emulsion creams (emulsion creams) are not too greasy and have good spreadability. Oil-in-water emulsion creams, often referred to as vanishing creams (vanishing creams), are easy to rub into the skin and are easy to be removed by water.

[0475] Water-in-oil emulsion formulations are generally composed of a hydrophilic component (e.g., water or other hydrophilic diluents) and a hydrophobic component (e.g., lipids, oils, or oily materials). The hydrophilic component is generally dispersed, i.e., present in the form of small particles and droplets within the hydrophobic component. Water-in-oil emulsions generally contain about 1% to about 98% of a dispersed hydrophilic phase and about 1% to about 50% of a hydrophobic phase. Commonly used additives in water-in-oil emulsion formulations include lanolin (containing sterols, cholesterol, hydroxycholesterol, triterpenes, or fatty alcohols), waxes, divalent soaps, sorbitan, borax, and oleic acid. In some embodiments, the water-in-oil emulsion refers to a water-in-silicone emulsion.

[0476] Oil-in-water emulsion formulations are usually composed of a hydrophilic component (e.g., water or other hydrophilic diluents) and a hydrophobic component (e.g., lipids, oils, or oily materials). The hydrophobic component is usually dispersed, i.e., present in the hydrophilic component in the form of small particles and droplets. Water-in-oil emulsions usually contain about 1% to about 98% of a hydrophilic phase and about 1% to about 50% of a dispersed hydrophobic phase. Commonly used additives in oil-in-water emulsion formulations include polysorbates (e.g., Tween 80, Tween 21, and Tween 40), methylcellulose, gum arabic, gum tragacanth, triethanolamine oleate, peanut oil, and cetearyl alcohol.

[0477] In one embodiment, topical preparation is an ointment preparation. Ointment is a greasy semisolid product of the active compound dissolved or dispersed. Ointment bases often affect the bioavailability of topical drugs, and this is due to their occlusion of the stratum corneum, which increases the flux (flux) of the drug through the skin and affects drug dissolution or in the skin and from the ointment to the distribution of the skin. Ointment is usually moisturizing, has benefits for dry skin, and owing to almost no other ingredients except base oil or fat, so the risk of allergy or stimulation is very low. The vehicle of ointment preparation, called ointment base, can be an oily base, an absorption base or a water-soluble base.

[0478] Oily bases are composed entirely of lipophilic substances. They are anhydrous, insoluble in water, and not easily removed with water. Oily bases are cheap, non-reactive, non-irritating, make great emollients, are protective and occlusive, and are not washable. Representative examples of oily bases include hydrocarbons (such as petrolatum, paraffin, liquid paraffin, microcrystalline wax, plastibase or Ceresi), vegetable oils and animal fats (such as coconut oil, beeswax, olive oil, lanolin, peanut oil, spermaceti, sesame oil or almond oil), hydrogenated and sulfated oils (such as hydrogenated castor oil, hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated corn oil or hydrogenated sulfated castor oil), alcohols / acids / esters (such as cetyl alcohol, stearic acid, stearyl alcohol, oleic acid, oleyl alcohol, palmitic acid, lauryl alcohol, lauric acid, myristyl alcohol, ethyl oleate, isopropyl myristate or glycol) and silicones (such as dimethylpropylsiloxane, methylphenylpolysiloxane, and sterol esters of dimethicone).

[0479] Absorbent matrices are known to absorb several times their own weight in water, but do not allow the matrix to absorb the drug. The advantages of absorbent matrices are their protective, occlusive and emollient properties, their ability to absorb liquids, and that they are not easily washed off, so they keep the incorporated compound in full contact with the skin. Representative examples of absorbent matrices include hydrophilic petrolatum and anhydrous lanolin.

[0480] Water-soluble bases, also called non-grease ointment bases, consist of water-soluble ingredients such as polyethylene glycol polymers (carbowax). Polyethylene glycol is water-soluble, non-volatile and inert. Other water-soluble bases include glyceryl monostearate, cellulose derivatives, sodium alginate, bentonite and carbopol 934.

[0481] In one embodiment, the topical preparation is a gel preparation. Gels are transparent or translucent semisolid preparations of one or more active ingredients in a suitable hydrophilic or hydrophobic matrix. Gels can be transparent or opaque, as well as polar hydroalcoholic or non-polar. Gels are prepared by special procedures required for a fusion process or gelling agent, a wetting agent, and a preservative. Gelling agents exhibit pseudoplastic properties, which give the preparation a thixotropic consistency. Gelling agents are typically used in a concentration of 0.5-10% to allow easy addition of active drugs before gel formation. Representative examples of agents used in gel preparations include tragacanth, fenugreek mucilage, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carbopol, pectin, poloxamer, alginates (such as sodium alginate, potassium alginate, or ammonium alginate), gelatin, starch, polyvinyl alcohol, povidone, propylene glycol, and ethylenediaminetetraacetic acid.

[0482] In one embodiment, the topical formulation is a paste formulation. Pastes are hard preparations that contain a high proportion of finely powdered solids, such as starch, zinc oxide, calcium carbonate, or talc. Pastes are generally less greasy than ointment formulations.

[0483] In one embodiment, the topical formulation is a lotion formulation. Lotions are low to medium viscosity products intended for unbroken skin. Lotions are applied to the external skin with bare hands, clean cloth, cotton wool or gauze. Lotions provide a cooling effect to the skin by evaporation of the solvent formulated therein. Typical additives in lotions include bentonite, sodium carboxymethylcellulose, alcohols and glycerin.

[0484] In one embodiment, the topical formulation is a liniment formulation. Liniments are liquid or semi-liquid products intended to be applied to the skin by friction or rubbing. They act as rubefacients, soothing agents, or stimulants. Typical vehicles for liniment formulations are alcohols, oils, or soap-based vehicles. Typical additives in liniment formulations include castor oil, cottonseed oil, peanut oil, sesame oil, and oleic acid.

[0485] A variety of optional components / ingredients may be included in topical formulations, including, but not limited to, absorbents, abrasives, anti-caking agents, defoaming agents, antimicrobial agents, binders, bioactive materials, buffers, fillers, chemical additives, cosmetic biocides, denaturants, cosmetic astringents, pharmaceutical astringents, external analgesics, film formers, humectants, opacifying agents, fragrances, pigments, colorants, essential oils, skin sensates, emollients, skin soothing agents, skin healing agents, pH adjusting agents, plasticizers, preservatives, preservative enhancers, propellants, reducing agents, additional skin conditioning agents, skin penetration enhancers, skin protectants, solvents, suspending agents, emulsifiers, thickeners, solubilizing agents, sunscreens, sunblocks, UV absorbers or scatterers, sunless tanning agents, antioxidants and / or free radical scavengers, chelating agents, agents, oil / sebum control agents, sweat control agents, sequestrants, anti-inflammatory agents, anti-androgens, depilatories, desquamation agents / exfoliants, organic hydroxy acids, vitamins and their derivatives and natural extracts.

[0486] An effective amount of a compound of Formula I to Formula VIII or a pharmaceutically acceptable salt or composition thereof can also be used to treat or prevent acne vulgaris in humans, which is caused by any bacteria that cause such acne, including Propionibacterium acnes and Streptococcus epidermidis.

[0487] An effective amount of a compound selected from Compound A to Compound L or a pharmaceutically acceptable salt or composition thereof can also be used to treat or prevent human acne vulgaris, which is caused by any bacteria including Propionibacterium acnes and Streptococcus epidermidis that cause such acne. In one embodiment, a method is provided, comprising administering to a human an effective amount of a compound described herein or a pharmaceutically acceptable salt or composition thereof, alone or in combination with an effective amount of an additional active agent (e.g., an antibiotic or anti-inflammatory agent), to treat acne vulgaris.

[0488] The severity of acne vulgaris can be classified as mild, moderate, or severe. Mild acne is typically defined by the presence of blocked skin follicles (called comedones) with occasional inflammatory lesions confined to the face. Moderate acne occurs when more inflammatory papules and pustules are present on the face, with some found on the trunk of the body. Severe acne occurs when nodules are characteristic lesions on the face and the trunk is extensively involved.

[0489] The method of the present invention includes identifying a target portion of skin affected by acne vulgaris and in need of treatment, and applying a compound of Formula I to Formula VIII or a pharmaceutically acceptable salt or composition thereof to the target portion of the skin. In some cases, the target portion of the skin may not appear to suffer from acne vulgaris, i.e., a compound of Formula I to Formula VIII or a pharmaceutically acceptable salt or composition as described herein can be used as a preventive therapy for acne vulgaris. A compound of Formula I to Formula VIII or a pharmaceutically acceptable salt or composition as described herein can be applied to the target skin portion at least once a day, twice a day, or more frequently every day during treatment, and if necessary, applied to the surrounding skin. Typically, a compound as described herein or a pharmaceutically acceptable salt or composition thereof is applied in the morning and / or before going to bed at night.

[0490] The treatment period is ideally a sufficient time for the active compound to reduce or eliminate the appearance of acne vulgaris on the target portion of the skin. The treatment period can last at least 1 week, about 2 weeks, about 4 weeks, about 8 weeks, or about 12 weeks. The treatment period can be extended for several months (about 3-12 months) or several years. The step of applying the compound or pharmaceutically acceptable salt or composition described herein can be completed by localized application, that is, by applying to the target area while minimizing the delivery to the skin surface that does not need treatment, or by more general or more extensive application to one or more skin surfaces.

[0491] Propionibacterium acnes (reclassified as Keratitis acnes in 2016) is a Gram-positive (rod-shaped) bacterium that is associated with acne and belongs to the genus Keratitis and the family Propionibacteriaceae. It is typically slow-growing and a facultative anaerobe, meaning that it tolerates the presence of oxygen but does not use it to grow. While this bacterium is involved in the maintenance of healthy skin, it can also cause many common skin conditions, such as acne vulgaris. The bacterium lives primarily deep in hair follicles and pores, where it uses sebum, cellular debris, and metabolic byproducts of the surrounding skin tissue as a source of energy and nutrients. Increased sebum production or clogged hair follicles can lead to bacterial growth, and this rapid growth can trigger inflammation, which can lead to symptoms of common skin conditions, such as folliculitis and acne vulgaris.

[0492] Staphylococcus epidermidis is a Gram-positive bacterium belonging to the genus Staphylococcus and family Staphylococcaceae that is part of the normal human flora, usually the skin flora or mucosal flora. It is a facultative anaerobe and can therefore grow in the presence or absence of oxygen. It is not usually pathogenic, but in patients with a compromised immune system, this bacterium can cause infection. S. epidermidis is able to form biofilms on plastics and its infections are often associated with catheters or surgical implants.

[0493] In one embodiment, the compound of Formula I to Formula VIII or its pharmaceutically acceptable salt or composition can be combined or used alternately with benzoyl peroxide. In the hair follicles of the skin, benzoyl peroxide oxidizes the protein of Propionibacterium acnes by forming oxygen free radicals and benzoic acid, thereby killing Propionibacterium acnes. These free radicals are believed to interfere with the metabolism and protein-making ability of bacteria. In addition, benzoyl peroxide has moderate effectiveness in breaking down acne and inhibiting inflammation. In one embodiment, the compound of Formula I to Formula VIII or its pharmaceutically acceptable salt is combined with benzoyl peroxide to be formulated into a topical preparation as described herein.

[0494] In one embodiment, the compounds of Formula I to Formula VIII or pharmaceutically acceptable salts or compositions as described herein can be combined or used alternately with retinoids. Retinoids are drugs that reduce inflammation, normalize the life cycle of hair follicle cells, and reduce sebum production. They are structurally related to vitamin A. Retinoids appear to affect the cell life cycle of the lining of the hair follicle; this helps prevent skin cells from accumulating in the hair follicle, which can cause blockage. Commonly used topical retinoids include adapalene, isotretinoin, retinol, tazarotene, and tretinoin. In one embodiment, the compounds of Formula I to Formula VIII or pharmaceutically acceptable salts thereof are combined with retinoids to be formulated into topical preparations as described herein.

[0495] In one embodiment, the compound or pharmaceutically acceptable salt or composition of Formula I to Formula VIII as described herein can be combined with antibiotics or used alternately. Antibiotics are often applied to the skin or taken orally to treat acne, and are considered to be effective because they have antimicrobial activity against Propionibacterium acnes and have the ability to reduce inflammation. Commonly used antibiotics include clindamycin, erythromycin, metronidazole, sulfacetamide and tetracyclines, such as doxycycline and minocycline. Other representative topical antibiotics include bacitracin, polymyxin b, neomycin, retapaline, mupirocin, praxine, gentamicin, sulfamethoxazole and ozenoxacin. Antibiotics as described herein can be applied to the skin, taken orally or applied in any other suitable manner as determined by those skilled in the art. Compounds as described herein are particularly effective in combination with antibiotics because they enhance the antimicrobial effect of antibiotics. In one embodiment, the compound of Formula I to Formula VIII or its pharmaceutically acceptable salt is combined with an antibiotic to be formulated into a topical preparation as described herein.

[0496] In one embodiment, the compounds of Formula I to Formula VIII or pharmaceutically acceptable salts or compositions as described herein can be combined or used in conjunction with azelaic acid. Azelaic acid is considered to be an effective acne treatment agent because it can reduce the accumulation of skin cells in hair follicles and has antibacterial and anti-inflammatory properties. In one embodiment, the compounds of Formula I to Formula VIII or pharmaceutically acceptable salts thereof are combined with antibiotics to form a topical formulation as described herein.

[0497] In one embodiment, the compounds of Formula I to Formula VIII or their pharmaceutically acceptable salts or compositions as described herein can be combined or used in conjunction with salicylic acid. Salicylic acid is a topically applied beta-hydroxy acid that has keratolytic properties in addition to preventing bacterial growth. In one embodiment, the compounds of Formula I to Formula VIII or their pharmaceutically acceptable salts are combined with salicylic acid to form a topical formulation as described herein.

[0498] In one embodiment, the compounds of Formula I to Formula VIII or their pharmaceutically acceptable salts or compositions as described herein can be combined or used alternately with niacinamide. Niacinamide can improve acne by reducing inflammation, inhibiting sebum production and promoting wound healing. In one embodiment, the compounds of Formula I to Formula VIII or their pharmaceutically acceptable salts are combined with salicylic acid to be formulated into topical preparations as described herein.

[0499] VII. Overall Synthesis

[0500] The compounds described herein can be prepared by methods known to those skilled in the art. In one non-limiting example, the disclosed compounds can be prepared using the routes provided below.

[0501] For convenience, compounds of the present invention having stereocenters may be drawn without stereochemical centers. Those skilled in the art will recognize that pure enantiomers and diastereomers may be prepared by methods known in the art. Examples of methods for obtaining optically active materials include at least the following.

[0502] i. Physical separation of crystals – a technique to manually separate macroscopic crystals of individual enantiomers. This technique can be used if crystals of individual enantiomers are present, i.e. the material is an agglomerate, and the crystals are visually distinct;

[0503] ii. Simultaneous crystallization – the technique of crystallizing the individual enantiomers separately from a solution of the racemate, which is only possible when the enantiomers are in the form of aggregates in the solid state;

[0504] iii. Enzymatic resolution – a technique that partially or completely separates racemates by virtue of the different reaction rates of the enantiomers with enzymes;

[0505] iv. Enzymatic asymmetric synthesis - a synthetic technique in which at least one step in the synthesis uses an enzymatic reaction to obtain an optically pure or enriched synthetic precursor of the desired enantiomer;

[0506] v. Chemical asymmetric synthesis – a synthetic technique that synthesizes the desired enantiomer from an achiral precursor under conditions that produce asymmetry (i.e. chirality) in the product, which can be achieved by a chiral catalyst or a chiral auxiliary;

[0507] vi. Diastereoisomeric separation - a technique of reacting a racemic compound with an optically pure reagent (chiral auxiliary) which converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization with the aid of their now more distinct structural differences, followed by removal of the chiral auxiliary to obtain the desired enantiomer;

[0508] vii. Primary and secondary asymmetric transformations - techniques in which the diastereomers from the racemate rapidly equilibrate to give rise to a predominance in solution of the diastereomer from the desired enantiomer, wherein preferential crystallization of the diastereomer from the desired enantiomer disturbs the equilibrium so that eventually in principle all of the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then liberated from the diastereomer;

[0509] viii. Kinetic resolution – This technique refers to the partial or complete resolution of racemates (or further resolution of partially resolved compounds) by means of the unequal reaction rates of enantiomers with chiral, non-racemic reagents or catalysts under kinetic conditions;

[0510] ix. Enantiospecific synthesis from non-racemic precursors - a synthetic technique in which the desired enantiomer is obtained from achiral starting materials and in which the stereochemical integrity is not compromised or is only minimally compromised during the synthetic process;

[0511] x. Chiral liquid chromatography – a technique that separates the enantiomers of a racemate in a liquid mobile phase by virtue of their different interactions with the stationary phase (including vial chiral HPLC). The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral materials to induce different interactions;

[0512] xi. Chiral gas chromatography – a technique whereby the racemate is volatilized and the enantiomers are separated by means of their different interactions in the gaseous mobile phase with a column containing a stationary non-racemic chiral adsorbent phase;

[0513] xii. Extraction with chiral solvents – a technique for separating enantiomers by causing one enantiomer to dissolve preferentially in a specific chiral solvent;

[0514] xiii.Transchiral membrane transport – a technique where the racemate is brought into contact with a thin membrane barrier. The barrier would normally separate two miscible fluids, one of which contains the racemate, and a driving force such as concentration or pressure differential results in preferential transport across the membrane barrier. The separation occurs due to the non-racemic chiral nature of the membrane which allows only one enantiomer of the racemate to pass; and

[0515] xiv. Simulated Moving Bed Chromatography Used in One Embodiment A wide variety of chiral stationary phases are commercially available.

[0516] VIII. Examples

[0517] Example 1. Synthesis of representative examples of the present invention

[0518] The synthesis of representative compounds of the present invention is described in Arafa et al., "Novel linear triarylguanidines, N-substituted guanidines and potential prodrugs as antiprotozalagents", European Journal of Medicinal Chemistry, 2008, 43, 2901-2908 (Compound A); Wang et al., "Evaluation of the Influence of Compound Structure on Stacked-DimerFormation in the DNA Minor Groove" Biochemistry, 2001, 40, 2511 (Compound B); WO2002 / 055025, Scheme 1 and page 22, paragraph 120 (Compound D); Giordani et al., "Green Fluorescent Diamidine as Diagnostic Probes for Trypanosomes" Antimicrobial Agents and Chemotherapy 2014, 58: 1793 (Compound M, Compound N, Compound P, Compound Q); Ismail MA, Boykin DW and Stephens CE, "An efficient synthesis of 2,5'-diarylbichalcophenes", Tetrahedron Letters, 2006, 47, pp. 795-797 (compound O); WO2009 / 051796, Example 1, Scheme 1 on pages 40 and 41 (compound R); Gonzalez et al., "Synthesis and antiparasitic evaluation of bis-2,5-[4-guanidinophenyl]thiophenes", European Journal of Medicinal Chemistry, 2007, 42, 552-557 (compound C); EP1726589, Example 3, Scheme 4 on page 27 and paragraph 142 (compound T).

[0519] Synthesis of Compound U

[0520]

[0521] 5-(4-Cyanophenyl)indole-3-carboxaldehyde (U-1)

[0522] To a solution of 5-bromoindole-3-carboxaldehyde (1.12 g, 5.0 mmol) and Pd(PPh3)4 (0.30 g, 0.26 mmol) in 20 mL of toluene under nitrogen atmosphere was added 10 mL of 2M NaHCO3 aqueous solution and 0.74 g (5.0 mmol) of 4-cyanophenylboronic acid in 5 mL of methanol. The mixture was stirred vigorously and heated under reflux overnight. The mixture was cooled and extracted with dichloromethane. The organic layer was dried and concentrated to dryness under reduced pressure to give 1.0 g (81%) of product, melting point 248-250°C. 1H-NMR (DMSO-d6) δ10.98 (d, 1H, J = 2), 8.40 (d, 1H, J = 2), 7.87 (dd, 4H, J = 8 and J = 2), 7.62 (s, 1H); 13C-NMR (DMS O-d6)δ185.2,145.7,139.4,137.2,132.8,132.7,127.6,124.9,122.9,119.4,119.0,118.4,113.2,109.3. C 16 H 10 Calculated value for N2O: C, 78.03; H, 4.09. Found: C, 77.73; H, 4.17.

[0523] 3-(5-Cyanobenzimidazol-2-yl)-5-(4-cyanophenyl)indole (U-2)

[0524] A solution of 5-(4-cyanophenyl)indole-3-carboxaldehyde (0.80 g, 3.25 mmol), 3,4-diaminobenzonitrile (0.44 g, 3.3 mmol) and sodium bisulfite (0.40 g, 3.9 mmol) in 5 mL DMF was heated under reflux overnight. After cooling, the mixture was poured onto crushed ice. The solid was collected by filtration and washed with aqueous sodium bicarbonate solution (2.5%) and water to give 1.0 g (85%) of an off-white solid, melting point 311-313 ° C. 1 H-NMR(DMSO-d6)δ8.82(s,1H),8.28(s,1H),7.93(s,4H),7.61(m,4H); 13 C-NMR(DMSO-d6)δ152.3,146.3,136.8,132.9,131.4,128.7,125.7,125.2,122.0,120.4,119.1,113.0,109.1,106.3,103.0; C 23 H 13 HRMS (FAB) mass calculated for N5 (M+H): 360.383; observed mass, 360.125.

[0525] 3-(5-Hydroxyamidinobenzimidazol-2-yl)-5-(4-hydroxyamidinophenyl)indole (U-3)

[0526] To a solution of hydroxylamine hydrochloride (0.72 g, 10.3 mmol) in 5 mL DMSO was added potassium tert-butoxide (1.16 g, 10.3 mmol) in portions under nitrogen. After the mixture was stirred for 30 minutes, 0.37 g (1.01 mmol) of 3-(5-cyanobenzimidazol-2-yl)-5-(4-cyanophenyl)indole was added, and the mixture was stirred at room temperature overnight. The mixture was poured into ice water and filtered to give the desired 3-(5-hydroxyamidinobenzimidazol-2-yl)-5-(4-hydroxyamidinophenyl)indole as a white solid, 0.43 g (98%); melting point 370°C (decomposition); 1 H-NMR(DMSO-d6)δ9.71(s,1H),9.60(s,1H),8.79(s,1H),8.23(d,1H,J=2.7),7 .84(d,2H,J=8.4),7.76(d,2H,J=8.4),7.60(m,5H),5.98(s,2H),5.91(s,4H); 13 C-NMR(DMSO-d6)δ172.1,152.3,150.8,150.4,142.3,136.3,132.5,131. 5,127.4,126.6,126.4,126.0,125.7,121.7,119.5,119.4,112.6,106.9. C 23 H 19 N7O 2. Calculated for 2.3H2O: C, 59.17; H, 5.09. Found: C, 59.11; H, 4.99.

[0527] 3-(5-acetoxyamidinobenzimidazol-2-yl)-5-(4-acetoxyamidinophenyl)indole

[0528] The above amidine oxime (0.35 g, 2.0 mmol) was dissolved in glacial acetic acid (5 mL) and acetic anhydride (0.5 mL, 6.5 mmol) was added. The mixture was stirred for 2 hours and the solvent was evaporated. The product was used in the next step without further characterization.

[0529] 3-(5-amidinobenzimidazol-2-yl)-5-(4-amidinophenyl)indoleacetic acid salt (Compound U)

[0530] The crude 3-(5-acetoxyamidinobenzimidazol-2-yl)-5-(4-acetoxyamidinophenyl)indole was subjected to catalytic hydrogenation in the presence of Pd / C to obtain 0.25 g (43% yield) of compound L, melting point>228°C. 1 H-NMR(DMSO-d6)δ8.86(s,1H),8.37(s,1H),8.12(s,1H),7.93(m,4H),7.62(m,4H),5.99(br,1H),1.82(s,11H); 13C-NMR(DMSO-d6)δ1 C 23 H 19 HRMS (FAB) mass calculated for N6 (M+H): 394.450; observed mass, 394.178. 23 H 19 N6.3.5CH3COOH . Calcd. for 3.0 H2O: C, 54.78, H, 5.97; N, 14.90. Found: C, 54.83, H, 5.79; N, 14.81.

[0531] General method for the synthesis of diamidine compounds

[0532] The diamidine compound was synthesized from the dinitrile compound by Method B or Method C. The substituted amidine or cyclized amidine compound (MD-102, MD-112, MD-113 and MD-129) was synthesized from the dinitrile compound by Method D.

[0533]

[0534] General Procedure for the Preparation of Dinitrile (Method A)

[0535] A mixture of 1,3-bis(bromomethyl)-benzene / substituted benzene (5mmol), 4-hydroxybenzonitrile or 4-hydroxy-substituted benzonitrile (10mmol) and anhydrous K2CO3 (2.07g, 15mmol) in 10mL DMF was heated at 45°C for 4 hours. The reaction mixture was then diluted with ice water (70mL) and stirred for 30 minutes. The white precipitate was filtered, washed with water, and dried in air. The white solid was then dissolved in an organic solvent (75mL) (DCM, methanol or THF). The organic phase was dried over anhydrous MgSO4. The MgSO4 was then filtered and the supernatant was concentrated using a rotary evaporator to obtain a crude product. The crude product was then ground in the presence of hexane, filtered and dried in vacuo to obtain a white solid with a yield of 80-90%.

[0536] General procedure for the preparation of diamididines as dihydrochloride salts (Method B)

[0537] 6.0 mL (6 mmol) of LiN (TMS) 2 (1 M in THF) was added to a cold stirred suspension of dinitrile (1 mmol) in 15 mL of dry THF. The reactants were stirred at room temperature for 24 hours. The mixture was then cooled and acidified with saturated ethanol-HCl to form a white solid. The mixture was stirred for 2 hours, after which all solvents were removed under vacuum to obtain a crude product. The crude product was then diluted with ether, and the mixture was filtered to obtain a white solid. The white solid was then diluted with 10 mL of ice water and alkalized with 2 M NaOH to obtain a white precipitate. The white precipitate was then filtered, washed with water, and dried in air. The solid was suspended in anhydrous ethanol (15 mL) and 5 mL of saturated ethanol HCl for 6 hours. The ethanol was then distilled off, and the product was ground and filtered in the presence of dry ether. The solid was dried in 80 ° C vacuum for 12 hours to obtain the diamidine dihydrochloride (65-75%) as a white solid.

[0538] General procedure for the preparation of diamididines as dihydrochloride salts (Method C)

[0539] Dinitrile (1mmol) is added to anhydrous ethanol (EtOH) saturated with hydrogen chloride (20mL) at 0 ℃ in a dry flask. Then the reaction mixture is sealed, slowly warmed to ambient temperature, and stirred for 7 days. Use rotary evaporator to remove ethanol. Anhydrous ether (20mL) is added to the reaction mixture, filter out the imidic acid ester dihydrochloride of precipitation, and dry under high vacuum. Make ammonia (using steel bottle) pass through the imidic acid ester in EtOH (10mL) and stir for one day. The reaction mixture is concentrated in vacuo. Then anhydrous ether is added, and the product is filtered and dried in a vacuum. By stirring 2-3 hours with saturated ethanol HCl (2mL), diamidamide is converted into its dihydrochloride. Remove solvent, and solid is dried in vacuo at 80 ℃ for 12 hours, to obtain the final product (65-75%).

[0540] General Procedure for the Preparation of Substituted or Cyclized Diamididines as Dihydrochloride Salts (Method D)

[0541] The nitrile compound is added to the anhydrous EtOH saturated with hydrogen chloride at 0 ℃ in a dry flask. Then the reaction mixture is sealed, slowly warmed to ambient temperature, and stirred until TLC no longer detects the nitrile compound. The reaction mixture is diluted with anhydrous ether. The imidic acid ester dihydrochloride of precipitation is filtered out under nitrogen and dried under high vacuum. Then the imidic acid ester and 2.5 equivalents of appropriate amines in EtOH are reacted 24 hours immediately. The reaction mixture is concentrated in vacuo. Then ether is added, and the product is filtered. The solid is suspended in 10mL ice water, and alkalized with 2M NaOH. The obtained white precipitate is filtered, washed with water, and air-dried. Saturated ethanol HCl is used to convert the free alkali into its dihydrochloride (white solid), which is dried in vacuo at 80 ℃ for 12h, to obtain the final product (65-75%).

[0542] Synthetic MD-100

[0543]

[0544] Synthesis of 4,4'-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))dibenzonitrile (10). Using method A, 1,3-bis(bromomethyl)-5-methylbenzene (8, 1.38 g, 5 mmol) and 4-hydroxybenzonitrile (9, 1.19 g, 10 mmol) were reacted in the presence of anhydrous K2CO3 (2.07 g, 15 mmol) in 10 mL DMF to give 1,3-bis(4-cyano-phenoxymethyl)-5-methyl-benzene (10, 1.58 g, 90%) as a white solid. 1H NMR (CDCl3): δ7.59 (d, J = 8.8 Hz, 4H), 7.26 (s, 1H), 7.22 (s, 2H), 7.02 (d, J = 8.8 Hz, 4H), 5.09 (s, 4H), 2.40 (s, 3H). 13 C NMR (CDCl3): δ161.9,139.3,136.4,134.1,128.3,123.7,119.2,115.6,104.3,70.1,21.4. C 23 H 18 N2O2Na[M+Na] + HRMS calculated value: 377.1266, found value: 377.1269.

[0545] Synthesis of 4,4′-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))dibenzamidine dihydrochloride (MD-100). Following procedure B, 10 (0.354 g, 1 mmol) was converted to MD-100 (MD-100, 0.33 g, 71%) as a brown solid. 1 H NMR (DMSO-d6): δ9.24(s,4H),8.90(s,4H),7.82(d,J=8.8Hz,4H),7.34(s,1H),7.25(s,2H),7.20(d,J=8.8Hz,4H),5.18(s,4H),2.32(s,3H). 13 C NMR (DMSO-d6): δ165.0,162.9,138.6,136.9,130.5,128.5,124.6,120.0,115.5,69.9,21.2. C 23 H 25 N4O2[M+H] + HRMS calculated value: 389.1972, found value: 389.1976.

[0546] 1,4-Bis[(4-amidino)-phenoxymethyl]benzene dihydrochloride (MD-101)

[0547] Using method A, 1,4-bis(bromomethyl)benzene (1.32 g, 5 mmol) and 4-hydroxybenzonitrile (1.19 g, 10 mmol) were reacted to give 1,4-bis(4-cyano-phenoxymethyl)benzene (1.74 g, 78%) as a white solid; 1 H NMR (CDCl3): 7.59 (d, 4H, J = 8.9Hz), 7.45 (s, 4H), 7.02 (d, J = 8.9Hz, 4H), 5.13 (s, 4H); 13C NMR (CDCl3): 161.82, 136.01, 134.07, 127.86, 119.10, 115.57, 104.45, 69.88; MS: HRMS-ESI-POS.: C 22 H 17 The calculated value of N2O2 m / z is 341.1285 (M + +1), m / z found 341.1283.

[0548] Following procedure B, the dinitrile (0.340 g, 1 mmol) was converted to 1,4-bis(4-amidino(phenoxymethyl))benzene dihydrochloride (0.33 g, 76%) as a light yellow solid. 1 H NMR (DMSO-d6): 9.25 (s, 4H), 9.02 (s, 4H), 7.85 (d, J = 8.9Hz, 4H), 7.51 (s, 4H), 7.23 (d, J = 9.0Hz, 4H), 5.26 (s, 4H); 13 C NMR (DMSO-d6): 165.16, 163.12, 136.67, 130.67, 128.49, 120.12, 115.64, 69.79; MS: HRMS-ESI-POS.: C 22 H 24 The calculated value of N4O2 m / z is 188.0944 (M / 2 + +2), m / z found 188.0936.

[0549] Synthetic MD-102

[0550]

[0551] Synthesis of 4,4'-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))bis(N-isopropylbenzamidine) dihydrochloride (MD-102). Using General Procedure D, the dinitrile (10, 0.35 g, 1 mmol) was converted to MD-102 (MD-102, 0.27 g, 50%) as a light yellow solid by reaction with isopropylamine (0.15 g, 2.5 mmol) in ethanol (10 mL) at room temperature for 24 hours. 1H NMR (DMSO-d6): δ9.43(d,J=8.0Hz,2H),9.33(s,2H),8.99(s,2H),7.73(d,J=8.8Hz,4H),7.36(s,1H),7 .27(s,2H),7.21(d,J=8.8Hz,4H),5.20(s,4H),4.09-4.04(m,2H),2.34(s,3H),1.26(d,J=6.4Hz,12H). 13 C NMR (DMSO-d6): δ162.1,161.2,138.1,136.7,130.3,128.1,124.3,121.2,114.9,69.5,54.9,44.9,21.3,21.0. C 29 H 38 N4O2[M+2H] 2+ HRMS calculated value of / 2: 237.1492, measured value 237.1482.

[0552] Synthetic MD-103

[0553]

[0554] Synthesis of 4,4'-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))bis(3-methoxybenzonitrile) (12). According to method A, 1,3-bis(bromomethyl)-5-methylbenzene (8, 1.4 g, 5 mmol) and 4-hydroxy-2-methoxybenzonitrile (11, 1.37 g, 10 mmol) were reacted in the presence of anhydrous K2CO3 (2.07 g, 15 mmol) in 10 mL DMF to give 4,4'-((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))bis(3-methoxybenzonitrile) (12, 1.57 g, 76%) as a white solid. 1 H NMR (DMSO-d6): δ7.41-7.39(m,4H),7.30(s,1H),7.24(s,2H),7.18(d,J=8.8Hz,2H),5.15(s,4H),3.80(s,6H),2.33(s,3H). 13 CNMR(DMSO-d6): δ151.8,149.2,138.0,136.5,128.5,126.3,124.6,119.2,114.7,113.4,102.9,69.9,56.0,21.0. C 25 H 23 N2O4[M+H] + HRMS calculated value: 415.1652, found 415.1643.

[0555] Synthesis of 4,4'-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))bis(3-methoxybenzamidine) dihydrochloride (MD-103). According to method B, dinitrile (12, 0.41 g, 1 mmol) was converted to give 4,4'-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))bis(3-methoxybenzamidine) dihydrochloride (MD-103, 0.39 g, 76%) as a brown solid. 1 H NMR (DMSO-d6): δ9.27(s,4H),8.97(s,4H),7.49-7.48(m,4H),7.33(s,1H),7.26-7.24(m,4H),5.18(s,4H),3.86(s,6H),2.34(s,3H). 13 C NMR (DMSO-d6): δ164.7,152.3,148.81,138.1,136.7,128.5,124.7,121.9,119.5,112.8,111.6,70.0,56.1,21.0. C 25 H 30 N4O4[M+2H] 2+ HRMS calculated value of / 2: 225.1128, measured value 225.1119.

[0556] 1,4-Bis[((4-amidino)-2-methoxy)-phenoxymethyl]2-fluorobenzene dihydrochloride (MD-104)

[0557] Following procedure B, the dinitrile (0.41 g, 1 mmol) was converted to 1,4-bis[((4-amidino)-2-methoxy)-phenoxymethyl]2-fluorobenzene dihydrochloride (0.37 g, 72%) as a brown solid. 1 HNMR (DMSO-d6): 9.32 (s, 4H), 9.04 (s, 4H), 7.61 (t, 2H, J = 7.2Hz), 7.53 (m, 4H), 7.39-7.28 (m, 4H), 5.27 (s, 4H), 3.863 (s, 6H); 13 CNMR(DMSO-d6):165.30,159.29(d,J C-F =250Hz),152.58,149.19,131.86(d,J C-F =2.9Hz),125.03(d,J C-F =3.6Hz),123.88(d,J C-F=14.7Hz),122.23,120.32,113.18,111.99,64.79(d,J C-F =3.2Hz),56.40; MS: HRMS-ESI-POS.: C 24 H 27 The calculated value of m / z for FN4O4 is 237.1003 (M / 2 + +2), m / z found 237.0995.

[0558] Synthetic MD-105

[0559]

[0560] (i) LiAlH4, THF, 0°C to room temperature, overnight (ii) PBr3, CH2Cl2, 0°C to room temperature, 4h.

[0561] Synthesis of diol (5-(tert-butyl)-1,3-phenylene) dimethanol (14). 5-tert-butylisophthalic acid (13, 4 g, 18 mmol) in THF (100 mL) was added dropwise to a solution of lithium aluminum hydride (1.5 g, 38 mmol) in THF (100 mL) under ice bath conditions. The reactants were stirred at 0 ° C for 1 hour, after which the reactants were heated at 60 ° C for 24 hours. The reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0 ° C and quenched with methanol and water. The quenched reactants were filtered through diatomaceous earth and washed with EtOAc (100 mL). The combined organic solvents were removed under reduced pressure and extracted with EtOAc (3×100 mL), dried over MgSO4 and concentrated to obtain the desired diol (5-(tert-butyl)-1,3-phenylene) dimethanol (14, 3.2 g, 94%). 1 HNMR(CDCl3): δ7.32(s,2H),7.19(s,1H),4.69(s,4H),1.33(s,6H). 13 C NMR (CDCl3): δ152.2, 141.1, 123.6, 123.1, 65.7, 34.9, 31.5. C 12 H 17 O[M-H2O] + HRMS calculated value: 177.1274, found: 177.1274.

[0562] Synthesis of 1,3-bis(4-cyano-phenoxymethyl)-5-(tert-butyl)benzene (16). PBr3 (2.5 mL, 26 mmol) was added dropwise to a solution of diol (5-(tert-butyl)-1,3-phenylene) dimethanol (14, 2.3 g, 11.8 mmol) in DCM at 0 °C. The reaction mixture was stirred at room temperature for 4 hours and then quenched with ice water. The solution was extracted with CH2Cl2 (3×100 mL), dried over MgSO4 and concentrated to give the desired dibromo compound (1,3-bis(bromomethyl)-5-(tert-butyl)benzene) (15, 3.4 g, 90%) as a white solid. Using method A, 1,3-bis(bromomethyl)-5-(tert-butyl)benzene (15, 1.6 g, 5 mmol) and 4-hydroxybenzonitrile (9, 1.19 g, 10 mmol) were reacted to give the dinitrile compound (16, 1.54 g, 78%) as a white solid. 1 HNMR(DMSO-d6): δ7.79 -7.78(m,4H),7.48(s,2H),7.36(s,1H),7.20-7.18(m,4H),5.20(s,4H),1.29(s,9H). 13 C NMR (CDCl3): δ161.8,151.3,136.1,134.2,124.8,119.1,115.9,103.0,69.9,34.5,31.1. C 26 H 25 N2O2[M+H] + HRMS calculated value: 397.1911, found value 397.1912.

[0563] Synthesis of 4,4'-(((5-(tert-butyl)-1,3-phenylene)bis(methylene))bis(oxy))dibenzamidine dihydrochloride (MD-105). Following Method B, 1,3-bis(4-cyano-phenoxymethyl)-5-(tert-butyl)benzene (16, 0.370 g, 1 mmol) was converted to give 4,4'-(((5-(tert-butyl)-1,3-phenylene)bis(methylene))bis(oxy))dibenzamidine dihydrochloride (MD-105, 0.35 g, 70%) as a brown solid. 1 H NMR (DMSO-d6): δ9.42(s,4H),9.21(s,4H),7.94(d,J=8.4Hz,4H),7.49(s,2H),7.39(s,1H),7.23(d,J=8.4Hz,4H),5.23(s,4H),1.28(s,9H). 13C NMR (DMSO-d6): δ165.7,163.5,152.5,137.0,131.0,125.6,120.3,116.1,70.7,35.2,31.8. C 26 H 31 N4O2[M+H] + HRMS calculated value: 431.2442, found 431.2425.

[0564] Synthetic MD-106

[0565]

[0566] (i) LiAlH4, THF, 0°C to room temperature, 16 h.

[0567] Synthesis of ((((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))bis(4,1-phenylene))dimethylamine dihydrochloride (MD-106). A solution of 1,3-bis(4-cyano-phenoxymethyl)-5-methyl-benzene (10, 1.0 g, 2.8 mmol) in THF (20 mL) was added dropwise to a suspension of LiAlH4 (0.32 g, 7.4 mmol) in THF under argon at 0°C, and the mixture was stirred at room temperature for 16 hours. H2O (5 mL) was added at 0°C to quench the reaction, followed by a 16% NaOH solution (2 mL). The mixture was stirred at room temperature for about 2 hours, followed by filtration through diatomaceous earth. The solution was then concentrated in vacuo to obtain the free diamine. The product residue was then dissolved in ethanol, followed by addition of HCl in ethanol (2 mL) to form a salt. The reaction mixture was evaporated in vacuo, followed by ether precipitation to obtain the product as a green solid. (MD-106, 1.0 g, 87%). 1 H NMR (DMSO-d6): δ8.45(s,6H),7.43(d,J=8.4Hz,4H),7.32(s,1H),7.22(s,2H),7.03(d,J=8.4Hz,4H),5.09(s,4H),2.32(s,3H). 13 C NMR (DMSO-d6): δ158.4,137.9,137.2,130.5,127.8,126.2,124.3,114.8,69.2,41.6,21.0. C 23 H 27 N2O2[M+H] + HRMS calculated value: 363.2079, found value: 363.2067.

[0568] Synthetic MD-107

[0569]

[0570] Synthesis of 4,4',4"-((benzene-1,3,5-triyltris(methylene))tris(oxy))tribenzonitrile (18). Using method A, 1,3,5-tris(bromomethyl)benzene (17, 1.54 g, 4.3 mmol) and 4-hydroxybenzonitrile (9, 1.64 g, 14 mmol) were reacted in the presence of anhydrous K2CO3 (2.35 g, 17 mmol) in 10 mL of DMF to give 4,4',4"-((benzene-1,3,5-triyltris(methylene))tris(oxy))tribenzonitrile (18, 1.69 g, 84%) as a white solid. 1 H NMR (DMSO-d6): δ7.77 (d, J = 9.2 Hz, 6H), 7.53 (s, 3H), 7.18 (d, J = 9.2 Hz, 6H), 5.24 (s, 6H). 13 CNMR(DMSO-d6): δ161.7,137.0,134.2,126.9,119.1,115.9,103.2,69.3. C 30 H 21 N3O3Na[M+Na] + HRMS calculated value: 494.1481, found value: 494.1481.

[0571] Synthesis of 4,4',4"-((benzene-1,3,5-triyltris(methylene))tris(oxy))tribenzamidine trihydrochloride (MD-107). Using method B, the trinitrile (18, 0.56 g, 1.2 mmol) was converted to 4,4',4"-((benzene-1,3,5-triyltris(methylene))tris(oxy))tribenzamidine trihydrochloride (MD-107) (MD-107, 0.58 g, 78%) as a brown solid. 1 H NMR (DMSO-d6): δ9.45 (s, 6H), 9.25 (s, 6H), 7.95 (d, J = 8.4Hz), 7.56 (s, 3H), 7.22 (d, J = 8.4Hz, 6H), 5.27 (s, 6H). 13 C NMR (DMSO-d6): δ164.7, 162.6, 137.1, 130.3, 126.9, 119.6, 115.1, 69.4. C 30 H 32 N6O3[M+2H] 2+ HRMS calculated value of / 2: 262.1262, measured value 262.1258.

[0572] Synthetic MD-108

[0573]

[0574] (i) 3 mol% Pd(PPh3)4, 6 mol% sodium ascorbate, 1 mol% CuSO4, 1:1 Et3N; DMSO (ii) H2, Pd / C, MeOH, overnight.

[0575] Synthesis of 4,4'-((5-methyl-1,3-phenylene)bis(acetylene-2,1-diyl))dibenzonitrile (21). 3,5-Dibromotoluene (19, 0.98 g, 3.9 mmol) was dissolved in 1:1 DMF-Et3N (6 mL). 3 mol% Pd(PPh3)4 and 4-ethynylbenzonitrile (1 g, 7.8 mmol) were added to this solution, and the mixture was stirred for 5 minutes. Further, 6 mol% sodium ascorbate solution and 1 mol% CuSO4 in DMF were added to the reaction mixture and stirred at 80°C for 4 h. The reaction mixture was extracted with ethyl acetate and then washed with ammonium chloride and brine. The combined organic layers were dried over anhydrous Na2SO4 and then concentrated in vacuo. The product was purified by column chromatography and obtained as a white solid (21, 0.67 g, 50%) using a 5:1 hexane:ethyl acetate system. 1 H NMR (CDCl3): δ7.66-7.59(m,8H),7.55(s,1H),7.38(s,2H),2.38(s,3H). 13 C NMR (CDCl3): δ38.9,133.1,132.3,132.2,128.1,122.8,118.6,111.9,92.9,88.3,21.2. C 25 H 14 N2Na[M+Na] + HRMS calculated value: 365.1055, found 365.1068.

[0576] Synthesis of 4,4'-((5-methyl-1,3-phenylene)bis(ethane-2,1-diyl))dibenzonitrile (22). To 10% Pd / C in THF (30 mL) under argon was added 4,4'-((5-methyl-1,3-phenylene)bis(acetylene-2,1-diyl))dibenzonitrile (21, 0.5 g, 1.46 mmol). The argon was replaced with H2 gas, and the reaction mixture was stirred overnight. The reaction mixture was quenched with CHCl2 and filtered through diatomaceous earth. Extraction was performed with CHCl2 and then washed with H2O. The combined organic layers were dried over anhydrous Na2SO4 and then concentrated under vacuum to give the product (22, 0.45 g, 87.6%) as a light yellow solid. 1H NMR (CDCl3): δ7.56(d,J=8.4Hz,4H), 7.24(d,J=8.4Hz,4H,), 6.81(s,2H), 6.67(s,1H), 2.95-2.90(m,4H), 2.85-2.81(m,4H), 2.29(s,3H). 13 C NMR (CDCl3): δ147.5,141.0,138.4,132.3,129.4,127.3,125.8,119.2,110.0,38.1,37.3,21.5. C 25 H 23 N2[M+H] + HRMS calculated value: 351.1856, found value: 351.1846.

[0577] Synthesis of 4,4'-((5-methyl-1,3-phenylene)bis(ethane-2,1-diyl))dibenzamidine dihydrochloride (MD-108). According to method B, the dinitrile compound (21, 0.35 g, 1 mmol) was converted into 4,4'-((5-methyl-1,3-phenylene)bis(ethane-2,1-diyl))dibenzamidine dihydrochloride (MD-108) (MD-108, 0.32 g, 70%) as a white solid. 1 H NMR (DMSO-d6): δ9.34(s,4H),9.12(s,4H),7.78(d,J=8.4Hz,4H),7.49(d,J=8.4Hz, ,4H),6.94(s,1H),6.90(s,2H),2.98-2.94(m,4H),2.85-2.81(m,4H),2.24(s,3H). 13 C NMR (DMSO-d6): δ165.5,148.4,141.0,137.3,129.1,128.2,126.9,125.6,125.5,36.9,36.6,21.1. C 25 H 30 N4[M+2H] 2+ HRMS calculated value of / 2: 193.1230, measured value 193.1222.

[0578] Synthetic MD-109

[0579]

[0580] (i) K2CO3·DMF, room temperature, overnight.

[0581] Synthesis of 4,4'-(((5-methyl-1,3-phenylene)bis(oxy))bis(methylene))dibenzonitrile (25). A mixture of orcinol (23, 0.5 g, 4.1 mmol), 4-cyanobenzyl bromide (24, 1.65 g, 8.4 mmol) and anhydrous K2CO3 (1.66 g, 12 mmol) in 10 mL of DMF was stirred overnight at room temperature. The reaction mixture was then diluted with ice water (70 mL) and stirred for 30 minutes. The yellow precipitate was filtered, washed with water, and air-dried. The yellow solid was then dissolved in dichloromethane (100 mL), dried over anhydrous MgSO4, filtered, and concentrated using a rotary evaporator. The crude product was triturated in the presence of hexanes, and the precipitate was filtered and then dried in vacuo to give 4,4′-(((5-methyl-1,3-phenylene)bis(oxy))bis(methylene))dibenzonitrile (25, 0.97 g, 66.5%) as a yellow solid. 1 H NMR (CDCl3): δ7.68 (d, J = 8.4 Hz, 4H), 7.53 (d, J = 8.4 Hz, 4H), 6.43 (d, J = 2.0 Hz, 2H), 6.39 (t, J = 2.0 Hz, 1H), 5.08 (s, 4H), 2.30 (s, 3H). 13 C NMR (CDCl3): δ159.5, 142.5, 140.9, 132.5, 127.7, 118.8, 111.9, 108.7, 99.5, 69.0, 22.0. C 23 H 18 N2O2Na[M+Na] + HRMS calculated value: 377.1266, found 377.1283.

[0582] Synthesis of 4,4′-(((5-methyl-1,3-phenylene)bis(oxy))bis(methylene))dibenzamidine dihydrochloride (MD-109). According to method C, dinitrile (25, 0.33 g, 0.93 mmol) was converted to 4,4′-(((5-methyl-1,3-phenylene)bis(oxy))bis(methylene))dibenzamidine dihydrochloride (MD-109, 0.3 g, 75%) as a white solid. 1 H NMR (DMSO-d6): δ9.45(s,4H),9.25(s,4H),7.86(d,J=7.6Hz,4H),7.64(d,J=8.0Hz,4H),6.50(s,1H),6.48(s,2H),5.20(s,4H),2.23(s,3H). 13C NMR (DMSO-d6): δ165.5,159.1,143.4,140.0,128.4,127.6,127.3,108.3,99.3,68.3,21.5. C 23 H 25 N4O2[M+H] + HRMS calculated value: 389.1978, found value 389.1960.

[0583] 1,3-Bis{(4-isopropylamidino)-phenoxymethyl}-2-fluorobenzene dihydrochloride (MD-110)

[0584]

[0585] According to method A, 1,3-bis(bromomethyl)-2-fluorobenzene (1.4 g, 5 mmol) and 4-hydroxybenzonitrile (1.19 g, 10 mmol) were reacted to give 1,3-bis(4-cyano-phenoxymethyl)-2-fluorobenzene (2.53 g, 70%) as a white solid; melting point 173-5°C; 1 H NMR (DMSO-d6): 7.78 (d, 4H, J = 8.4Hz), 7.59 (t, 2H, J = 7.2Hz), 7.29 (t, 1H, J = 7.2Hz), 7.23 (d, 4H, J = 8.4Hz), 5.3 (s, 4H); 13 C NMR(DMSO-d6): 161.4,158.4(d,J C-F =248Hz),134.0,130.7(d,J C-F =4.1Hz),124.2(d,J C-F =4.1Hz),123.1(d,J C-F =13.5Hz),118.7,115.6,103.3,63.8(d,J C-F =3.3Hz); MS: HRMS-ESI-POS.: C 22 H 15 Calculated value of FN2O2Na m / z 381.1015 (M + +Na), m / z found 381.1005.

[0586]

[0587] According to method D, dinitrile (0.35 g, 0.97 mmol) was converted to 1,3-bis{4-isopropylamidino(phenoxymethyl)-2-fluorobenzene dihydrochloride (0.38 g, 73%) as a white solid with isopropylamine (0.17 g, 2.92 mmol); melting point 269-70°C;1 H NMR (DMSO-d6): 9.48 (d, 2H, J = 8.0Hz,), 9.37 (s, 2H), 9.06 (s, 2H), 7.76 (d, 4H, J = 8.7Hz), 7.62 (t, 2H, J = 7.2Hz), 7.30 (t, 1H, J = 7.6Hz), 7.25 (d, 4H, J = 8.7Hz), 5.30 (s, 4H), 4.10 (dd, 2H, J = 13.6, 6.6Hz), 1.27 (d, 12H, J = 6.3Hz); 13 C NMR(DMSO-d6): 162.31,161.55,159.23(d,J C-F =249.7Hz),131.66(d,J C-F =3.4Hz),130.85,125.01(d,J C-F =3.6Hz),123.93(d,J C-F =14.6Hz),121.86,115.28,64.45(d,J C-F =3.5Hz), 45.42, 21.76; MS: HRMS-ESI-POS.: C 28 H 34 The calculated value of FN4O2 m / z is 477.2660 (M + +1), m / z found 477.2643; C 28 H 34 Analytical calculated values ​​for FN4O2.2HCl.1.19H2O: C, 58.79; H, 6.76; N, 9.79; found values: C, 58.49; H, 6.05; N, 9.85.

[0588] 1,3-Bis{(4-isopropylamidino-2-fluoro)-phenoxymethyl}-2-fluorobenzene dihydrochloride (MD-111)

[0589]

[0590] According to method A, 1,3-bis(bromomethyl)-2-fluorobenzene (1.4 g, 5 mmol) and 2-fluoro-4-hydroxybenzonitrile (1.37 g, 10 mmol) were reacted to produce 1,3-bis(2-fluoro-4-cyano-phenoxymethyl)-2-fluorobenzene (2.8 g, 71%) as a white solid; melting point 185-7°C; 1H NMR (DMSO-d6): 7.88 (d, 2H, J = 8.4Hz), 7.72 (d, 8.4Hz), 7.64 (t, 2H, J = 7.6Hz), 7 .54(t,2H,J=7.6Hz),7.33(t,1H,J=7.6Hz),7.23(d,4H,J=8.4Hz),5.37(s,4H); 13 C NMR (DMSO-d6): 158.50 (d, J C-F =250Hz),151.0(d,J C-F =248Hz),150.1(d,J C-F =11.0Hz),131.1(d,J C-F =4.4Hz),130.1(d,J C-F =3.75Hz),124.4(d,J C-F =4.28Hz),122.7(d,J C-F =15.4Hz),119.6(d,J C-F =21.4Hz),117.6(d,J C-F =3.4Hz),115.91(d,J C-F =2.25Hz),103.3(d,J C-F =8.73Hz),64.84(d,J C-F =4.21Hz); MS: HRMS-ESI-POS.: C 22 H 13 The calculated value of m / z for F3N2O2Na is 417.0827 (M + +Na), m / z found 417.0832.

[0591]

[0592] According to method D, dinitrile (0.32 g, 0.81 mmol) was converted to 1,3-bis(4-isopropylamidino-2-fluoro-phenoxymethyl)-2-fluorobenzene dihydrochloride (0.28 g, 70%) as a white solid using isopropylamine (0.14 g, 2.43 mmol); mp 193-5°C; 1 H NMR(DMSO-d6): 9.50(s,2H),9.21(s,2H),7.77(dd,2H,J=11.9,2.2Hz),7.69–7.62(m,4H),7.57(t,2H ,J=8.6Hz),7.33(t,1H,J=7.6Hz),5.39(s,4H),4.10(dt,2H,J=13.0,6.5Hz),1.27(d,12H,J=6.4Hz);13 C NMR(DMSO-d6): 160.01,158.90(d,J C-F =250.6Hz),151.95,149.85,149.63(d,J C-F =24.1Hz),131.56(d,J C-F =2.5Hz),125.91(d,J C-F =2.9Hz),124.68(d,J C-F =3.8Hz),123.08(d,J C-F =14.5Hz),121.60(d,J C-F =7.2Hz),116.63(d,J C-F =20.9Hz),114.91,64.89(d,J C-F =3.7Hz), 45.13, 21.25, MS: HRMS-ESI-POS.: C 28 H 32 The calculated value of m / z for F3N4O2 is 513.2472 (M + +1), m / z found 513.2450; C 22 H 19 Analytical calculated values ​​for F3N4O2.2HCl.1.25H2O: C, 55.31; H, 5.88; N, 9.21; found values: C, 55.39; H, 5.85; N, 8.95.

[0593] Synthetic MD-112

[0594]

[0595] Synthesis of 4,4'-(((5-methyl-1,3-phenylene)bis(oxy))bis(methylene))bis(N-propylbenzamidine) dihydrochloride (MD-112). According to Method D, dinitrile (10, 0.35 g, 0.98 mmol) was converted to 4,4'-(((5-methyl-1,3-phenylene)bis(oxy))bis(methylene))bis(N-propylbenzamidine) dihydrochloride (MD-112) (0.37 g, 70%) as a white solid by reaction with n-propylamine (0.14 g, 2.45 mmol) in ethanol (10 mL) at 49 °C for 24 h. 1H NMR (DMSO-d6): δ9.90(s,2H),9.53(s,2H),9.18(s,2H),7.79(d,J=8.4Hz,4H),7.63(d,J=8.4Hz,4H),6. 50–6.48(m,3H),5.19(s,4H),3.41-3.36(m,2H),2.23(s,3H),1.68-1.63(m,4H),0.95(t,J=7.2Hz,6H). 13 CNMR(DMSO-d6): δ162.5,159.1,142.7,140.2,128.5,128.3,127.6,108.3,99.7,68.3,44.2,21.5,20.9,11.2. C 29 H 37 N4O2[M+H] + HRMS calculated value: 473.2917, found 473.2940.

[0596] Synthetic MD-113

[0597]

[0598] Synthesis of 2,2'-((((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))bis(4,1-phenylene))bis(1,4,5,6-tetrahydropyrimidine) dihydrochloride (MD-113). According to Method D, dinitrile (10, 0.4 g, 1.12 mmol) was converted to 2,2'-((((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))bis(4,1-phenylene))bis(1,4,5,6-tetrahydropyrimidine) dihydrochloride (MD-113) (MD-113, 0.48 g, 75%) as a white solid by reaction with 1,3-diaminopropane (0.25 g, 3.4 mmol) in ethanol (10 mL) at 140°C. 1 H NMR (DMSO-d6): δ10.23(s,4H),7.82(d,J=8.0Hz,4H),7.63(d,J=8.0Hz,4H),6.51(s ,1H),6.48(s,2H),5.19(s,4H),3.48–3.37(m,8H),2.23(s,3H),1.98-1.95(m,4H). 13 CNMR(DMSO-d6): δ159.1,158.5,142.6,139.9,128.0,127.6,127.6,108.3,99.2,68.3,38.7,21.4,17.7. C 29 H 33N4O2[M+H] + HRMS calculated value: 469.2604, found value 469.2617.

[0599] 1,3-Bis{[4-amidino-2-methoxy]-phenoxymethyl]}-5-(tert-butyl)benzene dihydrochloride (MD-114)

[0600]

[0601] Following method A, 1,3-bis(bromomethyl)-5-(tert-butyl)benzene (1.2 g, 3.75 mmol) was reacted with 2-methoxy-4-hydroxybenzonitrile (1.2 g, 7.5 mmol) to give 1,3-bis(2-methoxy-4-cyano-phenoxymethyl)-5-(tert-butyl)benzene (1.35 g, 79%) as a white solid. 1 H NMR (CDCl3): 7.41 (s, 2H), 7.31 (s, 1H), 7.23 (dd, J = 8.3, 1.5Hz, 2H), 7.11 (d, J=1.4Hz,2H),6.93(d,J=8.4Hz,2H),5.19(s,4H),3.90(s,6H),1.32(s,9H); 13 C NMR(CDCl3): 152.36,152.05,149.70,136.07,126.26,124.48,123.58,119.1 8,114.46,113.45,104.31,71.17,56.21,34.81,31.29; MS: HRMS-ESI-POS.: C 28 H 28 Calculated value of N2O4Na m / z 479.1947 (M + +Na), m / z found 479.1942.

[0602]

[0603] Following method B, the dinitrile (0.35 g, 0.76 mmol) was converted to 1,3-bis(2-methoxy-4-cyano-phenoxymethyl)-5-(tert-butyl)benzene dihydrochloride (0.30 g, 72%) as a white solid; 1 H NMR (DMSO-d6): 9.33 (s, 4H), 9.04 (s, 4H), 7.55-7.46 (m, 6H), 7.35 (s, 1H), 7.28 (d, J = 9.2Hz, 2H), 5.21 (s, 4H), 3.86 (s, 6H), 1.29 (s, 9H); 13C NMR(DMSO-d6): 165.11,152.79.151.78,149.26,136.74,125.39,122.29,119.97,113.35,111.94,70.80,56.45,34.91,31.55; MS: HRMS-ESI-POS.: C 28 H 35 The calculated value of N4O4 m / z is 491.2658 (M + +1), m / z found 491.2645.

[0604] Synthetic BW-MD-115

[0605]

[0606] Synthesis of 4,4'-(((5-(tert-butyl)-1,3-phenylene)bis(methylene))bis(oxy))bis(3-fluorobenzonitrile) (27). Using Method A, 1,3-bis(bromomethyl)-5-(tert-butyl)benzene (15, 1.5 g, 4.7 mmol) and 2-fluoro-4-hydroxybenzonitrile (26, 1.3 g, 9.4 mmol) were reacted to produce 4,4'-(((5-(tert-butyl)-1,3-phenylene)bis(methylene))bis(oxy))bis(3-fluorobenzonitrile) (27, 1.52 g, 75%) as a white solid. 1 H NMR (DMSO-d6): δ7.85 (dd, J=11.2, 1.6Hz, 2H), 7.68-7.66 (m, 2H), 7.50 (s, 2H), 7.44 (t, J=8.8Hz, 2H), 7.36 (s, 1H), 5.29 (s, 4H), 1.29 (s, 9H). 13 C NMR(DMSO-d6): δ153.4,151.8(d,J C-F =186Hz),151.0,135.6,129.7(d,J C-F =4Hz),125.0,123.9,120.0(d,J C-F =21Hz),118.0(d,J C-F =3Hz),115.4(d,J C-F =3Hz),104.6(d,J C-F =9Hz),71.5,35.0,31.4. C 26 H 22 F2N2O2Na[M+Na] + HRMS calculated value: 455.1547, found value 455.1541.

[0607] Synthesis of 4,4'-(((5-tert-butyl-1,3-phenylene)bis(methylene))bis(oxy))bis(3-fluorobenzamidine) dihydrochloride (MD-115). According to method B, dinitrile (27, 0.35 g, 0.8 mmol) was converted to 4,4'-(((5-tert-butyl-1,3-phenylene)bis(methylene))bis(oxy))bis(3-fluorobenzamidine) dihydrochloride (MD-115) (0.30 g, 70.1%) as a brown solid. 1 H NMR (DMSO-d6): δ9.49 (s, 4H), 9.26 (s, 4H), 7.90 (dd, J = 12.4, 2.4Hz, 2H), 7. 81-7.79(m,2H),7.52-7.50(m,4H),7.39(s,1H),5.31(s,4H),1.28(s,9H). 13 CNMR(DMSO-d6): δ164.0,152.3,151.0(d,J C-F =11Hz),150.8(d,J C-F =177Hz),136.0,126.0(d,J C-F =3Hz),125.2,124.9,120.0(d,J C-F =7Hz),116.3(d,J C-F =20Hz),115.3,70.9,34.6,31.2. C 26 H 29 F2N4O2[M+H] + HRMS calculated value: 467.2272, found 467.2271.

[0608] Synthetic MD-116

[0609]

[0610] Synthesis of 3,3'-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))dibenzonitrile (29). Using method A, 1,3-bis(bromomethyl)-5-methylbenzene (8, 2.13 g, 7.7 mmol) and 3-cyanophenol (28, 2.05 g, 17 mmol) were reacted to produce 3,3'-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))dibenzonitrile (29, 2.6 g, 91%) as a white solid. 1 H NMR (CDCl3): δ7.38-7.36(m,2H),7.27-7.25(m,3H),7.22-7.19(m,6H),5.06(s,4H),2.41(s,3H). 13C NMR (CDCl3): δ158.8,139.3,136.6,130.6,128.3,125.0,123.6,120.2,118.8,117.9,113.4,70.2,21.5. C 23 H 18 N2O2Na[M+Na] + HRMS calculated value: 377.1266, found 377.1250.

[0611] Synthesis of 3,3′-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))dibenzamidine dihydrochloride (MD-116). Using method B, dinitrile (29, 0.32 g, 0.9 mmol) was converted to 3,3′-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))dibenzamidine dihydrochloride (MD-116) (0.32 g, 76%) as a white solid. 1 H NMR (DMSO-d6): δ9.40 (s, 4H), 9.07 (s, 4H), 7.53 (t, J = 8.0 Hz, 2H), 7.47 (s, 2H), 7.41-7.34 (m, 5H), 7.26 (s, 2H), 5.16 (s, 4H), 2.33 (s, 3H). 13 C NMR (DMSO-d6): δ165.6,158.7,138.5,137.0,130.8,129.5,128.5,124.6,120.7,120.5,114.5,69.9,21.2. C 23 H 25 N4O2[M+H] + HRMS calculated value: 389.1978, found value 389.1980.

[0612] Synthetic MD-117

[0613]

[0614] Synthesis of 4,4'-(((5-methyl-1,3-phenylene)bis(methylene))bis(sulfanediyl))dibenzonitrile (31). Using method A, 1,3-bis(bromomethyl)-5-methylbenzene (8, 0.93 g, 3.3 mmol) and 4-mercaptobenzonitrile (30, 1.0 g, 7.3 mmol) were reacted to produce 4,4'-(((5-methyl-1,3-phenylene)bis(methylene))bis(sulfanediyl))dibenzonitrile (1.12 g, 85%) as a white solid. 1HNMR (CDCl3): δ7.50 (d, J = 8.4 Hz, 4H), 7.28 (d, J = 8.4 Hz, 4H), 7.14 (s, 1H), 7.08 (s, 2H), 4.13 (s, 4H), 2.32 (s, 3H). 13 C NMR (DMSO-d6): δ144.3,139.0,136.2,132.1,128.9,127.1,126.1,118.7,108.4,36.7,21.2. C 23 H 19 N2S2[M+H] + HRMS calculated value: 387.0984, found 387.1003.

[0615] Synthesis of 4,4′-(((5-methyl-1,3-phenylene)bis(methylene))bis(sulfanediyl))dibenzamidine dihydrochloride (MD-117). According to method C, dinitrile (31, 0.30 g, 0.74 mmol) was converted to 4,4′-(((5-methyl-1,3-phenylene)bis(methylene))bis(sulfanediyl))dibenzamidine dihydrochloride (MD-117) (MD-117, 0.19 g, 50%) as a green solid. 1 H NMR (DMSO-d6): δ9.30 (s, 4H), 9.03 (s, 4H), 7.74 (d, J = 8.4Hz, 4H), 7.51 (d, J = 8.4Hz, 4H), 7.31 (s, 1H), 7.16 (s, 2H), 4.33 (s, 4H), 2.26 (s, 3H). 13 CNMR(DMSO-d6): δ164.9,144.8,138.1,136.8,128.6,128.5,126.5,126.3,124.1,35.0,20.9. C 23 H 25 N4S2[M+H] + HRMS calculated value: 421.1521, found 421.1532.

[0616] 1,3-Bis{(4-(2-imidazolinyl))-thiophenoxymethyl}-5-methylbenzene dihydrochloride (MD-118)

[0617]

[0618] Following procedure D, the dinitrile (0.386 g, 1 mmol) was converted to 1,3-bis{(4-(2-imidazolinyl))-thiophenoxymethyl}-5-methylbenzene dihydrochloride (0.39 g, 72%) as a brown solid by refluxing the imidate with 1,2-diaminoethane.1 H NMR (DMSO-d6): 10.73 (s, 4H), 7.96 (d, 4H, J = 8.6Hz), 7.54 (d, 4H, J = 8.6Hz), 7.32 (s, 1H), 7.16 (s, 2H), 4.36 (s, 4H), 3.98 (s, 8H), 2.26 (s, 3H); 13 C NMR (DMSO-d6): 164.00, 145.86, 138.05, 136.70, 129.01, 128.61, 126.32, 118.23, 44.19, 34.77, 20.88; MS: HRMS-ESI-POS.: C 27 H 29 The calculated value of N4S2 m / z is 473.1834 (M + +1), m / z found 473.1842.

[0619] 1,3-Bis{(4-amidino)-phenoxymethyl}-6-methylbenzene dihydrochloride (BW-MD-119)

[0620]

[0621] Under argon atmosphere, 3-bromo-4-methylbenzoic acid (5 g, 23.25 mmol) was added to 50 ml of dry THF in a three-necked round-bottom flask. The temperature of the reaction mixture was cooled to 0°C and a 3.0 M solution of methylmagnesium bromide (8.5 ml, 25.57 mmol) was added thereto and stirred for 2 hours. The temperature was further lowered to -65°C and a 1.6 M solution of n-butyllithium in hexane (29 mL, 46.5 mmol) was added thereto under continuous stirring. After a reaction time of 4 h, dry ice was added to the reaction mixture, which was sealed and stirred overnight. After the reaction was completed, the mixture was acidified and then filtered. This residue was placed together with methanol containing a catalytic amount of concentrated H2SO4 and refluxed overnight to form the methyl ester. After completion, the reaction mixture was cooled to room temperature, 10 ml of water was added thereto and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give dimethyl 4-methylisophthalate (3.92 g, 81%) as a white solid. 1 H NMR (CDCl3): 8.57 (d, J=1.7Hz, 1H), 8.04 (dd, J=8.0, 1.8Hz, 1H), 7.33 (d,, J=8.0Hz 1H), 3.92 (d, J=3.2Hz, 6H), 2.66 (s, 3H); 13C NMR (CDCl3): 167.34, 166.50, 145.73, 132.79, 132.12, 132.04, 129.90, 128.11, 52.36, 52.20, 22.03; MS: HRMS-ESI-POS.: C 11 H 12 O4 m / z calculated value 231.0633 (M + +Na), m / z found 231.0642.

[0622]

[0623] Under ice bath conditions, dimethyl 4-methylisophthalate (1 g, 4.8 mmol) in THF (20 mL) was added dropwise to a solution of lithium aluminum hydride (0.73 g, 19.2 mmol) in THF (30 mL). The reactants were stirred at 0 ° C for 1 h, and then stirred at room temperature overnight. The reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0 ° C and quenched with methanol and water. The quenched reactants were filtered through diatomaceous earth and washed with EtOAc (50 mL). The solvent was removed under reduced pressure and extracted with EtOAc (3 × 50 mL), dried over MgSO4 and concentrated to obtain the desired diol (4-methyl-1,3-phenylene) dimethanol (0.62 g, 85%) as a white solid. 1 H NMR (CDCl3): 7.32 (s, 1H), 7.14 (d, J = 1.8Hz, 2H), 4.60 (d, J = 14.4Hz, 4H), 2.29 (s, 3H); 13 C NMR (CDCl3): 139.13, 138.71, 135.34, 130.50, 126.45, 126.24, 65.14, 63.21, 18.45; MS: HRMS-ESI-POS.: C9H 12 O2 m / z calculated value 175.0735 (M + +Na), m / z found 175.0730.

[0624]

[0625] PBr3 (0.7 mL, 7.38 mmol) was added dropwise to a solution of the diol (0.511 g, 3.35 mmol) in DCM maintained at 0°C. The reaction mixture was stirred at room temperature for 4 h and then quenched with ice water. The solution was extracted with CH2Cl2 (3×25 mL), dried over MgSO4 and concentrated to give the desired dibromo compound (0.93 g, 90%) as a white solid. 1H NMR (CDCl3): 7.34 (d, J = 1.6 Hz, 1H), 7.28-7.24 (m, 1H), 7.17 (d, J = 7.8 Hz, 1H), 4.48 (d, J = 12.6 Hz, 4H), 2.41 (s, 3H); 13 C NMR (CDCl3): 137.81, 136.37, 136.10, 131.47, 130.64, 129.66, 33.10, 31.82, 18.70;

[0626]

[0627] Using method A, 2,4-bis(bromomethyl)-1-methylbenzene (0.9 g, 3.2 mmol) and 4-hydroxybenzonitrile (0.84 g, 7 mmol) were reacted to produce 1,3-bis(4-cyano-phenoxymethyl)-6-methyl-benzene (0.81 g, 72%) as a white solid; 1 HNMR(CDCl3): 7.59(dd,J=11.2,8.9Hz,4H),7.44(s,1H),7.36-7.27(m,2H),7.08-6.96(m,4H),5.09(d,J=1.6Hz,4H),2.38(s,3H); 13 C NMR(CDCl3): 162.05,162.01,137.10,134.28,134.21,134.15,133.81,131.18,128.02,12 7.87,119.24,115.68,115.59,104.59,104.44,70.08,68.74,18.83; MS: HRMS-ESI-POS.: C 23 H 18 The calculated value of N2O2 m / z is 377.1266 (M + +Na), m / z found 377.1256.

[0628]

[0629] According to method B, the dinitrile (0.35 g, 1 mmol) was converted to 1,3-bis{(4-amidino)-phenoxymethyl}-6-methylbenzene dihydrochloride (0.32 g, 70%) as a brown solid; 1H NMR(DMSO-d6): 9.33(d,J=9.8Hz,4H),9.14(d,J=6.6Hz,4H),7.90(dd,J=12.8,8.9Hz,4H) ,7.55(s,1H),7.41-7.35(m,1H),7.31-7.18(m,5H),),5.23(d,J=7.0Hz,4H),2.34(s,3H); 13 C NMR(DMSO-d6):164.73,162.73,162.61,136.74,134.52,133.87,130.45,130.24,130.20,1 28.21,127.95,119.70,119.59,115.15,115.08,69.45,68.36,18.29; MS: HRMS-ESI-POS.: C 23 H 24 The calculated value of N4O2 m / z is 389.1978 (M + +1), m / z found 389.1971.

[0630] Synthetic MD-120

[0631]

[0632] Synthesis of 4,4'-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))bis(3-fluorobenzonitrile) (32). Using Method A, 1,3-bis(bromomethyl)-5-methylbenzene (8, 0.99 g, 3.6 mmol) and 3-fluoro-4-hydroxybenzonitrile (26, 1.1 g, 7.9 mmol) were reacted to produce 4,4'-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))bis(3-fluorobenzonitrile) (32, 1.12 g, 80%) as a white solid. 1 H NMR (CDCl3): δ7.40-7.37(m,4H),7.28(s,1H),7.23(s,2H),7.04(t,J=8.4Hz,2H),5.17(s,4H),2.40(s,3H). 13 C NMR (CDCl3): δ152.2 (d, J C-F =242Hz),150.9(d,J C-F =4Hz),139.5,135.9,129.7(d,J C-F =4Hz),128.5,123.6,120.0(d,J C-F =21Hz),118.0(d,J C-F =2Hz),115.3(d,JC-F =2Hz),104.6(d,J C-F =8Hz),71.1,21.5. C 23 H 16 F2N2O2Na[M+Na] + HRMS calculated value: 413.1078, found 413.1087.

[0633] Synthesis of 4,4′-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))bis(3-fluorobenzamidine) dihydrochloride (MD-120). According to method B, dinitrile (32, 0.35 g, 0.9 mmol) was converted to 4,4′-(((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))bis(3-fluorobenzamidine) dihydrochloride (MD-120, 0.32 g, 72%) as a white solid. 1 H NMR(DMSO-d6): δ9.42(s,4H),9.24(s,4H),7.90(dd,J=12.0,2.0Hz,2H),7.78-7.76 (m,2H),7.49(t,J=8.8Hz,2H),7.38(s,1H),7.29(s,2H),5.30(s,4H),2.35(s,3H). 13 C NMR(DMSO-d6): δ163.8,150.9(d,J C-F =244Hz),150.6(d,J C-F =10Hz),138.3,136.2,128.5,125.8(d,J C-F =3Hz),124.5,119.8(d,J C-F =7Hz),116.1(d,J C-F =21Hz),151.0,70.3,20.9. C 23 H 23 F2N4O2[M+H] + HRMS calculated value: 425.1789, found 425.1777.

[0634] Synthetic MD-123

[0635]

[0636] (i) K2CO3·DMF, room temperature, overnight.

[0637] Synthesis of 4,4'-(((5-butyl-1,3-phenylene)bis(oxy))bis(methylene))dibenzonitrile (34). A mixture of olivetol (33, 1.4 g, 8.2 mmol), 4-cyanobenzyl bromide (24, 3.53 g, 18 mmol) and anhydrous K2CO3 (3.4 g, 24.6 mmol) in 100 mL of DMF was stirred overnight at room temperature. The reaction mixture was then diluted with ice water (50 ml) and extracted with ethyl acetate (3×100 mL), followed by washing with water and brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 4,4'-(((5-butyl-1,3-phenylene)bis(oxy))bis(methylene))dibenzonitrile (34) (34, 3.2 g, 95.0%) as an orange solid. 1 H NMR(CDCl3): δ7.67(d,J=8.4Hz,4H),7.53(d,J=8.4Hz,4H),6.44(d,J=2.0Hz,2H),6.40(t,J=2.0Hz ,1H),5.09(s,4H),2.56–2.52(m,2H),1.60-1.57(m,2H),1.33-1.27(m,4H),0.89(t,J=7.2Hz,3H). 13 C NMR (CDCl3): δ59.4,146.0,142.5,132.5,127.7,118.8,111.8,108.0,99.5,69.0,36.3,31.5,31.0,22.6,14.1. C 27 H 26 N2O2Na[M+Na] + HRMS calculated value: 433.1892, found 433.1873.

[0638] Synthesis of 4,4'-((5-pentyl-1,3-phenylene)bis(ethane-2,1-diyl))dibenzamidine dihydrochloride (MD-123). According to method C, dinitrile (34, 0.32 g, 0.78 mmol) was converted to 4,4'-((5-pentyl-1,3-phenylene)bis(ethane-2,1-diyl))dibenzamidine dihydrochloride (MD-123) (MD-123, 0.32 g, 80%) as a white solid. 1H NMR (DMSO-d6): δ9.47(s,4H),9.28(s,4H),7.87(d,J=8.4Hz,4H),7.65(d,J=8.4Hz,4H),6.51(t,J=2.0Hz,1H),6. 48(d,J=2.0Hz,2H),5.20(s,4H),2.50-2.46(m,2H),1.55–1.52(m.2H),1.29-1.20(m,4H),0.84(t,J=6.8Hz,3H). 13 CNMR(DMSO-d6): δ165.4,159.1,145.0,143.4,128.3,127.7,127.3,107.6,99.6,68.3,35.4,30.9,30.4,22.0,14.0. C 27 H 33 N4O2[M+H] + HRMS calculated value: 445.2604, found 445.2624.

[0639] Synthetic MD-124

[0640]

[0641] (i) K2CO3, DMF, room temperature, overnight.

[0642] Synthesis of 4,4'-(((5-(trifluoromethyl)-1,3-phenylene)bis(oxy))bis(methylene))dibenzonitrile (36). A mixture of 5-(trifluoromethyl)-1,3-diol (35, 0.7 g, 4.2 mmol), 4-cyanobenzyl bromide (24, 1.80 g, 9.21 mmol) and anhydrous K2CO3 (1.73 g, 12.6 mmol) in 20 mL of DMF was stirred overnight at room temperature. The reaction mixture was then diluted with ice water (50 mL) and stirred for 30 min. The gray precipitate was filtered, washed with water, and air-dried. The yellow solid was then dissolved in dichloromethane (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was triturated in the presence of hexanes, filtered, and dried in vacuo to give 4,4′-(((5-(trifluoromethyl)-1,3-phenylene)bis(oxy))bis(methylene))dibenzonitrile (36) (36, 1.48 g, 87.0%) as a gray solid. 1 H NMR (CDCl3): δ7.70 (d, J = 8.4 Hz, 4H), 7.54 (d, J = 8.4 Hz, 4H), 6.85 (d, J = 2.0 Hz, 2H), 6.71 (t, J = 2.0 Hz, 1H), 5.13 (s, 4H). 13C NMR (CDCl3): 159.8, 141.5, 132.7, 127.8, 118.7, 112.3, 105.4, 104.9, 104.8, 69.4. C 23 H 15 N2O2F3Na[M+Na] + HRMS calculated value: 431.0961, found 431.0983.

[0643] Synthesis of 4,4′-(((5-trifluoromethyl-1,3-phenylene)bis(oxy))bis(methylene))dibenzamidine dihydrochloride (MD-124). According to method C, dinitrile (36, 0.35 g, 0.85 mmol) was converted to 4,4′-(((5-trifluoromethyl-1,3-phenylene)bis(oxy))bis(methylene))dibenzamidine dihydrochloride (MD-124, 0.3 g, 70%) as a pale yellow solid. 1 HNMR (DMSO-d6): 9.43 (s, 4H), 9.20 (s, 4H), 7.87 (d, J = 8.4Hz, 4H), 7.68 (d, J = 8.4Hz, 4H), 7.03 (s, 1H), 6.99 (s, 2H), 5.32 (s, 4H). 13 C NMR (DMSO-d6): δ165.4,159.7,142.5,131.1(q,J C-F =32Hz),128.4,127.8,127.6(q,J C-F =240Hz),122.4,105.9,104.2,68.9. C 23 H 22 F3N4O2[M+H] + HRMS calculated value: 443.1695, found value 443.1687.

[0644] Synthetic MD-125

[0645]

[0646] i) 0°C, 10 min, HgCl2, 20 h; i) TFA, DCM, room temperature, 2 h.

[0647] Synthesis of p-[N′,N″-di(Boc)guanidino]phenol (39). p-Aminophenol (37, 1.64 g, 15.0 mmol) and N,N′-di(Boc)-S-methylisothiourea (38, 2.90 g, 10.0 mmol) were stirred in THF (100 mL) for 10 min, after which the reaction was cooled to 0°C. HgCl2 (2.99 g, 11.0 mmol) was slowly added to this solution and stirred for 20 h. The reaction mixture was concentrated and purified by column chromatography using 5:1 hexanes:EA as eluent to give p-[N′,N″-di(Boc)guanidino]phenol (39) (3.16 g, 60%) as a white solid. 1 H NMR (CDCl3): δ11.61 (s, 1H), 9.96 (s, 1H), 7.01 (d, J = 8.8 Hz, 2 H), 6.58 (d, J = 8.8 Hz, 2 H), 1.53 (s, 9 H), 1.44 (s, 9 H). 13 C NMR (CDCl3): δ156.1,155.7,153.3,126.7,116.4,84.0,80.4,28.3,28.2.C 17 H 26 N3O5[M+H] + HRMS calculated value: 352.1872, found value 352.1863.

[0648] Synthesis of 1,1'-((((5-methyl-1,3-phenylene)bis(methylene))bis(oxy))bis(4,1-phenylene))biguanidine bis(trifluoroacetate). Using method A, 1,3-bis(bromomethyl)-5-methylbenzene (0.36 g, 1.3 mmol), p-[N',N"-bis(Boc)guanidino]phenol (39, 1.0 g, 2.84 mmol) and K2CO3 (0.54 g, 3.9 mmol) were reacted to give 1,3-bis(trifluoroacetate) as a white solid. 2 -5-Methylbenzene(1,3-Bis 2 -5-methylbenzene)(40)(40, 0.74 g, 70%). Compound 40 (32 mg, 0.039 mmol) in DCM (2 mL) was treated with TFA (1 mL) for 2 h. The solvent was removed in vacuo to give 1,3-dimethoxybenzene as a white solid. 2 -5-Methylbenzene di(trifluoroacetate) (MD-125) (MD-125, 20 mg, 80%). 1 H NMR (MeOD): δ7.33(s,1H),7.23(s,2H),7.22-7.20(m,4H),7.09-7.07(m,4H),5.09(s,4H),2.36(s,3H).13 C NMR (MeOD): δ 159.8, 158.5, 139.8, 138.7, 128.8, 128.8, 128.6, 124.8, 117.2, 71.1, 21.4. C 23 H 27 N6O2[M+H] + HRMS calculated value: 419.2195, found 419.2212.

[0649] Synthetic MD-126

[0650]

[0651] (i) K2CO3, DMF, room temperature, overnight.

[0652] Synthesis of 4,4'-(((5-methoxy-1,3-phenylene)bis(oxy))bis(methylene))dibenzonitrile (42). A mixture of 5-methoxyresorcinol (41, 1.22 g, 8.7 mmol), 4-cyanobenzyl bromide (24, 3.74 g, 18 mmol) and anhydrous K2CO3 (3.6 g, 26.02 mmol) in 100 mL of DMF was stirred at room temperature overnight. The reaction mixture was then diluted with ice water (50 mL) and extracted with ethyl acetate (3×100 mL), followed by washing with water and brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated on a rotary evaporator and purified by column chromatography using 5:1 hexanes:EA as elution buffer to give 4,4'-(((5-methoxy-1,3-phenylene)bis(oxy))bis(methylene))dibenzonitrile (42) (42, 2.94 g, 71.0%) as a white solid. 1 HNMR (CDCl3): δ7.64 (d, J = 8.4 Hz, 4H), 7.51 (d, J = 8.4 Hz, 4H), 6.18 (t, J = 2.0 Hz, 1H), 6.16 (d J = 2.0 Hz, 2H), 5.06 (s, 4H), 3.75 (s, 3H). 13 CNMR(CDCl3): δ161.8,160.3,142.3,132.6,127.7,118.8,111.9,94.7,94.5,69.11,55.6. C 23 H 18 N2O3Na[M+Na] + HRMS calculated value: 393.1215, found value 393.1201.

[0653] Synthesis of 4,4′-(((5-methoxy-1,3-phenylene)bis(oxy))bis(methylene))dibenzamidine dihydrochloride (MD-126). According to Method C, dinitrile (42, 0.37 g, 0.99 mmol) was converted to 4,4′-(((5-methoxy-1,3-phenylene)bis(oxy))bis(methylene))dibenzamidine dihydrochloride (MD-126, 0.35 g, 75%) as a yellow solid using ammonia gas. 1 H NMR (DMSO-d6): δ9.44(s,4H),9.23(s,4H),7.86(d,J=8.0Hz,4H),7.65(d,J=8.0Hz,4H),6.31(s,1H),6.22(s,2H),5.21(s,4H),3.70(s,3H). 13 C NMR (DMSO-d6): δ165.4,161.2,159.8,143.2,128.3,127.6,94.7,94.1,68.4,55.3. C 23 H 25 N4O3[M+H] + HRMS calculated value: 405.1927, found value 405.1923.

[0654] 1,3-Bis{(4-amidino-2-fluoro)-benzyloxy}-5-(methoxy)benzene dihydrochloride (MD-127)

[0655]

[0656] A mixture of 5-(trifluoromethyl)-1,3-diol (0.42 g, 2.4 mmol), 4-cyano-2-fluorobenzyl bromide (1.07 g, 5.04 mmol) and anhydrous K2CO3 (0.99 g, 7.2 mmol) in 20 ml of DMF was stirred at 45 ° C for 4 h [TLC (Hex: EtOAc 4: 1) monitoring]. The reaction mixture was then diluted with ice water (30 ml) and stirred for 30 min. The white precipitate was filtered, washed with water, and air-dried. The off-white precipitate was then dissolved in dichloromethane (50 ml), dried over anhydrous Na2SO4, filtered, concentrated with a rotary evaporator and dried in vacuo to give 1,3-bis{(4-cyano-2-fluoro)-benzyloxy}-5-trifluoromethylbenzene (0.73 g, 70%) as a white solid; 1 H NMR (CDCl3): 7.67 (t, J=7.5Hz, 2H), 7.51 (s, 2H), 7.42 (d, J=9.3Hz, 2H), 6.89 (s, 2H), 6.75 (s, 1H), 5.19 (s, 4H); 13C NMR (DMSO-d6): 159.53 (d, J C-F =251.1Hz),159.45,130.13(d,J C-F =4.4Hz),129.29(d,J C-F =14.0Hz),128.54(d,J C-F =4.1Hz),119.16(d,J C-F =24.4Hz),117.30(d,J C-F =2.8Hz),113.58(d,J C-F =9.4Hz),105.06,104.97(d,J C-F(CF3) =4.0Hz),63.42(d,J C-F =4.4Hz); MS: HRMS-ESI-POS.: C 23 H 13 Calculated value of N2O2F5Na m / z 467.077 (M + +Na), m / z found 467.0468.

[0657]

[0658] Dinitrile (0.30 g, 0.68 mmol) was added to anhydrous EtOH (20 mL) saturated with hydrogen chloride at 0 ° C in a dry flask. The reaction mixture was then sealed, slowly warmed to ambient temperature, and stirred for 7 days. Ethanol was removed using a rotary evaporator. Anhydrous ether (20 mL) was added to the reaction mixture, and the precipitated imidate dihydrochloride was filtered off and dried under high vacuum. Ammonia (using a steel bottle) was passed through the imidate in EtOH (10 mL) and stirred for 1 day. The reaction mixture was concentrated in vacuo. Anhydrous ether was then added, and the product was filtered and dried in an oil pump. The free base was converted to its dihydrochloride by stirring the diamidine with saturated ethanol HCl (2 mL) for 2-3 h. The solvent was thoroughly removed, and the obtained product was vacuum dried at 80 ° C for 12 h to obtain 1,3-bis{(4-amidino-2-fluoro)-benzyloxy}-5-trifluoromethylbenzene dihydrochloride (0.3 g, 60%) as a white solid. 1 H NMR (DMSO-d6): 9.42 (s, 4H), 9.23 (s, 4H), 7.83 (t, J = 7.2Hz, 4H), 7.76 (d, J = 10.5Hz, 2 H), 7.70 (d, J = 7.9Hz, 2 H),7.08(s,1H),7.04(s,2H),5.35(s,4H); MS: HRMS-ESI-POS.: C 23 H 20The calculated value of N4O2F5 m / z is 479.1506 (M + +1), m / z found 479.1512.

[0659] 1,3-Bis{(4-amidino)-phenethyl}-5-trifluoromethylbenzene dihydrochloride (MD-128)

[0660]

[0661] 1:1 DMF-Et3N (10 ml) was added to 3,5-dibromotrifluorotoluene (1.57 g, 5.2 mmol). 3 mol% Pd(PPh3)4 and 4-ethynylbenzonitrile (1.32 g, 10.4 mmol) were added to the solution and stirred for 5 minutes. Further, 6 mol% sodium ascorbate solution and 1 mol% CuSO4 in DMF were added to the reaction mixture and stirred at 80 °C for 4 h. The reaction mixture was extracted with ethyl acetate and then washed with ammonium chloride and brine. The combined organic layers were dried over anhydrous Na2SO4 and then concentrated in vacuo. The product was purified by column chromatography and obtained as a white solid (1.23 g, 60%) using a 5:1 hexane: ethyl acetate system. 1 H NMR(CDCl3)7.88(s,1H),7.79(s,2H),7.70–7.61(m,8H); 13 C NMR (CDCl3): δ137.70,132.39,132.36,128.79,127.19,124.06,118.40,112.55,90.90,90.03; MS: HRMS-ESI-POS.: C 25 H 11 Calculated value of N2F3Na m / z 419.0772 (M + +Na), m / z found 419.0771.

[0662]

[0663] To 10% Pd / C in THF (30 ml) under argon was added 4,4'-((5-trifluoromethyl-1,3-phenylene)bis(acetylene-2,1-diyl))dibenzonitrile ((1.23 g, 3.1 mmol). The argon was replaced with H2 gas, and the reaction mixture was stirred overnight. The reaction mixture was quenched with CH2Cl2 and filtered through celite. Extraction was performed with CH2Cl2 and then washed with water. The combined organic layers were dried over anhydrous Na2SO4 and then concentrated in vacuo to give the product as a white solid (1.22 g, 97.3%). 1H NMR(CDCl3)δ7.58(d,J=8.2Hz,4H),7.22(d,J=8.3Hz,6H),7.00(s,1H),2.94(s,8H);); 13 C NMR(DMSO-d6): 146.56,141.85,132.40,132.18,129.40,123.38(dd,J C-F(CF3) =7.7,3.5Hz),123.19,123.15,123.12,119.04,110.30,37.78,37.03); MS: HRMS-ESI-POS.: C 25 H 19 Calculated value of N2F3Na m / z 427.1377 (M + +Na), m / z found 427.1398.

[0664]

[0665] Dinitrile (0.31 g, 0.76 mmol) was added to anhydrous EtOH (20 mL) saturated with hydrogen chloride at 0 ° C in a dry flask. The reaction mixture was then sealed, slowly warmed to ambient temperature, and stirred for 7 days. Ethanol was removed using a rotary evaporator. Anhydrous ether (20 mL) was added to the reaction mixture, and the precipitated imidate dihydrochloride was filtered off and dried under high vacuum. Ammonia (using a steel bottle) was passed through the imidate in EtOH (10 mL) and stirred for 1 day. The reaction mixture was concentrated in vacuo. Anhydrous ether was then added, and the product was filtered and dried in an oil pump. The free base was converted to its dihydrochloride by stirring the diamidine with saturated ethanol HCl (2 mL) for 2-3 h. The solvent was completely removed, and the obtained product was vacuum dried at 80 ° C for 12 h to obtain 1,3-bis{(4-amidino)-benzyloxy}-5-trifluoromethylbenzene dihydrochloride (0.31 g, 62%) as a white solid. 1 H NMR (DMSO-d6): δ9.24(s,4H),9.12(s,4H),7.76(d,J=8.2Hz,4H),7.51(m,5H),7.46(s,2H),2.9 9(s,8H); NMR(CDCl3)δ7.58(d,J=8.2Hz,4H),7.22(d,J=8.3Hz,6H),7.00(s,1H),2.94(s,8H);); 13C NMR (DMSO-d6): 165.40, 147.92, 142.59, 132.70, 129.05, 128.13, 125.75, 122.75, 36.46, 56.13; MS: HRMS-ESI-POS.: C 25 H 26 Calculated value of N4F3 m / z 439.2110 (M + +1), m / z found 439.2111.

[0666] 1,3-Bis{(4-amidino)-phenoxymethyl}-benzene dihydrochloride (DB 2559)

[0667] Using method A, a mixture of 1,3-bis(bromomethyl)-benzene (1.30 g, 5 mmol) and 4-hydroxybenzonitrile (1.19, 10 mmol) was reacted to give 1,3-bis{(4-cyano)-phenoxymethyl}-benzene (2.6 g, 76%) as a white solid; 1 H NMR (DMSO-d6): 7.78 (d, 4H, J = 8.8Hz), 7.55 (s, 1H), 7.45 (s, 3H), 7.19 (d, 4H, J = 8.8Hz), 5.23 (s, 4H); 13 C NMR (DMSO-d6): 161.7, 136.5, 134.2, 128.8, 127.6, 127.2, 119.1, 115.9, 103.1, 69.5; MS: HRMS-ESI-POS.: C 22 H 22 Calculated value of N4O2Na m / z 363.1109 (M + +Na), m / z found 363.1105.

[0668] According to method B, the dinitrile (0.34 g, 1 mmol) was converted to 1,3-bis{(4-amidino)phenoxymethyl}-benzene dihydrochloride (0.35 g, 74%) as a white solid; melting point 168-70°C; 1 HNMR (DMSO-d6): 9.35 (s, 4H), 9.18 (s, 4H), 7.91 (d, 4H, J = 8.8Hz), 7.59 (s, 1H), 7.46 (s, 3H), 7.23 (d, 4H, J = 8.8Hz), 5.27 (s, 4H); 13 C NMR (DMSO-d6): 164.7, 162.5, 136.7, 130.2, 128.8, 127.6, 127.1, 119.7, 115.1, 69.5; MS: HRMS-ESI-POS.: C 22 H23 The calculated value of N4O2 m / z is 375.1816 (M + +1), m / z found 375.1816; C 22 H 22 Analytical calculated values ​​for N4O2.2HCl.1.25H2O: C, 56.23; H, 5.68; N, 11.92; found values: C, 56.48; H, 5.66; N, 11.85.

[0669] 1,3-Bis{(4-(2-imidazolinyl))-phenoxymethyl}-benzene dihydrochloride (DB 2538)

[0670] According to method D, dinitrile (0.34 g, 10 mmol) was converted to argonite dihydrochloride, and the argonite dihydrochloride was reacted with 1,2-diaminoethane to give diimidazoline dihydrochloride (0.36 g, 72%) as a white solid; melting point 245-7°C; 1 H NMR (DMSO-d6): 10.73 (s, 4H), 8.12 (d, 4H, J = 8.4Hz), 7.58 (s, 1H), 7.46 (s, 3H), 7.26 (d, 4H, J = 8.4Hz), 5.28 (s, 4H), 3.96 (s, 8H); 13 C NMR (DMSO-d6): 163.9, 162.9, 136.6, 131.0, 128.8, 127.7, 127.2, 115.4, 114.3, 69.5, 44.0; MS: HRMS-ESI-POS.: C 26 H 27 The calculated value of N4O2 m / z is 427.2148 (M + +1), m / z found 427.2134; C 26 H 26 Analytical calculated values ​​for N4O2.2HCl.0.75H2O: C, 60.97; H, 5.81; N, 10.97; found values: C, 60.88; H, 5.89; N, 10.90.

[0671] 1,3-Bis{(4-(2-imidazolinyl))-phenoxymethyl}-5-methylbenzene dihydrochloride (MD-129)

[0672] According to method C, the dinitrile (0.354 g, 1 mmol) was converted to 1,3-bis{4-(2-imidazolinyl)-phenoxymethyl-5-methylbenzene dihydrochloride (0.38 g, 72%) as a white solid, melting point 274-6°C; 1H NMR (DMSO-d6): 10.9 (s, 4H), 8.09 (d, 4H, J = 8.0Hz), 7.68 (d, 4H, J = 8.0Hz), 6.52 (s, 1H), 6.49 (s, 2H), 5.22 (s, 4H), 4.0 (s, 8H), 2.42 (s, 3H); 13 C NMR (DMSO-d6): 164.4, 159.0, 144.1, 128.9, 127.7, 121.4, 108.3, 99.3, 68.2, 44.2, 21.4; MS: HRMS-ESI-POS.: C 27 H 29 The calculated value of N4O2 m / z is 441.2291 (M + +1), m / z found 441.2292; C 27 H 24 Analytical calculated values ​​for N4O2.2HCl.1.55H2O: C, 60.09; H, 6.17; N, 10.39; found values: C, 60.38; H, 5.99; N, 10.33.

[0673] 1,3-Bis{(4-amidino)-phenoxymethyl}-2-fluorobenzene dihydrochloride (DB 2573)

[0674] According to method A, 1,3-bis(bromomethyl)-2-fluorobenzene (1.4 g, 5 mmol) and 4-hydroxybenzonitrile (1.19 g, 10 mmol) were reacted to give 1,3-bis(4-cyano-phenoxymethyl)-2-fluorobenzene (2.53 g, 70%) as a white solid; melting point 173-5°C; 1 H NMR (DMSO-d6): 7.78 (d, 4H, J = 8.4Hz), 7.59 (t, 2H, J = 7.2Hz), 7.29 (t, 1H, J = 7.2Hz), 7.23 (d, 4H, J = 8.4Hz), 5.3 (s, 4H); 13 C NMR(DMSO-d6): 161.4,158.4(d,J C-F =248Hz),134.0,130.7(d,J C-F =4.1Hz),124.2(d,J C-F =4.1Hz),123.1(d,J C-F =13.5Hz),118.7,115.6,103.3,63.8(d,J C-F =3.3Hz); MS: HRMS-ESI-POS.: C 22 H 15 Calculated value of FN2O2Na m / z 381.1015 (M+ +Na), m / z found 381.1005.

[0675] According to method B, the dinitrile (0.358 g, 1 mmol) was converted to 1,3-bis{(4-amidino)-phenoxymethyl}-2-fluorobenzene dihydrochloride (0.36 g, 71%) as a white solid; melting point 175-7°C; 1 H NMR (DMSO-d6): 9.22 (s, 4H), 8.95 (s, 4H), 7.87 (d, 4H, J = 9.2Hz), 7.64 (t, 2H, J = 7.6Hz), 7.31 (t, 1H, J = 7.6Hz), 7.29 (d, 4H, J = 9.2Hz), 5.31 (s, 4H); 13 C NMR(DMSO-d6): 164.7,162.4,158.8(d,J C-F =248Hz),131.2(d,J C-F =3.7Hz),130.3,124.6(d,J C-F =3.7Hz),123.4(d,J C-F =14.5Hz),119.9,115.0,64.1(d,J C-F =2.98Hz), MS: HRMS-ESI-POS.: C 22 H 22 The calculated value of FN4O2 m / z is 393.1721 (M + +Na), m / z found 393.1707; C 22 H 21 FN4O2.2HCl.1.5H2O.0.2C4H 10 Anal. Calcd. for O 9 ether: C, 54.07; H, 5.57; N, 11.07; Found: C, 54.38; H, 5.27; N, 10.89.

[0676] 1,3-Bis{(4-(2-imidazolinyl))-phenoxymethyl}-2-fluorobenzene dihydrochloride (DB 2510)

[0677] According to method D, the dinitrile (0.358 g, 1 mmol) was converted to the diimidazoline dihydrochloride (0.38 g, 70%) as a white solid; melting point 250-2°C; 1 H NMR (DMSO-d6): 10.81 (s, 4H), 8.15 (d, 4H, J = 7.6Hz), 7.64 (t, 2H, J = 7.2Hz), 7.33-7.30 (m, 5H, J = 7.6Hz), 5.23 (s, 4H), 3.39 (s.8H);13 C NMR(DMSO-d6): 163.8,162.7,154.6(d,J C-F =248Hz),130.0(d,J C-F =4.2Hz),124.4(d,J C-F =2.25Hz),123.2(d,J C-F =15.2Hz),115.2,114.4,64.5(d,J C-F =3.5Hz), 43.9; MS: HRMS-ESI-POS.: C 26 H 26 The calculated value of FN4O2 m / z is 445.2034 (M + +Na), m / z found 440.2047; C 26 H 25 Analytical calculated values ​​for FN4O2.2HCl.1.75H2O: C, 56.88; H, 5.60; N, 10.20; found values: C, 58.99; H, 5.63; N, 10.41.

[0678] 1,3-Bis{(4-amidino-2-fluoro)-phenoxymethyl}-2-fluorobenzene dihydrochloride (DB 2558)

[0679] According to method A, 1,3-bis(bromomethyl)-2-fluorobenzene (1.4 g, 5 mmol) and 2-fluoro-4-hydroxybenzonitrile (1.37 g, 10 mmol) were reacted to produce 1,3-bis(2-fluoro-4-cyano-phenoxymethyl)-2-fluorobenzene (2.8 g, 71%) as a white solid; melting point 185-7°C; 1 H NMR (DMSO-d6): 7.88 (d, 2H, J = 8.4Hz), 7.72 (d, 8.4Hz), 7.64 (t, 2H, J = 7.6Hz), 7 .54(t,2H,J=7.6Hz),7.33(t,1H,J=7.6Hz),7.23(d,4H,J=8.4Hz),5.37(s,4H); 13 C NMR (DMSO-d6): 158.50 (d, J C-F =250Hz),151.0(d,J C-F =248Hz),150.1(d,J C-F =11.0Hz),131.1(d,J C-F =4.4Hz),130.1(d,J C-F =3.75Hz),124.4(d,J C-F =4.28Hz),122.7(d,J C-F=15.4Hz),119.6(d,J C-F =21.4Hz),117.6(d,J C-F =3.4Hz),115.91(d,J C-F =2.25Hz),103.3(d,J C-F =8.73Hz),64.84(d,J C-F =4.21Hz); MS: HRMS-ESI-POS.: C 22 H 13 The calculated value of m / z for F3N2O2Na is 417.0827 (M + +Na), m / z found 417.0832.

[0680] According to method B, the dinitrile (0.394 g, 1 mmol) was converted to 1,3-bis(4-amidino-2-fluoro-phenoxymethyl)-2-fluorobenzene dihydrochloride (0.303 g, 71%) as a white solid; melting point 2255-7°C; 1 H NMR (DMSO-d6): 9.27 (br, 8H), 7.88 (dd, 2H, J = 2.4Hz, J = 12.0Hz), 7.78 (dd, 2H, 2H, J = 1.6Hz, J = 8.4Hz), 7.66 (t, 2H, 2H, J = 7.6Hz), 7.61 (d, 2H, J = 8.8Hz), 7.34 (d, 1H, J = 7.6Hz), 5.40 (s, 4H); 13 CNMR(DMSO-d6):164.3,159.35(d,J C-F =249Hz),151.31(d,J C-F =245Hz),150.88(d,J C-F =11.0Hz),152.1(d,J C-F =4.5Hz),126.33(d,J C-F =3.0Hz),125.14(d,J C-F =3.0Hz),123.44(d,J C-F =14.0Hz),120.65(d,J C-F =7Hz),116.71(d,J C-F =21.0Hz),115.5,65.42(d,J C-F =2.98Hz), MS: HRMS-ESI-POS.: C 22 H 20 The calculated value of m / z for F3N4O2 is 429.1533 (M + +1), m / z found 429.1536; C22 H 19 Analytical calculated values ​​for F3N4O2.2HCl.0.75H2O: C, 51.32; H, 4.40; N, 10.88; found values: C, 51.47; H, 4.39; N, 10.69.

[0681] 1,3-Bis{(4-(2-imidazolinyl)-2-fluoro)-phenoxymethyl}-2-fluorobenzene dihydrochloride (DB 2554)

[0682] According to method D, the dinitrile (0.394 g, 1 mmol) was converted to the diimidazoline dihydrochloride (0.4 g, 70%) as a white solid; melting point 218-20°C; 1 H NMR (DMSO-d6): 10.78 (br, 4H), 8.12 (d, 2H, J = 12.0Hz), 8.02 (d, 2H, J = 9.2Hz), 7.63 (t, 2H,J=7.6Hz),7.58(t,2H,J=8.4Hz),7.32(t,1H,J=7.6Hz),5.43(s,4H),3.99(s,8H); 13 C NMR(DMSO-d6): 164.2,159.12(d,J C-F =250Hz),151.68(d,J C-F =247Hz),151.3(d,J C-F =10.5Hz),131.74(d,J C-F =4.5Hz),126.6(d,J C-F =3.3Hz),124.91(d,J C-F =4.5Hz),123.18(d,J C-F =14.5Hz),116.61(d,J C-F =21.0Hz),116.3,115.18(d,J C-F =7.5Hz),65.73(d,J C-F =4.0Hz), MS: HRMS-ESI-POS.: C 26 H 24 The calculated value of m / z for F3N4O2 is 481.1846 (M + +1), m / z found 481.1857; C 26 H 23 Analytical calculated values ​​for F3N4O2.2HCl.1.1H2O: C, 54.47; H, 4.78; N, 9.77; found values: C, 54.10; H, 4.76; N, 9.65.

[0683] 1,3-Bis{[4-(2-imidazolyl)-2-methoxy)-phenoxymethyl]}-2-fluorobenzene dihydrochloride (DB 2555)

[0684] According to method A, 1,3-bis(bromomethyl)-2-fluorobenzene (1.4 g, 5 mmol) and 4-hydroxy-2-methoxybenzonitrile (1.37 g, 10 mmol) were reacted to produce 1,3-bis{(4-cyano-2-methoxy)-phenoxymethyl}-2-fluorobenzene (2.8 g, 71%) as a white solid; melting point 185-7°C; 1 H NMR (DMSO-d6): 7.59 (t, 2H, J = 7.2Hz), 7.45-7.41 (m, 4H), 731-7.27 (m 3H), 5.25 (s, 4H), 3.82 (s, 6H); 13 C NMR (DMSO-d6): 159.2 (d, J C-F =247Hz),152.01,149.59,131.91(d,J C-F =3Hz)126.74,125.02(d,J C-F =4.0Hz),123.77(d,J C-F =14Hz),119.64,115.22,113.88,103.69,64.76,56.41; MS: HRMS-ESI-POS.: C 24 H 19 Calculated value of m / z for FN2O4Na: 441.1226 (M + +Na), m / z found 441.1237.

[0685] According to method D, the dinitrile (0.418 g, 1 mmol) was converted to the diimidazoline dihydrochloride (0.43 g, 70%) as a white solid; melting point 237-9°C; 1 H NMR (DMSO-d6): 10.79 (s, 4H), 7.84 (d, 2H, J = 2.0Hz), 7.77 (dd, 2H, J = 2.0Hz, J = 8.4Hz), 7.62 (t, 2H, J=7.6Hz), 7.40 (d, J=8.4Hz), 7.32 (t, 1H, J=7.6Hz), 5.29 (s, 4H), 3.97 (s, 8H), 3.86 (s, 6H); 13 C NMR(DMSO-d6): 164.1,159.01(d,J C-F =250Hz),152.4,148.9,131.5(d,J C-F =3.0Hz),124.9(d,J C-F=4.0Hz),123.0(d,J C-F =15.0Hz),122.8,114.4,112.8,112.1,64.4(d,J C-F =3.5Hz), 56.2, 44.1; MS: HRMS-ESI-POS.: C 28 H 30 The calculated value of FN4O4 m / z is 505.2246 (M + +1), m / z found 505.2248; C 28 H 29 Analytical calculated values ​​for F3N4O4.2HCl.1.85H2O: C, 54.83; H, 5.83; N, 8.90; found values: C, 55.01; H, 5.67; N, 9.02.

[0686] Example 2. Antibacterial activity against Escherichia coli

[0687] The fold sensitization of selected compounds of the present invention was determined. Escherichia coli was cultured overnight in nutrient broth at 37°C before treatment. The bacteria were then incubated for 20 hours with various concentrations of erythromycin in the presence or absence of the compounds shown below. Based on OD 600 Measurement of bacterial density. Based on the IC of erythromycin 90 , use the following formula to calculate the sensitivity increase (sensitization multiple):

[0688] Sensitization factor (SF) = IC of erythromycin in the absence of compound 90 IC of erythromycin in the presence of compound 90

[0689] It was also determined that Cytotoxicity in cells. H9c2 cells were maintained in DMEM (Dulbecco's modified Eagle medium) supplemented with 10% fetal bovine serum (MidSci; S01520HI) and 1% penicillin-streptomycin (Sigma-Aldrich; P4333) at 37°C and 5% CO2. H9c2 cells were seeded in 96-well plates one day before the experiment. Different concentrations of diamidine compounds were added to H9c2 cells. The cells were then incubated with the compounds at 37°C and 5% CO2 for 24 hours. Cell viability was tested by CCK-8. Specifically, after 24 hours of incubation, 10 μL CCK-8 was added to each well. After 3 hours of incubation at 37°C, the absorbance at 450nm was recorded by a plate reader. The results of the sensitization multiple and cytotoxicity are given in Table 1.

[0690] Table 1. MIC sensitization activity against Escherichia coli

[0691]

[0692]

[0693]

[0694] Example 3. Sensitization of Escherichia coli (Gram-negative bacteria) to clarithromycin

[0695] The minimum inhibitory concentration (MIC) of clarithromycin for Escherichia coli is 50 mcg / ml. Bacteria were cultured with different concentrations of clarithromycin in the presence or absence of bacterial sensitizer compound D at 37°C for 24 hours. Then, the OD 600 The bacterial growth density was determined and the results are given in Table 2.

[0696]

[0697] Table 2. MICs of clarithromycin against Escherichia coli at different concentrations.

[0698]

[0699] Example 4. Sensitization of Escherichia coli (Gram-negative bacteria) to novobiocin

[0700] The minimum inhibitory concentration (MIC) of novobiocin against Escherichia coli is 100 mcg / ml. Bacteria were cultured with different concentrations of novobiocin in the presence or absence of bacterial sensitizer compound D at 37°C for 24 hours. The OD 600 The bacterial growth density was determined and the results are given in Table 3.

[0701]

[0702] Table 3. MICs of novobiocin against Escherichia coli at different concentrations.

[0703]

[0704] Example 5. Sensitization of Escherichia coli (Gram-negative bacteria) to rifampicin

[0705] The minimum inhibitory concentration (MIC) of rifampicin against Acinetobacter baumannii is 5 mcg / ml. Bacteria were cultured with different concentrations of antibiotics in the presence or absence of bacterial sensitizer compound D at 37°C for 24 hours. OD 600 The bacterial growth density was determined and the results are given in Table 4.

[0706]

[0707] Table 4. MICs of rifampicin against Acinetobacter baumannii at different concentrations.

[0708]

[0709] Example 6: Highly effective small molecule sensitizers that enhance the sensitivity of Gram-negative bacteria to existing antibiotics

[0710] Instruments and Reagents. All solvents were reagent grade and purchased from Fisher Scientific and Aldrich. Reagents and antibiotics were purchased from Aldrich, Oakwood or VWR. The stationary phase for chromatographic purification was silica gel (230×400 mesh, Sorbtech). Silica gel TLC plates were purchased from Sorbtech. 1 H-NMR (400 MHz) and 13 C-NMR (100 MHz) spectra were recorded on a Bruker Avance 400 MHz NMR spectrometer. Mass spectrometry was performed on an ABI API 3200 (ESI-Triple Quadruple). HPLC was performed on a Shimadzu Prominence UFLC (column: Waters C18 3.5 μM, 4.6×100 mm). OD 600 and fluorescence intensity were recorded on a Perkin Elmer Enspire UV / Vis / fluorescence plate reader.

[0711] Bacterial strains: Escherichia coli (ATCC 25922), Acinetobacter baumannii (ATCC 17978), Klebsiella pneumoniae (43816), Stenotrophomonas maltophilia (ATCC 31559), Salmonella typhimurium (ATCC 14028), Citrobacter werkmanii (ATCC 51114), Staphylococcus aureus (ATCC 12600) and methicillin-resistant Staphylococcus aureus (MRSA, ATCC 33592) strains were purchased from ATCC. NR698 was provided.

[0712] Bacterial culture and MIC determination: Gram-negative bacteria were cultured in Mueller Hinton II cation-adjusted broth. Gram-positive bacteria were cultured in LB broth. Mycobacterium smegmatis was cultured in Middlebrook 7H9 broth. The MIC of the antibiotic itself was determined by making two-fold serial dilutions of the antibiotic. The MIC of the antibiotic in the presence of a bacterial sensitizer was determined by making two-fold serial dilutions of the antibiotic in the presence or absence of a constant concentration of the bacterial sensitizer. MIC testing was performed in 96-well plates with a final volume of 200 μl of Mueller Hinton II cation-adjusted broth in each well. 5 × 10 5 CFU / ml bacteria and incubated at 37°C with continuous shaking at 200 rpm for 24 h. 600 Determine bacterial density. Bacterial growth % = OD of antibiotic-treated group 600 OD of non-antibiotic-treated group 600 The MIC was determined as the concentration that inhibited more than 90% of bacterial growth.

[0713] Determination of sensitization factor and calculation of FIC index: sensitization factor = MIC of single antibiotic / MIC of antibiotic in the presence of sensitizer. For example, the MIC of rifampicin against Escherichia coli is 10 μg / ml, and the MIC of rifampicin measured in the presence of 5 μg / ml MD-124 is 0.019 μg / ml, so the sensitization factor of 5 μg / ml MD-124 on the sensitivity of Escherichia coli to rifampicin is 10 μg / ml / 0.019 μg / ml = 512 times. Since the MIC is determined by two-fold serial dilution of the antibiotic, the sensitization factor can be a multiple of 2.

[0714] The FIC index between compounds a and b was calculated according to the following formula:

[0715]

[0716] FIC < 0.5: synergistic effect; FIC between 0.5 and 1: additive effect; FIC between 1 and 2: no interaction; FIC > 4: antagonistic effect.

[0717] Bacterial resistance frequency study: Escherichia coli was grown overnight in Mueller Hinton II cation-adjusted broth and concentrated to approximately 5 × 10 9 CFU / ml. Then a volume of 200 μl was added to about 5×10 9 CFU / ml (equal to 1×10 9CFU) was transferred to a solid Mueller Hinton agar plate (100 mm petri dish) containing 2 to 6 times the MIC of the antibiotic, with or without 10 μg / ml MD-124. The plate was then incubated at 37°C for 48 h. The colonies formed on the plate were then recorded and the frequency of resistance was calculated. The frequency of resistance to the antibiotic or MD-124 and antibiotic combination was calculated by dividing the number of colonies formed after 48 h by the total CFU initially inoculated on the plate.

[0718] Calculation of resistance frequency to MD-124: For the combination of trovafloxacin and MD-124, 2-fold, 3-fold, and 4-fold MIC of trovafloxacin were used, and each combination had 3 replicates. Therefore, for the combination of trovafloxacin and MD-124, it was 3 combination conditions, each condition had 3 replicates, and the CFU amount tested was: 10 per agar plate 9 CFU × 3 replicates per combination × 3 combinations = 9 × 10 9 CFU. The same number of CFU was tested for both the novobiocin / MD-124 and clindamycin / MD-124 combinations. Therefore, a total of 2.7 × 10 10 CFU. There were colonies resistant to MD-124 and antibiotic combinations. In order to find out whether these resistant strains were resistant to MD-124 or antibiotics, these colonies were subjected to another antibiotic combination: MD-124 and rifampicin. The results showed that MD-124 was still able to enhance the sensitivity of these resistant strains to rifampicin and had the same efficacy against wild-type E. coli, indicating that these 6 combinations of treatments for resistant strains were not resistant to MD-124. From 2.7×10 10 No strains resistant to 10 μg / ml MD-124 were found in the CFU.

[0719] The frequency of resistance to MD-124 was calculated as:

[0720]

[0721] Lysozyme assay evaluates the disruption of the outer membrane of Gram-negative bacteria by bacterial sensitizers. Lysozyme assay was performed based on the method reported in the literature. Escherichia coli was cultured overnight in Mueller Hinton II cation-adjusted broth, centrifuged at 3000 g for 10 min, washed with HEPES buffer (pH = 7.2), and then centrifuged again to obtain a bacterial pellet. The pellet was then gently suspended in HEPES buffer containing 5 mM NaCN to obtain an OD 600Between 0.8 and 1.0 of the Escherichia coli suspension. In a 96-well plate, provide 100 μl of a lysozyme solution (100 μg / ml) containing 50 or 100 μg / ml of a bacterial sensitizer in HEPES buffer in each well. Add 100 μl of the Escherichia coli suspension to each well. The final concentration of lysozyme is 50 μg / ml. Incubate the plate at room temperature for 10 min and record the OD 600 E. coli was also incubated with the bacterial sensitizer in the absence of lysozyme to test whether the bacterial sensitizer directly induces bacterial lysis. E. coli incubated with lysozyme alone or without any treatment was also used as a negative control.

[0722] Evaluation of exogenous LPS and Mg 2+ Effects of bacterial sensitizers. The sensitization to LPS (ranging from 0 to 40 μM) or Mg was determined as described above (Bacterial culture and MIC determination section). 2+ MIC of bacterial sensitizer and antibiotic combination in the presence of (range 0 to 20 mM).

[0723] E. coli strains expressing MCR-1 and NDM-1 were constructed. E. coli (ATCC 25922) was transformed with pGDP2MCR-1 (Addgene, pGDP2MCR-1, plasmid #118404) to generate colistin-resistant strains. E. coli (ATCC 25922) was transformed with pGDP1 NDM-1 (Addgene, plasmid #112883, pGDP1 NDM-1) to generate strains resistant to a wide range of β-lactam antibiotics. The successful construction of E. coli strains overexpressing MCR-1 and NDM-1 was verified by their increased resistance to polymyxin B and β-lactam antibiotics (ampicillin, ceftazidime, and meropenem), respectively.

[0724] The antibiotic absorption in the presence and absence of MD-100 was directly compared by HPLC studies. Escherichia coli (ATCC 25922) was grown overnight in Mueller Hinton II cation-adjusted broth at 37°C to an OD of 0.8 to 1.0. 600Density. 50 μl of E. coli stock solution, 200 μl of 5 mg / ml O-CH3 neomycin and 100 μl of 10 mM MD-100 were added to 20 ml of fresh Mueller Hinton II cation-adjusted broth. In another group, the same amount of E. coli stock solution and O-CH3 neomycin were used in the absence of MD-100. E. coli was then incubated at 37°C with continuous shaking at 200 rpm for 20 h. Afterwards, the E. coli suspension was centrifuged at 3000 g for 10 min, and the culture medium was removed to obtain a bacterial pellet. The pellets from these two groups were resuspended in PBS to reach the same OD of 2.0 600 . 10 μM internal standard was added to this E. coli suspension. 1 ml of E. coli in each group in PBS was lysed by sonication on ice for 15 min, after which 2 ml of MeOH was added, and the mixture was then centrifuged at 3000g for 5 min, and the supernatant was analyzed by HPLC. 20 μl of each sample was injected into Shimadzu Prominence UFLC (column: Waters C18, 3.5 μM, 4.6×100 mm, injection loop volume: 20 μl). The mobile phase was acetonitrile (ACN) / H2O (with 0.05% trifluoroacetic acid in the aqueous phase), and its ratio was defined as: 20% to 55% ACN, 0 to 10 min; 55% to 65% ACN, 10 to 20 min; 65% to 20% ACN, 20 to 25 min. The internal standard used here is neomycin because neomycin has very similar structure and chemical properties compared to the analyte O-CH3 neomycin.

[0725] Dansyl-PMBN displacement assay. Dansyl-PMBN was synthesized according to literature procedures. Dansyl-PMBN was dissolved in H2O to make a 500 μM stock solution. The bacterial sensitizer was dissolved in ethanol to make a 10 mM stock solution. Escherichia coli (ATCC 25922) was cultured overnight at 37°C in Mueller Hinton II cation-adjusted broth. The E. coli stock solution was centrifuged at 3000g for 10 min, washed with HEPES buffer (pH = 7.2), and then centrifuged again to obtain a bacterial pellet. The pellet was then gently suspended in HEPES buffer to obtain an OD 600 The experiment was performed on a 96-well plate. 100 μl of an Escherichia coli suspension containing 10 μM dansyl-PMBN was provided in each well, and then different concentrations of bacterial sensitizers were added to each well to reach a final concentration of 0 to 200 μM. The mixture was then incubated at room temperature for 3 min, and the fluorescence intensity (E x=340nm; E m =520nm).

[0726] Bacterial sensitizers were tested for cytotoxicity of mammalian cells. Cell viability was assessed by using a cell counting kit-8 (CCK-8, Dojindo, Japan). HEK293 or NIH3T3 cells were seeded in 96-well plates to reach 80% confluence one day before the experiment. The cells were then incubated with various concentrations of bacterial sensitizers at 37°C and 5% CO2 for 24h, and then 10 μL of CCK-8 solution was added to each well, and the plate was incubated for another 2h at 37°C and 5% CO2. The optical density at 450nm was recorded with a plate reader; and the results were calculated as the percentage of viability compared to the untreated control.

[0727] Development of sensitizers for Gram-negative bacteria

[0728] Compounds were synthesized and tested for their ability to enhance the sensitivity of E. coli to narrow spectrum antibiotics (Tables 5A and 5B). The structures of the compounds are given in Table 5A and the activity, sensitization and cytotoxicity of the compounds are given in Table 5B.

[0729] Table 5A

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737] In the presence or absence of 10 μM indicated compounds, bacterial strains (as indicated in Table 5B) were cultured at 37°C for 20 h with various concentrations of rifampicin. The MIC, sensitization, cytotoxicity and MIC of mycobacteria were tested according to the methods described herein. As described herein, the sensitization multiple refers to the ability of a compound to reduce the MIC of an antibiotic (e.g., rifampicin or erythromycin) to certain bacterial strains. The sensitization activity of the test compound to Bacillus subtilis was tested using erythromycin. The sensitization activity of the test compound to MRSA was tested using rifampicin. The sensitization activity of the test compound to Escherichia coli was tested using rifampicin. The results are given in Table 5B.

[0738] Table 5B

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760] Selected data from Table 5B are described below (Table 6).

[0761] Compounds at 10 μM were tested for sensitization of bacteria using rifampicin as an antibiotic; IC was tested on HEK293 cells 50 MD-129, 113, 102, 106 and 112 showed no sensitizing activity up to 10 μM.

[0762] Scheme 1. Structures of bacterial sensitizers synthesized and evaluated.

[0763]

[0764] E. coli was cultured with various concentrations of rifampicin at 37°C for 20 h in the presence or absence of 5 μg / ml MD-124. The OD 600 Several compounds were able to enhance the sensitivity of E. coli to narrow spectrum antibiotics, some of which were able to enhance the sensitivity by 32-fold at 10 μg / ml or less (Table 7).

[0765] Table 6

[0766]

[0767]

[0768] BW-MD-124 (MD-124) showed excellent bacterial sensitization activity and was selected for further biological evaluation ( Figure 1A 5μg / ml of MD-124 can enhance the sensitivity of Escherichia coli to rifampicin by 512 times, thereby reducing the MIC of rifampicin from 10μg / ml to 0.02μg / ml ( Figure 1B Escherichia coli (5×10 5 CFUs / ml), and recorded the OD at different time points 600 MD-124 itself showed no effect on bacterial growth at the same concentration ( Figure 1C ). These results suggest that MD-124 has no direct antibacterial effect and acts as an adjuvant to other antibiotics.

[0769] Table 7

[0770]

[0771]

[0772] The chessboard assay showed that MD-124 enhanced the sensitivity of Escherichia coli to rifampicin in a concentration-dependent manner, reaching more than 16,000 times when about 10 μg / ml of MD-124 was used, and the MIC of rifampicin was 0.6 ng / ml. Figure 1D). The fractional inhibitory concentration (FIC) index calculated based on the chessboard assay was 0.09 (the MIC of MD-124 itself against E. coli was 50 μg / ml), indicating a strong synergistic effect between MD-124 and rifampicin. The sensitization ability of MD-124 varied significantly within the range of 3 to 12 μg / ml, and therefore a chessboard assay was performed with MD-124 varying between 0 and 10 μg / ml ( Figure 1E 5 μg / ml MD-124 can enhance the sensitivity of E. coli to a wide range of existing antibiotics, including narrow-spectrum antibiotics such as clarithromycin (256 times), erythromycin (128 times), and neomycin (64 times) and broad-spectrum antibiotics such as trovafloxacin (32 times), polymyxin B (32 times), and chloramphenicol (8 times). Figure 1H When MD-124 was used with narrow-spectrum antibiotics, the sensitization factor achieved was higher than that achieved when MD-124 was used with broad-spectrum antibiotics. When combined with MD-124, the MICs of various narrow-spectrum antibiotics tested dropped to about 1 μg / ml or less, which is similar to the MICs of broad-spectrum antibiotics against Escherichia coli ( Figure 1H and Table 8). Compared with previously discovered bacterial sensitizers such as pentamidine and polymyxin B nonapeptide (PMBN), MD-124 exhibited stronger sensitization activity ( Figure 1G ). For example, 20 μg / ml of pentamidine and PMBN were shown to increase the sensitivity of Escherichia coli to rifampicin by 4 and 16 times, respectively, while 5 μg / ml of MD-124 was able to increase the sensitivity by 512 times. In addition to Escherichia coli, MD-124 also showed a sensitizing effect on a variety of other Gram-negative bacterial strains such as Acinetobacter baumannii, Klebsiella pneumoniae, and Salmonella typhimurium, among which the resistant strains were listed as WHO priority 1 pathogens that urgently need new antibiotics ( Figure 1F ).

[0773] Table 8

[0774]

[0775] Frequency of resistance to MD-124

[0776] Because bacteria can rapidly develop resistance to new antimicrobial agents, the frequency of E. coli resistance to MD-124 was assessed. Briefly, E. coli were cultured with varying concentrations of antibiotic (2 to 7 times the MIC) in the presence and absence of 10 μg / ml MD-124. The frequency of bacterial resistance to the MD-124 / antibiotic combination and the antibiotic itself was then calculated ( Figure 2D). E. coli showed 2 to 3 orders of magnitude lower resistance frequency to the MD-124 / antibiotic combination than to the antibiotics themselves (Figure 2). For colonies resistant to both MD-124 and the antibiotic combination, it was necessary to determine whether the resistant strains were resistant to MD-124 or the antibiotics used in the combination. Therefore, the combination therapy-resistant colonies were subsequently subjected to another antibiotic combination: MD-124 and rifampicin ( Figure 2B MD-124 was still effective in enhancing the susceptibility of these strains to rifampicin, with the same efficacy as against wild-type E. coli. This result suggests that these resistant strains are not resistant to MD-124. 10 No strains resistant to 10 μg / ml MD-124 were found in the CFU, and the resistance frequency was <1 / 2.7×10 10 (<3.7×10 -11 ). The frequency of resistance here is not defined based on direct inhibitory / bactericidal effects like traditional antibiotics, but rather on the sensitizing effect of MD-124. These studies show that: 1) MD-124 can reduce the frequency of bacterial resistance to antibiotics when used in combination; 2) bacteria show a lower frequency of resistance to MD-124 than to antibiotics; and 3) even if bacteria show resistance to one antibiotic / MD-124 combination, simply switching to another antibiotic / MD-124 combination will regain the sensitizing effect on resistant strains.

[0777] Mechanism of bacterial sensitization activity

[0778] The mechanism of bacterial sensitization activity was then investigated. Because MD-124 can enhance the sensitivity of Gram-negative bacteria to a variety of antibiotics, and the outer membrane is the main barrier to the absorption of antibiotics, the ability of MD-124 to disrupt the bacterial outer membrane was determined. Figure 3A MD-124 and MD-100 were used to study the mechanism of sensitization. MD-124 was shown to be impaired in its ability to enhance the sensitivity of the outer membrane "leaky" mutant of Escherichia coli strain NR698 ( Figure 3B), the strain is already sensitive to narrow-spectrum antibiotics such as clarithromycin and erythromycin. At a concentration of 5 μg / ml, it was shown that MD-124 enhanced the sensitivity of wild-type Escherichia coli to clarithromycin by 256 times, and enhanced the sensitivity of NR698 by 4 times. The same phenomenon was also observed when MD-100 was used for wild-type and NR698 Escherichia coli (Fig. 7). Such results show that if the bacterial strain has increased permeability due to impaired outer membrane integrity, the sensitization ability of MD-124 and MD-100 will be weakened. This is consistent with the sensitization mechanism of MD-124 on the bacterial outer membrane. The destruction of MD-124 to the bacterial outer membrane was then determined by lysozyme assay. In short, lysozyme (14KDa) can decompose peptidoglycan and cause bacterial lysis. However, lysozyme cannot penetrate the intact Gram-negative bacterial outer membrane. In the case of damaged Gram-negative bacterial membranes, lysozyme will be able to diffuse through the damaged membrane and enzymatically cleave peptidoglycan, causing bacterial lysis. In the presence of 25 μg / ml MD-124 or 50 μg / ml MD-100, lysozyme caused rapid bacterial lysis, whereas in the absence of the sensitizer, no cell lysis was observed ( Figure 3C , left histogram in each pair). MD-124 and MD-100 do not cause bacterial lysis by themselves ( Figure 3C , right histogram in each pair). These results indicate that MD-124 is able to disrupt membrane integrity. 25 μg / ml polymyxin B and 50 μg / ml pentamidine, used here as positive controls, also caused bacterial lysis when incubated with lysozyme. 25 μg / ml MD-124 showed similar potency to 25 μg / ml polymyxin B and was more effective than 50 μg / ml pentamidine in disrupting the bacterial outer membrane. The results also showed a positive correlation between the ability of various bacterial sensitizers to disrupt the outer membrane in the lysozyme assay and their ability to enhance the sensitivity of E. coli to rifampicin ( Figure 3D The structures and sensitization multiples of these bacterial sensitizers can be found in Scheme 1 and Table 6). The outer membrane destruction ability was based on the lysozyme assay as described above, and all bacterial sensitizers used the same concentration. 25 μg / ml bacterial sensitizer was used in the lysozyme assay. The bacterial sensitization activity was measured based on the sensitization multiple of Escherichia coli to rifampicin, which is listed in Table 1 in detail. MD-102, 106 and 129 failed to enhance the sensitivity of Escherichia coli, so the sensitization multiple was determined to be 1.

[0779] Next, the intracellular concentrations of antibiotics in the presence and absence of MD-100 were compared to assess the membrane permeability of MD-100. Antibiotic concentrations within bacteria were directly measured by analyzing bacterial lysates using HPLC after treatment with and without MD-100. Figure 3EAs shown, the relative intracellular concentration of an inactive novobiocin analog (O-methyl novobiocin, Scheme 2) was greatly increased in the presence of MD-100. In order to avoid killing the bacteria after intracellular enrichment, inactive O-methyl novobiocin was used. Overall, these results show that MD-124 enhances bacterial sensitivity by permeating the membrane and allowing increased antibiotic entry.

[0780] Solution 2

[0781]

[0782] Study on the molecular mechanism of bacterial sensitizers

[0783] Various experiments were then performed to examine the molecular targets. Addition of additional LPS to the culture medium abolished the sensitizing effect of MD-124 and MD-100 ( Figure 4A , Table 9 and Figure 7B ). Briefly, E. coli was treated with 5 μg / ml MD-124 (about 10 μM) and different concentrations of LPS (from 0 to 40 μM) for 20 h. Then, OD 600 The MIC of rifampicin alone was 10 μg / ml.

[0784] Table 9

[0785]

[0786] Mg 2+ Inhibited the bacterial sensitization activity of MD-124 against Escherichia coli in a concentration-dependent manner ( Figure 4B , Table 10). Briefly, 5 μg / ml MD-124 (approximately 10 μM) and different concentrations of Mg 2+ (from 0 to 15 mM) for 20 h. Then the OD 600 The MIC of rifampicin alone was 10 μg / ml.

[0787] Mg 2+ It can bridge adjacent lipid A and enhance membrane integrity. Therefore, high concentrations of this divalent cation can replace the diamidine, thereby exerting an antagonistic effect on MD-124. This phenomenon was also observed on MD-100. The culture medium for E. coli is Muller Hinton Broth (cation-adjusted), which already contains at least 0.5 mM Mg 2+ ,therefore Figure 4B "Mg 2+ The zero concentration point represents the exogenous Mg 2+ The amount of Mg in the culture medium is not 2+ The free magnesium concentration in human blood is between 0.55 and 0.75 mM, indicating that the physiological concentration of Mg2+ The sensitizing ability of MD-124 will not be affected. A fluorescent conjugate of a polymyxin-B derivative (dansyl-PMBN, Scheme 3) that shows increased fluorescence intensity upon binding to the lipid A portion of LPS was used to further explore this issue. In the presence of another component that can also bind to lipid A, dansyl-PMBN will be displaced, resulting in a decrease in fluorescence intensity.

[0788] Table 10

[0789]

[0790] Option 3

[0791]

[0792] As MD-124 was gradually added to the mixture of E. coli and 10 μM dansyl-PMBN, the fluorescence intensity of dansyl-PMBN steadily decreased in a concentration-dependent manner, indicating that MD-124 bound to lipid A ( Figure 4C ). Pentamidine and MD-100 were also able to replace dansyl-PMBN, although not as much as MD-124. A mutant of the lipid A strain was constructed that overexpressed the mobilized colistin resistance-1 (mcr-1) gene, which would modify the phosphate groups on lipid A, inducing a decrease in the negative charge density of the outer membrane of Gram-negative bacteria and leading to resistance to colistin. 26,27 Two sets of mcr-1 overexpressing strains, mcr-1A and mcr-1B, were used to test the response of MD-124 to modified lipid A. The MICs of polymyxin B against these two sets of strains were 10 and 30 μg / ml, respectively, while the MIC against the wild type was 1.2 μg / ml (Table 11).

[0793] Table 11

[0794]

[0795] Although 3 μg / ml MD-124 enhanced the susceptibility of wild-type E. coli to rifampicin by 16-fold, it only enhanced the susceptibility of mcr-1B strains by 4-fold, and 5 μg / ml MD-124 was required to restore the 32-fold sensitization of mcr-1B strains (Figure 4E). This shows that the activity of MD-124 is reduced when lipid A is modified, confirming that lipid A is the molecular target of MD-124. It is worth mentioning that 3 μg / ml MD-124 can still enhance the susceptibility of mcr-1A (MIC10 μg / ml) strains to rifampicin by 32-fold, which means that mcr-1 strains with this level of polymyxin B resistance have not achieved resistance to MD-124 (Figure 4E). The MIC of clinically isolated mcr-1 overexpressing strains to polymyxin B is usually 10 μg / ml or less, indicating the effectiveness of MD-124 against these clinical strains. Even those mcr-1 strains that showed stronger resistance to polymyxin B (MIC 30 μg / ml) were only slightly resistant to MD-124, increasing the concentration required to enhance sensitivity 32-fold from 3 μg / ml to 5 μg / ml. Collectively, these results not only indicate that lipid A is the molecular target of MD-124, but also suggest the therapeutic potential of MD-124 in combating polymyxin-resistant bacteria induced by mcr-1. MD-124 was also found to enhance the sensitivity of mcr-1 overexpressing strains to many other antibiotics besides rifampicin (Table 16).

[0796] The sensitization effect of MD-124 on various clinically relevant strains and drug-resistant strains, especially Gram-negative bacteria in the ESKAPE class of pathogens, was then examined. The checkerboard assay showed that MD-124 was able to enhance the susceptibility of Acinetobacter baumannii to rifampicin, reducing the MIC of rifampicin from 5 μg / ml to 0.04 and 0.01 μg / ml when 5 and 7 μg / ml of the sensitizer were used, respectively. Figure 5A The FIC index between MD-124 and rifampicin was calculated to be 0.14. Similar sensitization effects on Acinetobacter baumannii were also observed in the presence of neomycin by the chessboard assay, and the FIC index between MD-124 and neomycin was determined to be 0.20 ( Figure 5B 5 μg / ml MD-124 also enhanced the sensitivity of Acinetobacter baumannii to a variety of other antibiotics such as clarithromycin, fusidic acid and clindamycin, reaching 64, 128 and 8 times of sensitivity, respectively (Table 12).

[0797] Table 12

[0798]

[0799] Another ESKAPE pathogen, Klebsiella pneumoniae, is also sensitive to MD-124. Figure 5C and Figure 5D As shown, MD-124 can enhance the sensitivity of Klebsiella pneumoniae to rifampicin and clarithromycin by 512 times or more; 10 μg / ml MD-124 reduces the MIC of rifampicin and clarithromycin from more than 20 μg / ml to 0.2 μg / ml or less. The FIC index between MD-124 and rifampicin or clarithromycin was determined to be 0.15 and 0.16, respectively. Many other antibiotics (such as clindamycin, chloramphenicol, fusidic acid and neomycin) can also be used in combination with 5 μg / ml MD-124 to inhibit the growth of Klebsiella pneumoniae (Table 13).

[0800] Table 13

[0801]

[0802] Carbapenem-resistant Enterobacteriaceae have attracted increasing attention and are listed as a priority pathogen for the research and development of new antibiotics by the WHO. To test the effect of MD-124 on carbapenem-resistant bacteria, an NDM-1 expressing Escherichia coli strain was constructed to induce carbapenem resistance. Compared with the wild type, the NDM-1 expressing Escherichia coli strain showed a 30- to 100-fold increase in MICs to β-lactam antibiotics such as ampicillin, ceftazidime, and the carbapenem antibiotic meropenem (Table 14 and Table 12).

[0803] Table 14

[0804]

[0805] Compared to wild-type, NDM-1 expressing E. coli strains did not show significant changes in MICs to other antibiotic families (Table 15 vs. Table 8). MD-124 was able to enhance the sensitivity of NDM-1 expressing E. coli strains with the same potency as wild-type E. coli. MD-124 enhanced the sensitivity of NDM-1 expressing E. coli to rifampicin in a concentration-dependent manner, reducing the MIC of rifampicin from 10 μg / ml to 0.02 and 0.012 μg / ml when 5 and 10 μg / ml of MD-124 were used (Table 15 vs. Table 8). Figure 5E MD-124 also showed a synergistic effect with rifampicin, and the FIC index was calculated to be 0.09. MD-124 enhanced the sensitivity of carbapenem-resistant Escherichia coli to other narrow-spectrum antibiotics such as clarithromycin and neomycin and broad-spectrum antibiotics such as trovafloxacin and chloramphenicol (Table 15).

[0806] Table 15

[0807]

[0808] The mcr-1 gene-induced polymyxin-resistant and colistin-resistant strains are threatening the last line of defense for antimicrobial therapy. MD-124 was observed to enhance the susceptibility of mcr-1-expressing Escherichia coli (MIC of polymyxin B is 30 μg / ml) to rifampicin and several other antibiotics ( Fig. 5F , Table 16).

[0809] Table 16

[0810]

[0811] MD-124 and rifampicin showed a synergistic effect against mcr-1 expressing E. coli, with a calculated FIC index of 0.37. It is noteworthy that MD-124 showed a slightly decreased sensitization ability against this mcr-1 expressing strain compared to wild-type E. coli ( Figure 1D contrast Fig. 5F ). However, 5 μg / ml MD-124 still made the MIC of rifampicin and clarithromycin to 0.2μg / ml or lower against this mcr-1-induced polymyxin B-resistant strain. Surprisingly, MD-124 enhanced the susceptibility of this strain to polymyxin B, changing the MIC from 30 to 1μg / ml. This result means that MD-124 can convert this polymyxin B-resistant strain into a polymyxin B-susceptible strain ( Figure 8 ).

[0812] The effect of MD-124 in an ex vivo skin burn infection model was determined. For topical administration, the compound was formulated into a hydroxypropylmethylcellulose gel. Briefly, human skin (approximately 1 cm × 1 cm) was burned with a soldering iron (95°C) for 10 s; 5 CFU Escherichia coli were inoculated onto the burned skin and incubated at 37°C for 1 hour. Afterwards, the skin was loaded with hydroxypropyl methylcellulose gel containing different antibiotics and incubated at 37°C for 24 hours. After 24 hours of incubation, the skin samples were homogenized, and the supernatant was serially diluted and plated on agar plates, from which the number of bacteria on the skin was counted. Although neither 4‰ (w / w) novobiocin nor 1.5‰ MD-124 achieved significant inhibition of Escherichia coli growth by themselves, the combination of novobiocin and MD-124 effectively reduced the bacterial load ( 1.24 × 10 μg / mL) compared to the vehicle group. Fig. 6A ). 1‰ polymyxin B hydroxypropyl methylcellulose gel was used as a positive control. To further investigate the range and effectiveness of MD-124, the combination of MD-124 and clindamycin was tested against resistant Gram-negative bacteria. MD-124 and clindamycin were also effective in treating skin infections caused by NDM-1-expressing Escherichia coli, reducing bacterial loads by more than 1000-fold compared to clindamycin alone ( Figure 6BThe dosage is equivalent to or lower than the 0.5-2% antibiotic commonly used in ointment preparations.

[0813] MD-124 was shown to restore the effectiveness of polymyxin B against mcr-1 expressing E. coli. Specifically, we investigated whether the MD-124-polymyxin B combination was effective in treating MCR-1 bacterial infection in this skin burn model ( Figure 6C Polymyxin B alone (3‰, w / w) had only a minor effect compared to the vehicle group ( Figure 6C In contrast, the MD-124-polymyxin B combination (3‰ (w / w) polymyxin B and 1.5‰ (w / w)) reduced the bacterial load by approximately 200-fold ( Figure 6C ). Taken together, these results show that the sensitizing effect of MD-124 allows the use of narrow-spectrum antibiotics in the treatment of Gram-negative bacterial infections and restores the sensitivity of resistant strains to some of the antibiotics tested.

[0814] The effect of phosphatidylcholine on the sensitizing activity of MD-124 was also determined. Escherichia coli was treated with 10 μM MD-124 (about 5 μg / ml) and a combination of rifampicin and different concentrations of phosphatidylcholine (from 0 to 320 μM) at 37°C for 20 h, and then the OD was measured. 600 And the sensitivity enhancement factor was calculated as described above. Fig. 9 Displayed in.

[0815] Example 7. Antibacterial activity against MRSA

[0816] The fold sensitization of selected compounds described herein against Gram-positive bacteria was determined.

[0817]

[0818] DB2560 (also referred to herein as MD-100 and as shown above) enhances the sensitivity of Gram-positive bacteria such as Bacillus subtilis to traditional antibiotics. The MIC of DB2560 against wild-type Bacillus subtilis is 50 μg / ml. Fig. 10AAs shown, 5.5 μg / ml DB2560 alone (i.e., without any additional antibiotics) failed to significantly affect bacterial growth (growth density was 80% compared to the control (untreated) group). The MIC of rifampicin against Bacillus subtilis in the presence of 5.5 μg / ml DB2560 was 0.037 μg / ml, and rifampicin had almost no inhibitory effect at this concentration. The sensitization factor and FIC index were calculated to be 256 times and 0.11, respectively. In the presence and absence of DB2560, the MIC of erythromycin was determined to be 1.5 and 50 μg / mL, which gave DB2560 a 32-fold sensitization and a FIC index of 0.14. DB2560 at a concentration of 5.5 μg / ml enhanced the sensitivity of Bacillus subtilis to a wide range of antibiotics with unique antimicrobial mechanisms, such as clindamycin (16-fold), clarithromycin (32-fold), novobiocin (4-fold), methicillin (4-fold), entrapenem (4-fold), and trovafloxacin (8-fold).

[0819] The fact that DB2560 significantly enhanced the susceptibility of Bacillus subtilis to rifampicin, erythromycin, and clindamycin suggests that the Gram-positive bacterial membrane is a very effective barrier to these antibiotics. DB2560 at a concentration of 2.7 μg / ml enhanced the susceptibility of MRSA to existing antibiotics such as rifampicin (32-fold) ( Fig. 10B ) and trovafloxacin (16 times). Rifampicin is the first line of defense against MRSA, and many MRSA strains are resistant to rifampicin through the overexpression of efflux pumps and other mechanisms. The combination of bacterial sensitizers as described herein (such as DB2560) and rifampicin can be used more as a more effective therapeutic agent against MRSA.

[0820] Many antibiotics, such as erythromycin, rifampicin, and trovafloxacin, have significantly higher MICs against MRSA than against wild-type E. coli, meaning that even narrow-spectrum antibiotics such as rifampicin, which are the first line of defense against MRSA, can cause significant collateral damage to benign Gram-negative bacteria like E. coli before killing MRSA. As a proof of concept, the relative ratios of E. coli and MRSA or B. subtilis and MRSA were measured in the presence and absence of the compound MD-108 ( Fig.11A and Fig. 11B). Trovafloxacin (16 ng / ml) will preferentially inhibit E. coli, making MRSA the dominant species (78% of the bacterial population). When 1.5 μg / ml MD-108 and 8 ng / ml trovafloxacin are provided, MRSA inhibition is achieved, making E. coli the dominant species (89% of the bacterial population). At 16 ng / ml trovafloxacin, the relative survival between B. subtilis and MRSA is 1:1, while at 8 ng / ml trovafloxacin and 1.5 μg / ml MD-108, B. subtilis will dominate the composition (99.5%).

[0821] Although the foregoing invention has been described in detail by way of illustration and example for the purpose of clear understanding, it will be apparent to one of ordinary skill in the art based on the teachings of the present invention that certain changes and modifications may be made to the present invention without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. A method for treating a bacterial infection, the method comprising administering a compound of formula IV to a host in need thereof or a pharmaceutically acceptable salt thereof in L 2 Selected from v and w are independently selected from 0, 1, 2, 3 and 4; R is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano; R 3 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, carbocycle, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryl, heterocyclyl, -COOR, -C(O)R, fluorine, chlorine, bromine, and iodine; X 8 and X 9 independently selected from O, S, NH and Se; X 10 Selected from Se, S or NH; R 4 and R 5 is independently selected at each occurrence from the group consisting of hydrogen and C1-C6 alkyl; and R 6 and R 7 At each occurrence, independently selected from the group consisting of:

2. A method for enhancing the therapeutic effect of antibiotics during the treatment of bacterial infections, the method comprising administering to a host in need thereof a compound of formula IV or a pharmaceutically acceptable salt thereof, in L 2 Selected from v and w are independently selected from 0, 1, 2, 3 and 4; R is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano; R 3 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, carbocycle, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryl, heterocyclyl, -COOR, -C(O)R, fluorine, chlorine, bromine, and iodine; X 8 and X 9 independently selected from O, S, NH and Se; X 10 Selected from Se, S or NH; R 4 and R 5 is independently selected at each occurrence from the group consisting of hydrogen and C1-C6 alkyl; and R 6 and R 7 At each occurrence, independently selected from the group consisting of:

3. The method according to claim 1 or 2, wherein formula IV is selected from or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1 or 2, wherein Formula IV is a compound of the following structure: or a pharmaceutically acceptable salt thereof.

5. A method for treating Gram-positive or Gram-negative bacterial infection comprising administering a compound of formula VI or a pharmaceutically acceptable salt thereof, in R 9 and R 12 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano; R 10 and R 11 independently selected at each occurrence from the group consisting of hydroxy, C1-C6 alkanoyl, carbocycle, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -C(O)R, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, bromine, iodine, thiol, and cyano; and R 3 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, carbocycle, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryl, heterocyclyl, -COOR, -C(O)R, fluorine, chlorine, bromine and iodine.

6. The method according to claim 5, wherein the formula VI is a compound of the formula: or a pharmaceutically acceptable salt thereof.

7. The method according to claim 5, wherein Formula VI is selected from:

8. A pharmaceutical composition comprising a compound of formula IV or formula VI, optionally in a pharmaceutically acceptable carrier, in combination with an effective amount of an antibiotic: or a pharmaceutically acceptable salt thereof, the pharmaceutical composition being used for treating a bacterial infection in a host in need thereof, wherein: L 2 Selected from v and w are independently selected from 0, 1, 2, 3 and 4; X 8 and X 9 independently selected from O, S, NH and Se; X 10 Selected from Se, S or NH; R is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano; R 3 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, carbocycle, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryl, heterocyclyl, -COOR, -C(O)R, fluorine, chlorine, bromine, and iodine; R 4 and R 5 is independently selected at each occurrence from the group consisting of hydrogen and C1-C6 alkyl; and R 6 and R 7 At each occurrence, independently selected from the group consisting of: R 9 and R 12 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, aliphatic, carbocyclic, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, chlorine, bromine, iodine, thiol, and cyano; and R 10 and R 11 independently selected at each occurrence from the group consisting of hydroxy, C1-C6 alkanoyl, carbocycle, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, N(R 3 )2, -NHSO2 alkyl, -N(alkyl)SO2 alkyl, -NHSO2 aryl, -N(alkyl)SO2 aryl, -NHSO2 alkenyl, -N(alkyl)SO2 alkenyl, -NHSO2 alkynyl, -N(alkyl)SO2 alkynyl, NO2, -COOH, -CONH2, -C(O)R, -P(O)(OH)2, -S(O)R 3 、-SO2R 3 、-SO3R 3 、-SO2N(R 3 )2.-OSO2R 3 、-N(R 3 )SO2R 3 , azido, aryl, heteroaryl, heterocyclyl, fluorine, bromine, iodine, thiol and cyano.

9. A method for treating bacterial infection, comprising administering a compound of Formula II, Formula III or Formula V to a host in need thereof or a pharmaceutically acceptable salt thereof in L 1 Selected from L 2 Selected from X 3 In each occurrence, independently selected from C(R 3 )2. O, S and NR 4 The group composed of; X 4 Selected independently from CR at each occurrence 3 and N; X 6 , X 7 , X 8 and X 9 independently selected from O, S, NH and Se; X 10 Selected from Se, S or NH; R 3 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkanoyl, carbocycle, C2-C6 alkenyl, C2-C6 alkynyl, heteroaryl, aryl, heterocyclyl, -COOR, -C(O)R, fluorine, chlorine, bromine, and iodine; R 4 and R 5 is independently selected at each occurrence from the group consisting of hydrogen and C1-C6 alkyl; and R 6 and R 7 At each occurrence, independently selected from the group consisting of:

10. The method of claim 9, wherein Formula II is selected from or a pharmaceutically acceptable salt thereof.

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