Novel compounds and therapeutic uses thereof

Abstract

The invention relates to novel compounds with the ability to link an immune response to a pathogen, to the use of said compounds in a disease or disorder mediated and / or caused by an infective agent, to compositions containing said compounds, processes for their preparation and to novel intermediates used in said process.

Description

[0001] NOVEL COMPOUNDS AND THERAPEUTIC USES THEREOF

[0002] FIELD OF THE INVENTION

[0003] The invention relates to novel compounds with the ability to link an immune response to a pathogen, to the use of said compounds in a disease or disorder mediated and / or caused by an infective agent, to compositions containing said compounds, processes for their preparation and to novel intermediates used in said process.

[0004] BACKGROUND OF THE INVENTION

[0005] There is a need to find novel ways to recruit an individual’s immune system to fight disease. The human immune system continually surveys the body seeking foreign signals to identify potentially harmful pathogens or mutated human cells (that could become a cause of cancerous growth) and target them for elimination. Natural antibodies exist that can be recruited to said pathogens or mutated human cells to drive the immune system to eliminate the threat. The invention details the use of a novel set of compounds that are designed to attract these natural antibodies in such a way as to be able to maximise the efficacy of immune recruitment while minimising potential side effects.

[0006] There is an urgent need to identify novel ways of treating bacterial, viral and fungal infections. Drug resistance is becoming a major global health threat. For example, more than 2 million people in the US were infected with bacteria resistant to at least one class of antibiotics (Centers for Disease Control and Prevention, 2013). Overall, the identification of new antibiotics targeting resistant strains of gram-negative organisms has been particularly difficult, in part due to the complex and evolving strategy these bacteria use to prevent antibiotic action (e.g., production of antibiotic inactivating enzymes, ability to transfer of resistance between strains, efflux pumps to prevent intracellular action) coupled with their naturally impermeable cell membranes that make it hard to identify drugs that penetrate into the cell and inhibit key targets. Further, many strains utilize multiple resistance mechanisms making it difficult for a single antibiotic to overcome.

[0007] An innovative approach to the treatment of infectious disease was disclosed in WO 01 / 45734 which describes a set of novel immunity linkers. Examples of said linker moieties include compounds or agents which are recognised by the immune system of said individual as foreign and which would therefore trigger an immune response. One such example is a carbohydrate molecule capable of binding to a human anti-alpha-galactosyl antibody (i.e. galactosyl-alpha-1,3-galactosyl-beta-1 ,4-N-acetylglucosamine) which results in redirection of the natural human serum antibody anti-alpha-galactosyl. The resultant effect of said immunity linker molecule is that the immune response of the individual is diverted from the pre-existing immune response of said individual towards the target, i.e. the pathogen.

[0008] More recently, a further example of a carbohydrate molecule capable of binding to human serum antibodies has been described. For example, anti-Rhamnose (i.e. L-Rhamnose) has been shown to result in target cell destruction (Kiessling et al (2014) ChemBioChem 15(10), 1393-1398; US 2014 / 0112975; Li et al (2016) ACS Chem. Biology 11(5), 1205-1209).

[0009] Furthermore, complexes comprising anti-Rhamnose antibodies have been shown to magnify antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) which therefore confirm utility in the anti-cancer field (Zhou et al (2022) Journal of Medicinal Chemistry 65, 323-332).

[0010] There is therefore a need for alternative compounds for the treatment of a disease or disorder mediated and / or caused by an infective agent.

[0011] SUMMARY OF THE INVENTION

[0012] According to a first aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein:

[0013] R1represents a halogen atom; and n represents an integer selected from 1 to 5.

[0014] BRIEF DESCRIPTION OF THE FIGURES

[0015] Figure 1 : Results of C3b deposition study involving Example 1 , 20% depleted human serum and anti-rhamnose antibodies.

[0016] DETAILED DESCRIPTION OF THE INVENTION

[0017] WO 2018 / 203087 describes a conjugate which comprises a cationic peptide (that is shown to specifically bind to bacteria) and one or more rhamnose units connected via a linker. Suitable examples of cationic peptides include polymyxin B (or polymyxin nonapeptide, colistin or a derivative thereof). This family of cationic peptides bind to lipid A on the bacterial cell surface and, when conjugated to rhamnose linkers, will present rhamnose, resulting in anti-rhamnose antibody (anti-Rha) recruitment and cell killing. Resistance rates are likely to be low as lipid A is important in the survival of gram-negative bacteria. In fact, even polymyxin-resistant strains retain binding sites for cationic peptides and as such the peptide-rhamnose conjugate.

[0018] The novel mechanisms described in WO 2018 / 203087 are particularly attractive due to not being impacted by antibiotic resistance mechanisms but provide effectiveness against multidrug resistant strains. Furthermore, the combination of the broad spectrum bacterial binding capability of a cationic peptide with the unique ability to specifically recruit naturally occurring anti-rhamnose antibodies to the bacterial surface, and re-direct these antibodies to promote complement activation, phagocytosis and killing is very attractive. Therefore, the compounds described in WO 2018 / 203087 claimed to have the potential to provide a novel therapy for bacterial infections with broad-spectrum activity.

[0019] However, antimicrobial peptides (such as polymyxin and derivatives thereof) are often associated with having a liability for renal toxicity (Nation et al (2019) Antibiotics 8, 24).

[0020] Surprisingly, the inventors of the present invention have discovered that a halo substituted phenylalanine at the N-terminus of polymyxin provides unexpected advantages regarding reduction of cytotoxicity, in particular renal cytotoxicity. Data is presented herein in Tables 2 to 4 which demonstrates that the halo substituted phenylalanine compounds of the present invention retained the antibacterial activity (see Table 4) and antibody recruitment activity (see Table 2) of the resultant complex but surprisingly demonstrated significantly reduced cytotoxicity against the renal cell line hRPTEC when compared with a representative example from WO 2018 / 203087 (see Table 3). Furthermore, data is presented herein in Table 5 which demonstrates the in vivo effectiveness of a compond of the invention.

[0021] In one embodiment, R1represents fluorine or chlorine. In a further embodiment, R1represents fluorine.

[0022] In one embodiment, n represents an integer selected from 1 to 4. In a further embodiment, n represents an integer selected from 1 to 3. In a yet further embodiment, n represents an integer selected from 1 or 2. In one particular embodiment, n represents an integer which is 1. In an alternative particular embodiment, n represents an integer which is 2. In one embodiment, n represents 1 and R1represents fluoro or chloro. In a further embodiment, n represents 1 and R1represents fluoro. In a further embodiment, n represents 1 and R1represents 2-fluoro, 2-chloro, 3-fluoro or 4-fluoro. In a yet further embodiment, n represents 1 and R1represents 2-fluoro, 3-fluoro or 4-fluoro. In a yet further embodiment, n represents 1 and R1represents 2-chloro, 3-fluoro or 4-fluoro. In a yet further embodiment, n represents 1 and R1represents 3-fluoro or 4-fluoro. In a still yet further embodiment, n represents 1 and R1represents 4-fluoro.

[0023] In one embodiment, n represents 2 and R1represents fluoro. In a further embodiment, n represents 2 and R1represents 2,3-difluoro, 2,4-difluoro, 2,5-difluoro, 2,6-difluoro, 3,4- difluoro or 3,5-difluoro. In a yet further embodiment, n represents 2 and R1represents 2,4- difluoro, 2,5-difluoro or 3,5-difluoro.

[0024] In one embodiment, n either represents 1 and R1represents 2-chloro, 3-fluoro or 4-fluoro or n represents 2 and R1represents 2,4-difluoro, 2,5-difluoro or 3,5-difluoro.

[0025] It will be appreciated that the compounds of the invention comprise three key components:

[0026] (1) Rhamnose

[0027] The rhamnose portion of the molecule represents the first of the three components of the compounds of the invention. The rhamnose portion of the compound is represented by the following formula (II): wherein the dotted line represents the attachment to the linker portion of the compound.

[0028] Rhamnose (Rha, Rham) is a naturally occurring deoxy sugar and is known chemically as (2R,3R,4R,5R,6S)-6-methyloxane-2,3,4,5-tetrol (also known as isodulcit, o-L-Rhamnose, L- Rhamnose, L-Mannomethylose, o-L-Rha, o-L-Rhamnoside, o-L-Mannomethylose, 6-Deoxy- L-mannose, Rhamnopyranose and Rhamnopyranoside). It can be classified as either a methyl-pentose or a 6-deoxy-hexose. Rhamnose occurs in nature in its L-form as L- rhamnose (6-deoxy-L-mannose). It will be appreciated that minor modifications to the rhamnose moiety of the compound of the present invention while retaining the antibody recruitment properties of rhamnose are within the scope of the invention, for example, it could be envisaged that the D-Rhamnose analogue may be utilised.

[0029] (2) Linker

[0030] The linker portion of the molecule represents the second of the three components of the compounds of the invention. The purpose of the linker is to provide the optimal linking arrangement (distance and orientation) between the antibody recruiting rhamnose moiety (1) and the antimicrobial peptide moiety (3). The linker portion of the compound is represented by the following formula (III): wherein the dotted lines represent the attachment to the rhamnose moiety (left hand side) and the antimicrobial peptide moiety (right hand side).

[0031] It will be appreciated that minor modifications to the linker of the compound of the present invention while retaining the optimal linking arrangement (distance and orientation) between the antibody recruiting rhamnose moiety (1) and the antimicrobial peptide moiety (3) are within the scope of the invention. Examples of related linker moieties may be found in WO 2017 / 060729, WO 2018 / 185494, WO 2018 / 185495, WO 2018 / 051085, WO 2018 / 203087, WO 2020 / 201743, WO 2020 / 074909 and WO 2020 / 074911 , the linkers of which are herein incorporated by reference.

[0032] (3) Antimicrobial Peptide

[0033] The antimicrobial portion of the molecule represents the third of the three components of the compounds of the invention. The purpose of the antimicrobial portion is to bind to a specific pathogen or infective agent.

[0034] The antimicrobial portion of the compound is represented by a polymyxin derivative having the following formula (IV):

[0035] wherein R1and n are as defined herein and wherein the dotted line represents the attachment to the linker portion of the compound.

[0036] It will be appreciated that minor modifications to the antimicrobial portion of the compound of the present invention while retaining the antibacterial activity, antibody recruitment activity and reduction of cytotoxicity, in particular renal cytotoxicity, are within the scope of the invention.

[0037] In one embodiment, the invention provides a compound of formula (I) which comprises a compound of Examples 1-6 or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention provides a compound of formula (I) which comprises a compound of Examples 1-5 or a pharmaceutically acceptable salt thereof. In one embodiment, the invention provides a compound of formula (I) which is the free base or the trifluoroacetate or acetate salt of a compound of Examples 1-6. In a further embodiment, the invention provides a compound of formula (I) which is the free base or the trifluoroacetate or acetate salt of a compound of Examples 1-5. In a further embodiment, the invention provides a compound of formula (I) which is the free base or the acetate salt of a compound of Examples 1-6. In a yet further embodiment, the invention provides a compound of formula (I) which is the free base or the acetate salt of a compound of Examples 1-5. In a still yet further embodiment, the invention provides a compound of formula (I) which is the free base of a compound of Examples 1-6. In a still yet further embodiment, the invention provides a compound of formula (I) which is the free base of a compound of Examples 1-5. In an alternative embodiment, the invention provides a compound of formula (I) which is the acetate salt of a compound of Examples 1-6. In a further alternative embodiment, the invention provides a compound of formula (I) which is the acetate salt of a compound of Examples 1-5. A reference to a compound of formula (I) and sub-groups thereof also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N- oxides, esters, isotopes and protected forms thereof, for example, as discussed below; preferably, the salts or tautomers or isomers or N-oxides or solvates thereof; and more preferably, the salts or tautomers or N-oxides or solvates thereof, even more preferably the salts or tautomers or solvates thereof. Hereinafter, compounds and their ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides, esters, isotopes and protected forms thereof as defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".

[0038] Compounds of formula (I) can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of formula (I) include the salt forms of the compounds.

[0039] The salts of the present invention can be synthesized from the parent compound that contains a basic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the base forms of these compounds with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. Alternatively, such salts may be prepared by utilizing ion exchange resin methodology.

[0040] Acid addition salts (mono- or di-salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di-salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L- lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1 ,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L- pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L- tartaric, thiocyanic, p-toluenesulfonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.

[0041] One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is the trifluoroacetate or acetate salt, more particularly the acetate salt.

[0042] Where the compounds of formula (I) contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (I).

[0043] The compounds of the invention may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed.

[0044] The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

[0045] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Pharmaceutically acceptable solvates of the compound of the invention are within the scope of the invention.

[0046] Compounds of formula (I) containing an amine function may also form N-oxides. A reference herein to a compound of formula (I) that contains an amine function also includes the N- oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.

[0047] N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0048] It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All such prodrugs of compounds of the invention are included within the scope of the invention. Examples of pro-drug functionality suitable for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in “Design of Prodrugs” by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in “Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention.

[0049] Also included within the scope of the compound and various salts of the invention are polymorphs thereof.

[0050] Compounds of formula (I) may exist in a number of different geometric isomeric, and tautomeric forms and references to compounds of formula (I) include all such forms. For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced by formula (I). The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of the invention, i.e. compounds of formula (I), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0051] Examples of isotopes suitable for inclusion in the compounds of the invention comprise isotopes of hydrogen, such as2H (D) and3H (T), carbon, such as11C,13C and14C, fluorine, such as18F, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O.

[0052] Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The compounds of formula (I) can also have valuable diagnostic properties in that they can be used for detecting or identifying the formation of a complex between a labelled compound and other molecules, peptides, proteins, enzymes or receptors. The detecting or identifying methods can use compounds that are labelled with labelling agents such as radioisotopes, enzymes, fluorescent substances, luminous substances (for example, luminol, luminol derivatives, luciferin, aequorin and luciferase), etc. The radioactive isotopes tritium, / .e.3H (T), and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0053] Substitution with heavier isotopes such as deuterium, / .e.2H (D), may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[0054] Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining target occupancy.

[0055] Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.

[0056] Methods for the Preparation of Compounds of Formula (I)

[0057] In this section, as in all other sections of this application unless the context indicates otherwise, references to formula (I) also include all other sub-groups and examples thereof as defined herein. The compounds pertaining to the invention described herein may be prepared in a stepwise synthetic sequence as illustrated in the Schemes below. Compounds of formula (I) can be prepared in accordance with synthetic methods well known to the skilled person. For example, one skilled in the art will appreciate that the chemical steps and choice of protecting groups may be managed in any order to enable synthetic success.

[0058] According to a further aspect of the invention there is provided a process for preparing a compound of formula (I) as hereinbefore defined which comprises:

[0059] (a) reacting a compound of formula (V): with a compound of formula (VI): where R1and n are as defined hereinbefore and Boc represents an amine protecting group which is tertbutoxycarbonyl; followed by

[0060] (b) deprotecting the Boc protecting groups of the product of step (a) to prepare a compound of formula (I).

[0061] Step (a) typically comprises reacting the compound of formula (V) with the compound of formula (VI) in the presence of HATU, NEta and DMF.

[0062] Step (b) typically comprises TFA in DCM. Compounds of formula (V) may be prepared according to the methods described in Intermediate 4 herein.

[0063] Compounds of formula (VI) may be prepared according to the methods described in Intermediates A to E herein.

[0064] It will be appreciated that the intermediates of compounds (V) and (VI) constitute novel compounds and therefore form an additional aspect of the invention. Thus, according to a further aspect of the invention, there is provided a compound of formula (V) or a compound of formula (VI) as defined herein.

[0065] Pharmaceutical Compositions

[0066] While it is possible for the compound of formula (I) to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation).

[0067] Thus, according to a further aspect, the invention provides a pharmaceutical composition, and methods of making a pharmaceutical composition comprising (e.g. admixing) at least one compound of the invention where L represents a cationic anti-microbial peptide, together with one or more pharmaceutically acceptable excipients and optionally other therapeutic or prophylactic agents, as described herein.

[0068] The pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents, fillers or bulking agents, granulating agents, coating agents, release-controlling agents, binding agents, disintegrants, lubricating agents, preservatives, antioxidants, buffering agents, suspending agents, thickening agents, flavouring agents, sweeteners, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions. Examples of excipients for various types of pharmaceutical compositions are set out in more detail below.

[0069] The term “pharmaceutically acceptable” as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity (i.e. generally recognised as safe (GRAS)), irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation. Pharmaceutical compositions containing compounds of the invention can be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[0070] The pharmaceutical compositions can be in any form suitable for parenteral, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery. The delivery can be by bolus injection, short term infusion or longer-term infusion and can be via passive delivery or through the utilisation of a suitable infusion pump or syringe driver.

[0071] Pharmaceutical formulations adapted for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, co-solvents, surface active agents, organic solvent mixtures, cyclodextrin complexation agents, emulsifying agents (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gellable polymers for forming polymeric gels, lyophilisation protectants and combinations of agents for, inter alia, stabilising the active ingredient in a soluble form and rendering the formulation isotonic with the blood of the intended recipient. Pharmaceutical formulations for parenteral administration may also take the form of aqueous and nonaqueous sterile suspensions which may include suspending agents and thickening agents (R. G. Strickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, Vol 21 (2) 2004, p 201-230).

[0072] The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules, vials and prefilled syringes, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.

[0073] The pharmaceutical formulation can be prepared by lyophilising a compound of the invention. Lyophilisation refers to the procedure of freeze-drying a composition. Freeze- drying and lyophilisation are therefore used herein as synonyms.

[0074] Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. Pharmaceutical compositions of the present invention for parenteral injection can also comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.

[0075] Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as sunflower oil, safflower oil, corn oil or olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of thickening or coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0076] The compositions of the present invention may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various anti-bacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include agents to adjust tonicity such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminium monostearate and gelatin.

[0077] In one preferred embodiment of the invention, the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion. For intravenous or subcutaneous administration, the solution can be dosed as is, or can be injected into an infusion bag (containing a pharmaceutically acceptable excipient, such as 0.9% saline or 5% dextrose), before administration.

[0078] In another preferred embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration.

[0079] The compound of the invention may be formulated with a carrier and administered in the form of nanoparticles, the increased surface area of the nanoparticles assisting their absorption. In addition, nanoparticles offer the possibility of direct penetration into the cell. Nanoparticle drug delivery systems are described in “Nanoparticle Technology for Drug Delivery”, edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, published 13thMarch 2006. Nanoparticles for drug delivery are also described in J. Control. Release, 2003, 91 (1-2), 167-172, and in Sinha et a / ., Mol. Cancer Ther. August 1 , (2006) 5, 1909.

[0080] The pharmaceutical compositions typically comprise from approximately 1% (w / w) to approximately 95% (w / w) active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient or combination of excipients. Preferably, the compositions comprise from approximately 20% (w / w) to approximately 90%(w / w) active ingredient and from 80% (w / w) to 10% of a pharmaceutically acceptable excipient or combination of excipients. The pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, tablets or capsules.

[0081] The pharmaceutically acceptable excipient(s) can be selected according to the desired physical form of the formulation and can, for example, be selected from diluents (e.g. solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and cosolvents), disintegrants, buffering agents, lubricants, flow aids, release controlling (e.g. release retarding or delaying polymers or waxes) agents, binders, granulating agents, pigments, plasticizers, antioxidants, preservatives, flavouring agents, taste masking agents, tonicity adjusting agents and coating agents.

[0082] The skilled person will have the expertise to select the appropriate amounts of ingredients for use in the formulations. For example, tablets and capsules typically contain 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and / or 0-99% (w / w) fillers / or bulking agents (depending on drug dose). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, 0-5% (w / w) pigments. Slow release tablets would in addition contain 0-99% (w / w) release-controlling (e.g. delaying) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w / w) polymers, 0-3% (w / w) pigments, and / or 0-2% (w / w) plasticizers.

[0083] Parenteral or subcutaneous formulations typically contain 0-20% (w / w) buffers, 0-50% (w / w) co-solvents, and / or 0-99% (w / w) Water for Injection (WFI) (depending on dose and if freeze dried). Formulations for intramuscular depots may also contain 0-99% (w / w) oils.

[0084] The compounds of the invention can also be formulated as solid dispersions. Solid dispersions are homogeneous extremely fine disperse phases of two or more solids. Solid solutions (molecularly disperse systems), one type of solid dispersion, are well known for use in pharmaceutical technology (see (Chiou and Riegelman, J. Pharm. Sci., 60, 1281- 1300 (1971)) and are useful in increasing dissolution rates and increasing the bioavailability of poorly water-soluble drugs.

[0085] The pharmaceutical formulations may be presented to a patient in “patient packs” containing an entire course of treatment in a single package, usually a blister pack. Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient’s supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician’s instructions. One example of a patient pack includes a prefilled syringe. Such pre-filled syringes already contain the drug substance. The front-end portion of a pre-filled syringe to which a needle is to be attached is sealed with a nozzle cap. Prior to injection, the nozzle cap is removed from the front-end portion and a needle is attached thereto. A gasket is then slid by pushing a plunger rod toward the front-end portion so that the drug is expelled.

[0086] Compositions for nasal delivery include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.

[0087] Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound. Solutions of the active compound may also be used for rectal administration.

[0088] Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.

[0089] The compound of the invention will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain from 1 nanogram to 2 grams of active ingredient, e.g. from 1 nanogram to 2 milligrams of active ingredient. Within these ranges, particular subranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (for example 1 microgram to 10 milligrams, e.g. 0.1 milligrams to 2 milligrams of active ingredient).

[0090] The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.

[0091] Therapeutic Uses

[0092] According to a further aspect of the invention, there is provided a compound of formula (I) as defined herein for use in therapy.

[0093] According to a further aspect of the invention, there is provided a compound of formula (I) as defined herein for use in the treatment of a disease or disorder mediated and / or caused by an infective agent.

[0094] According to a further aspect of the invention, there is provided the use of a compound of formula (I) as defined herein in the manufacture of a medicament for use in the treatment of a disease or disorder mediated and / or caused by an infective agent.

[0095] According to a further aspect of the invention, there is provided a method of treating a disease or disorder mediated and / or caused by an infective agent which comprises administering to an individual in need thereof a compound of formula (I) as defined herein.

[0096] Examples of infective agents include any pathogen such as a bacteria, fungus, parasite or virus. Thus, in one embodiment, the disease or disorder mediated by and / or caused by an infective agent is bacterial infection.

[0097] Examples of such as bacterial infection include infection by the following bacteria: Staphylococcus sp. such as Staphylococcus aureus (including methicillin resistant Staphylococcus aureus (MRSA)), Clostridia sp (e.g. Clostridium difficile, Clostridium tetani and Clostridium botulinum), Enterobacter species, Mycobacterium tuberculosis, Shigella sp. such as Shigelladysenteriae, Campylobacter sp. such as Campylobacter jejuni, Enterococcus sp. such as Enterococcus faecalis, Bacillus anthracis, Yersinia pestis, Bordetella pertussis, Streptococcal species, Salmonella thyphimurim, Salmonella enterica, Chlamydia species, Treponemapallidum, Neisseria gonorrhoeae, Borreliaburgdorferi, Vibrio cholerae, Corynebacterium diphtheriae, Helicobacter pylori, Gram-negative pathogens, such as Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli (and including strains that are resistant to one or more classes of antibiotics, especially multi-drug resistant (MDR) strains). In view of the fact that Polymyxin derivatives (such as those present within the compounds of the invention) are typically selective for Gram-negative bacteria, it will be appreciated that the present invention finds particular utility in treating bacterial infection by Gram-negative pathogens, such as Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli (and including strains that are resistant to one or more classes of antibiotics, especially multi-drug resistant (MDR) strains).

[0098] The compound of the invention is generally administered to a subject in need of such administration, for example a human or animal patient, preferably a human.

[0099] The compound of the invention will typically be administered in amounts that are therapeutically or prophylactically useful and which generally are non-toxic. However, in certain situations (for example in the case of life threatening diseases), the benefits of administering a compound of the invention may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer a compound of the invention in amounts that are associated with a degree of toxicity.

[0100] The compound of the invention may be administered over a prolonged term (i.e. chronic administration) to maintain beneficial therapeutic effects or may be administered for a short period only (i.e. acute administration). Alternatively, they may be administered in a continuous manner or in a manner that provides intermittent dosing (e.g. a pulsatile manner).

[0101] A typical daily dose of the compound of the invention can be in the range from 100 picograms to 100 milligrams per kilogram of body weight, more typically 5 nanograms to 25 milligrams per kilogram of bodyweight, and more usually 10 nanograms to 15 milligrams per kilogram (e.g. 10 nanograms to 10 milligrams, and more typically 1 microgram per kilogram to 20 milligrams per kilogram, for example 1 microgram to 10 milligrams per kilogram) per kilogram of bodyweight although higher or lower doses may be administered where required. The compound of the invention can either be administered on a daily basis or on a repeat basis every 2, or 3, or 4, or 5, or 6, or 7, or 10 or 14, or 21, or 28 days for example.

[0102] Alternatively, the compound of the invention can be administered by infusion, multiple times per day.

[0103] The compound of the invention may be administered in a range of doses, for example 1 to 1500 mg, 2 to 800 mg, or 5 to 500 mg, e.g. 2 to 200 mg or 10 to 1000 mg, particular examples of doses including 10, 20, 50 and 80 mg. The compound of the invention may be administered once or more than once each day. The compound of the invention can be administered continuously (i.e. taken every day without a break for the duration of the treatment regimen). Alternatively, the compound of the invention can be administered intermittently (i.e. taken continuously for a given period such as a week, then discontinued for a period such as a week and then taken continuously for another period such as a week and so on throughout the duration of the treatment regimen). Examples of treatment regimens involving intermittent administration include regimens wherein administration is in cycles of one week on, one week off; or two weeks on, one week off; or three weeks on, one week off; or two weeks on, two weeks off; or four weeks on two weeks off; or one week on three weeks off - for one or more cycles, e.g. 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more cycles.

[0104] In one particular dosing schedule, a patient will be given an infusion of a compound of the invention for periods of one hour daily for up to ten days in particular up to five days for one week, and the treatment repeated at a desired interval such as two to four weeks, in particular every three weeks.

[0105] More particularly, a patient may be given an infusion of a compound of the invention for periods of one hour daily for 5 days and the treatment repeated every three weeks.

[0106] In another particular dosing schedule, a patient is given an infusion over 30 minutes to 1 hour followed by maintenance infusions of variable duration, for example 1 to 5 hours, e.g. 3 hours.

[0107] In a further particular dosing schedule, a patient is given a continuous infusion for a period of 12 hours to 5 days, and in particular a continuous infusion of 24 hours to 72 hours.

[0108] Ultimately, however, the quantity of compound of the invention administered and the type of composition used will be commensurate with the nature of the disease or physiological condition being treated and will be at the discretion of the physician.

[0109] It will be appreciated that the compound of the invention can be used as a single agent or in combination with other therapeutic agents. Combination experiments can be performed, for example, as described in Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regulat 1984;22: 27-55. Where the compound of the invention is administered in combination therapy with one, two, three, four or more other therapeutic agents (preferably one or two, more preferably one), the agents can be administered simultaneously or sequentially. In the latter case, the two or more agents will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. When administered sequentially, they can be administered at closely spaced intervals (for example over a period of 5-10 minutes) or at longer intervals (for example 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s). These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days.

[0110] It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the invention being administered, their route of administration, the particular tumour being treated and the particular host being treated. The optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.

[0111] The weight ratio of the compound of the invention and the one or more other therapeutic agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound of the invention and the other therapeutic agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and / or depending on the evaluation of the physician prescribing the compound of present invention. A particular weight ratio for the compound of the invention and another therapeutic agent may range from 1 / 10 to 10 / 1 , more in particular from 1 / 5 to 5 / 1 , even more in particular from 1 / 3 to 3 / 1 .

[0112] EXAMPLES

[0113] The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples. Compounds are named using an automated naming package (ChemDraw) or are as named by the chemical supplier. The following synthetic procedures are provided for illustration of the methods used; for a given preparation or step the precursor used may not necessarily derive from the individual batch synthesised according to the step in the description given.

[0114] Analytical Methods

[0115] Wherein examples and preparations cite analytical data, the following analytical methods were used unless otherwise specified:

[0116] NMR

[0117] 1H NMR spectra were recorded at room temperature on a JEOL ECZ400S / L1 or JEOL 400YH spectrometer (400 MHz). Data are presented as follows: chemical shift in ppm, integration, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublet) and coupling constant in Hz. Solvents used for samples are specified in the specific experimental procedures for each compound.

[0118] UPLC-MS (Method A)

[0119] Instrument: Waters Acquity UPLC H-Class system; Column: Acquity CSH C18 1.7 pm 2.1 x 50 mm (cat. 186005296 from Waters). Injection volume: 0.5 pL. Eluent A: 5% acetonitrile in water (volume), eluent B: 5% water in acetonitrile (volume), both eluents contained 0.1 % (volume) formic acid. Gradient: 0-0.2 min 0% B, 0.2-3.5 min gradient 0% to 100% B, 3.5 to 4.5 min 100%. Flow 0.4 mL.min1; temperature: 40 °C; photodiode array: 215-350 nm.

[0120] UPLC-MS (Method B)

[0121] UPLC-MS analysis was carried out on a Waters Acquity UPLC system consisting of an Acquity l-Class Sample Manager-FL, Acquity l-Class Binary Solvent Manager and an Acquity UPLC Column Manager. UV detection was afforded using an Acquity UPLC PDA detector (scanning from 210 to 400 nm), whilst mass detection was achieved using an Acquity QDa detector (mass scanning from 100-1250 Da; positive and negative modes simultaneously), and ELS detection was achieved using an Acquity UPLC ELS Detector.

[0122] Acidic 2min: 0.1 % v / v formic acid in 10mM ammonium formate [Eluent A]; 0.1 % v / v formic acid in MeCN [Eluent B]; flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2pL and 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 x 50 mm, 1.7 pm).

[0123] Basic 2 min: As UPLC method B using 0.1 % ammonia in 10 mM ammonium bicarbonate [Eluent A]; 0.1 % ammonia in MeCN [Eluent Bj; flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2pL and 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 x 50 mm, 1 .7 pm).

[0124] UPLC Method C

[0125] UPLC-MS analysis was carried out on a Waters Acquity UPLC system consisting of an Acquity l-Class Sample Manager-FL, Acquity l-Class Binary Solvent Manager and an Acquity UPLC Column Manager. UV detection was afforded using an Acquity UPLC PDA detector (scanning from 210 to 400 nm), whilst mass detection was achieved using an Acquity QDa detector (mass scanning from 100-1250 Da; positive and negative modes simultaneously), and ELS detection was achieved using an Acquity UPLC ELS Detector.

[0126] UPLC conditions: 0.1% ammonia in 10 mM ammonium bicarbonate [Eluent A]; 0.1 % ammonia in MeCN [Eluent Bj; flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2pL and 1.5 minutes equilibration time between samples on a Waters Acquity UPLC BEH C18 column (2.1 x 50 mm, 1.7 pm).

[0127] UPLC Method D (TFA 4 min) UPLC-MS analysis was carried out on a Waters Acquity UPLC system consisting of an Acquity l-Class Sample Manager-FL, Acquity l-Class Binary Solvent Manager and an Acquity UPLC Column Manager. UV detection was afforded using an Acquity UPLC PDA detector (scanning from 210 to 400 nm), whilst mass detection was achieved using an Acquity QDa detector (mass scanning from 100-1250 Da; positive and negative modes simultaneously), and ELS detection was achieved using an Acquity UPLC ELS Detector.

[0128] UPLC conditions: 0.05% v / v trifluoroacetic acid in water [Eluent A]; 0.05% v / v trifluoroacetic acid in MeCN [Eluent B]; flow rate 0.8mL / min; column oven 50°C; sample manager 20°C; injection volume 2pL and 1.5 minutes equilibration time between samples, on a Waters Acquity UPLC CSH C18 column (2.1 x 50 mm, 1.7 pm).

[0129] Abbreviations

[0130] Wherein the following abbreviations have been used, the following meanings apply:

[0131] Boc is tert-butyloxycarbonyl;

[0132] Cbz is benzyloxycarbonyl;

[0133] CV is column volume; d is doublet;

[0134] Dab is 2,4-diaminobutyric acid;

[0135] Dap is 2,3-diaminopropionic acid

[0136] DCM is dichloromethane;

[0137] DMF is dimethylformamide;

[0138] DMSO is dimethylsulfoxide;

[0139] DMSO-D6 is deuterated DMSO;

[0140] ESI is electrospray ionisation technique; eq. is equivalent;

[0141] FMOC is 9-fluorenylmethyloxycarbonyl; g is gram;

[0142] HATU is O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate;

[0143] L is litre;

[0144] Leu is leucine; m is multiplet; mg is milligram;

[0145] M is molar;

[0146] MeCN is acetonitrile;

[0147] MeOH is methanol;

[0148] MeOD is deuteriomethanol;

[0149] MHz is megaHertz; mL is millilitre; mmol is millimole;

[0150] MS is mass spectrometry;

[0151] MTBE is methyl tert-butyl ether;

[0152] NH3is ammonia;

[0153] NMR is nuclear magnetic resonance;

[0154] Phe is phenylalanine;

[0155] Ppm is parts per million;

[0156] Rt is retention time; s is singlet; t is triplet;

[0157] Thr is threonine;

[0158] TFA is trifluoroacetic acid; pL is microlitre;

[0159] UPLC is ultra performance liquid chromatography; and v is volume.

[0160] Preparation of Intermediates

[0161] Intermediate A

[0162] H-Rhe(4-F)-Dab(Boc)-Thr-Dap(Boc)-cvclo-fDab-Dab(Boc)-DPhe-Leu-Dab(Boc)- Dab(Boc)-Thr]

[0163] (Step 1) CBz-Dab(Boc)-Thr-CO2Me

[0164] (2S)-2-(Benzyloxycarbonylamino)-4-(tert-butoxycarbonylamino)butanoic acid (44.9 g, 128 mmol, 1 eq.) was dissolved in A / ,A / -dimethylformamide (100 mL) and dichloromethane (50 mL). Methyl (2S,3R)-2-amino-3-hydroxy-butanoate hydrochloride (26.3 g, 147 mmol, 1.15 eq.) was dissolved in A / , / V-dimethylformamide (50 mL) and dichloromethane (70 mL). Triethylamine (39.9 g, 395 mmol, 55.0 mL, 3.1 eq.) was then added slowly, forming a thick white suspension, which was then diluted with dichloromethane (180 mL). 1- [Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (97.8 g, 257 mmol, 2 eq.) was added in portions over 20 minutes while cooling the reaction in an ice bath. Following addition, the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate (1 L) and aqueous hydrochloric acid (1 M, 500 mL). The layers were separated, and the aqueous layer extracted with ethyl acetate (2 x 1 L) and the combined organic layers were washed with saturated aqueous sodium bicarbonate (4 x 900 mL) and brine (3 x 1 .2 L). The solution was dried over magnesium sulfate, filtered and the solvent removed under vacuum. The resultant yellow gum was left overnight in a vacuum oven at 80°C to yield the title product as a yellow gum (89.3 g).

[0165] 1H NMR (396 MHz, DMSO-d6): 6 [ppm] = 7.97 (d, J = 8.5 Hz, 1 H), 7.49 (d, J = 7.9 Hz, 1 H), 7.37-7.27 (m, 5H), 6.82 (t, J = 5.1 Hz, 1 H), 5.07 (d, J = 4.8 Hz, 1 H), 5.00 (s, 2H), 4.29 (dd, J = 8.5, 3.0 Hz, 1 H), 4.19-4.11 (m, 2H), 3.61 (s, 3H), 3.12-2.93 (m, 2H), 1.79 (td, J = 13.3, 6.9 Hz, 1 H), 1.59 (td, J = 14.2, 6.7 Hz, 1 H), 1.37 (s, 9H), 1.05 (d, J = 6.7 Hz, 3H).

[0166] (Step 2) CBz-Dab(Boc)-Thr-CO2H

[0167] CBz-Dab(Boc)-Thr-CO2Me (Step 1 ) (89.3 g, 114 mmol, 1 eq.) was dissolved in tetrahydrofuran (100 mL) and water (100 mL). Lithium hydroxide, monohydrate (6.30 g, 150 mmol, 1 .3 eq.) was dissolved in water (150 mL) and added slowly to the stirring solution. The reaction was left to stir for 80 mins. The reaction mixture was concentrated under vacuum and tert-butyl methyl ether (500 mL) was added. The mixture was acidified to pH ~6 with aqueous hydrochloric acid (4 M). The phases were separated, and to the aqueous phase tert-butyl methyl ether (500 mL) was added. The aqueous layer was acidified to pH ~3 with aqueous hydrochloric acid (4 M). The phases were again separated and the aqueous was extracted with tert-butyl methyl ether (500 mL). The combined organic layers were washed with brine (300 mL).

[0168] The solvent was removed under vacuum, to furnish the title compound as an amorphous white solid (59.8 g).

[0169] UPLC-MS (Method A): (ESIneg): m / z = [M - H]' 452.2.

[0170] 1H NMR (396 MHz, DMSO-d6): 5 [ppm] = 12.52 (s, 1 H), 7.80 (d, J = 8.5 Hz, 1 H), 7.49 (d, J = 7.9 Hz, 1 H), 7.37-7.27 (m, 5H), 6.82 (t, J = 5.1 Hz, 1 H), 5.01 (s, 2H), 4.21-4.11 (m, 3H), 3.05- 2.94 (m, 2H), 1.80 (td, J = 13.2, 7.3 Hz, 1 H), 1.59 (td, J = 14.4, 6.1 Hz, 1 H), 1.45-1.26 (s, 9H), 1.04 (d, J = 6.1 Hz, 3H).

[0171] (Step 3) Cbz-Dab(Boc)-Thr-Dap(Boc)-OMe

[0172] CBz-Dab(Boc)-Thr-CO2H (Step 2) (51.8 g, 114 mmol, 1 eq.) was dissolved in N,N- dimethylformamide (75 mL) and dichloromethane (200 mL). Methyl (2S)-2-amino-3-(tert- butoxycarbonylamino)propanoate (30.1 g, 140 mmol, 1.2 eq.) was dissolved in dichloromethane (250 mL) and added to the reaction mixture. Triethylamine (34.9 g, 344 mmol, 48.0 mL, 3 eq.) and 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (76.2 g, 200 mmol, 1.8 eq.) were then added to the reaction mixture. The solution was stirred at room temperature for 2 hr. Additional N,N- dimethylformamide (50 mL) was added and the solution left to stir overnight. The solution was concentrated under vacuum and partitioned between tert-butyl methyl ether (1 L) and aqueous hydrochloric acid (1 N, 500 mL). The layers were separated and the aqueous extracted with tert-butyl methyl ether (1 L, 2 x 750 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (3 x 1.2L), brine (3 x 900 mL), and dried over magnesium sulfate. The solids were filtered and washed with ethyl acetate and tertbutyl methyl ether. The solution was concentrated under vacuum to yield the title product as a pale orange-pink solid (93.3 g).

[0173] UPLC-MS (Method A): MS (ESIPos): m / z = [M - Boc + H]+554.3.1H NMR (396 MHz, DMS0-d6): 6 [ppm] = 8.01 (d, J = 7.5 Hz, 1 H), 7.73 (d, J = 8.1 Hz, 1 H), 7.52 (d, J = 7.9 Hz, 1 H), 7.35-7.29 (m, 5H), 6.87 (t, J = 5.7 Hz, 1 H), 6.77 (t, J = 4.7 Hz, 1 H), 5.01 (s, 2H), 4.34-4.29 (m, 1 H), 4.22-4.19 (m, 1 H), 4.11-4.06 (m, 1 H), 3.95-3.92 (m, 1 H), 3.58 (s, 3H), 3.29-3.23 (m, 2H), 3.01-2.94 (m, 3H), 1.80 (dd, J = 13.5, 6.4 Hz, 1 H), 1.60 (q, J = 7.3 Hz, 1 H), 1.36 (d, J = 3.2 Hz, 18H), 1.04 (d, J = 6.2 Hz, 3H).

[0174] (Step 4) Cbz-Dab(Boc)-Thr-Dap(Boc)-OH

[0175] Cbz-Dab(Boc)-Thr-Dap(Boc)-Ome (Step 3) (28.0 g, 42.8 mmol, 1 eq.) was dissolved in tetrahydrofuran (300 mL), and a solution of lithium hydroxide monohydrate (1.89 g, 45.0 mmol, 1 .05 eq.) in water (100 mL) was added. This was stirred for 30 min. The tetrahydrofuran was removed under reduced pressure and the remaining aqueous fraction diluted with water (50 mL) and ethyl acetate (200 mL). The stirring solution was acidified to pH 3 with aqueous hydrochloric acid (2 M). The organic phase separated, and the aqueous phase extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give the title product as an off white solid (30.0 g).

[0176] UPLC-MS (Method A): MS (ESIneg): m / z = [M - H]’ 638.3.

[0177] 1H NMR (396 MHz, MeOD-d4): 5 [ppm] = 7.35-7.25 (m, 5H), 5.08 (s, 2H), 4.48-4.45 (m, 1 H), 4.31 (d, J = 3.6 Hz, 1 H), 4.21-4.17 (m, 2H), 3.54 (dd, J = 14.2, 3.9 Hz, 1 H), 3.42-3.36 (m, 1 H), 3.19-3.08 (m, 2H), 1.99-1.95 (m, 1 H), 1.78-1.73 (m, 1 H), 1.41-1.37 (m, 18H), 1.19-1.16 (m, 3H).

[0178] (Step 5) Cbz-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)- Dab(Boc)-Thr]

[0179] CBz-Dab(Boc)-Thr-Dap(Boc)-OH (Step 4) (1.10 eq, 12.72 g, 19.9 mmol) and (BOC)3 Polymyxin B heptapeptide (prepared according to Li et al, Synthesis 2015, 47, 2088-2092) (1.10 eq, 12.72 g, 19.9 mmol) (1.00 eq, 19.20 g, 18.1 mmol) were dissolved in DCM (1.28L) and DMF (320mL), N,N-Diisopropylethylamine (4.00 eq, 13 mL, 72.3 mmol) was then added and the solution allowed to stir for 10 minutes before adding O-(7- Azabenzotriazol-l-ylJ-N.N.N'.N'-tetramethyluronium hexafluorophosphate (HATU) (1.20 eq, 8.25 g, 21.7 mmol) . The reaction was allowed to stir overnight. The reaction was concentrated to a thick oil, water (500 mL) was added, and the resulting mixture allowed to stir for 2 hours, water (500 mL) was added and the solid allowed to digest overnight. The mixture was filtered and the white solid dried to constant mass product 1 (27.50 g, 16.3 mmol, 90 % yield).

[0180] UPLC-MS (Method B): m / z 843.0 [M+2H]2+

[0181] 1HNMR (400 MHz, DMSO-D6) 6 8.68 - 8.56 (m, 2H), 8.57 - 8.33 (m, 2H), 8.17 (d, J = 8.7 Hz, 2H), 8.04 (s, 5H), 7.99 - 7.79 (m, 4H), 7.76 (d, J = 8.5 Hz, 1 H), 7.62 - 7.37 (m, 3H), 7.37 - 7.23 (m, 11 H), 7.21 (d, J = 4.4 Hz, 7H), 7.14 (dt, J = 8.6, 4.1 Hz, 1 H), 7.08 (s, 1 H), 6.94 (s, 1 H), 6.88 - 6.70 (m, 1 H), 6.70 - 6.51 (m, 2H), 5.13 - 4.75 (m, 7H), 4.48 - 4.00 (m, 4H), 4.00 - 3.74 (m, 4H), 2.85 (s, 38H), 2.67 (d, J = 17.0 Hz, 4H), 1.73 (d, J = 15.4 Hz, 15H), 1.53 (dd, J = 34.0, 7.2 Hz, 6H), 1.43 - 1.28 (m, 114H), 1 .28 - 1.11 (m, 5H), 0.99 (td, J = 6.9, 3.8 Hz, 17H), 0.87 - 0.75 (m, 3H), 0.64 (dd, J = 16.1, 6.5 Hz, 12H).

[0182] (Step 6) H-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)- Dab(Boc)-Thr]

[0183] Palladium on activated carbon (10%) (1.98 eq, 2.30 g, 21.6 mmol) was slurried with water (50mL) into a solution of Cbz-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu- Dab(Boc)-Dab(Boc)-Thr] (Step 5) (1.00 eq, 23.00 g, 10.9 mmol) in Ethanol (875mL), and the resulting mixture was stirred vigorously. The atmosphere was exchanged for hydrogen gas by backfilling from a balloon.

[0184] After 23 h, the reaction mixture was filtered through celite eluting with EtOH (ca. 3 L). The filtrate was concentrated under reduced pressure to afford an off-white foam (ca. 23 g). The foam was dissolved in DMF (70 mL) and precipitated with H2O (250 mL), stirring for 4 h. The water was filtered and any collected solid returned to the source flask using MeOH. The solution was concentrated to a brownish glassy solid (20 g). The solid was dissolved in chloroform (250 mL) and allowed to stir for 30 min. Heptane (500 mL) was added slowly over 15 min, stirring for ca. 20 min and allowed to settle for 1 h before decanting the liquid away to afford the title compound, (18.50 g) as a white solid.

[0185] UPLC-MS (Method B) m / z 773.9 [M-2H]2’, 775.8 [M+2H]2+.

[0186] (Step 7) Cbz-Phe(4-F)-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu-

[0187] Dab(Boc)-Dab(

[0188] H-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)-Dab(Boc)-Thr] (Step

[0189] 6) (1.00 eq, 18.70 g, 11.8 mmol) and (2S)-2-(benzyloxycarbonylamino)-3-(4- fluorophenyl)propanoic acid (1.20 eq, 4.50 g, 14.2 mmol) were dissolved in DMF (650mL), N,N-Diisopropylethylamine (6.00 eq, 12 mL, 70.9 mmol) was added followed by HATU (1.20 eq, 5.40 g, 14.2 mmol) and the yellow solution stirred overnight at room temperature. The reaction mixture was concentrated to 150 mL then water (200 mL) was added dropwise while stirring. The formed orange solid was then collected via suction filtration. This solid was then triturated with DCM (100 mL), then the isolated solid was triturated with a mixture of MeOH / MeCN 1 :1 (200 mL) and collected by suction filtration and dried to give the title product (18.10 g) as a creamy solid.

[0190] UPLC-MS (Method B, basic) m / z 923.5 [M-2H]2’

[0191] 1H NMR (400 MHz, DMSO-D6) 5 8.70 - 8.58 (m, 1 H), 8.54 - 8.42 (m, 1 H), 8.29 - 8.15 (m, 2H), 8.11 - 8.02 (m, 1 H), 8.02 - 7.96 (m, 1 H), 7.96 - 7.85 (m, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.37 - 7.14 (m, 15H), 7.07 (t, J = 8.8 Hz, 3H), 7.02 - 6.91 (m, 1 H), 6.89 - 6.74 (m, 2H), 6.71 - 6.52 (m, 3H), 5.08 (s, 1 H), 4.98 - 4.86 (m, 3H), 4.50 - 4.13 (m, 10H), 4.03 - 3.93 (m, 1 H), 3.90 (d, J = 8.2 Hz, 1 H), 3.88 - 3.80 (m, 1 H), 3.23 - 3.18 (m, 1 H), 3.14 - 2.93 (m, 11 H), 2.84 - 2.74 (m, 2H), 2.71 - 2.62 (m, 1 H), 1.99 - 1 .69 (m, 8H), 1.69 - 1 .58 (m, 3H), 1.58 - 1.46 (m, 3H), 1.44 - 1.31 (m, 58H), 1.30 - 1.15 (m, 2H), 1.03 (dd, J = 6.4, 2.5 Hz, 7H), 0.96 - 0.80 (m, 1 H), 0.70 (d, J = 6.6 Hz, 3H), 0.66 (d, J = 6.3 Hz, 3H).

[0192] (Step 8) H-Phe(4-F)-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu-

[0193] Dab(Boc)-Dab(Boc)-Thr] (Intermediate A)

[0194] To a solution of Cbz-Phe(4-F)-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu- Dab(Boc)-Dab(Boc)-Thr] (Step 7) (1.00 eq, 44.70 g, 23.4 mmol) in ethanol (1000mL) was added a suspension of palladium on activated carbon (10%) (2.01 eq, 5.00 g, 47.0 mmol) in water (100mL). The atmosphere was exchanged for nitrogen gas then from nitrogen to hydrogen by backfilling from a balloon and the reaction mixture was allowed to stir under an atmosphere of hydrogen at room temperature overnight. The reaction mixture was filtered through celite eluting with: EtOH (ca. 1000 mL) The resulting solution was concentrated under reduced pressure to afford 36.7g of crude as a white solid. The obtained crude was split in two and purified by column chromatography on silica gel (2 x 220 g cartridge, dry loading on silica, using 1g of silica / 1 g of material) using a gradient of MeOH (2 to 20%, v / v) in DCM. The fractions were monitored by TLC (10% MeOH in DCM) Rf = 0.45, using ninhydride as a stain and then combined. Solvent was evaporated under reduced pressure to provide the desired product 1 (18.70 g, 11.8 mmol, 50% yield) as a white solid.

[0195] UPLC-MS (Method C) m / z 776.0 [M+2H]2+

[0196] 1H NMR (400 MHz, DMSO-D6) 6 8.67 - 8.39 (m, 1 H), 8.27 - 7.84 (m, 4H), 7.29 - 7.21 (m, 5H), 7.21 - 7.15 (m, 1 H), 7.15 - 6.90 (m, 1 H), 6.90 - 6.75 (m, 2H), 6.72 - 6.54 (m, 3H), 5.07 (d, J = 4.7 Hz, 1 H), 4.90 (d, J = 5.5 Hz, 1 H), 4.49 - 4.05 (m, 8H), 4.04 - 3.95 (m, 1 H), 3.95 - 3.81 (m, 2H), 3.17 - 2.94 (m, 10H), 2.94 - 2.86 (m, 2H), 2.85 - 2.71 (m, 2H), 1.97 - 1.60 (m, 10H), 1.59 - 1.47 (m, 3H), 1.46 - 1.33 (m, 60H), 1.32 - 1.20 (m, 1 H), 1.07 - 1.00 (m, 8H), 0.98 - 0.79 (m, 1 H), 0.71 (d, J = 6.7 Hz, 4H), 0.67 (d, J = 6.3 Hz, 3H).

[0197] Intermediate B

[0198] H-Phe(3-F)-Dab(Boc)-Thr-Dap(Boc)-cvclo-(Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)-

[0199] Intermediate B was prepared from H-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe- Leu-Dab(Boc)-Dab(Boc)-Thr] (Intermediate A, Step 6) and (2S)-2- (benzyloxycarbonylamino)-3-(3-fluorophenyl)propanoic acid, followed by Cbz deprotection under the conditions described for Intermediate A, steps 7 and 8, to afford the title compound as a white solid.

[0200] UPLC-MS (Method C) m / z 856.5 [M-2H]2’, 858.4 [M+2H]2+.

[0201] Intermediate C H-Phe(3,5-diF)-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)-

[0202] Dab(Boc)-Thr]

[0203] Intermediate C was prepared from H-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe- Leu-Dab(Boc)-Dab(Boc)-Thr] (Intermediate A, Step 6) and (2S)-2- (benzyloxycarbonylamino)-3-(3,5-difluorophenyl)propanoic acid, followed by Cbz deprotection under the conditions described for Intermediate A, steps 7 and 8, to afford the title compound as a white solid. UPLC-MS (Method C) m / z 865.4 [M-2H]2’, 867.4 [M+2H]2+.

[0204] Intermediate D

[0205] Intermediate D was prepared from H-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe- Leu-Dab(Boc)-Dab(Boc)-Thr] (Intermediate A, Step 6) and (2S)-2- (benzyloxycarbonylamino)-3-(2,4-difluorophenyl)propanoic acid followed by Cbz deprotection under the conditions described for Intermediate A, steps 7 and 8, to afford the title compound as a white solid. UPLC-MS (Method C) m / z 867.4 [M+2H]2+.

[0206] Intermediate E

[0207] H-Phe(2,5-diF)-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)- Dab(Boc)-Thr]

[0208] Intermediate 5 was prepared from H-Dab(Boc)-Thr-Dap(Boc)- cyclo-[Dab-Dab(Boc)-DPhe-

[0209] Leu-Dab(Boc)-Dab(Boc)-Thr] and (2S)-2-(benzyloxycarbonylamino)-3-(2,5- difluorophenyl)propanoic acid followed by Cbz deprotection under the conditions described for Intermediate A, steps 7 and 8, to afford the Title compound as a white solid.

[0210] UPLC-MS (Method C) m / z 865.4 [M-2H]2’, 867.4 [M+2H]2+.

[0211] Intermediate 1

[0212] Benzyl 3-r2-oxo-2-r2-f2-f(2R,3R,4R,5R,6S)-3,4,5-trihvdroxy-6-methyl-tetrahvdro-pyran-

[0213] 2-ylloxyethoxy]ethylaminolethoxyl-5-phenyl-benzoate

[0214] To a solution of (2R,3R,4R,5R,6S)-2-[2-(2-aminoethoxy)ethoxy]-6-methyl-tetrahydropyran- 3 ,4,5-triol (WO 2020 / 074909, 1.40 eq, 5.93 g, 23.6 mmol) and 2-(3-benzyloxycarbonyl-5- phenyl-phenoxy)acetic acid (WO 2020 / 201743, 1.00 eq, 6.50 g, 16.9 mmol) in DMF (360mL) was added N,N-Diisopropylethylamine (5.00 eq, 15 ml_, 84.3 mmol) followed by (HATU) (1 .70 eq, 10.90 g, 28.7 mmol) and the reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated and the obtained crude was combined to the crude obtained from previous experiment on 5.58 mmol scale (total of 22.48 mmol scale). The material was split in two batches, then each then purified by reverse phase chromatography (Teledyne, 375 g, C18, loading with DMF), using a gradient of acetonitrile (0.1% NH3) in water (0.1% NH3) from 5 to 30% over 3CV then from 30 to 70% over 10 CV to afford the title compound (11.10 g, 18.0 mmol, 80% yield) as a brownish gum.

[0215] UPLC-MS (Method B, basic) m / z= 596.5 [M+H]1H NMR (400 MHz, DMSO-D6) 58.25 (t, J = 5.8 Hz, 1 H), 7.83 (t, J = 1.5 Hz, 1 H), 7.73 - 7.68 (m, 2H), 7.56 - 7.45 (m, 6H), 7.45 - 7.33 (m, 4H), 5.39 (s, 2H), 4.73 (t, J = 4.9 Hz, 2H), 4.67 (s, 2H), 4.58 - 4.50 (m, 2H), 3.64 - 3.24 (m, 13H), 3.17 (td, J = 9.4, 5.4 Hz, 1 H), 1.12 (d, J = 6.2 Hz, 3H).

[0216] Intermediate 2

[0217] 3-r2-Oxo-2-r2-r2-r(2R,3R,4R,5R,6S)-3,4,5-trihvdroxy-6-methyl-tetrahvdropyran-2- ylloxyethoxylethylaminolethoxyl-5-phenyl-benzoic acid

[0218] To a solution of benzyl 3-[2-oxo-2-[2-[2-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl- tetrahydropyran-2-yl]oxyethoxy]ethylamino]ethoxy]-5-phenyl-benzoate (Intermediate 1 , 1.00 eq, 11.10 g, 18.6 mmol) in ethanol (200mL) was added a suspension of palladium on activated carbon (10%) (0.960 eq, 1.90 g, 17.9 mmol) in water (30mL) . The atmosphere was exchanged for hydrogen gas by backfilling from a balloon and the reaction mixture was allowed to stir under an atmosphere of hydrogen at room temperature overnight. The reaction mixture was filtered through celite eluting with: EtOH (ca. 500 mL) The resulting solution was concentrated under reduced pressure to afford the title compound (8.82 g,17.4 mmol, 94 % yield) as a white solid.

[0219] UPLC-MS (Method B, acidic) m / z= 506.2 [M+H]+

[0220] 1H NMR (400 MHz, DMSO-D6) 5 8.29 (s, 1 H), 7.92 (t, J = 1.5 Hz, 1 H), 7.69 - 7.62 (m, 2H), 7.60 (dd, J = 2.6, 1.3 Hz, 1 H), 7.52 - 7.44 (m, 3H), 7.43 - 7.35 (m, 1 H), 4.68 (d, J = 7.7 Hz, 3H), 3.80 (dd, J = 3.4, 1.7 Hz, 1 H), 3.76 - 3.68 (m, 1 H), 3.67 - 3.44 (m, 9H), 3.35 (t, J = 9.5 Hz, 1 H), 1.24 (d, J = 6.2 Hz, 3H).

[0221] Intermediate 3

[0222] Methyl 3-r2-r2-r2-r2-r2-r2-r2-r2-rr3-r2-oxo-2-r2-r2-r(2R,3R,4R,5R,6S)-3,4,5-trihvdroxy-6- methyl-tetrahydropyran-2-ylloxyethoxylethylamino]ethoxyl-5-phenyl- benzoyllaminolethoxylethoxylethoxylethoxylethoxylethoxylethoxylethoxy] propanoate

[0223] To a solution of methyl 3-[2-[2-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]- ethoxy]ethoxy]ethoxy]ethoxy]propanoate hydrochloride (WO 2020 / 201743, 1.40 eq, 6.00 g, 12.2 mmol) in a mixture of DMF (155mL) and DMSO (13mL) was added 3-[2-oxo-2-[2-[2- [(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl-tetrahydropyran-2- yl]oxyethoxy]ethylamino]ethoxy]-5-phenyl-benzoic acid (Intermediate 2, 1.00 eq, 4.40 g, 8.70 mmol) . Then N,N-Diisopropylethylamine (4.00 eq, 6.1 mL, 34.8 mmol) was added followed by HATU (2.00 eq, 6619 mg, 17.4 mmol) and the reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated, and the obtained crude was purified by reverse phase chromatography (Teledyne, 370 g, C18, loading with DMF / DMSO), using a gradient of acetonitrile (0.1 % NH3) in water (0.1 % NH3) from 5 to 25% over 3CV then from 25 to 60% over 10 CV to afford the title compound (6.84 g,6.49 mmol, 75 % yield) as a brown oil

[0224] UPLC-MS (Method B, basic): m / z 960.6 [M+NH4]+

[0225] 1H NMR (400 MHz, DMSO-D6) 5 8.68 (t, J = 5.6 Hz, 1 H), 8.19 (t, J = 5.8 Hz, 1 H), 7.79 - 7.70 (m, 3H), 7.53 - 7.46 (m, 2H), 7.46 - 7.38 (m, 3H), 4.73 (t, J = 4.7 Hz, 2H), 4.63 (s, 2H), 4.58 - 4.52 (m, 2H), 3.67 - 3.36 (m, 50H), 3.32 - 3.26 (m, 2H), 3.17 (td, J = 9.3, 5.5 Hz, 1 H), 2.53 (t, J = 6.2 Hz, 2H), 1.12 (d, J = 6.2 Hz, 3H).

[0226] Intermediate 4

[0227] 3-r2-r2-r2-r2-r2-r2-r2-r2-rr3-r2-Oxo-2-r2-r2-r(2R,3R,4R,5R,6S)-3,4,5-trihvdroxy-6-methyl- tetrahvdropyran-2-ylloxyethoxylethylamino]ethoxyl-5-phenyl- benzoyllaminolethoxylethoxylethoxylethoxylethoxylethoxylethoxylethoxylpropionic acid)

[0228] Methyl 3-[2-[2-[2-[2-[2-[2-[2-[2-[[3-[2-oxo-2-[2-[2-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6- methyl-tetrahydropyran-2-yl]oxyethoxy]ethylamino]ethoxy]-5-phenyl- benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoate (Intermediate 3, 1.00 eq, 6.84 g, 6.67 mmol) was suspended in water (250mL) then triethylamine (60.0 eq, 56 mL, 400 mmol) was added and the resulting mixture was stirred vigorously for 2 hours. The reaction mixture was concentrated under reduced pressure then MeCN was added, and the solvent was removed to afford the desired product (7.24 g,) as a brownish oil.

[0229] UPLC-MS (Method B min, acidic): m / z = 927.5 [M-H]-

[0230] 1H NMR (400 MHz, DMSO-D6) 6 8.69 (t, J = 5.6 Hz, 1 H), 8.21 (t, J = 5.8 Hz, 1 H), 7.77 (t, J = 1.5 Hz, 1 H), 7.76 - 7.71 (m, 2H), 7.53 - 7.47 (m, 2H), 7.45 (dd, J = 2.5, 1.4 Hz, 1 H), 7.43 - 7.38 (m, 2H), 4.63 (s, 2H), 4.55 (d, J = 1.6 Hz, 1 H), 3.65 - 3.35 (m, 48H), 3.31 (q, J = 5.9 Hz, 3H), 3.17 (t, J = 9.4 Hz, 1 H), 2.40 (t, J = 6.4 Hz, 2H), 1.12 (d, J = 6.2 Hz, 3H).

[0231] Preparation of Examples

[0232] Example 1 f3-r2-r2-r2-r2-r2-r2-r2-r2-rr3-r2-Oxo-2-r2-r2-r(2R,3R,4R,5R,6S)-3,4,5-trihvdroxy-6-methyl- tetrahvdropyran-2-ylloxyethoxylethylaminolethoxyl-5-phenyl- benzoyllaminolethoxylethoxylethoxylethoxylethoxylethoxylethoxylethoxylpropionyl} -Phe(4-F)-Dab-Thr-Dap-cyclo-[Dab-Dab-DPhe-l_eu-Dab-Dab-Thr]

[0233] (Step 1) Preparation of: {3-[2-[2-[2-[2-[2-[2-[2-[2-[[3-[2-Oxo-2-[2-[2- [(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl-tetrahydropyran-2- yl]oxyethoxy]ethylamino]ethoxy]-5-phenyl- benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionyl} -Phe(4-F)-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)-Dab(Boc)- Thr]

[0234] To a clear solution of 3-[2-[2-[2-[2-[2-[2-[2-[2-[[3-[2-oxo-2-[2-[2-[(2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyl-tetrahydropyran-2-yl]oxyethoxy]ethylamino]ethoxy]-5-phenyl- benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid) (Intermediate 4, 1.05 eq, 2.07 g, 2.00 mmol) and Intermediate A (1.00 eq, 3.85 g, 1.91 mmol) in DMF (105mL) was added triethylamine (5.00 eq, 1.3 mL, 9.54 mmol) followed by HATU (1.20 eq, 871 mg, 2.29 mmol) and the reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated and the obtained crude was purified by reverse phase chromatography (Teledyne, 375 g, C18, loading with DMF), using a gradient of acetonitrile (0.1 % NH3) (5 to 40%, v / v) over 2 CV then (40 to 75%, v / v) over 10 CV in water (0.1% NH3) to afford the title product (4.00 g, 1 .52 mmol, 79.83% yield) as a white solid. m / z (method B, basic) m / z 874.3 [M-3H]3'

[0235] (Step 2) Preparation of Example 1

[0236] 2,2,2-Trifluoroacetic acid (280 eq, 21 mL, 277 mmol) was added to a suspension of the product from Step 1 (1 .00 eq, 2.60 g, 0.990 mmol) in DCM (35mL) and water (0.3mL) at 0°C and the reaction was allowed to stir at room temperature for 50 min. Then an additional portion of 2,2,2-trifluoroacetic acid (70.0 eq, 5.3 mL, 69.3 mmol) was added at 0°C and the reaction was allowed to stir again at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography over C18 (375 g cartridge, using DMF to load) eluting with a gradient of MeCN (0.1 % TFA) (5% to 45%; v / v, 10 CV) in water (0.1 % TFA). Fractions were combined and concentrated under reduced pressure. The residue was then freeze-dried to afford the desired product (2.46 g, 0.914 mmol, 92 % yield) as a white solid.

[0237] UPLC-MS (Method C, acidic) m / z 1063.2 [M+2H]2+, 709.3 [M+3H]3+

[0238] Examples 2-5 were prepared according to the method of Example 1 , with data shown in Table 1 :

[0239] CEN-C-P3731 PCT

[0240] Table 1

[0241] CEN-C-P3731 PCT

[0242] CEN-C-P3731 PCT

[0243] Example 6

[0244] {3-r2-r2-r2-r2-r2-r2-r2-r2-rr3-r2-Oxo-2-r2-r2-r(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl- tetrahvdropyran-2-ylloxyethoxylethylamino]ethoxyl-5-phenyl- benzoyllaminolethoxylethoxylethoxylethoxylethoxylethoxylethoxylethoxylpropionyl} -Phe(2-CI)-Dab-Thr-Dap-cvclo-rDab-Dab-DPhe-Leu-Dab-Dab-Thrl.

[0245] (Step 1) FMOC-Phe(2-CI)-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe- Leu-Dab(Boc)-Dab(Boc)-Thr]

[0246] H-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)-Dab(Boc)-Thr] (prepared according to Intermediate A, step 6, 150 mg, 0.097 mmol) and (2S)-3-(2- chlorophenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino) propanoic acid (49 mg, 0.12 mmol) were dissolved in DMF (3.4mL) and dichloromethane (4.3 mL). N,N- Diisopropylethylamine (6.00 eq, 0.1 mL) was added followed by HATU (1 .20 eq, 44 mg, 0.12 mmol) and the yellow solution stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and azeotroped with toluene to result in a yellow solid. The crude product was purified by reverse-phase column chromatography over C18 (23g cartridge) eluting with a gradient of acetonitrile (0.1% NH3) in water (0.1% NH3) from 5% to 60% over 2 CV followed 60% to 100% over 10 CV, to afford the desired product as a white solid (121 mg, 64%).

[0247] UPLC-MS (Method B, basic) m / z 877.5 [M+2H-2Boc]2+, 927.5 [M+2H-Boc]2+

[0248] (Step 2) H-Phe(2-CI)-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu- Dab(Boc)-Dab(Boc)-Thr]

[0249] FMOC-Phe(2-CI)-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)- Dab(Boc)-Thr] (121 mg, 0.062 mmol) was dissolved in DMF (3.5 mL) and piperidine (1.2 mL) was stirred vigorously for 3h. The mixture was concentrated under reduced pressure and the crude product purified by reverse-phase column chromatography over C18 eluting with a gradient of acetonitrile (0.1% NH3) 5%-50% v / v in water (0.1% NH3) over 2 CV followed by 50% - 100% v / v acetonitrile (0.1 % NH3) in water (0.1% NH3) over 15 CV to afford the desired product as a white solid (45 mg, 42%).

[0250] UPLC-MS (Method B, basic) m / z 864.6 [M-2H]2’

[0251] (Step 3) {3-[2-[2-[2-[2-[2-[2-[2-[2-[[3-[2-Oxo-2-[2-[2-[(2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyl-tetrahydropyran-2-yl]oxyethoxy]ethylamino]ethoxy]-5-phenyl- benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionyl} -Phe(2-CI)-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab-Dab(Boc)-DPhe-Leu-Dab(Boc)- Dab(Boc)-Thr]

[0252] To a clear solution of 3-[2-[2-[2-[2-[2-[2-[2-[2-[[3-[2-oxo-2-[2-[2-[(2R,3R,4R,5R,6S)-3,4,5- trihydroxy-6-methyl-tetrahydropyran-2-yl]oxyethoxy]ethylamino]ethoxy]-5-phenyl- benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid) (Intermediate 4, 24 mg, 0.026 mmol) in DMF (5 mL) was added triethylamine (0.018 mL, 0.13 mmol) followed by a solution of H-Phe(2-CI)-Dab(Boc)-Thr-Dap(Boc)-cyclo-[Dab- Dab(Boc)-DPhe-Leu-Dab(Boc)-Dab(Boc)-Thr] (45 mg, 0.026 mmol) in DMF (5mL). HATU (12 mg, 0.031 mmol) was added and the reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated and the obtained crude material was purified by reverse phase chromatography (12 g, C18), using a gradient of acetonitrile (0.1 % NH3) 0%-40% v / v in water (0.1 % NH3) over 2 CV followed by 40% - 100% v / v acetonitrile (0.1% NH3) in water (0.1 % NH3) over 10 CV to afford the desired product (26 mg, 38% yield) as a white solid.

[0253] UPLC-MS (Method B, basic) m / z 879.7 [M-3H]3’

[0254] (Step 4) Preparation of Example 6

[0255] 2,2,2-Trifluoroacetic acid (1 .7 mL) was added dropwise to a suspension of the product from Step 3 (26 mg, 0.0098 mmol) in DCM (4 mL) and the reaction was allowed to stir at room temperature for 15 min. The reaction mixture was quenched with the addition of MTBE (10ml), and the reaction mixture was concentrated under reduced pressure. The crude material was purified by preparative HPLC using water / acetonitrile gradient (containing 0.1 % TFA) . Product-containing fractions were freeze-dried to afford the desired product (17 mg, 64% yield) as a white solid.

[0256] UPLC-MS (Method D, acidic) m / z 1071.9 [M+2H]2+, 714.8 [M+3H]3+; Rt 1.15 min.

[0257] Reference 1

[0258] Prepared according to Example 3 of WO 2018 / 203087.

[0259] BIOLOGICAL ASSAYS

[0260] 1. IqG Recruitment Assay

[0261] Table 2 shows the recruitment of IgG anti-rhamnose antibodies to the surface of E.coli. Polymyxin B (PMB) which does not contain an antibody-recognition element, is used as a negative control.

[0262] Plate based antibody recruitment assay using an anfi-Rhamnosa antibody. Fluorescence based assay was used to demonstrate binding of Example compounds to Escherichia co / / bacteria and binding to monoclonal hlgG1 anti-Rhamnose antibodies. A fluorescently labelled anti human IgG was used to detect the anti~Rhamnose antibody binding.

[0263] Method

[0264] The assays were carried out in biack 96 well flat-bottomed plates (ThermoSclentific). Escherichia ccii (ATCC 700973) was grown in RPMI 1640 (Invitrogen - 11835030), supplemented with 10% LB broth (Miller) to mid exponential phase. Subsequently, the bacteria were washed once with Hank's Balanced Salt Solution with calcium and magnesium (HBSS+ / +) and then resuspended in HBSS+ / + at a bacterial density of 8x107colony farming units (CFU) / mL. 1 .8x107CFU were then incubated for 60 minutes in the presence of human anti-Rhamnese monoclonal antibody (Genscript, SJ9941 IB230-12) at a final concentration of 100 pg / mL with Example 1-6 compounds (see Table 2) or Polymyxin B at 0.3 to 20 pM end concentration or a vehicle only control, at 25*C and shaking at 300 rpm. The bacteria were then centrifuged, and the supernatant removed prior to addition of 1QQ pL of the FITC labelled secondary antibody (Goat pAb anti-human IgG Fc - FITC (Abeam, Ab97224)). The samples were incubated for 30 minutes at 25°C with shaking at 300 rpm. The bacteria were then washed with 100 pL HBSS + / + and resuspended in 200 pL HBSS + / +. 50pL was transferred to a black 96-well flat-bottom microplate (ThermoSclentific, 175325) containing 15DpL HBSS + / + to create a 1 :4 dilution, and the fluorescence measured using a CLARIOstar plate reader (BMG Labtoch). Relative fluorescence values for all samples were recorded and data was analysed using GraphPad Prism. All samples were run in technical triplicates and biological experiments repeated as indicated in the table.

[0265] Table 2: IgG recruitment to the surface of E.coli ATCC 700973

[0266] 2. In vitro Renal Cell Toxicity Assay

[0267] The renal cell toxicity of the compounds was assessed in an in vitro assay using human renal proximal tubule epithelial cells (RPTECs).

[0268] Human RPTEC cells were seeded into black clear bottom collagen coated 96-well plates in appropriate media. Cells were incubated at 37°C, 5 % CO2 for 72 hr when media was then changed to serum free media. Cells were incubated for a further 24 hr and then compound treated. Test compound was diluted in vehicle and serial dilutions are made to 0.1 % vehicle in RPTEC media. Test compounds at 8 concentrations in triplicate were then incubated for 24 hr. Sertraline and L-buthionine-sulfoximine were simultaneously run as positive controls. At the end of the incubation period, the cells were loaded with the relevant dye, and the plate then scanned using an automated confocal fluorescent cellular imager, ArrayScan® XTI (Thermo Scientific Cellomic s) at 37 °C, 5 % CO2, following which cellular ATP content was measured using CellTiter-Glo® (Promega). A dose-response curve was fitted, and concentration at which 50% maximum effect is observed was determined and reported as the AC50.

[0269] The results of this assay are shown in Table 3: Table 3: In vitro Renal Cell Toxicity Assay

[0270] The results from this assay demonstrate that the compounds of Examples 1 to 6 of the invention demonstrated significantly reduced cytotoxicity compared with the Reference Example 1 (i.e. Example 3 from WO 2018 / 203087).

[0271] 3. Antimicrobial Susceptibility Testing

[0272] The in vitro antimicrobial activity (MIC) of Reference Example 1 and Examples 1-6 was determined against Escherichia coli ATCC25922, K. pneumoniae NCTC 13438, K. pneumoniae AR039, Pseudomonas aeruginosa ATCC27853, Pseudomonas aeruginosa AR064, Acinetobacter baumanii AR296 and Acinetobacter baumanii AR307 by broth microdilution using cation adjusted Mueller-Hinton broth (caMHB; Becton-Dickinson 212322) according to CLSI guidelines M07-A11 . (CLSI M07-A11 (2018). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, 11th Edition. Clinical and Laboratory Standards Institute, Wayne, PA 19087, USA).

[0273] Bacterial inocula were prepared by suspending several well-isolated single colonies in sterile phosphate-buffered saline (PBS) to a density equivalent to a 0.5 McFarland standard. These suspensions were then diluted in caMHB to provide a final bacterial density of 2 to 8 * 105CFU / mL when added to assay plates containing diluted test articles. Assay plates were incubated in air at 37°C for 18 hours, and the MIC determined as the lowest concentration of test articles that inhibited visible bacterial growth.

[0274] The results of this assay are shown in Table 4: Table 4: Antimicrobial Susceptibility Testing Minimum Inhibitory Concentration

[0275] (pg / ml) of Examples 1-5 and Reference Example 1

[0276] The results from this assay demonstrate that the compounds of Examples 1 to 6 of the invention demonstrated equivalent antibacterial activity against the tested strains compared with the Reference Example 1 (i.e. Example 3 from WO 2018 / 203087).

[0277] 4. In vivo efficacy against E. coli thigh infection in mice

[0278] The in vivo efficacy of the compound of Example 1 was evaluated in a mouse thigh infection model of Escherichia coli ATCC25922 in the presence and absence of an anti-rhamnose human lgG1 monoclonal antibody (clone 023.102, Bryson, S. (2016). Journal of Immunology 96(11), 4723-4730). The results are summarized in Table 5.

[0279] Groups of 5 male C57 / BI-6 mice were made neutropenic by subcutaneous administration of cyclophosphamide on days -4 (150 mg / kg) and -1 (100 mg / kg). On Day 0, animals were inoculated intramuscularly with 8 *104CFU per thigh of Escherichia coli ATCC25922. At the same time, the antibody-treated group was treated with the anti-rhamnose antibody (human lgG1 , clone 023.102) administered SC (2.1 mg / kg). At 2 h, the CFU count was determined from 5 mice (pre-treatment group). The remaining treatment groups (five per group) were treated with a subcutaneous injection of the test article (6 mg / kg free base equivalent) at +2, +8, +14 and +20 hr post-infection. Twenty-six hours after infection, the mice were euthanized humanely. The thighs of each animal were harvested, homogenized, serially diluted and quantitative tissue burden (CFU / g) measured. Decrease of the total CFU count of each thigh as compared to control counts at 26 hrs post-infection was determined for each dose group. Table 5 shows the geometric mean burden in each of the groups. Treatment with the compound of Example 1 alone, at a total dose of 24 mg / kg (6 mg / kg / dose Q6h) resulted in a 2.57 logw reduction in bacterial counts compared to non-treated control.

[0280] Treatment with the compound of Example 1 at a total dose of 24 mg / kg (6 mg / kg / dose Q6h) in the presence of 2.1 mg / kg of anti-rhamnose monoclonal antibody, resulted in a 3.57 logw reduction in bacterial counts compared to non-treated control.

[0281] Table 5 In vivo efficacy versus E. coli ATCC25922 thigh infection in neutropenic mice

[0282] Thus, the compound of Example 1 is able to reduce the bacterial burden in a mouse model of infection. In the presence of anti-rhamnose antibodies, an additional logw reduction of bacterial burden was observed when compared with the compound alone.

[0283] 5. C3b Deposition

[0284] Flow cytometry was used to demonstrate a functional effect of anti-rhamnose recruitment, namely the deposition of complement to the bacterial cells, as described below.

[0285] Flow cytometric complement deposition assay with human serum

[0286] The assays were carried out in polystyrene 96-well U bottom plates (Costar). E. coli K1 :O18ac:H7 (American Type Culture Collection, ATCC 700973) was grown in RPMI 1640 (Gibco 11835030) supplemented with 10% LB broth, Miller (Merck L3522) to late exponential phase. Subsequently, the bacteria were washed in Hank's Balanced Salt Solution with calcium and magnesium (HBSS+ / +) and then resuspended in assay buffer, i.e., PBS with 1% bovine serum albumin (BSA, Sigma A2153) at a concentration of 2x109CFU / mL. 1x108CFU were then incubated with 0.3, 1 , and 3 pM of Example 1 (see Figure 1 and Table 6) or assay buffer alone, in the presence of 20% depleted human serum (Pel-Freez 34010-1) and 50 pg / mL affinity purified anti-rhamnose antibodies derived from human gamma-globulin (Sigma G4386) at 37°C with shaking for 20 min in a total volume of 100 pL.

[0287] After this time, 100 pL from each well was transferred into a new 96 well V bottom plate (ThermoScientific, M419270) and the bacteria were pelleted by centrifugation at 4°C and the supernatants discarded. The bacteria were then resuspended in 100 pL of PE-labelled antihuman C3b / iC3b antibody (Biolegend 846104; clone 3E7 / C3b) at a final concentration of 4 pg / mL in PBS and incubated at 25°C with shaking for 30 min. After two final washes with 200 pL HBSS+ / +, the bacteria were resuspended in HBSS+ / + and their fluorescence profile as an indicator for complement deposition evaluated on a Cytoflex flow cytometer (Beckman Coulter). The median fluorescent intensity (MFI) was recorded in the PE channels. Data from all samples were analysed using CytExpert software (Beckman Coulter). All samples were run in technical triplicates and biological experiment repeated as indicated in the table.

[0288] Table 6 and Figure 1 demonstrate the deposition of C3b / iC3b from human serum to the surface of the bacteria using the flow cytometry assay described above. The fold shift over background was calculated by dividing the MFI obtained in the presence of the Example (3 pM) by the MFI obtained in the absence of Example, i.e., in the presence of vehicle. The shift in fluorescence intensity (PE) occurred due to detection of covalently bound complement components C3b / iC3b to the surface of the bacteria. Figure 1 shows that the deposition of C3b is related to the concentration of the compound of the Example.

[0289] Table 6. C3b deposition: Fold change in MFI over no compound control

[0290] Statement of Government Funding

[0291] The present invention was made with U.S. Government support under Agreement Number 75A50122C00028, awarded by the U.S. Department of Health and Human Services. The U.S. Government has certain rights in the present invention.

Claims

CLAIMS1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:wherein:R1represents a halogen atom; and n represents an integer selected from 1 to 5.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1represents fluorine or chlorine.

3. The compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, wherein R1represents fluorine.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein n represents an integer selected from 1 to 4.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein n represents an integer selected from 1 to 3.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein n represents an integer selected from 1 or 2.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein n represents an integer which is 1 .

8. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein n represents an integer which is 2.

9. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein n represents 1 and R1represents fluoro.

10. The compound according to any one of claims 1 , 2 or 4 to 7 or a pharmaceutically acceptable salt thereof, wherein n represents 1 and R1represents 2-chloro, 2-fluoro, 3-fluoro or 4-fluoro.11 . The compound according to any one of claims 1 , 2, 4 to 7 or 10 or a pharmaceutically acceptable salt thereof, wherein n represents 1 and R1represents 2- chloro, 3-fluoro or 4-fluoro.

12. The compound according to any one of claims 1 to 7 or 9 to 11 or a pharmaceutically acceptable salt thereof, wherein n represents 1 and R1represents 4-fluoro.

13. The compound according to any one of claims 1 to 6 or 8 or a pharmaceutically acceptable salt thereof, wherein n represents 2 and R1represents fluoro.

14. The compound according to any one of claims 1 to 6, 8 or 13 or a pharmaceutically acceptable salt thereof, wherein n represents 2 and R1represents 2,3-difluoro, 2,4-difluoro, 2,5-difluoro, 2,6-difluoro, 3,4-difluoro or 3,5-difluoro.

15. The compound according to any one of claims 1 to 6, 8, 13 or 14 or a pharmaceutically acceptable salt thereof, wherein n represents 2 and R1represents 2,4- difluoro, 2,5-difluoro or 3,5-difluoro.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from any one of Examples 1-6: {3-[2-[2-[2-[2-[2-[2-[2-[2-[[3-[2-Oxo-2-[2-[2-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl- tetrahydropyran-2-yl]oxyethoxy]ethylamino]ethoxy]-5-phenyl- benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionyl}-Phe(4- F)-Dab-Thr-Dap-cyclo-[Dab-Dab-DPhe-Leu-Dab-Dab-Thr] (Example 1 );{3-[2-[2-[2-[2-[2-[2-[2-[2-[[3-[2-Oxo-2-[2-[2-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl- tetrahydropyran-2-yl]oxyethoxy]ethylamino]ethoxy]-5-phenyl- benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionyl}-Phe(3- F)-Dab-Thr-Dap-cyclo-[Dab-Dab-DPhe-Leu-Dab-Dab-Thr] (Example 2);{3-[2-[2-[2-[2-[2-[2-[2-[2-[[3-[2-Oxo-2-[2-[2-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl- tetrahydropyran-2-yl]oxyethoxy]ethylamino]ethoxy]-5-phenyl-benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionyl}- Phe(3,5-di-F)-Dab-Thr-Dap-cyclo-[Dab-Dab-DPhe-Leu-Dab-Dab-Thr] (Example 3); {3-[2-[2-[2-[2-[2-[2-[2-[2-[[3-[2-Oxo-2-[2-[2-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl- tetrahydropyran-2-yl]oxyethoxy]ethylamino]ethoxy]-5-phenyl- benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionyl}- Phe(2,4-di F)-Dab-Thr-Dap-cyclo-[Dab-Dab-DPhe-Leu-Dab-Dab-Thr] (Example 4);{3-[2-[2-[2-[2-[2-[2-[2-[2-[[3-[2-Oxo-2-[2-[2-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl- tetrahydropyran-2-yl]oxyethoxy]ethylamino]ethoxy]-5-phenyl- benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionyl}- Phe(2,5-di F)-Dab-Thr-Dap-cyclo-[Dab-Dab-DPhe-Leu-Dab-Dab-Thr] (Example 5);{3-[2-[2-[2-[2-[2-[2-[2-[2-[[3-[2-Oxo-2-[2-[2-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl- tetrahydropyran-2-yl]oxyethoxy]ethylamino]ethoxy]-5-phenyl- benzoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionyl}-Phe(2- CI)-Dab-Thr-Dap-cyclo-[Dab-Dab-DPhe-Leu-Dab-Dab-Thr] (Example 6).

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

18. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, for use in therapy.

19. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 for use in the treatment of a disease or disorder mediated and / or caused by an infective agent.

20. Use of a compound of formula (I) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17, in the manufacture of a medicament for use in the treatment of a disease or disorder mediated and / or caused by an infective agent.

21. A method of treating a disease or disorder mediated and / or caused by an infective agent which comprises administering to an individual in need thereof a compound of formula (I) as defined in any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 17.

22. A process for preparing a compound of formula (I) according to claim 1 which comprises:(a) reacting a compound of formula (V):with a compound of formula (VI):where R1and n are as defined in any of claims 1 to 15 and Boc represents an amine protecting group which is tertbutoxycarbonyl; followed by(b) deprotecting the Boc protecting groups of the product of step (a) to prepare a compound of formula (I).

23. The process according to claim 22, wherein step (a) comprises reacting the compound of formula (V) with the compound of formula (VI) in the presence of HATU, NEta and DMF.

24. The process according to claim 22 or claim 23, wherein step (b) comprises TFA in DCM.

25. A compound of formula (V) or a compound of formula (VI) as defined in claim 22.

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