Carbazole compounds and their use in therapy, in the treatment of a respiratory infection

Abstract

The present invention relates to compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, (I) wherein: one of R2 and R3 is H, and the other is (CRaRb)nY; Y is selected from CO2Rc, CN and CONReRf; R4 is selected from H, halo, CN, alkyl and alkoxy; R6 is selected from H, F, Br, I, COOH, CN, CORd, CO2Rd, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, OH, SRd, SORd, SO2Rd, SO2NRdRd, NHSO2Rd, an aryl group and a heteroaryl group, wherein said aryl or heteroaryl group is optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy; R7 is selected from H, halo, alkyl, and alkoxy; R9 is selected from H, CORd, alkyl, haloalkyl, aryl, CO-aryl, CO-haloaryl, aralkyl and haloaralkyl; R1, R5 and R8 are H; each Ra, Rb, Rc, Rd, Re and Rf is independently selected from H, alkyl and haloalkyl; n is 1 to 6; for use in the treatment or prevention of a mycobacterial infection. Further aspects of the invention relate to a subgroup of compounds of formula (Ia), pharmaceutical compositions comprising the same, and their use in the treatment or prevention of a mycobacterial infection.

Description

[0001] CARBAZOLE COMPOUNDS AND THEIR USE IN THERAPY, IN THE TREATMENT OF A RESPIRATORY INFECTION

[0002] The present invention relates to compounds that have therapeutic applications in the treatment of mycobacterial infections, including, but not limited to, Mycobacterium tuberculosis.

[0003] BACKGROUND TO THE INVENTION

[0004] Tuberculosis (TB) is one of the leading infectious causes of death worldwide and the emergence of extensively drug- resista nt (XDR) strains of Mycobacterium tuberculosis (Mtb) threatens decades of progress in the treatment of this disease. In 2021, the World Health Organisation estimated that 1.6 million people died of tuberculosis, and 10.6 million new cases were contracted.1Of those who developed active TB in 2021 , an estimated 450,000 have rifampicin-resistant or multidrug-resistant TB (RR- or MDR-TB).1There is, therefore, an urgent need for the identification of new drug candidates to strengthen the antitubercular drug development pipeline. Alongside the inhibition of previously unexploited biochemical pathways, there are some key features which are also desirable in antitubercular drugs. Ideally, a new drug would shorten the treatment duration, demonstrate the ability to kill both drug susceptible and drug resistant strains of Mtb, have a simple dosage and administration regimen and have proven efficacy against nonreplicating populations.2These features are primarily required in order to improve patient compliance and to prevent the emergence of drug resistant strains. A new anti-TB drug should also be compatible with existing antiretroviral drugs to allow for the treatment of those with HIV-TB co-infection.2

[0005] The carbazole scaffold was first reported in 1872, when carbazole was isolated from coal tar by Graebe and Glazer.34Almost a century later, in 1965, the first carbazole alkaloid, murrayanine was isolated from Murraya koenigii Spreng by Chakraborty et al.35Importantly, murrayanine was found to have antifungal activity, and so was the first carbazole alkaloid with a proven biological activity.36In recent years a wide range of synthetic antimicrobial carbazoles have been reported in the literature with potent activities against the fungal pathogen Candida albicans,37’33the Gram-positive ESKAPE pathogens Enterococcus faecalis,3040Methicillin-resistant Staphylococcus aureus (MRSA)38’40’4041and the Gramnegative ESKAPE pathogens Escherichia coli3340Klebsiella pneumoniae40and Pseudomonas aeruginosa ,40The field has also recently been reviewed by Patil et al.42 In 2005, Ma et a / .43reported the identification of a small group six antitubercular carbazole alkaloids from the stem bark of Micromelum hirsutum, the most potent of which was found to have an MIC of 59 pM against Mtb H3?Rv with minimal cytotoxicity against the Vero cell line. The four most potent compounds from this series featured an aldehyde moiety in the 3- position. This work was built upon by Choi et al.44in 2006, and Borger et al45in 2016, who identified potent synthetic antitubercular carbazoles with MIC values as low as 1.5 pM and SI values of > 10. Again, the presence of oxygenated functional groups in the 3-position of the carbazole scaffold appear frequently among the most potent and selective examples, as do C-2 hydroxyl groups. However, the metabolic liabilities associated with the aldehyde and phenol moieties prevalent among these compounds make them challenging candidates for development as antitubercular drug candidates.

[0006] Previous work investigating the potential for non-steroidal anti-inflammatory drugs (NSAIDs) to be repurposed as anti-mycobacterial agents identified carprofen (CRP) as a compound of interest. Carprofen is a propionic acid with a central carbazole core and exhibits moderate potency (MIC = 40 pg / ml against Mtb H37RV) and low cytotoxicity providing it with a high selectivity (SI = 25) for toxicity to Mtb over the RAW 264.7 murine cell line.11Further characterisation of the effect of carprofen on Mtb demonstrated that carprofen is able to inhibit whole-cell efflux mechanisms and disrupt biofilm formation, two key mechanisms of intrinsic antimicrobial resistance. Transcriptomic profiling suggested that carprofen may target respiration by disrupting the membrane potential of Mtb.46

[0007] The present invention seeks to provide carprofen analogues which have therapeutic applications in the treatment of mycobacterical infections. More specifically, the Applicants have explored the influence of A- and C-ring regiochemistry and substitution on the antitubercular activity and mammalian cell cytotoxicity of various carprofen analogues.

[0008] STATEMENT OF INVENTION

[0009] The present invention relates to compounds having therapeutic applications in the treatment of mycobacterical infections, for example, tuberculosis.

[0010] A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,

[0011] wherein: one of R2 and R3 is H, and the other is (CRaRb)nY;

[0012] Y is selected from CO2RC, CN and CONReRf;

[0013] R4is selected from H, halo, CN, alkyl and alkoxy;

[0014] R6is selected from H, F, Br, I, COOH, CN, CORd, CC^Rd, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, OH, SRd, SORd, SO2Rd, SO2NRdRd, NHSO2Rd, an aryl group and a heteroaryl group, wherein said aryl or heteroaryl group is optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy;

[0015] R? is selected from H, halo, alkyl, and alkoxy;

[0016] Rg is selected from H, CORd, alkyl, haloalkyl, aryl, CO-aryl, CO-haloaryl, aralkyl and haloaralkyl;

[0017] R1 , Rs and Rs are H; each Ra, Rb, Rc, Rd, Re and Rf is independently selected from H, alkyl and haloalkyl; n is 1 to 6; for use in the treatment or prevention of a mycobacterial infection.

[0018] A second aspect of the invention relates to a compound of formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein: one of R2 and R3 is (CRaRb)nY and the other is H;

[0019] Y is selected from CO2RC, CN and CONReRt each Ra, Rb,Rc, Re and Rfis independently selected from H, alkyl and haloalkyl; n is 1 to 6;

[0020] R4is selected from H, halo, CN, alkyl and alkoxy; and

[0021] R6is selected from an aryl group and a heteroaryl group, wherein said aryl or heteroaryl group is which is optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxyl.

[0022] Advantageously, certain preferred compounds according to the above aspects demonstrate improved antitubercular activity, while also reducing toxicity to mammalian cells.

[0023] Further studies were undertaken to profile the activity of the compounds described herein in infection models and performing target identification studies.

[0024] DETAILED DESCRIPTION

[0025] A first aspect of the invention relates to a compound of formula (I) as described above, for use in the treatment or prevention of a mycobacterial infection.

[0026] “Alkyl” is defined herein as a straight-chain or branched alkyl radical, preferably C1.20 alkyl, more preferably C 2 alkyl, even more preferably C1.10 alkyl or C1.6 alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. More preferably, the alkyl is a C1.3 alkyl.As used herein, the term “aryl” refers to a Ce-12 aromatic group, which may be benzocondensed, for example, phenyl or naphthyl. Preferably, the aryl group is phenyl.

[0027] “Haloalkyl” is defined herein as a straight-chain or branched alkyl radical as defined above, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, that is substituted with one or more halogen atoms (that may be the same or different), such as fluorine, chlorine, bromine, and iodine. Preferably, the haloalkyl is a C1.20 haloalkyl, more preferably a C1.12 haloalkyl, even more preferably a C O haloalkyl or a Ci-e haloalkyl, or a C1.3 haloalkyl. Preferred examples are CF3 and CHF2, with CF3 being particularly preferred.

[0028] “Alkoxy” is defined herein as an oxygen atom bonded to an alkyl group as defined above, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy and hexoxy. Preferably, the alkoxy is a C1.20 alkoxy, more preferably a C 2 alkoxy, even more preferably C O alkoxy or a Ci-e alkoxy, or a C1.3 alkoxy. A preferred example is methoxy (-OCH3). “Haloalkoxy” is defined herein as an alkoxy group as described above substituted with one or more halogen atoms (that may be the same or different), such as fluorine, chlorine, bromine, and iodine. Preferably, the haloalkoxy is a C1.20 haloalkoxy, more preferably a Ci. 12 haloalkoxy, even more preferably a C1.10 haloalkoxy or a C1.6 haloalkoxy, or a C1.3 haloalkoxy.

[0029] “Heteroaryl” is defined herein as a monocyclic or bicyclic C2-12 aromatic ring comprising one or more heteroatoms (that may be the same or different), such as oxygen, nitrogen or sulphur. Examples of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyridinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridazinyl, isoxazolyl, pyrimidinyl, pyrazinyl, triazinyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl etc. and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl etc.; or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl etc. and benzo derivatives thereof, such as quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl etc.

[0030] “Aralkyl’ is defined herein as an alkyl group as defined above substituted by one or more aryl groups as defined above.

[0031] “Haloaralkyl” is defined herein as an aralkyl group as defined above substituted by one or more halogen atoms (that may be the same or different), such as fluorine, chlorine, bromine, and iodine.

[0032] In one preferred embodiment, each Ra, Rb, Rc, Rd, Re and Rf is independently selected from H and alkyl, more preferably H and Me.

[0033] In one preferred embodiment, Y is CO2RC. Preferably, Rcis H or alkyl, more preferably H or Me.

[0034] In one preferred embodiment, one of Raand Rb is alkyl (preferably Me), and the other is H, or Raand Rb are both H.

[0035] In one preferred embodiment: one of R2and R3is H, and the other is (CRaRb)nCO2Rc;

[0036] R6is selected from H, F, Br, alkyl, haloalkyl, alkoxy, an aryl group and a heteroaryl group, wherein said aryl or heteroaryl group is optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy; Ri, R4, Rs, R7 and R8and R9are H; and

[0037] Ra, b, Rcand Rdare each independently selected from H, alkyl and haloalkyl.

[0038] In one preferred embodiment, R3is H and R2is (CRaRb)nCO2Rc.

[0039] In one preferred embodiment, n is 1 to 3, more preferably 1 or 2, more preferably 1.

[0040] In one preferred embodiment, R3 is H and R2is CH(Me)CO2H or CH(Me)CO2Me, more preferably, CH(Me)CO2H.

[0041] In one preferred embodiment, R4is selected from H, halo, CN, Ci-6-alkyl and Ci-6-alkoxy.

[0042] In one preferred embodiment, R4is H.

[0043] In one preferred embodiment, Re is an aryl group which is optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy.

[0044] In one preferred embodiment, Re is a phenyl group optionally substituted by one or more substituents selected from Ci-6-alkyl and Ci-6-alkoxy.

[0045] In one preferred embodiment, R2is H and R3is (CRaRb)nCO2Rc.

[0046] In one preferred embodiment, R2is H and R3is CH2CO2H or CH2CO2Me. More preferably, R2is H and R3is CH2CO2Me.

[0047] In one preferred embodiment, Re is selected from H, F, Br, alkyl, haloalkyl and alkoxy.

[0048] In one preferred embodiment, Re is selected from H, F, Br, CF3, OMe and Me.

[0049] In one preferred embodiment, R? is H or halo, more preferably, H or Cl.

[0050] In one preferred embodiment, R9is H.

[0051] In one preferred embodiment:

[0052] Re is selected from H, F, Br, I, Ci-e-alkyl, Ci-6-haloalkyl, Ci-6-alkoxy; and

[0053] R1, R4, R5, R7, Rs and R9are all H.

[0054] In one preferred embodiment, Re is Ci-6-haloalkyl, more preferably CF3; and

[0055] R1, R4, R5, R7, Rs and R9are all H. In one preferred embodiment:

[0056] R2is H;

[0057] Rs is (CRaRb)nCO2Rc;

[0058] R6is Ci-6-alkoxy; and R1, R4, Rs, R7, Rs and Rgare all H.

[0059] Preferred compounds of formula (I) include compounds (41)-(54) shown below.

[0060] A further aspect of the invention relates to a compound for use in the treatment or prevention of a mycobacterial infection, wherein said compound is selected from the

[0061]

[0062] In one preferred embodiment, the compound is selected from compounds 10-14, 26, 28, 29, 42 and 44-47 as described above, compound 42 being highly preferred.

[0063] A further aspect of the invention relate to compounds as described herein, including those of formulae (I) and (la).

[0064] Another aspect of the invention relates to a pharmaceutical composition comprising a compound as described herein, including a compound of formula (I) or (la) as defined herein, and a pharmaceutically acceptable diluent, excipient or carrier.

[0065] THERAPEUTIC APPLICATIONS

[0066] The compounds described herein have therapeutic applications in the treatment and / or prevention of mycobacterial infections, for example, but not limited to, tuberculosis and tuberculosis-like respiratory infections, and the symptoms thereof.

[0067] In one embodiment, the compounds described herein are for use in treating a respiratory infection in a subject.

[0068] In one preferred embodiment, the respiratory infection is tuberculosis. Symptoms of tuberculosis typically include, for example, persistent cough, coughing up blood and / or mucus, fever, chills, night sweats, loss of appetite and unintentional weight loss.

[0069] In one preferred embodiment, the respiratory infection is a tuberculosis-like respiratory infection. As used herein, “tuberculosis-like respiratory infection” refers to a respiratory infection having similar symptoms to those described above for tuberculosis.

[0070] In one preferred embodiment, the subject is immunocompromised. As used herein, “immunocompromised” refers to a subject having a weakened immune system, i.e. a reduced ability to fight infections and other diseases. For example, an immunocompromised subject may have a lack of structural lung integrity such as in cystic fibrosis, chronic obstructive pulmonary disease (COPD), asthma or bronchitis.

[0071] Mycobacterium is a genus within the order Actinomycetales that comprises a large number of well characterised species, several of which are associated with human and animal disease such as tuberculosis, leprosy and respiratory impairment such as COPD due to non-tuberculous mycobacterial infection. Examples include, but are not limited to, Mycobacterium africanum, Mycobacterium bovis, Mycobacterium canetti, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium microti, Mycobacterium tuberculosis, M. intracellulare, M. abscessus, M. ulcerance, M. colombiense, M. smegmatis and M. chelonae.

[0072] In one preferred embodiment, the mycobacterial infection is M. tuberculosis.

[0073] In one preferred embodiment, the mycobacterial infection is M. bovis.

[0074] In one preferred embodiment, the mycobacterial infection is M. abscessus. M. abscessus causes TB-like respiratory infections, particularly in immunocompromised subjects who have a lack of structural lung integrity such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchitis, as well as skin and soft tissue infections.

[0075] Historically, the application of whole-cell phenotypic assays has been the source of almost all of the clinically approved antitubercular drugs as well as the majority of drug candidates currently in clinical trials. This approach evaluates compound libraries against actively replicating bacteria to identify hit compounds which directly inhibit bacterial growth. The key advantage of this method over the target-based approach is that any hits obtained can pass through the mycobacterial cell envelope and avoid significant efflux or inactivation. Thus, many potential hits which have unsuitable physicochemical properties for an antitubercular drug are excluded at an early stage of the drug discovery process. This provides an advantageous starting point for further optimisation.3However as the biological target of any hit is initially unknown a robust method for its identification is required before structurebased medicinal chemistry can be employed for compound optimisation.3This process can be technically challenging and time-consuming.

[0076] The ideal phenotypic screening assay would make use of Mtb. However, the use of Mtb in the laboratory poses a significant safety risk and requires specialised containment facilities. This has led to the use of model organisms in the early stages of antitubercular drug discovery3The most frequently used and most studied model organisms for Mtb are M. bovis Bacillus Calmette-Guerin (BCG) and Mycobacterium smegmatis, both of which can be handled in a biosafety level 2 containment facility. M. bovis BCG is a slow-growing mycobacterium which is very closely related to Mtb, with a genome that is > 99.95% identical.4M. smegmatis is fast-growing allowing for more rapid assay turnaround than for Mtb or M. bovis BCG. However, it not as closely related to Mtb, having a genome that is only 70% identical.5Several studies have explored the efficacy of these organisms as models for Mtb and it has generally been observed that hits observed with M. bovis BCG are more likely to have activity against Mtb than those observed against M. smegmatis, with fewer Mtb hits missed.6-8However, M. smegmatis and M. abscessus can find use as a model for MDR-TB as it has an intrinsic resistance to a large number of antimicrobial drugs including rifampicin and isoniazid.9

[0077] Broadly, high-throughput screening techniques for antitubercular compounds can be separated into two groups: agar-based or liquid culture-based. For agar-based approaches, the presence or absence of visible bacterial growth on agar-based media is used to determination drug efficacy.10-12The high-throughput spot inhibition (HT-SPOTi) assay is an agar-based assay, which is amenable to use in a 96-well plate format. This method involves the testing of each drug candidate across a concentration gradient, and so it can be used to for direct MIC determination, providing an advantage over other agar-based screening techniques such as the proportion method or the zone-of-inhibition assay.10The HT-SPOTi assay has been applied to a number of antitubercular drug discovery campaigns11’13 14including the development of a highly potent and selective hybrid SQ109 and BM212 pyrrole compound.15Liquid culture-based high-throughput screening assays may determine compound MICs by visual assessment of cell growth, measurement of the optical density, the use of redox dyes,16-19or mycobacteria expressing fluorescent or luminescent proteins.20-22The most common redox dye-based assay is the resazurin microtiter assay (REMA),16’17which relies on the reduction of blue resazurin to the pink and highly fluorescent resorufin in the presence of actively respiring cells.23The MIC can then be determined visually or with the use of a spectrofluorometer.16 19

[0078] To ensure that the potency observed in an in vitro screening assay will also be observed under the more challenging conditions encountered during TB infection additional assays are required to validate hit compounds.24Numerous assays have been developed for this purpose with the aim of modelling a different aspect of the TB disease-state. These include testing compounds against Mtb inside macrophages104-108and under conditions of nutrient depletion,30altered pH31or hypoxia.3233

[0079] In one preferred embodiment, the mycobacterial infection is a drug resistant strain of mycobacterium.

[0080] In one preferred embodiment, the mycobacterial infection is a rifampicin-resistant strain of mycobacterium.

[0081] In one preferred embodiment, the mycobacterial infection is a multidrug resistant strain of mycobacterium.

[0082] In one preferred embodiment, the mycobacterial infection is a drug resistant strain of M. tuberculosis.

[0083] In one preferred embodiment, the mycobacterial infection is a a rifampicin-resistant strain of M. tuberculosis.

[0084] In one preferred embodiment, the mycobacterial infection is a multidrug resistant strain of M. tuberculosis.

[0085] In one preferred embodiment, the compounds described herein are capable of reversing antibiotic resistance. Without wishing to be bound by theory, it is believed that antibiotic resistance reversal properties arise through inhibition of drug efflux and biofilm formation.

[0086] In one preferred embodiment, the compounds described herein are capable of killing both replicating and non-replicating mycobacteria.

[0087] In one preferred embodiment, the compounds described herein exhibit pleiotropic mechanisms of action against different physiological states (both replicating and nonreplicating) of M. tuberculosis.

[0088] Another aspect of the invention relates to a method of treating or preventing a mycobacterial infection in a subject, said method comprising administering to the subject a compound as defined herein. Another aspect of the invention relates to a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing a mycobacterial infection.

[0089] Another aspect of the invention relates to the use of a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating or preventing a mycobacterial infection in a subject.

[0090] As used herein the phrase “preparation of a medicament” includes the use of the components of the invention directly as the medicament in addition to their use in any stage of the preparation of such a medicament.

[0091] COMPOUNDS OF FORMULA (la)

[0092] Another aspect of the invention relates to compounds of formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein: one of R2and R3is (CRaRb)nY and the other is H;

[0093] Y is selected from CO2RC, ON and CONReRf; each Ra, Rb, Rc, Re and Rf is independently selected from H, alkyl and haloalkyl; n is 1 to 6;

[0094] R4 is selected from H, halo, CN, alkyl and alkoxy; and

[0095] Re is selected from an aryl group which is optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxyl.

[0096] In one preferred embodiment, each Ra, Rb, Rc, Rd, Re and Rfis independently selected from H and alkyl, more preferably H and Me. In one preferred embodiment, Y is CO2R0 Preferably, Rcis H or alkyl, more preferably H or Me.

[0097] In one preferred embodiment, one of Raand Rb is alkyl (preferably Me), and the other is H, or Raand Rb are both H. In one preferred embodiment, R3is H and R2 is (CRaRb)nCO2Rc.

[0098] In one preferred embodiment, n is 1 to 3, more preferably 1 or 2, more preferably 1.

[0099] In one preferred embodiment, R3is H and R2is CH(Me)CC>2H or CH(Me)CC>2Me, more preferably, CH(Me)CC>2H.

[0100] In one preferred embodiment, R4 is selected from H, halo, CN, Ci-6-alkyl and Ci-6-alkoxy. In one preferred embodiment, R4 is H.

[0101] In one preferred embodiment, Re is an aryl group which is optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxyl.

[0102] In one preferred embodiment, Re is a phenyl group optionally substituted by one or more substituents selected from Ci-6-alkyl and Ci-6-alkoxy. In one preferred embodiment, Re is a phenyl group optionally substituted by one or more substituents selected from Me and OMe.

[0103] In one preferred embodiment, the compound of the invention is selected from the following: and pharmaceutically acceptable salts and hydrates thereof. Compounds 12 and 13 are particularly preferred.

[0104] Another aspect of the invention relates to compounds of formula (la), or a pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing a mycobacterial infection, or for treating a respiratory disease, for example, tuberculosis, or a tuberculosis-like disease. Preferred embodiments in this respect are as set out for compounds of formula (I) above under the heading “Therapeutic Applications”.

[0105] PROCESS

[0106] A further aspect of the invention relates to processes for preparing compounds as defined herein. Further details of the synthetic processes are set forth in the accompanying examples section.

[0107] In order to facilitate the derivatisation of carprofen via Pd-catalysed coupling chemistry, commercially-sourced carprofen was first converted to the corresponding methyl ester 1 by Fischer esterification.47This was followed by Boc protection of the carbazole nitrogen to give the fully protected carprofen derivative, 2 (Scheme 1).

[0108]

[0109] Scheme 1. Synthesis of protected intermediate 2 for synthesis of carbazoles, i) pTSA, MeOH, reflux, 18 h, ii) Boc2O, DMAP, MeCN, RT, 1h.

[0110] This derivative was then taken forward into Suzuki-Miyaura coupling reactions with a range of boronic acids to afford compounds (3-7, Table 1). Similarly, carbazoles 8 and 9 were prepared by the Buchwald-Hartwig amination of 2 with the cyclic amines piperidine and morpholine, respectively (Table 2). Compounds 3-9 were then sequentially Boc-deprotected and de-esterified to give the final compounds 10-16 for screening (Table 3).

[0111] To explore the influence of A-ring substituents and regiochemistry on the activity of carprofen analogues, a second series of carprofen analogues were prepared. First, a Buchwald-Hartwig amination was performed between 4-chloroiodobenzene and the appropriate aniline (17, 18, 19 or 20) to give diarylamines 21-24 (Scheme 2).

[0112]

[0113] 0both derived from compound 23

[0114] The substituted anilines (18, 19) required for this step were prepared from the corresponding nitrophenylacetic acids by Fischer esterification followed by nitro reduction (Scheme 3). Scheme 3: Synthesis of methyl acetate-substituted anilines

[0115] Diarylamines 21-24 then underwent oxidative cyclisation with Pd(OAc)2 in pivalic acid, under conditions reported by Leigault et al. to afford carbazoles 25-29. The cyclisation of 23 produced regioisomers 27 and 28 which were both isolated. Carbazoles 26-29 were then de-esterified with sodium hydroxide in methanol and dichloromethane to afford acids 30-33 (Scheme 2).

[0116] A third series of carbazoles was prepared via a similar approach to that employed for the second; first, diarylamines 34-40 were prepared by Buchwald-Hartwig amination between the appropriate aryl halide and methyl 2-(4-aminophenyl)acetate (Table 4). Aryl bromides were used for the majority of the amination reactions, as aryl iodides are more challenging substrates in the Buchwald-Hartwig amination.48This allowed for reactions to be run for a 2 h while maintaining good to excellent yields under the same conditions.

[0117] Diarylamines 34-40 were cyclised to carbazoles 41-47 under modified oxidative cyclisation conditions (Table 5). For these conversions, copper acetate was added to the reaction mixture to increase the rate of re-oxidation of Pd(0) to Pd(ll), increasing the reaction rate. This approach has been reported in acetic acid by Ackermark et al. This approach allowed for the shortening of the reaction time to 6 h and was generally observed to improve the yields obtained. Carbazoles 41-47 were then de-esterified to give the acetic acids 48-54 as before (Table 6).

[0118] Compounds in which Y is CN or CONReRf can be prepared by analogous methods to the acids. For example, starting from 4-nitrophenylacetic acid, the amides can be synthesised using standard amide coupling reagents (activation and addition of the amine), and then the materials taken through the same sequence of steps. Alternatively, the nitriles can be prepared via a dehydration of the corresponding amide RCONH2, (e.g. oxalic chloride and Et3N) and then taken through the same synthetic route. As a further alternative, the product esters can be prepared as described and then converted to the amides via transamidation (or hydrolysis of the ester and acid activation and addition of the amine), and then amides with RCONH2 groups can be dehydrated to the nitrile groups (e.g. oxalic chloride and Et3N).

[0119] PHARMACEUTICAL COMPOSITIONS

[0120] For use according to the present invention, the compounds or physiologically acceptable salt, ester or other physiologically functional derivative thereof, described herein, may be presented as a pharmaceutical formulation, comprising the compounds or physiologically acceptable salt, ester or other physiologically functional derivative thereof, together with one or more pharmaceutically acceptable carriers, excipients or diluents therefor and optionally other therapeutic and / or prophylactic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The pharmaceutical compositions may be for human or animal usage in human and veterinary medicine.

[0121] Examples of such suitable excipients for the various different forms of pharmaceutical compositions described herein may be found in the “Handbook of Pharmaceutical Excipients, 2ndEdition, (1994), Edited by A Wade and PJ Weller. The carrier, or, if more than one be present, each of the carriers, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.

[0122] Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).

[0123] Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Examples of suitable diluents include ethanol, glycerol and water.

[0124] The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s), buffer(s), flavouring agent(s), surface active agent(s), thickener(s), preservative(s) (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.

[0125] Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.

[0126] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

[0127] Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.

[0128] Pharmaceutical formulations include those suitable for oral, topical (including dermal, buccal and sublingual), rectal or parenteral (including subcutaneous, intradermal, intramuscular and intravenous), nasal and pulmonary administration e.g., by inhalation. The formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0129] Pharmaceutical formulations suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent. Moulded tablets may be made by moulding an active compound with an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored. Capsules may be prepared by filling an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner. Cachets are analogous to capsules wherein an active compound together with any accessory ingredient(s) is sealed in a rice paper envelope. An active compound may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged, e.g., in a sachet.

[0130] Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.

[0131] Formulations for oral administration include controlled release dosage forms, e.g., tablets wherein an active compound is formulated in an appropriate release - controlling matrix, or is coated with a suitable release - controlling film. Such formulations may be particularly convenient for prophylactic use. Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by admixture of an active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds. Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles.

[0132] Injectable preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use. Alternatively, an active compound may be in powder form which is constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.

[0133] An active compound may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implantation, e.g., subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long-acting formulations are particularly convenient for prophylactic use.

[0134] Formulations suitable for pulmonary administration via the buccal cavity are presented such that particles containing an active compound and desirably having a diameter in the range of 0.5 to 7 microns are delivered in the bronchial tree of the recipient.

[0135] As one possibility such formulations are in the form of finely comminuted powders which may conveniently be presented either in a pierceable capsule, suitably of, for example, gelatin, for use in an inhalation device, or alternatively as a self-propelling formulation comprising an active compound, a suitable liquid or gaseous propellant and optionally other ingredients such as a surfactant and / or a solid diluent. Suitable liquid propellants include propane and the chlorofluorocarbons, and suitable gaseous propellants include carbon dioxide. Self-propelling formulations may also be employed wherein an active compound is dispensed in the form of droplets of solution or suspension.

[0136] Such self-propelling formulations are analogous to those known in the art and may be prepared by established procedures. Suitably they are presented in a container provided with either a manually-operable or automatically functioning valve having the desired spray characteristics; advantageously the valve is of a metered type delivering a fixed volume, for example, 25 to 100 microlitres, upon each operation thereof.

[0137] As a further possibility an active compound may be in the form of a solution or suspension for use in an atomizer or nebuliser whereby an accelerated airstream or ultrasonic agitation is employed to produce a fine droplet mist for inhalation.

[0138] Formulations suitable for nasal administration include preparations generally similar to those described above for pulmonary administration. When dispensed such formulations should desirably have a particle diameter in the range 10 to 200 microns to enable retention in the nasal cavity; this may be achieved by, as appropriate, use of a powder of a suitable particle size or choice of an appropriate valve. Other suitable formulations include coarse powders having a particle diameter in the range 20 to 500 microns, for administration by rapid inhalation through the nasal passage from a container held close up to the nose, and nasal drops comprising 0.2 to 5% w / v of an active compound in aqueous or oily solution or suspension.

[0139] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.

[0140] Formulations suitable for topical formulation may be provided for example as gels, creams or ointments. Such preparations may be applied e.g. to a wound or ulcer either directly spread upon the surface of the wound or ulcer or carried on a suitable support such as a bandage, gauze, mesh or the like which may be applied to and over the area to be treated.

[0141] Liquid or powder formulations may also be provided which can be sprayed or sprinkled directly onto the site to be treated, e.g. a wound or ulcer. Alternatively, a carrier such as a bandage, gauze, mesh or the like can be sprayed or sprinkle with the formulation and then applied to the site to be treated.

[0142] According to a further aspect of the invention, there is provided a process for the preparation of a pharmaceutical or veterinary composition as described above, the process comprising bringing the active compound(s) into association with the carrier, for example by admixture.

[0143] In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. The invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound as described herein into conjunction or association with a pharmaceutically or veterinarily acceptable carrier or vehicle.

[0144] SALTS / ESTERS

[0145] The compounds of the invention can be present as salts or esters, in particular pharmaceutically and veterinarily acceptable salts or esters.

[0146] Pharmaceutically acceptable salts of the compounds of the invention include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g. hydrohalic acids such as hydrochloride, hydrobromide and hydroiodide, sulphuric acid, phosphoric acid sulphate, bisulphate, hemisulphate, thiocyanate, persulphate and sulphonic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Ci-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid. Salts which are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates. Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2-hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesulphonate, benzenesulphonate, p- chlorobenzenesulphonate and p-toluenesulphonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoric and sulphonic acids.

[0147] Esters are formed either using organic acids or alcohols / hydroxides, depending on the functional group being esterified. Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (Ci-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide. Alcohols include alkanealcohols of 1- 12 carbon atoms which may be unsubstituted or substituted, e.g. by a halogen).

[0148] ENANTIOMERS / TAUTOMERS

[0149] In all aspects of the present invention previously discussed, the invention includes, where appropriate all enantiomers, diastereoisomers and tautomers of the compounds of the invention. The person skilled in the art will recognise compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and / or tautomers may be isolated / prepared by methods known in the art.

[0150] Enantiomers are characterised by the absolute configuration of their chiral centres and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Such conventions are well known in the art (e.g. see ‘Advanced Organic Chemistry’, 3rdedition, ed. March, J., John Wiley and Sons, New York, 1985).

[0151] Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone.

[0152] STEREO AND GEOMETRIC ISOMERS

[0153] Some of the compounds of the invention may exist as stereoisomers and / or geometric isomers - e.g. they may possess one or more asymmetric and / or geometric centres and so may exist in two or more stereoisomeric and / or geometric forms. The present invention contemplates the use of all the individual stereoisomers and geometric isomers of those compounds, and mixtures thereof. The terms used in the claims encompass these forms, provided said forms retain the appropriate functional activity (though not necessarily to the same degree).

[0154] The present invention also includes all suitable isotopic variations of the compound or a pharmaceutically acceptable salt thereof. An isotopic variation of a compound of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as2H,3H,11C,13C,14C,15N,17O,180,31P,32P,35S,18F and36CI, respectively. Certain isotopic variations of the agent and pharmaceutically acceptable salts thereof, for example, those in which a radioactive isotope such as3H or14C is incorporated, are useful in drug and / or substrate tissue distribution studies. Tritiated, i.e. ,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e.,2H, 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. For example, the invention includes compounds of general formula (I) where any hydrogen atom has been replaced by a deuterium atom. Isotopic variations of the agent of the present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents. ATROPISOMERS

[0155] Some of the compounds of the invention may exist as atropisomers. Atropisomers are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers. The invention encompasses all such atropisomers.

[0156] PRODRUGS

[0157] The invention further includes the compounds of the present invention in prodrug form, i.e. covalently bonded compounds which release the active parent drug in vivo. Such prodrugs are generally compounds of the invention wherein one or more appropriate groups have been modified such that the modification may be reversed upon administration to a human or mammalian subject. Reversion is usually performed by an enzyme naturally present in such subject, though it is possible for a second agent to be administered together with such a prodrug in order to perform the reversion in vivo. Examples of such modifications include ester (for example, any of those described above), wherein the reversion may be carried out by an esterase etc. Other such systems will be well known to those skilled in the art.

[0158] SOLVATES

[0159] The present invention also includes solvate forms of the compounds of the present invention. The terms used in the claims encompass these forms. Preferably, the solvate is a hydrate.

[0160] COMBINATIONS

[0161] A further aspect of the invention relates to a combination comprising a compound as described herein and one or more additional active agents. In a particularly preferred embodiment, the one or more compounds of the invention are administered in combination with one or more additional active agents, for example, existing drugs available on the market. In such cases, the compounds of the invention may be administered consecutively, simultaneously or sequentially with the one or more other active agents. Another aspect of the invention relates to combinations comprising a compound as described herein and a further pharmaceutically active agent for use in treating or preventing mycobacterial infections.

[0162] Drugs in general can be more effective when used in combination. In particular, combination therapy is desirable in order to avoid an overlap of major toxicities, mechanism of action and resistance mechanism(s). Furthermore, it is also desirable to administer most drugs at their maximum tolerated doses with minimum time intervals between such doses. The major advantages of combining drugs are that it may promote additive or possible synergistic effects through biochemical interactions and also may decrease the emergence of resistance.

[0163] Beneficial combinations may be suggested by studying the activity of the test compounds with agents known or suspected of being valuable in the treatment of a particular disorder. This procedure can also be used to determine the order of administration of the agents, i.e. before, simultaneously, or after delivery. Such scheduling may be a feature of all the active agents identified herein.

[0164] POLYMORPHS

[0165] The invention further relates to the compounds of the present invention in their various crystalline forms, polymorphic forms and (an)hydrous forms. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such forms by slightly varying the method of purification and or isolation form the solvents used in the synthetic preparation of such compounds.

[0166] ADMINISTRATION

[0167] The pharmaceutical compositions of the present invention may be adapted for rectal, nasal, intrabronchial, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intraarterial and intradermal), intraperitoneal or intrathecal administration. Preferably the formulation is an orally administered formulation. The formulations may conveniently be presented in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose. By way of example, the formulations may be in the form of tablets and sustained release capsules, and may be prepared by any method well known in the art of pharmacy. Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, gellules, drops, cachets, pills or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution, emulsion or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or as a bolus etc. Preferably, these compositions contain from 1 to 250 mg and more preferably from 10-100 mg, of active ingredient per dose.

[0168] For compositions for oral administration (e.g. tablets and capsules), the term “acceptable carrier” includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl-methylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of Wintergreen, cherry flavouring and the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art.

[0169] A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.

[0170] Other formulations suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.

[0171] Other forms of administration comprise solutions or emulsions which may be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally or intramuscularly, and which are prepared from sterile or sterilisable solutions. Injectable forms typically contain between 10 - 1000 mg, preferably between 10 - 250 mg, of active ingredient per dose.

[0172] The pharmaceutical compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders.

[0173] An alternative means of transdermal administration is by use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. The active ingredient can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required.

[0174] DOSAGE

[0175] A person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation. Typically, a physician will determine the actual dosage which will be most suitable for an individual patient, and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy. The dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

[0176] The dosage amount will further be modified according to the mode of administration of the compound. For example, to achieve an “effective amount” for acute therapy, parenteral administration of a compound is typically preferred. An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful. Typically, the parenteral dose will be about 0.01 to about 100 mg; preferably between 0.1 and 20 mg, in a manner to maintain the concentration of drug in the plasma at a therapeutically effective concentration. The compounds may be administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg. The precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.

[0177] The compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to achieve one or more of the therapeutic indications disclosed herein. Typically, a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 500 mg or about 0.1 to about 50 mg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about 50 mg or about 0.5 to about 20 mg.

[0178] No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention. The compounds of this invention, which may have good bioavailability, may be tested in one of several biological assays to determine the concentration of a compound which is required to have a given pharmacological effect.

[0179] The invention is further described by way of the following non-limiting examples, and with reference to the following figure, wherein:

[0180] Figure 1 shows the effect of Carprofen and Compound 42 on Mycobacterium tuberculosis H37Rv (Mtb); relative growth versus concentration (pg / mL).

[0181] EXAMPLES

[0182] Middlebrook 7H9 Broth

[0183] Middlebrook 7H9 broth powder (1.88 g, M7H9, BD Difco™), glycerol (50%, 1.6 ml), and Tween 80 (1 ml, 20%) were dissolved in double distilled water (360 ml) and sterilised by autoclaving at 121 °C for 10 minutes. Prior to use, this broth was supplemented by the addition of sterile albumin dextrose catalase (Remel™) to 10% of the total volume of the media.

[0184] Middlebrook 7H10 Agar

[0185] Middlebrook 7H10 agar powder (7.4 g, M7H10, BD Difco™) and glycerol (50%, 4 ml) were dissolved in double distilled water (360 ml) and sterilised by autoclaving 121 °C for 10 minutes. Prior to use, this broth was supplemented by the addition of sterile oleic acid albumin dextrose catalase (BD Difco™) to 10% of the total volume of the media.

[0186] 50% Glycerol Solution

[0187] Glycerol (25 ml) was mixed with double distilled water (25 ml). This was filter sterilised, when required.

[0188] Complete RPMI

[0189] An aliquot (50 ml) was removed from a bottle (500 ml) of liquid Roswell Park Memorial Institute (RPMI) 1640 media with L-glutamine (Gibco®) and discarded. The volume removed was then replaced with fetal bovine serum (FBS, Sigma Aldrich, Non-LIS origin, sterile filtered, heat-inactivated).

[0190] Growth and Maintenance of Cell Cultures

[0191] Mycobacterium bovis BCG

[0192] Liquid cultures of M. bovis BCG were grown in a medium comprised of M7H9 broth. The cultures were grown at 37 °C with rolling at 2 rpm. Cultures of a 100 ml volume were grown in 500 ml roller bottles (VWR) so that the volume of culture was 20% of the total volume of the vessel. Alternatively, cultures were also grown at 37 °C with shaking at 180 rpm, when required due to equipment failure. In this case, 10 ml cultures were grown in 50 ml centrifuge tubes so that the volume of culture was 20% of the total volume of the vessel. The growth of M. bovis BCG cultures was observed by measuring the ODeoo in a cell density meter. A sample of the culture was diluted as appropriate in sterile M7H9 medium to ensure that measurements fell within the linear range of the cell density meter (< 0.8). A total volume of 1 ml was used in a disposable cuvette. A measurement of the ODeoo was then made against a blank sample comprised only of sterile M7H9 medium. When rolling cultures of M. bovis BCG cultures were passaged, this was performed by transferring a sample of the passaged culture (1 ml) into a new vessel containing sterile M7H9 broth (100 ml). The culture was then grown at 37 °C with rolling at 2 rpm. When shaking M. bovis BCG cultures were passaged, this was performed by transferring a sample of the passaged culture (100 pl) into a new vessel containing sterile M7H9 broth (10 ml). The culture was then grown at 37 °C with shaking at 180 rpm. Solid cultures of M. bovis BCG were grown on M7H10 agar. Colonies were observed after 14 days of growth at 37 °C. THP-1

[0193] Liquid cultures of THP-1 cells were grown in tissue culture flasks in complete RPMI. Cultures were grown with no shaking in a CO2 incubator (37 °C in a 5% CO2). The growth of the cultures was monitored my light microscopy with an inverted light microscope. THP-1 cells were passaged by first transferring the liquid culture from the tissue culture flask into a centrifuge tube and then pelleting the cells by centrifugation (270 x g, 5 min). The supernatant was discarded, and the pellet was washed by resuspension in PBS (5 ml) and subsequent pelleting by centrifugation (270 x g, 25 °C, 5 min). The pellet was the resuspended in fresh, complete RPMI (5 ml). An aliquot (10 pl) of the suspension was stained with Trypan Blue solution (0.4%, 10 pl) and an aliquot of the stained cells (10 pl) was transferred to a haemocytometer for cell counting under an inverted light microscope. After determination of the cell density, the suspension was divided between as many tissue culture flasks as required and was diluted in the appropriate quantity of complete RPMI to achieve a cell density of 1x105cells / ml in each of the new cultures at a total volume of 5 ml.

[0194] Chemical Syntheses

[0195] General Methods

[0196] All solvents and reagents were obtained commercially and were used as provided. Thin layer chromatography was performed with Machery-Nagel Polygram® silica 60 polyester sheets, 0.2 mm thickness, IIV254 indicator, 40 x 80 mm plate size. Thin layer chromatography plates were visualised under an UV lamp or were stained with ninhydrin, potassium permanganate, bromocresol green or phosphomolybdic acid solutions. Column chromatography was performed using Merck silica gel 60 (40-63 pm).

[0197] 1H and13C NMR spectroscopic data were obtained with Bruker Avance 300, Bruker Avance III 400, Bruker Avance Neo 500, Bruker, Avance III 600 and Bruker Avance Neo 700 spectrometers. Chemical shifts (5) are reported in parts per million (ppm) and references to the deuterated solvent or an additional standard where required. The coupling constants ( ) were measured in Hertz (Hz) with couplings given as singlet (s), doublet (d), triplet (t), quartet (q). Where appropriate, COSY, HMQC and HMBC experiments were carried out to aid signal assignment.

[0198] Melting points were determined using an Electrothermal IA9000 melting point apparatus and are uncorrected. Infra-red spectra were obtained using a Bruker Alpha FT-IR spectrometer. LC-MS data was collected using a Waters Acquity Ultra Performance LC system connected to a Waters micromass ZQ mass spectrometer which scanned in the mlz range from 100 to 1000. High resolution mass spectrometry data was collected on an Agilent 6510 Q TOF mass spectrometer, or an Orbitrap Q Exactive mass spectrometer.

[0199] Methyl 2-(6-chloro-9H-carbazol-2-yl)propanoate (1)

[0200] Bhatthula, B. kumar goud, Kanchani, J. reddy, Arava, V. reddy & Subha, M. C. S. Total synthesis of carbazole alkaloids. Tetrahedron 75, 874-887 (2019).

[0201] To a solution of carprofen (100 mg, 0.37 mmol) in MeOH (5 ml), was added pTSA monohydrate (8.00 mg, 0.04 mmol). The reaction mixture was heated to reflux and stirred for 18 h. The reaction was allowed to cool to RT before the solvent was removed from the reaction mixture under reduced pressure. The crude product was dissolved in EtOAc (20 ml) and washed with saturated NaHCOs(aq) (3 x 20 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed to afford the product as an off-while solid (93 mg, 88%). M.p 116-120 °C; IR (neat, Vmax / crm1): 3358, 1715;1H NMR (700 MHz; CDCI3) 5 8.16 (1 H, s, NH), 7.97 (1 H, s, 5-ArH), 7.93 (1 H, d, J = 8.0 Hz, 4-ArH), 7.37-7.31 (2H, m, 2 x ArH), 7.28 (1 H, d, J = 8.5 Hz, 8-ArH), 7.18 (1 H, dd, J = 8.0, 1.6 Hz, 3-ArH), 3.89 (1 H, q, J = 7.2 Hz, CHCH3), 3.70 (3H, s, CO2CH3), 1.59 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (176 MHz; CDCI3) 5 175.5, 140.5, 139.3, 138.2, 126.0, 125.0, 124.4, 121.8, 120.8, 120.0, 119.8, 111.7, 109.7, 52.3, 46.0, 19.1 ; m / z [ES+] 288 ([M + H]+, 7%); 230 ([37M-COOMe]+, 35%), 228 ([35M-COOMe]+, 100%), , 35%); m / z [HRMS, ES+] found [M + H]+288.0782, Ci6Hi535CINO2requires 288.0786.

[0202] Methyl 2-(3-nitrophenyl)acetate

[0203] Moreau, E., Fortin, S., Lacroix, J., Patenaude, A., Rousseau, J. L. C. & C-Gaudreault, R. N- Phenyl-N'-(2-chloroethyl)ureas (CEUs) as potential antineoplastic agents. Part 3: Role of carbonyl groups in the covalent binding to the colchicine-binding site. Bioorg. Med. Chem. 16, 1206-1217 (2008). ,

[0204] To a solution of 3-nitrophenylacetic acid (1.50 g, 8.28 mmol) in MeOH (20 ml), was added para-toluene sulfonic acid (pTSA) monohydrate (150 mg, 0.79 mmol) and the reaction mixture was stirred at reflux for 18 h. The reaction was cooled to RT and the solvent was removed under reduced pressure. The crude product was dissolved in EtOAc (20 ml) and washed with saturated NaHCOs(aq) (3 x 20 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford the product as a colourless, low melting point, crystalline solid (1.44 g, 89%). IR (neat, Vmax / crn-1): 2954, 1734, 1524, 1348;1H NMR (700 MHz; CDCh) 6 8.16 (1 H, m, 2-ArH), 8.15-8.14 (1 H, m, 4- ArH), 7.63-7.62 (1 H, m, 6-ArH), 7.51 (1 H, t, J = 7.9 Hz, 5-ArH), 3.74 (2H, s, CH2), 3.73 (3H, s, CO2CH3);13C NMR (176 MHz; CDCh) 6 170.9, 148.5, 135.9, 135.7, 129.6, 124.5, 122.5, 52.5, 40.6; m / z [ES+] 136 ([M - COOMe]+, 100%).

[0205] Methyl 2-(4-nitrophenyl)acetate

[0206] Kannan Sivaraman, K., Paiardini, A., Siehczyk, M., Ruggeri, C., Oellig, C. A., Dalton, J. P., Scammells, P. J., Drag, M. & McGowan, S. Synthesis and Structure-Activity Relationships of Phosphonic Arginine Mimetics as Inhibitors of the M1 and M17 Aminopeptidases from Plasmodium falciparum. J. Med. Chem. 56, 5213-5217 (2013).

[0207] To a solution of 4-nitrophenylacetic acid (1.50 g, 8.28 mmol) in MeOH (20 ml), was added pTSA monohydrate (150 mg, 0.79 mmol) and the reaction mixture was stirred at reflux for 20 h. The reaction was cooled to RT and the solvent was removed under reduced pressure The crude product was dissolved in EtOAc (20 ml) and washed with saturated NaHCOs(aq) (3 x 20 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford the product as a white solid (1.47 g, 91 %). Mp 57.1-59.4 °C (lit 50-57 °C);252 1H NMR (700 MHz; CDCI3) 6 8.19 (2H, d, J = 8.7 Hz, 3-ArH),

[0208] 7.46 (2H, d, J = 8.7 Hz, 2-ArH), 3.74 (2H, s, CH2), 3.72 (3H, s, CO2CH3);13C NMR (176 MHz; CDCI3) 6 170.7, 147.4, 141.4, 130.4, 123.9, 52.5, 40.9; m / z [ES+] 196 ([M + H]+, 50%), 136 ([M - COOMe]+, 55%).

[0209] Methyl 2-(4-nitrophenyl)propanoate

[0210] Schmidt, J., Schierle, S., Gellrich, L., Kaiser, A. & Merk, D. Structural optimization and in vitro profiling of N -phenylbenzamide-based farnesoid X receptor antagonists. Bioorg. Med. Chem. 26, 4240-4253 (2018).

[0211] To a solution of 2-(4-nitrophenyl)propionic acid (3.00 g, 15.4 mmol) in MeOH (30 ml) was added pTSA monohydrate (290 mg, 1.54 mmol). The reaction mixture was heated to reflux and stirred for 20 h. The reaction was cooled, and the solvent was removed under reduced pressure. The crude product was dissolved in EtOAc (30 ml) and washed with saturated NaHCOs(aq) (3 x 30 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford the product as a red oil (3.08 g, 98%).1H NMR (700 MHz; CDCI3) 6 8.18 (2H, d, J = 8.7 Hz, 3-ArH), 7.47 (2H, d, J = 8.7 Hz, 2-ArH), 3.84 (1 H, q, J = 7.2 Hz, CHCH3), 3.68 (3H, s, CO2CH3), 1.54 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (176 MHz; CDCI3) 6 173.8, 147.8, 147.3, 128.7, 124.0, 52.5, 45.4, 18.6; m / z [ES+] 150 ([M - COOMe]+, 100%).

[0212] Methyl 2-(3-aminophenyl)acetate

[0213] Moreau, E., Fortin, S., Lacroix, J., Patenaude, A., Rousseau, J. L. C. & C-Gaudreault, R. N- Phenyl-N'-(2-chloroethyl)ureas (CElls) as potential antineoplastic agents. Part 3: Role of carbonyl groups in the covalent binding to the colchicine-binding site. Bioorg. Med. Chem. 16, 1206-1217 (2008). To methyl 2-(3-nitrophenyl)acetate (1.25 g, 6.40 mmol) in MeOH (18 ml) was added Pd / C (10 wt%, 125 mg). The reaction vessel was flushed with argon and then placed under a hydrogen atmosphere. The reaction mixture was stirred at RT for 20 h. The reaction vessel was evacuated of H2while flushing with argon. The reaction mixture was then filtered through Celite®with MeOH and the solvent was removed from the filtrate under reduced pressure to afford the product as a colourless oil (1.05 g, 99%). IR (neat, vmax / cnr1): 3446, 3369, 1724, 1605, 1259, 1144;1H NMR (600 MHz; CDCh) 6 7.10 (1H, t, J = 7.7 Hz, 5-ArH), 6.66 (1H, d, J = 7.7 Hz, 6-ArH), 6.61 (1H, s, 2-ArH), 6.59 (1 H, d, J = 7.7 Hz, 4-ArH), 3.68 (3H, s, CO2CH3), 3.53 (2H, s, CH2);13C NMR (151 MHz; CDCh) 6 172.3, 146.8, 135.2, 129.7, 119.6, 116.0, 114.1, 52.2, 41.4; m / z [ES+] 166 ([M + H]+, 100%).

[0214] Methyl 2-(4-aminophenyl)acetate

[0215] Kasagami, T., Kim, l.-H., Tsai, H.-J., Nishi, K., Hammock, B. D. & Morisseau, C. Salicylate- urea-based soluble epoxide hydrolase inhibitors with high metabolic and chemical stabilities. Bioorg. Med. Chem. Lett. 19, 1784-1789 (2009).

[0216] To methyl 2-(4-nitrophenyl)acetate (1.00 g, 5.12 mmol) in MeOH (15 ml) was added Pd / C (10 wt%, 100 mg). The vessel was flushed with argon, placed under a hydrogen atmosphere and stirred at RT for 20 h. The reaction mixture was filtered through Celite®, washed with MeOH and the solvent was removed from the filtrate under reduced pressure. The crude product was dissolved in water and the pH was adjusted to 2 with HCI<aq) (1 M). The aqueous layer was washed with EtOAc (3 x 20 ml). The pH of the aqueous layer was adjusted to 8 by the addition of NaHCOs and the aqueous layer was extracted with EtOAc (3 x 20 ml). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford the product as a pale-yellow oil (750 mg, 89%).1H NMR (700 MHz; CDCh) 6 7.06 (2H, d, J = 8.4 Hz, 2-ArH), 6.65 (1 H, d, J = 8.4 Hz, 3-ArH), 3.67 (3H, s, CO2CH3), 3.51 (2H, s, CH2);13C NMR (176 MHz; CDCh) 6 172.6, 145.2, 130.1, 124.0, 115.4, 51.9, 40.3; m / z [ES+] 166 ([M + H]+, 100%).

[0217] Methyl 2-(4-aminophenyl)propanoate Schmidt, J., Schierle, S., Gellrich, L., Kaiser, A. & Merk, D. Structural optimization and in vitro profiling of N -phenylbenzamide-based farnesoid X receptor antagonists. Bioorg. Med. Chem. 26, 4240-4253 (2018).

[0218] To methyl 2-(4-nitrophenyl)propanoate (2.50 g, 12.0 mmol) in MeOH (30 ml) was added Pd / C (10 wt%, 250 mg). Formic acid (0.30 ml, 7.95 mmol) was added, the vessel was flushed with argon and then placed under a hydrogen atmosphere. The reaction was left to stir for 20 h at RT. The vessel was purged of hydrogen, and the reaction mixture was filtered through Celite®with MeOH. The solvent was removed from the filtrate under reduced pressure and the crude product was dissolved in EtOAc (30 ml) and washed with HCI(aq) (0.5 M, 3 x 30 ml). The pH of the aqueous layer was adjusted to 8 by the addition of NaHCOs. The aqueous layer was then extracted with EtOAc (3 x 30 ml) to afford the product as a brown oil (2.06 g, 96%).1H NMR (400 MHz; CDCh) 6 7.09 (2H, d, J = 8.3 Hz, 2-ArH), 6.65 (2H, d, J = 8.3 Hz, 3-ArH), 3.68-3.60 (4H, m, CHCH3& CO2CH3), 1.45 (3H, d, J = 7.3 Hz, CHCH3);13C NMR (101 MHz; CDCI3) 6 175.6, 145.4, 130.8, 128.5, 115.5, 52.0, 44.7, 18.7; m / z [ES+] 180 ([M + H]+, 95%), 120 ([M - COOMe]+, 100%).

[0219] 4-Chloro-N-phenylaniline

[0220] Panigrahi, R., Panda, S., Behera, P. K., Sahu, S. K. & Rout, L. Recyclable bimetallic CuMoO 4 nanoparticles for C-N cross-coupling reaction under mild conditions. New J. Chem. 43, 19274-19278 (2019). ,

[0221] Aniline (0.90 ml, 10 mmol), 1-chloro-4-iodobenzene (3.58 g, 15.0 mmol), palladium acetate (35 mg, 1.5 mol%), tri-terf-butyl phosphonium tetrafluoroborate (90 mg, 0.3 mol%) and sodium terf-butoxide (1.25 g, 13.0 mmol) were added to anhydrous toluene (30 ml) under an argon atmosphere. The reaction mixture was heated to reflux and stirred for 20 h. The reaction mixture was filtered through Celite® with EtOAc and the solvent was removed from the filtrate under reduced pressure. The crude product was then purified by flash column chromatography (10% EtOAc in petroleum ether) to afford the product as a purple solid (660 mg, 32%). Mp 72-73 °C (lit. 71-73 °C); Panigrahi, R., Panda, S., Behera, P. K., Sahu, S. K. & Rout, L. Recyclable bimetallic CuMoO 4 nanoparticles for C-N cross-coupling reaction under mild conditions. New J. Chem. 43, 19274-19278 (2019). IR (neat, Vmax / crn-1): 3400, 1584, 1305;1H NMR (700 MHz; CDCh) 6 7.28 (2H, app t, J = 7.9 Hz, 3’- ArH), 7.21 (2H, d, J = 8.8 Hz, 3-ArH), 7.05 (2H, d, J = 8.7 Hz, 2’-ArH), 6.99 (2H, d, J = 8.8 Hz, 2-ArH), 6.96 (1 H, t, J = 7.4 Hz, 4’-ArH);13C NMR (176 MHz; CDCh) 6 142.8, 142.0, 129.6, 129.4, 125.6, 121.7, 119.0, 118.2; m / z [ES+] 206 ([37M + H]+, 35%), 204 ([35M + H]+, 100%).

[0222] Methyl 2-(3-((4-chlorophenyl)amino)phenyl)acetate Pd(OAc)2XPhos toluene

[0223] Methyl 2-(3-aminophenyl)acetate (350 mg, 2.12 mmol), 1-chloro-4-iodobenzene (632 mg, 2.65 mmol) palladium acetate (19 mg, 4 mol%), XPhos (80 mg, 8 mol%) and Cs2COs (990 mg, 3.04 mmol) were added to anhydrous toluene (10 ml) under an argon atmosphere. The reaction mixture was heated to 100 °C and stirred for 24 h. The solvent was removed from the reaction mixture under reduced pressure and the crude product was purified by flash column chromatography (15% EtOAc in petroleum ether) to afford the product as a colourless crystalline solid (452 mg, 77%). Mp 72-73 °C; IR (neat, vmax / cnr1): 3369, 1733, 1322;1H NMR (700 MHz; CDCh) 6 7.24-7.19 (3H, m, 3-ArH & 5’-ArH), 7.01-6.97 (2H, m, 2-ArH), 6.97-6.93 (2H, m, 2’-ArH & 6’-ArH), 6.85 (1 H, d, J = 7.6 Hz, 4’-ArH), 5.75 (1 H, s, NH), 3.70 (3H, s, CO2CH3), 3.58 (2H s, CH2);13C NMR (176 MHz; CDCh) 6 172.1 , 143.1 , 141.7, 135.5, 129.8, 129.4, 125.9, 122.4, 119.2, 118.9, 116.7, 52.2, 41 .3; m / z [ES+] 278 ([37M + H]+, 35%), 276 ([35M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+276.0783, Ci5Hi535CINO2requires 276.0791.

[0224] Methyl 2-(4-((4-chlorophenyl)amino)phenyl)acetate

[0225] Methyl 2-(4-aminophenyl)acetate (300 mg, 1.82 mmol), 1-chloro-4-iodobenzene (541 mg, 2.27 mmol), palladium acetate (20 mg, 5 mol%), XPhos (86 mg, 10 mol%) and CS2CO3 (858 mg, 2.63 mmol) were added to anhydrous toluene (10 ml) under an argon atmosphere. The reaction mixture was heated to reflux and stirred for 48 h. The solvent was removed from the reaction mixture under reduced pressure and the crude product was purified by flash column chromatography (5-30% EtOAc in petroleum ether) to afford the product as a paleyellow solid (286 mg, 57%). Mp 94-96 °C; IR (neat, vmax / cm-1): 3375, 2949, 1720, 1592;1H NMR (700 MHz; CDCI3) 6 7.20 (2H, d, J = 8.8 Hz, 3’-ArH), 7.18 (2H, d, J = 8.4 Hz, 3-ArH), 7.00 (2H, d, J = 8.4 Hz, 2-ArH), 6.97 (2H, d, J = 8.8 Hz, 2’-ArH), 5.66 (1 H, s, NH), 3.70 (3H, s, CO2CH3), 3.57 (2H, s, CH2);13C NMR (176 MHz; CDCI3) 6 172.5, 142.0, 141.8, 130.4, 129.4, 127.1 , 125.7, 118.9, 118.4, 52.2, 40.6; m / z [ES+] 276 ([35M + H]+, 100%); 278 ([37M + H]+, 35%); m / z [HRMS, ES+] found [M + H]+276.0786, Ci5Hi535CINO2requires 276.0790.

[0226] Methyl 2-(4-((4-chlorophenyl)amino)phenyl)propanoate

[0227] Methyl 2-(4-aminophenyl)propanoate (500 mg, 2.79 mmol), 1-chloro-4-iodobenzene

[0228] (832 mg, 3.49 mmol), palladium acetate (31.5 mg, 5 mol%), XPhos (133 mg, 10 mol%) and CS2CO3 (1.18 g, 3.63 mmol) were added to anhydrous toluene (15 ml) under an argon atmosphere. The reaction mixture was heated to reflux and stirred for 24 h. The solvent was removed from the reaction mixture under reduced pressure and the crude product was purified by flash column chromatography (10-30% EtOAc in n-hexane) to afford the product as a brown oil (344 mg, 45%). IR (neat, Vmax / crm1): 3374, 1718, 1593;1H NMR (700 MHz; CDCI3) 6 7.20 (4H, m, 3-ArH & 3’-ArH), 6.99 (2H, d, J = 8.8 Hz, 2’-ArH), 6.97 (2H, d, J = 8.8 Hz, 2-ArH), 5.76 (1 H, s, NH), 3.71-3.67 (4H, m, CHCH3& CO2CH3), 1.50 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (176 MHz; CDCh) 6 175.5, 142.0, 141.9, 133.5, 129.4, 128.6, 125.6, 118.9, 118.3, 52.2, 44.8, 18.7; m / z [ES+] 290 ([35M + H]+, 100%), 292 ([37M + H]+, 40%), 290 ([35M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+290.0940, CI6HI735CINO2requires 290.0942.

[0229] Methyl 2-(4-(phenylamino)phenyl)acetate

[0230] Methyl 2-(4-aminophenyl)acetate (200 mg, 1.21 mmol), bromobenzene (0.16 ml, 1.50 mmol), palladium acetate (14 mg, 5 mol%), XPhos (58 mg, 10 mol%) and CS2CO3 (512 mg, 1.57 mmol) were added to anhydrous toluene (8 ml) under an argon atmosphere. The reaction mixture was heated to reflux and stirred for 2 h. The solvent was removed from the reaction mixture under reduced pressure and the crude product was purified by flash column chromatography (10-30% EtOAc in n-hexane) to afford the product as a colourless oil (210 mg, 72%). IR (neat, vmax / crn-1): 3362, 1723, 1592;1H NMR (700 MHz; CDCh) 6 7.26 (2H, dd, J = 8.6, 7.4 Hz, 3-ArH), 7.17 (2H, d, J = 8.7 Hz, 3’-ArH), 7.06 (2H, dd, J = 8.6, 1.1 Hz, 2-ArH), 7.03 (2H, d, J = 8.7 Hz, 2’-ArH), 6.93 (1 H, tt, J = 7.4, 1.1 Hz, 4-ArH), 5.69 (1 H, s, NH), 3.70 (3H, s, CO2CH3), 3.57 (2H, s, CH2);13C NMR (176 MHz; CDCh) 6 172.5, 143.2, 142.3, 130.3, 129.5, 126.5, 121.1 , 118.1 , 117.9, 52.2, 40.6; m / z [ES+] 242 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+242.1171 , CI5HI6NO2requires 242.1176.

[0231] Methyl 2-(4-((4-fluorophenyl)amino)phenyl)acetate Methyl 2-(4-aminophenyl)acetate (200 mg, 1.21 mmol), 4-fluoroiodobenzene (333 mg, 1.50 mmol), palladium acetate (14 mg, 5 mol%), XPhos (58 mg, 10 mol%) and CS2CO3 (512 mg, 1.57 mmol) were added to anhydrous toluene (8 ml) under an argon atmosphere. The reaction mixture was heated to reflux and stirred for 18 h. The solvent was removed from the reaction mixture under reduced pressure and the crude product was purified by flash column chromatography (5-20% Et20 in n-hexane) to afford the product as a white solid (211 mg, 67%d). Mp: 53-56 °C; IR (neat, Vmax / cm’1): 3360, 1719, 1610, 1500;1H NMR (700 MHz; CDCI3) 6 7.15 (2H, d, J = 8.6 Hz, 3’-ArH), 7.03 (2H, dd, J = 9.0, 4.7 Hz, 3-ArH), 7.00-6.95 (2H, m, 3-ArH), 6.93 (2H, d, J = 8.6 Hz, 2’-ArH), 5.58 (1 H, s, NH), 3.70 (3H, s, CO2CH3), 3.56 (2H, s, CH2);13C NMR (176 MHz; CDCI3) 6 172.6, 158.2 (d,1CF= 241 Hz), 143.1 , 139.0, 130.4, 126.1 , 120.6 (d, J = 8.8 Hz,), 117.1 , 116.1 (d, J = 22.9 Hz), 52.2, 40.5;19F NMR (282 MHz; CDCI3) 6 -122.1 (4-F); m / z [ES+] 260 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+260.1078, C15H15FNO2 requires 260.1081.

[0232] Methyl 2-(4-((4-(trifluoromethyl)phenyl)amino)phenyl)acetate

[0233] Methyl 2-(4-aminophenyl)acetate (300 mg, 1.82 mmol), 4-iodobenzenotrifluoride (617 mg, 2.27 mmol), palladium acetate (20 mg, 5 mol%), XPhos (86 mg, 10 mol%) and CS2CO3 (768 mg, 2.36 mmol) were added to anhydrous toluene (12 ml) under an argon atmosphere. The reaction mixture was heated to reflux and stirred for 18 h. The solvent was removed from the reaction mixture under reduced pressure and the crude product was purified by flash column chromatography (20% Et2O in n-hexane) to afford the product as white crystalline solid (483 mg, 86%). Mp 88-89 °C; IR (neat, vmax / cm-1): 3369, 1718, 1605, 1530;1H NMR (700 MHz; CDCI3) 6 7.46 (2H, d, J = 8.3 Hz, 3-ArH), 7.24 (2H, d, J = 8.6 Hz, 3’-ArH), 7.10 (2H, d, J = 8.6 Hz, 2’-ArH), 7.03 (2H, d, J = 8.3 Hz, 2-ArH), 5.90 (1 H, s, NH), 3.71 (3H, s, CO2CH3), 3.60 (2H, s, CH2);13C NMR (151 MHz; CDCI3) 6 172.4, 146.8, 140.3, 130.6, 128.5, 126.9, 124.7 (q,1JCF= 270 Hz), 121.9, 121.7, 121.8 (q,2CF = 32.2 Hz), 120.2, 115.4, 52.3, 40.6;19F NMR (282 MHz; CDCI3) 6 -61.7 (CF3); m / z [ES+] 310 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+310.1049, C16H15F3NO2 requires 310.1049. Methyl 2-(4-((3-chlorophenyl)amino)phenyl)acetate

[0234] Methyl 2-(4-aminophenyl)acetate (250 mg, 1.51 mmol), 1-bromo-3-chlorobenzene (0.22 ml, 1.9 mmol), palladium acetate (17 mg, 5 mol%), XPhos (72 mg, 10 mol%) and CS2CO3 (641 mg, 1.96 mmol) were added to anhydrous toluene (10 ml) under an argon atmosphere. The reaction mixture was heated to reflux and stirred for 2 h. The solvent was removed from the reaction mixture under reduced pressure and the crude product was purified by flash column chromatography (10-30% EtOAc in n-hexane) to afford the product as a colourless oil (378 mg, 91 %). IR (neat, vmax / cm-1): 3371 , 1722, 1590, 1515;1H NMR (700 MHz; CDCI3) 5 7.21 (2H, d, J = 8.6 Hz, 3’-ArH), 7.15 (1 H, app t, J = 8.1 Hz, 5-ArH), 7.06 (2H, d, J = 8.6 Hz, 2’ -ArH), 7.04 (1 H, app t, J = 2.1 Hz, 2-ArH), 6.89 (1 H, ddd, J = 8.0, 2.1 , 1.0 Hz, ArH), 6.86 (1 H, ddd, J = 8.0, 2.1 , 1.0 Hz, ArH), 3.71 (3H, s, CO2CH3), 3.59 (2H, s, CH2);13C NMR (176 MHz; CDCI3) 6 172.4, 144.8, 141.0, 135.2, 130.5, 127.8, 120.8, 119.3, 116.9, 115.4, 52.2, 40.6; m / z [ES+] 278 ([37M + H]+, 30%), 276 ([35M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+276.0786, Ci5Hi535CINO2requires 276.0786.

[0235] Methyl 2-(4-(p-tolylamino)phenyl)acetate

[0236] Methyl 2-(4-aminophenyl)acetate (250 mg, 1.51 mmol), 4-bromotoluene (0.24 ml,

[0237] 1.9 mmol), palladium acetate (17 mg, 5 mol%), XPhos (72 mg, 10 mol%) and CS2CO3 (641 mg, 1.96 mmol) were added to anhydrous toluene (10 ml) under an argon atmosphere. The reaction mixture was heated to reflux and stirred for 2 h. The solvent was removed from the reaction mixture under reduced pressure and the crude product was purified by flash column chromatography (10-30% EtOAc in n-hexane) to afford the product as a colourless oil (314 mg, 86%). IR (neat, vmax / cm-1): 3379, 1726, 1610, 1505;1H NMR (700 MHz; CDCI3) 5 7.15 (2H, d, J = 8.6 Hz, 3’-ArH), 7.09 (2H, d, J = 8.3 Hz, 3-ArH), 7.00 (1 H, d, J = 8.3 Hz, 2-ArH), 6.98 (1 H, d, J = 8.6 Hz, 2’-ArH), 3.70 (3H, s, CO2CH3), 3.56 (2H, s, CH2), 2.31 (3H, s, ArCH3);13C NMR (176 MHz; CDCI3) 6 172.6, 143.0, 140.3, 131.3, 130.3, 130.0, 125.9, 119.1 , 117.2, 52.2, 40.6, 20.8; m / z [ES+] 256 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+256.1335, CI6HI8NO2requires 256.1332.

[0238] Methyl 2-(4-((4-methoxyphenyl)amino)phenyl)acetate

[0239] Methyl 2-(4-aminophenyl)acetate (250 mg, 1.51 mmol), 4-bromoanisole (0.24 ml, 1.9 mmol), palladium acetate (17 mg, 5 mol%), XPhos (72 mg, 10 mol%) and CS2CO3 (641 mg, 1.96 mmol) were added to anhydrous toluene (10 ml) under an argon atmosphere. The reaction mixture was heated to reflux and stirred for 2 h. The solvent was removed from the reaction mixture under reduced pressure and the crude product was purified by flash column chromatography (10-30% EtOAc in petroleum ether) to afford the product as a yellow oil (295 mg, 76%). IR (neat, vmax / crn-1): 3381 , 1724, 1607, 1511 ;1H NMR (700 MHz; CDCI3) 6 7.12 (2H, d, J = 8.5 Hz, 3’-ArH), 7.07 (2H, m, 3-ArH), 6.89 (2H, d, J = 7.4 Hz, 2’- ArH), 6.86 (2H, m, 2-ArH), 3.80 (3H, s, OCH3), 3.69 (3H, s, CO2CH3), 3.54 (2H, s, CH2);13C NMR (176 MHz; CDCI3) 6 172.6, 155.6, 144.1 , 135.6, 130.3, 125.3, 122.4, 116.2, 114.8, 55.7, 52.1 , 40.5; m / z [ES+] 272 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+272.1278, CI6HI8NO3requires 272.1282.

[0240] Methyl 2-(4-((4-bromophenyl)amino)phenyl)acetate Methyl 2-(4-aminophenyl)acetate (300 mg, 1.82 mmol), 1 ,4-dibromobenzene (2.14 g, 9.08 mmol), palladium acetate (20 mg, 5 mol%), XPhos (86 mg, 10 mol%) and CS2CO3 (858 mg, 2.63 mmol) were added to anhydrous toluene (10 ml) under an argon atmosphere. The reaction mixture was heated to reflux and stirred for 18 h. The solvent was removed from the reaction mixture under reduced pressure and the crude product was purified by flash column chromatography (10-30% EtOAc in petroleum ether) to afford the product as a brown solid (140 mg, 24%). Mp 94-97 °C; IR (neat, Vmax / crrn1): 3363, 1703, 1585;1H NMR (700 MHz; CDCI3) 6 7.33 (2H, d, J = 8.9 Hz, 2-ArH), 7.18 (2H, d, J = 8.6 Hz, 3’-ArH), 7.00 (2H, d, J = 8.6 Hz, 2’-ArH), 6.91 (2H, d, J = 8.9 Hz, 3-ArH), 3.70 (3H, s, CO2CH3), 3.58 (2H, s, CH2);13C NMR (176 MHz; CDCI3) 6 172.5, 142.5, 141.6, 132.3, 130.4, 127.2, 119.1 , 118.6, 112.8, 52.2, 40.6; m / z [ES+] 322 ([81M + H]+, 100%), 320 ([79M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+320.0278, Ci5Hi579BrNO2requires 320.0281.

[0241] 3-Chloro-9H-carbazole (25) Akermark, B., Eberson, L., Jonsson, E. & Pettersson, E.

[0242] Palladium-promoted cyclization of diphenyl ether, diphenylamine, and related compounds.

[0243] J. Org. Chem. 40, 1365-1367 (1975).

[0244] 4-Chloro- / V-phenylaniline (102 mg, 0.50 mmol), palladium acetate (22.4 mg, 0.10 mmol) potassium carbonate (14.0 mg, 0.10 mmol) and pivalic acid (450 mg, 4.4 mmol) were heated to 130 °C and stirred for 18 h. To the reaction mixture CH2CI2 (20 ml) was added and it was and washed with saturated NaHCOs(aq) (3 x 20 ml). The organic layer was then filtered through Celite®with EtOAc. The solvent was removed from the filtrate under reduced pressure and the crude product was purified by flash column chromatography (5% EtOAc in petroleum ether) to afford the product as light pink solid (44 mg, 44%). Mp 194- 197 °C; IR (neat, Vmax / cnr1): 3401 , 1436;1H NMR (700 MHz; CDCI3) 6 8.06 (1 H, br s, NH), 8.04-8.01 (2H, m, 4-ArH & 5-ArH), 7.47-7.41 (2H, m, 7-ArH & 8-ArH), 7.39-7.33 (2H, m, 1-ArH & 2-ArH), 7.26-7.23 (1 H, m, 6-ArH);13C NMR (176 MHz; CDCI3) 6 140.1 , 137.9, 126.7, 126.1 , 125.1 , 124.7, 122.7, 120.7, 120.2, 120.0, 111.7, 110.9; m / z [HRMS, ES+] found [M]+201.0341 , CI2H8N35CI requires 201.0340. Methyl 2-(6-chloro-9H-carbazol-2-yl)acetate and Methyl 2-(6-chloro-9H-carbazol-4- yl)acetate (27 (top) and 28 (bottom))

[0245] Methyl 2-(3-((4-chlorophenyl)amino)phenyl)acetate (300 mg, 1.09 mmol), palladium acetate (45 mg, 0.20 mmol), potassium carbonate (27.5 mg, 0.20 mmol) and pivalic acid (1.75 g,

[0246] 17.1 mmol) were stirred at 100 °C for 18 h. The reaction mixture was allowed to cool to RT before being filtered through Celite® with MeOH. The solvent was removed from the eluent under reduced pressure. The crude product was dissolved in Et20 (30 ml) and the organic layer washed with saturated NaHCOs(aq) (5 x 30 ml). The organic layer was then dried over anhydrous Na2SC>4 and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (20-50% Et2O in petroleum ether) to afford two regioisomers:

[0247] Ortho-isomer (27Y Yellow crystalline solid (80 mg, 27%); Mp 186-189 °C; IR (neat, Vmax / crm1): 3360, 1716;1H NMR (700 MHz; CDCI3) 6 8.18 (1 H, br s, NH), 8.07 (1 H, s, 5-ArH), 7.41- 7.34 (2H, m, 2-ArH & 7-ArH), 7.30 (2H, m, 1-ArH & 8-ArH), 7.10 (1 H, d, J = 7.2 Hz, 3-ArH), 4.21 (2H, s, CH2), 3.75 (3H, s, CO2CH3);13C NMR (176 MHz; CDCI3) 6 171.8, 140.5, 138.0, 129.1 , 126.6, 125.8, 125.1 , 124.1 , 122.1 , 122.0, 121.3, 111.6, 110.2, 52.4, 39.9; m / z [ES+] 274 ([35M + H]+, 4%), , 216 ([37M - COOMe]+, 35%), 214 ([35M - COOMe]+, 100%); m / z [HRMS, ES+] found [M + H]+274.0630, CI5HI335CINO2requires 274.0629.

[0248] Para-isomer (28): Off-white crystalline solid (60 mg, 20%); Mp 165-167 °C; IR (neat, Vmax / crn-1): 3389, 1726;1H NMR (700 MHz; CDCI3) 6 8.08 (1 H, br s, NH), 7.98 (1 H, d, J =

[0249] 2.1 Hz, 5-ArH), 7.94 (1 H, d, J = 8.3 Hz, 4-ArH), 7.35-7.31 (3H, m, 1-ArH, 7-ArH & 8-ArH), 7.15 (1 H, dd, J = 8.3 Hz, 3-ArH), 3.79 (2H, s, CH2), 3.72 (3H, s, CO2CH3);13C NMR (176 MHz; CDCI3) 6 172.4, 140.4, 138.1 , 132.6, 126.0, 125.1 , 124.5, 121.8, 121.4, 120.7, 120.1 , 111.7, 111.6, 52.3, 41.8; m / z [ES+] 216 ([37M - COOMe]+, 15%), 214 ([35M - COOMe]+, 45%); m / z [HRMS, ES] found [M]+273.0555, CI5HI235CINO2requires 273.0551.

[0250] Methyl 2-(6-chloro-9H-carbazol-3-yl)acetate (26)

[0251] Methyl 2-(4-((4-chlorophenyl)amino)phenyl)acetate (170 mg, 0.62 mmol), palladium acetate (28.0 mg, 0.12 mmol), potassium carbonate (17.0 mg, 0.12 mmol) and pivalic acid (1.00 g 10.5 mmol) were stirred at 100 °C for 24 h. The reaction was cooled to RT and filtered through Celite® with MeOH. The solvent was removed from the eluent under reduced pressure. The crude product was dissolved in Et2O (20 ml) and the organic layer was washed with saturated NaHCOs(aq) (3 x 20 ml). The solvent was removed from the organic layer under reduced pressure and the crude product purified by flash column chromatography (5 - 30% EtOAc in petroleum ether) to afford the product as a yellow solid (61 mg, 36%). Mp 139-143 °C; IR (neat, Vmax / cnr1): 3347, 1717;1H NMR (700 MHz; CDCI3) 5 8.07 (1 H, br s, NH), 7.99 (1 H, s, 5-ArH), 7.91 (1 H, s, 4-ArH), 7.37-7.31 (4H, m, 1-ArH, 2- ArH, 7-ArH & 8-ArH), 3.79 (2H, s, CH2), 3.72 (3H, s CO2CH3);13C NMR (176 MHz; CDCI3) 5 172.8, 139.9, 138.2, 128.0 126.2, 125.5, 125.1 , 124.4, 122.9, 121.3, 120.3, 111.7, 111.0, 52.2, 41.3; m / z [ES+] 274 ([35M + H]+, 7%), 216 ([37M - COOMe]+, 30%), 214 ([35M - COOMe]+, 100%); m / z [HRMS, ES+] found [M]+273.0561 , CI5HI235CINO2requires 273.0551.

[0252] Methyl 2-(6-chloro-9H-carbazol-3-yl)propanoate (29)

[0253] Methyl 2-(4-((4-chlorophenyl)amino)phenyl)propanoate (200 mg, 0.69 mmol), palladium acetate (31.0 mg, 0.14 mmol), potassium carbonate (19.0 mg, 0.14 mmol) and pivalic acid (1.20 g 11.7 mmol) were stirred at 100 °C and for 10 h. The reaction was cooled to RT and filtered through Celite® with MeOH. The solvent was removed from the eluent under reduced pressure. The crude product was dissolved in Et2O (20 ml) and the organic layer was washed with saturated NaHCOs(aq) (3 x 20 ml). The solvent was removed from the organic layer under reduced pressure and the crude product purified by flash column chromatography (10-30% EtOAc in n-hexane) to afford the product as a brown waxy solid (109 mg, 55%). IR (neat, Vmax / crn’1): 3354, 1710;1H NMR (600 MHz; CD3OD) 5 8.02 (1 H, d, J = 1.9 Hz, 5-ArH), 7.94 (1 H, d, J = 1.8 Hz, 4-ArH), 7.39 (2H, m, 1-ArH & 8-ArH), 7.33 (1 H, dd, J = 8.5, 1.8 Hz, 2-ArH), 7.31 (1 H, dd, J = 8.6, 1.9 Hz, 7-ArH), 3.91 (1 H, q, J = 7.2 Hz, CHCH3), 3.65 (3H, s, CO2CH3), 1.55 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (151 MHz; CD3OD) 5 177.4, 141.3, 140.2, 132.8, 126.8, 126.6, 125.4, 125.1 , 123.6, 120.6, 120.0, 112.9, 112.1 , 52.4, 46.5, 19.5; m / z [ES-] 288 ([37M - H]’, 35%), 286 ([35M - H]’, 100%); m / z [HRMS, ES-] found [M - H]’ 286.0640, Ci6Hi335CINO2requires 286.0630.

[0254] Methyl 2-(9H-carbazol-3-yl)acetate (43)

[0255] Methyl 2-(4-(phenylamino)phenyl)acetate (150 mg, 0.62 mmol), palladium acetate (28 mg, 0.12 mmol), copper acetate (282 mg, 1.55 mmol), potassium carbonate (17 mg, 0.12 mmol) and pivalic acid (1.00 g, 10.6 mmol) were stirred at 100 °C for 6 h. The reaction was cooled to RT and filtered through Celite® with EtOAc. The solvent was removed from the eluent under reduced pressure. The crude product was dissolved in EtOAc (20 ml) and the organic layer was washed with saturated NaHCOs(aq) (3 x 20 ml). The solvent was removed from the organic layer in vacuo and the product purified by flash column chromatography (10-30% EtOAc in n-hexane) to afford the product as a white solid (93 mg, 63%). Mp 127-131 °C; IR (neat, vmax / cm-1): 3389, 1727;1H NMR (700 MHz; CDCI3) 6 8.06 (1 H, br s, NH), 8.05 (2H, app dt, J = 7.8, 1.0 Hz, 5-ArH), 7.98 (1 H, d, J = 1.6 Hz, 4-ArH), 7.43-7.38 (2H, m, 7-ArH & 8-ArH), 7.34 (2H, m, 1-ArH & 2-ArH), 7.23 (1 H, ddd, J = 7.8, 6.4, 1.7 Hz, 6-ArH), 3.81 (2H, s, CH2), 3.72 (3H, s, CO2CH3);13C NMR (176 MHz; CDCI3) 6 173.0, 140.0, 138.8, 127.2, 126.1 , 125.1 , 123.8, 123.2, 121.1 , 120.5, 119.6, 110.80, 110.77, 52.2, 41.4; m / z [ES+] 240 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+240.1016, CI5HI4NO2requires 240.1019. Methyl 2-(6-fluoro-9H-carbazol-3-yl)acetate (41)

[0256] Methyl 2-(4-((4-fluorophenyl)amino)phenyl)acetate (125 mg, 0.48 mmol), palladium acetate (22.0 mg, 0.10 mmol), potassium carbonate (13 mg, 0.10 mmol) and pivalic acid (837 mg 8.20 mmol) were stirred at 100 °C for 6 h. The reaction was cooled to RT, filtered through Celite®, washedwith EtOAc and the solvent was removed under reduced pressure. The crude product was dissolved in EtOAc (20 ml) and the organic layer was washed with saturated NaHCOs(aq) (3 x 20 ml). The solvent was removed from the organic layer in vacuo and the product was purified by flash column chromatography (10-30% EtOAc in n-hexane) to afford the product as a white solid (41 mg, 33%). Mp 134-140 °C; IR (neat, vmax / cnr1): 3360, 1722;1H NMR (700 MHz; CDCh) 6 8.02 (1H, br s, NH), 7.91 (1H, s, 4-ArH), 7.68 (1H, dd, J = 8.8, 2.6 Hz, 5-ArH), 7.38-7.34 (2H, m, 1-ArH & 2-ArH), 7.32 (1H, dd, J = 8.7, 4.6 Hz, 8-ArH), 7.14 (1H, app td, J = 9.0, 2.6 Hz, 7-ArH), 3.79 (2H, s, CH2), 3.72 (3H, s, CO2CH3);13C NMR (176 MHz; CDCI3) 6 172.9, 157.7 (d,1CF = 235.8 Hz), 139.8, 136.2, 127.8, 125.2, 123.8 (d, J = 8.8 Hz), 123.5 (d, J = 5.3 Hz), 121.3, 113.9 (d, J = 24.6 Hz), 111.3 (d, J = 10 .6 Hz), 111.1, 106.1 (d, J = 22.9 Hz), 52.2, 41.3;19F NMR (282 MHz; CDCI3) 6 -124.3 (6-F); m / z [ES+] 258 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+258.0925, C15H13FNO2 requires 258.0925.

[0257] Methyl 2-(6-(trifluoromethyl)-9H-carbazol-3-yl)acetate (42)

[0258] Methyl 2-(4-((4-(trifluoromethyl)phenyl)amino)phenyl)acetate (200 mg, 0.65 mmol), palladium acetate (29.0 mg, 0.13 mmol), copper acetate (295 mg, 1.63 mmol), potassium carbonate (18.0 mg, 0.13 mmol) and pivalic acid (1.13 g, 11.1 mmol) were stirred at 100 °C for 6 h. The reaction was cooled to RT, filtered through Celite®, washed with EtOAc andthe solvent removed under reduced pressure. The crude product was dissolved in EtOAc (20 ml) and the organic layer was washed with saturated NaHCOs(aq) (3 x 20 ml). The solvent was removed from the organic layer in vacuo and the product purified by flash column chromatography (10-30% EtOAc in n-hexane) to afford the product as a white solid (87 mg, 44%). Mp 138-142 °C; IR (neat, vmax / cm-1): 3324, 1716, 1612;1H NMR (700 MHz; CDCI3) 6 8.31 (1 H, s, NH), 8.27 (1 H, s, 5-ArH), 7.97 (1 H, s, 4-ArH), 7.62 (1 H, dd, J = 8.5, 1.2 Hz, 7-ArH), 7.42 (1 H, d, J = 8.5 Hz, 8-ArH), 7.36 (2H, m, 1-ArH & 2-ArH), 3.81 (2H, s, CH2), 3.74 (3H, s, CO2CH3);13C NMR (176 MH;, CDCI3) 6 172.9, 141.4, 139.2, 128.2, 125.9, 124.7 (q,1CF = 271 Hz), 123.3, 122.9 (q, J = 4.1 Hz) 122.8, 121.8 (q, J = 32.3 Hz), 121.3, 118.06 (q, J = 4.1 Hz), 111.2, 110.8, 52.3, 41.3;19F NMR (282 MHz; CDCI3) 6 -60.4 (CF3); m / z [ES-] 306 ([M - H]’, 100%); m / z [HRMS, ES-] found [M - H]’ 306.0738, C16H11F3NO2 requires 306.0747.

[0259] Methyl 2-(7-chloro-9H-carbazol-3-yl)acetate (44)

[0260] Methyl 2-(4-((3-chlorophenyl)amino)phenyl)acetate (300 mg, 1.09 mmol), palladium acetate (49.0 mg, 0.22 mmol), copper acetate (495 mg, 2.72 mmol), potassium carbonate (30.0 mg, 0.22 mmol) and pivalic acid (1.89 g, 18.5 mmol) were stirred at 100 °C for 6 h. The reaction was cooled to RT and filtered through Celite® with EtOAc. The eluent was then washed with saturated NaHCOs(aq) (4 x 80 ml). The solvent was removed from the organic layer under reduced pressure and the crude product was purified by flash column chromatography (10 - 30% EtOAc in n-hexane) to afford the product as a white solid (172 mg, 58%). Mp 104-106 °C; IR (neat, vmax / cm-1): 3359, 1724, 1634;1H NMR (700 MHz; CDCI3) 6 8.07 (1 H, s, NH), 7.93-7.90 (2H, m, 4-ArH & 5-ArH), 7.38 (1 H, d, J = 1.8 Hz, 8-ArH), 7.36-7.32 (2H, m, 1- ArH & 2-ArH), 7.18 (1 H, dd, J = 8.3, 1.8 Hz, 6-ArH), 3.79 (2H, s, CH2), 3.72 (3H, s, CO2CH3);13C NMR (176 MHz; CDCI3) 6 172.9, 140.4, 139.0, 131.7, 127.5, 125.6, 123.2, 121.9, 121.3, 121.0, 120.2, 111.0, 110.8, 52.2, 41.3; m / z [ES-] 274 ([37M - H]’, 100%), 272 ([35M - H]-, 100%); m / z [HRMS, ES-] found [M - H]’ 272.0475, CI5HII35CINO2requires 272.0484.

[0261] Methyl 2-(6-methyl-9H-carbazol-3-yl)acetate (45)

[0262] Methyl 2-(4-(p-tolylamino)phenyl)acetate (200 mg, 0.78 mmol), palladium acetate (35.0 mg, 0.16 mmol), copper acetate (356 mg, 1.96 mmol), potassium carbonate (22.0 mg, 0.16 mmol) and pivalic acid (1.36 g, 13.3 mmol) were stirred at 100 °C for 6 h. The reaction was cooled to RT and filtered through Celite® with EtOAc. The eluent was then washed with saturated NaHCOs(aq) (4 x 80 ml). The solvent was removed from the organic layer under reduced pressure and the crude product was purified by flash column chromatography (10 - 30% EtOAc in n-hexane) to afford the product as an off-white solid (126 mg, 63%). Mp 114— 116 °C; IR (neat, vmax / cm-1): 3357, 1723;1H NMR (700 MHz; CDCI3) 6 7.94 (2H, br m, 4-ArH & NH), 7.84 (1 H, s, 5-ArH), 7.34 (1 H, d, J = 8.3 Hz, 1-ArH), 7.32-7.28 (2H, m, 2-ArH & 8- ArH), 7.23 (1 H, d, J = 6.3 Hz, 7-ArH), 3.79 (2H s, CH2), 3.71 (3H, s, CO2CH3), 2.52 (3H, s, ArCH3);13C NMR (176 MHz; CDCI3) 6 173.0, 139.1 , 138.2, 128.9, 127.4, 127.0, 124.9, 123.7, 123.4, 121.0, 120.4, 110.7, 110.4, 52.2, 41.5, 21.6; m / z [ES+] 254 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+254.1176, CI6HI6NO2requires 254.1176.

[0263] Methyl 2-(6-methoxy-9H-carbazol-3-yl)acetate (46)

[0264] Methyl 2-(4-((4-methoxyphenyl)amino)phenyl)acetate (200 mg, 0.74 mmol), palladium acetate (33.0 mg, 0.15 mmol), copper acetate (334 mg, 1.84 mmol), potassium carbonate (20.0 mg, 0.15 mmol) and pivalic acid (1.28 g, 12.5 mmol) were stirred at 100 °C for 6 h. The reaction was cooled to RT and filtered through Celite® with EtOAc. The eluent was washed with saturated NaHCOs(aq) (4 x 80 ml). The solvent was then removed from the organic layer under reduced pressure and the crude product purified by flash column chromatography (10 - 30% EtOAc in n-hexane) to afford the product as a white crystalline solid (135 mg, 68%). Mp 57-61 °C; IR (neat, vmax / cm-1): 3391 , 1731 ;1H NMR (700 MHz; CDCI3) 6 7.94 (1 H, m, 4-ArH), 7.91 (1 H, br s, NH) 7.52 (1 H, d, J = 2.4 Hz, 5-ArH), 7.34- 7.27 (3H, m, 1-ArH, 2-ArH & 8-ArH), 7.05 (1 H, dd, J = 8.7, 2.4 Hz, 7-ArH), 3.92 (3H, s, OCH3), 3.80 (2H, s, CH2), 3.72 (3H, s, CO2CH3);13C NMR (151 MHz; CDCI3) 6 173.1 , 153.9, 139.5, 134.8, 127.1 , 124.6, 123.7, 123.6, 120.9, 115.4, 111.5, 111.0, 103.1 , 56.1 , 52.2, 41.4; m / z [ES+] 270 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+270.1125, Ci6Hi6NO3requires 270.1125.

[0265] Methyl 2-(6-bromo-9H-carbazol-3-yl)acetate (47)

[0266] Methyl 2-(4-((4-bromophenyl)amino)phenyl)acetate (125 mg, 0.39 mmol), palladium acetate (18.0 mg, 0.08 mmol), copper acetate (177 mg, 0.98 mmol), potassium carbonate (11.0 mg, 0.08 mmol) and pivalic acid (678 mg, 6.64 mmol) were stirred at 100 °C for 6 h. The reaction was cooled to RT and filtered through Celite® with EtOAc. The solvent was removed from the eluent under reduced pressure, the crude product was dissolved in EtOAc (20 ml) and the organic layer was washed with saturated NaHCO3(aq) (3 x 20 ml).

[0267] The solvent was removed from the organic layer in vacuo and the crude product purified by flash column chromatography (10 - 30% EtOAc in n-hexane) to afford the product as a brown solid (27 mg, 22%). Mp 132-138 °C; IR (neat, Vmax / crn’1): 3358, 1720, 1607, 1511 ;1H NMR (700 MHz; CDCI3) 5 8.14 (1 H, d, J = 2.0 Hz, 5-ArH), 8.09 (1 H, s, NH), 7.91 (1 H, s, 4- ArH), 7.48 (1 H, dd, J = 8.5, 2.0 Hz, 7-ArH), 7.37-7.33 (2H, m, 1-ArH & 2-ArH), 7.28 (1 H d, J = 8.5 Hz, 8-ArH), 3.79 (2H, s, CH2), 3.72 (3H, s, CO2CH3);13C NMR (176 MHz; CDCI3) 5 172.8, 139.1 , 138.5, 128.8, 128.0, 125.6, 125.0, 123.3, 122.8, 121.2, 112.4, 112.2, 111.0, 52.2, 41.3; m / z [ES+] 320 ([81M + H]+, 100%), 318 ([79M + H]+, 100%); m / z [HRMS, ES-] found [7M - H]- 315.9968, Ci5Hii79BrNO2requires 315.9979.

[0268] 2-(6-Chloro-9H-carbazol-4-yl)acetic acid (31)

[0269] To a solution of methyl 2-(6-chloro-9 / 7-carbazol-4-yl)acetate (35.0 mg, 0.13 mmol) in a mixture of CH2CI2 (4 ml) and MeOH (0.5 ml) was added NaOH in MeOH (2 M, 2 ml, 4 mmol). The reaction mixture was stirred at RT for 36 h. The solvent was then removed under reduced pressure and the crude product was dissolved in water and washed with Et20 (3 x 20 ml). The aqueous layer was then acidified by addition of HCIfaq) (1 M) and extracted with Et20 (3 x 20 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude product was recrystallised (Et20 and pentane) to afford the product as an off-white crystalline solid (6.6 mg, 20%). Mp. 150-154 °C; IR (neat, Vmax / crm1): 3397, 3337, 2975, 2900, 1696;1H NMR (700 MHz; CD3OD) 5 8.09 (1 H, d, J = 2.0 Hz, 5-ArH), 7.42 (1 H, d, J = 8.6 Hz, 8-ArH), 7.40-7.31 (3H, m, 2-ArH, 3-ArH & 7-ArH), 7.04 (1H, d, J = 7.3 Hz, 1-ArH), 4.15 (2H, s, CH2);13C NMR (176 MHz; CD3OD) 5 175.2, 142.3, 139.8, 130.7, 127.1, 126.0, 125.0, 124.9, 122.6, 122.4, 122.1, 112.6, 110.9, 40.8; m / z [ES+] 260 ([35M + H]+, 10%), 216 ([37M - COOH]+, 30%), 214 ([35M - COOH]+, 100%); m / z [HRMS, ES+] found [M]+259.0399, CI4HI035CINO2requires 259.0395.

[0270] 2-(6-Chloro-9H-carbazol-2-yl)acetic acid (32)

[0271] To a solution of methyl 2-(6-chloro-9 / 7-carbazol-2-yl)acetate (20.0 mg, 0.07 mmol) in a mixture of CH2CI2 (2.5 ml) and MeOH (0.4 ml) was added NaOH in MeOH (2 M, 1.2 ml, 2.4 mmol). The reaction mixture was stirred at RT for 36 h. The solvent was then removed under reduced pressure and the crude product was dissolved in water and washed with Et2O (3 x 20 ml). The aqueous layer was then acidified by addition of HCI(aq) (1 M) and extracted with Et2O (3 x 20 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude product was recrystallised (Et2O and pentane) to afford the product as a pale brown solid (4.3 mg, 23%). Mp - Slowly decomposes 221-238 °C; IR (neat, vmax / cm-1): 3402, 2920, 2536, 1695;1H NMR (700 MH;, CD3OD) 5 7.99 (1 H, d, J = 2.1 Hz, 5-ArH), 7.97 (1 H, d, J = 8.0 Hz, 4-ArH), 7.41-7.35 (2H, m, 1-ArH & 8-ArH), 7.30 (1 H, dd, J = 8.5, 2.1 Hz, 7-ArH), 7.10 (1 H, dd, J = 8.0, 1.5 Hz, 3- ArH), 3.74 (2H, s, CH2);13C NMR (176 MHz; CD3OD) 5 176.0, 142.2, 139.9, 134.4, 126.2, 125.3, 125.0, 122.2, 121.5, 121.0, 120.4, 112.7, 112.6, 42.6; m / z [ES+] 260 ([35M + H]+, 10%), 216 ([37M - COOH]+, 30%), 214 ([35M - COOH]+, 100%); m / z [HRMS, ES+] found [M]+259.0400, CI4HIO35CIN02requires 259.0395.

[0272] 2-(6-Chloro-9H-carbazol-3-yl)acetic acid (30)

[0273] To a solution of methyl 2-(6-chloro-9H-carbazol-3-yl)acetate (35.0 mg, 0.13 mmol) in a mixture of CH2CI2(4 ml) and MeOH (0.5 ml) was added NaOH in MeOH (2 M, 2 ml, 0.4 mmol). The reaction mixture was stirred at RT for 36 h. The solvent was then removed under reduced pressure and the crude product was dissolved in water and washed with Et2O (3 x 20 ml). The aqueous layer was then acidified by addition of HCI<aq) (1 M) and then extracted with Et2O (3 x 20 ml). The organic layer was then dried over anhydrous Na2SO4and the solvent was removed under reduced pressure. The crude product was recrystallised (Et2O and pentane) to afford the product as an off-white crystalline solid (10.6 mg, 32%). Mp -slowly decomposes 215-232 °C; IR (neat, Vmax / cm-1): 3404, 3347, 3020, 2948, 2921 , 1693;1H NMR (700 MHz; CD3OD) 5 8.01 (1 H, d, J = 2.1 Hz, 5-H), 7.94 (1 H, s, 4-ArH), 7.40-7.35 (2H, m, 1-ArH & 8-ArH), 7.33 (1 H, dd, J = 8.3, 1.7 Hz, 2-ArH), 7.31 (1 H, dd, J = 8.5, 2.1 Hz, 7-ArH), 3.74 (2H, s, CH2);13C NMR (176 MHz; CD3OD) 5 176.4, 141.0, 140.0, 128.7, 126.6, 126.4, 125.3, 125.0, 123.5, 121.8, 120.5, 112.8, 111.8, 41.9; m / z [ES+] 262 ([37M + H]+, 10%), 260 ([35M + H]+, 45%), 216 ([37M + H - COOH]+, 25%), 214 ([35M - COOH]+, 75%); m / z [HRMS, ES+] found [M]+259.0398, CI4H35CINO2requires 259.0395.

[0274] 2-(6-Chloro-9H-carbazol-3-yl)propanoic acid (33)

[0275] To a solution of methyl 2-(6-chloro-9 / 7-carbazol-3-yl)propanoate (70.0 mg, 0.24 mmol) in a mixture of CH2CI2 (4 ml) and MeOH (0.5 ml) was added NaOH in MeOH (2 M, 2 ml, 4 mmol). The reaction mixture was stirred at RT for 48 h. The solvent was removed under reduced pressure and the crude product was dissolved in water and washed with Et2O (3 x 20 ml). The aqueous layer was then acidified by addition of HCIfaq) (1 M) and extracted with Et20 (3 x 20 ml). The organic layer was then dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford the crude product which was recrystallised (Et20 and pentane) to afford the product as a white solid (13.3 mg, 20%). Mp 166-170 °C; IR (neat, Vmax / cnr1): 3420 br, 2924 br, 1697, 1240;1H NMR (600 MHz; CD3OD) 5 8.02 (1 H, d, J = 2.1 Hz, 5-ArH), 7.98 (1 H, s, 4-ArH), 7.42-7.36 (3H, m, 1-ArH, 2-ArH & 8-ArH), 7.31 (1 H, dd, J = 8.6, 2.1 Hz, 7-ArH), 3.87 (1 H, q, J = 7.2 Hz, CHCH3), 1.55 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (151 MHz; CD3OD) 5 179.2, 141.2, 140.2, 133.3, 127.0, 126.5, 125.4, 125.1 , 123.5, 120.6, 120.0, 112.9, 112.0, 46.7, 19.6; m / z [ES-] 274 ([37M - H]’, 30%), 272 ([35M - H]-, 100%); m / z [HRMS, ES-] found [M - H]- 272.0468, CI5HII35CINO2requires 272.0484.

[0276] 2-(9H-Carbazol-3-yl)acetic acid (50)

[0277] To a solution of methyl 2-(9 / 7-carbazol-3-yl)acetate (50.0 mg, 0.21 mmol) in CH2CI2 (2.6 ml) was added NaOH in MeOH (2 M, 0.84 ml, 1.68 mmol). The reaction mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure and the crude product was dissolved in water and washed with EtOAc (3 x 20 ml). The aqueous layer was then acidified by the addition of HCI(aq) (1 M) and extracted with EtOAc (3 x 20 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude product was then recrystallised (Et2O and pentane) to afford the product as a white solid (14 mg, 30%). Mp 235-237 °C; IR (neat, Vmax / crn-1): 3392, br 2850, 1690;1H NMR (600 MHz; CD3OD) 6 8.03 (1 H, d, J = 7.9 Hz, 5-ArH), 7.96 (1 H, d, J =

[0278] 1.9 Hz, 4-ArH), 7.41 (1 H, d, J = 8.2 Hz, 8-ArH), 7.39 (1 H, d, J = 8.3 Hz, 1-ArH), 7.34 (1 H, ddd, J = 8.2, 7.0, 1.2 Hz, 7-ArH), 7.30 (1 H, dd, J = 8.3, 1.9 Hz, 2-ArH), 7.13 (1 H, ddd, J = 7.9, 7.0, 1.0 Hz, 6-ArH), 3.74 (2H, s, CH2);13C NMR (151 MHz; CD3OD) 5 176.7, 141.8, 140.5, 127.9, 126.6, 126.1 , 124.5, 124.1 , 121.6, 120.9, 119.7, 111.7, 111.6, 42.1 ; m / z [ES+] 226 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+226.0863, C14H12NO2 requires 226.0863.

[0279] 2-(6-Fluoro-9H-carbazol-3-yl)acetic acid (48)

[0280] To a solution of methyl 2-(6-fluoro-9H-carbazol-3-yl)acetate (26.5 mg, 0.10 mmol) in CH2CI2 (1.10 ml) was added NaOH in MeOH (2 M, 0.4 ml, 0.8 mmol). The reaction mixture was stirred at RT for 3 h. The solvent was under reduced pressure and the crude product was dissolved in water and washed with EtOAc (3 x 20 ml). The aqueous layer was then acidified by the addition of HCI<aq) (1 M) and extracted with EtOAc (3 x 20 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford the product as an off-white solid (20.2 mg, 81%). Mp 216-219 °C; IR (neat, Vmax / crn’1): 3403, 2849 br, 1690;1H NMR (600 MHz; CD3OD) 5 7.94 (1 H, d, J = 1.4 Hz, 4-ArH), 7.73 (1 H, dd, J = 9.2, 2.6 Hz, 5-ArH), 7.41-7.36 (2H, m, 1-ArH & 8-ArH), 7.33 (1 H, dd, J = 8.4, 1.4 Hz, 2-ArH), 7.12 (1 H, app td, J = 9.1 , 2.6 Hz, 7-ArH), 3.74 (2H, s, CH2);13C NMR (151 MHz; CD3OD) 5 176.6, 158.5 (d,1CF = 234.1 Hz), 141.6, 138.2, 128.6, 126.2, 124.5 (d, J = 10.6 Hz), 124.2 (d, J = 3.0 Hz) 121.9, 114.1 (d, J = 25.7 Hz) 112.4 (d, J = 9 Hz), 111.9, 106.2 (d, J = 22.7 Hz), 42.0;19F NMR (282 MHz; CDCI3) 6 -127.3 (6-F); m / z [ES+] 244 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+244.0772, C14H11FNO2 requires 244.0768.

[0281] 2-(6-Trifluoromethyl)-9H-carbazol-3-yl)acetic acid (49)

[0282] To a solution of methyl 2-(6-(trifluoromethyl)-9 / 7-carbazol-3-yl)acetate (50.0 mg, 0.16 mmol) in CH2CI2 (1.95 ml) was added NaOH in MeOH (2 M, 0.64 ml, 1.28 mmol). The reaction mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure and the crude product dissolved in water and washed with EtOAc (3 x 20 ml). The aqueous layer was then acidified by the addition of HCIfaq) (1 M) and extracted with EtOAc (3 x 20 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford the product as a brown solid (31.4 mg, 66%). Mp 158-162 °C; IR (neat, vmax / cm-1): 3398, 2852 br, 1699;1H NMR (600 MHz; CD3OD) 5 8.33 (1 H, s, 5-ArH), 8.02 (1 H, d, J = 1.4 Hz, 4-ArH), 7.60 (1 H, d, J = 8.5 Hz, 7-ArH), 7.52 (1 H, d, J = 8.5 Hz, 8-ArH), 7.43 (1 H, d, J = 8.4 Hz, 1-ArH), 7.37 (1 H, dd, J = 8.4, 1.4 Hz, 2-ArH), 3.77 (2H, s, CH2);13C NMR (151 MHz; CD3OD) 5 176.5, 143.4, 141.2, 127.0 (q,1CF = 270.8 Hz), 129.1 , 127.2, 124.0, 123.7, 123.2 (q, J = 3.5 Hz), 122.0, 121.8 - 121.4 (m), 118.5 (q, J = 4.0 Hz), 112.1 , 112.0, 41.9;19F NMR (282 MHz; CDCI3) 6 -61.5 (CF3); m / z [ES-] 292 ([M - H]-, 100%); m / z [HRMS, ES+] found [M + H]+294.0733, C15H11F3NO2 requires 294.0736.

[0283] 2-(6-Bromo-9H-carbazol-3-yl)acetic acid (54)

[0284] To a solution of methyl 2-(6-bromo-9 / 7-carbazol-3-yl)acetate (15.0 mg, 0.05 mmol) in CH2CI2 (0.60 ml) was added NaOH in MeOH (2 M, 0.4 ml, 0.8 mmol). The reaction mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure and the crude product dissolved in water and washed with EtOAc (3 x 10 ml). The aqueous layer was then acidified by the addition of HCIfaq) (1 M) and extracted with EtOAc (3 x 10 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent removed under reduced pressure to afford the product as an off-white solid (9.2 mg, 64%). Mp 194-197 °C; IR (neat, Vmax / cm-1): 3404, 2920, 1691 ;1H NMR (600 MHz; CD3OD) 5 8.17 (1 H, d, J = 2.0 Hz, 5-ArH), 7.95 (1 H, s, 4-ArH), 7.44 (1 H, dd, J = 8.6, 2.0 Hz, 7-ArH), 7.40 (1 H, d, J = 8.3 Hz, 1-ArH), 7.34 (2H, m, 2-ArH & 8-ArH), 3.75 (2H, s, CH2);13C NMR (151 MHz; CD3OD) 5 176.5, 141.0, 140.4, 129.2, 128.8, 126.8, 126.0, 123.7, 123.5, 121.9, 113.4, 112.2, 111.9, 42.0; m / z [ES-] 304 ([81M - Hp, 100%), 302 ([79M - Hp, 100%); m / z [HRMS, ES-] found [M - Hp 301.9813, Ci4H979BrNO2requires 301.9822.

[0285] 2-(7-Chloro-9H-carbazol-3-yl)acetic acid (51)

[0286] To a solution of 2-(7-chloro-9 / 7-carbazol-3-yl)acetic acid (100 mg, 0.37 mmol) in CH2CI2 (4.5 ml) was added NaOH in MeOH (2 M, 1.5 ml, 3.0 mmol). The reaction mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure and the crude product dissolved in water and washed with EtOAc (3 x 20 ml). The aqueous layer was then acidified by the addition of HCI<aq) (1 M) and extracted with EtOAc (3 x 20 ml). The organic layer was dried over anhydrous Na2SO4and the solvent removed under reduced pressure to afford the product as a white solid (62.4 mg, 66%). Mp: 214-218 °C; IR (neat, Vmax / cnr1): 3389, 2917 br, 1690;1H NMR (600 MHz; CD3OD) 5 7.98 (1 H, d, J = 8.3 Hz, 5-ArH), 7.95 (1 H, s, 4-ArH), 7.43-7.37 (2H, m, 1-ArH & 8-ArH), 7.33 (1 H, d, J = 8.3 Hz, 2-ArH), 7.12 (1 H, d, J = 8.3 Hz, 6-ArH), 3.75 (2H, s, CH2);13C NMR (151 MHz; CD3OD) 5 176.5, 142.4, 140.9, 132.1 , 128.4, 126.8, 123.9, 122.9, 122.0, 121.7, 120.0, 111.8, 111.6, 42.0; m / z [ES-] 260 ([37M - Hp, 35%), 258 ([35M - Hp, 100%); m / z [HRMS, ES+] found [M + H]+260.0474, Ci4Hn35CINO2requires 260.0473.

[0287] 2-(6-Methoxy-9H-carbazol-3-yl)acetic acid (53)

[0288] To a solution of methyl 2-(6-methoxy-9 / 7-carbazol-3-yl)acetate (50.0 mg, 0.19 mmol) in CH2CI2 (2.2 ml) was added NaOH in MeOH (2 M, 0.8 ml, 1.6 mmol). The reaction mixture was stirred at RT for 3 h and the solvent removed under reduced pressure. The crude product was then dissolved in water and washed with EtOAc (3 x 20 ml). The aqueous layer was acidified by the addition of HCI(aq) (1 M) and extracted with EtOAc (3 x 20 ml). The organic layer was dried over anhydrous Na2SC>4 and the solvent removed under reduced pressure. The crude product was then recrystallised (Et2O and pentane) to afford the product as a pale-yellow solid (11.4 mg, 24%). Mp 173-177 °C; IR (neat, Vmax / crn-1): 3428, 2937 br, 1697;1H NMR (600 MHz; CD3OD) 5 7.93 (1 H, d, J = 1.4 Hz, 4-ArH), 7.57 (1 H, d, J = 2.5 Hz, 5-ArH), 7.35 (1 H, d, J = 8.3 Hz, 1-ArH), 7.32 (1 H, d, J = 8.8 Hz, 8-ArH), 7.27 (1 H, dd, J = 8.3, 1.4 Hz, 2-ArH), 7.00 (1 H, dd, J = 8.8, 2.5 Hz, 7-ArH), 3.88 (3H, s, OCH3), 3.73 (2H, s, CH2);13C NMR (151 MHz; CD3OD) 5 176.7, 154.9, 141.2, 136.8, 127.8, 125.6, 124.5, 124.4, 121.6, 116.0, 112.4, 111.7, 103.7, 56.4, 42.1 ; m / z [ES+] 256 ([M + H]+, 100%); m / z [HRMS, ES+] found [M - H]’ 238.0862, CI5HI2NO3requires 238.073.

[0289] 2-(6-Methyl-9H-carbazol-3-yl)acetic acid (52)

[0290] To a solution of methyl 2-(6-methyl-9 / 7-carbazol-3-yl)acetate (100 mg, 0.39 mmol) in CH2CI2(4.5 ml) was added NaOH in MeOH (2 M, 1.5 ml, 3.0 mmol). The reaction mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure and the crude product dissolved in water and washed with EtOAc (3 x 20 ml). The aqueous layer was then acidified by the addition of HCI<aq) (1 M) and extracted with EtOAc (3 x 20 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent removed under reduced pressure. The crude product was then recrystallised (Et2O and pentane) to afford the product as a pale-yellow solid (35.3 mg, 37%). Mp 211-215 °C; IR (neat, Vmax / crm1): 3400, 2859 br, 1693;1H NMR (600 MHz; CD3OD) 5 7.91 (1 H, d, J = 1.4 Hz, 4-ArH), 7.82 (1 H, d, J = 1.6 Hz, 5- ArH), 7.35 (1 H, d, J = 8.5 Hz, 1-ArH), 7.30 (1 H, d, J = 8.2 Hz, 8-ArH), 7.27 (1 H, dd, J = 8.5, 1.4 Hz, 2-ArH), 7.18 (1 H, dd, J = 8.2, 1.6 Hz, 7-ArH), 3.73 (2H s, CH2), 2.48 (3H, s, ArCH3);13C NMR (151 MHz; CD3OD) 5 176.7, 140.8, 140.1 , 128.9, 127.9, 127.7, 125.8, 124.4, 124.3, 121.5, 120.8, 111.5, 111.4, 42.1 , 21.5; m / z [ES+] 240 ([M + H]+, 100%); m / z [HRMS, ES-] found [M - H]- 240.1019, CI5HI2NO2requires 240.1019. tert- Butyl 3-chloro-6-( 1 -methoxy- 1 -oxopropan-2-yl)-9H-carbazole-9-carboxylate (2)

[0291] Methyl 2-(6-chloro-9H-carbazol-2-yl)propanoate (660 mg, 2.3 mmol), di-terf-butyl dicarbonate (950 mg, 4.36 mmol) and DMAP (280 mg, 2.3 mmol) were added to anhydrous acetonitrile (10 ml) and stirred at RT for 1 h. The solvent was removed under reduced pressure and the crude product purified by flash column chromatography (1-5% EtOAc in n-hexane) to afford the product as a white solid (842 mg, 95%). Mp 131-133 °C; IR (neat, Vmax / crn-1): 2979, 1736, 1708;1H NMR (700 MHz; CDCI3) 6 8.27 (1 H, s, 1-ArH), 8.23 (1 H, d, J = 8.9 Hz, 8-ArH), 7.90 (1 H, d, J = 2.2 Hz, 5-ArH), 7.87 (1 H, d, J = 8.0 Hz, 4-ArH), 7.39 (1 H, dd, J = 8.9, 2.2 Hz, 7-ArH), 7.31 (1 H, dd, J = 8.0, 1.7 Hz, 3-ArH), 3.90 (1 H, q, J = 7.2 Hz, CHCH3), 3.68 (3H, s, CO2CH3), 1.77 (9H, s, C(CH3)3), 1.60 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (176 MHz; CDCI3) 6 175.0, 150.9, 140.6, 139.3, 137.3, 128.8, 127.1 , 127.0, 124.0, 123.0, 120.0, 119.4, 117.5, 115.7, 84.6, 52.3, 46.1 , 28.5, 19.1 ; m / z [ES-] 386 ([35M - H]’, 5%), 288 ([37M - H - Boe]’, 33%), 286 ([35M - H - Boe]’, 100%); m / z [HRMS, ES+] found [M]+387.1228, C2IH22NO435CI requires 387.1232. tert-Butyl 3-(1-methoxy-1-oxopropan-2-yl)-6-phenyl-9H-carbazole-9-carboxylate (3)

[0292] A solution of terf-butyl 3-chloro-6-(1-methoxy-1-oxopropan-2-yl)-9H-carbazole-9-carboxylate (200 mg, 0.52 mmol), phenyl boronic acid (94.0 mg, 0.77 mmol), palladium acetate (6 mg, 5 mol%), XPhos (25 mg, 10 mol%), and potassium fluoride (90.0 mg, 1.55 mmol) in anhydrous dioxane (2.5 ml) was stirred at reflux for 18 h. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (2- 20% EtOAc in n-hexane) to afford the product as a white crystalline solid (210 mg, 95% yield). Mp 49-52 °C; IR (neat, vmax / cm-1): 2976, 1722, 1152, 1132;1H NMR (700 MHz; CDCI3) 6 8.34 (1 H, d, J = 8.5 Hz, 8-ArH), 8.31 (1 H, s, 1-ArH), 8.15 (1 H, d, J = 2.0 Hz, 5- ArH), 7.97 (1 H, d, J = 7.9 Hz, 4-ArH), 7.72-7.68 (3H, m, 7-ArH & 2’-ArH), 7.50-7.46 (2H, m, 3’-ArH), 7.38-7.35 (1 H, m, 4’-ArH), 7.32 (1 H, dd, J = 7.9, 2.0 Hz, 3-ArH), 3.92 (1 H, q, J = 7.2 Hz, CHCH3), 3.69 (3H, s, CO2CH3), 1.79 (9H, s, C(CH3)3), 1.61 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (176 MHz, CDCI3) 6 175.2, 151.2, 141.4, 140.1 , 139.3, 138.3, 136.5, 129.0, 127.4, 127.2, 126.4, 126.2, 125.1 , 122.8, 119.9, 118.1 , 116.6, 115.7, 84.3, 52.3, 46.2, 28.6, 19.1 ; m / z [ES+] 429 ([M]+, 14%); 374 ([MH -fBu]+, 100%), 314 ([M -fBu - COOMe]+, 49%); m / z [HRMS, ES+] found [M]+429.1933, C27H27NO4 requires 429.1935. tert-Butyl 2-(1-methoxy-1-oxopropan-2-yl)-6-(p-tolyl)-9H-carbazole-9-carboxylate (4)

[0293] A solution of tert-butyl 3-chloro-6-(1-methoxy-1-oxopropan-2-yl)-9H-carbazole-9-carboxylate (250 mg, 0.64 mmol), p-tolylboronic acid (131 mg, 0.97 mmol), palladium acetate (7.2 mg, 5.0 mol%), XPhos (30 mg, 10 mol%), and potassium fluoride (112 mg, 1.93 mmol) in anhydrous dioxane (3 ml) was heated at reflux for 18 h. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (2- 20% EtOAc in n-hexane) to afford the product as a white solid (246 mg, 86%). Mp 127-132 °C: IR (neat, Vmax / cm’1): 2972 br, 1722, 1150, 1130;1H NMR (600 MHz; CDCI3) 6 8.33-8.29 (2H, m, 1-ArH & 8-ArH), 8.13 (1 H, s, 5-ArH), 7.97 (1 H, d, J = 8.0 Hz, 4-ArH), 7.68 (1 H, d, J = 8.7 Hz, 7-ArH), 7.60 (2H, d, J = 7.8 Hz, 2’-ArH), 7.32 (1 H, d, J = 8.0 Hz, 3-ArH), 7.29 (2H, d, J = 7.8 Hz, 3’-ArH), 3.92 (1 H, q, J = 7.2 Hz, CHCH3), 3.69 (3H, s, CO2CH3), 2.42 (3H, s, ArCH3), 1.79 (9H, s, C(CH3)3), 1.61 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (151 MHz; CDCI3) 5 175.3, 151.2, 140.0, 139.3, 138.4, 138.1 , 137.0, 136.4, 129.7, 127.3, 126.3, 126.1 , 125.1 , 122.8, 119.9, 117.8, 116.6, 115.7, 84.2, 52.3, 46.1 , 28.6, 21.3, 19.2; m / z [ES+] 443 ([M]+, 7%); 388 ([MH — ‘Bu]+, 100%), 328 ([M-‘Bu-COOMe]+, 49%); m / z [HRMS, ES+] found [M]+443.2086, C28H29NO4 requires 443.2091. tert-Butyl 2-(1-methoxy-1-oxopropan-2-yl)-6-(4-methoxyphenyl)-9H-carbazole-9- carboxylate (5)

[0294] A solution of terf-butyl 3-chloro-6-(1-methoxy-1-oxopropan-2-yl)-9H-carbazole-9-carboxylate (250 mg, 0.64 mmol), 4-methoxyphenylboronic acid (147 mg, 0.97 mmol), palladium acetate (7.2 mg, 5.0 mol%), XPhos (30 mg, 10 mol%), and potassium fluoride (112 mg, 1.93 mmol) in anhydrous dioxane (3 ml) was heated at reflux for 18 h. The solvent was removed under reduced pressure and the crude product purified by flash column chromatography (2-20% EtOAc in n-hexane) to afford the product as a white solid (223 mg, 75%). Mp 136-139 °C; IR (neat, Vmax / cnr1): 3021 , 1730, 1151 , 1128;1H NMR (600 MHz; CDCI3) 6 8.34-8.30 (2H, m, 1-ArH & 8-ArH), 8.10 (1 H, s, 5-ArH), 7.96 (1 H, d, J = 8.0 Hz, 4-ArH), 7.68-7.59 (3H, m, 7-ArH & 2’-ArH), 7.32 (1 H, d, J = 8.0 Hz, 3-ArH), 7.02 (1 H, d, J = 7.2 Hz, 3’-ArH), 3.92 (1 H, q, J = 7.2 Hz, CHCH3), 3.87 (3H, s, ArOCH3), 3.69 (3H, s, CO2CH3), 1.79 (9H, s, C(CH3)3), 1.62 (3H, d, J = 7.2 Hz, CHC / 73);13C NMR (151 MHz; CDCI3) 6 175.3, 159.1 , 151.2, 140.0,

[0295] 139.3, 137.9, 136.1 , 133.9, 128.4, 126.1 , 126.1 , 125.1 , 122.8, 119.9, 117.6, 116.6, 115.7,

[0296] 114.4, 84.2, 55.5, 52.3, 46.2, 28.6, 19.2; m / z [ES+] 459 ([M]+, 7%); 404 ([MH -fBu]+, 100%), 344 ([M -fBu - COOMe]+, 34%); m / z [HRMS, ES+] found [M]+459.2037, C28H29NO5 requires 459.2040. tert-Butyl 2-(1-methoxy-1-oxopropan-2-yl)-6-(3-methoxyphenyl)-9H-carbazole-9- carboxylate (6)

[0297] A solution of terf-butyl 3-chloro-6-(1-methoxy-1-oxopropan-2-yl)-9H-carbazole-9-carboxylate (250 mg, 0.64 mmol), 3-methoxyphenylboronic acid (147 mg, 0.97 mmol), palladium acetate (7.2 mg, 5 mol%), XPhos (30 mg, 10 mol%), and potassium fluoride (112 mg, 1.93 mmol) in anhydrous dioxane (3 ml) was heated at reflux for 18 h. The solvent was removed under reduced pressure and the crude product purified by flash column chromatography (2-20% EtOAc in n-hexane) to afford the product as a colourless oil (252 mg, 85%). IR (neat, Vmax / crn-1): 2977, 1722, 1151 , 1130;1H NMR (600 MHz; CDCh) 6 8.38-8.28 (2H, m, 1-ArH & 8-ArH), 8.15 (1 H, s, 5-ArH), 7.97 (1 H, d, J = 7.9 Hz, 4-ArH), 7.69 (1 H, d, J = 8.7 Hz, 7- ArH), 7.40 (1 H, t, J = 7.5 Hz, 5’-ArH), 7.33 (1 H, d, J = 7.9 Hz, 3-ArH), 7.30 (1 H, d, J = 7.5 Hz, 6’ -ArH), 7.23 (1 H, s, 2’ -ArH), 6.92 (1 H, d, J = 7.5 Hz, 4’ -ArH), 3.90 (4H, m, CHCH3& ArOCHj), 3.69 (3H, s, CO2CH3), 1.79 (9H, s, C(CH3)3), 1.61 (3H, d, J = 7.2 Hz, CHCH- ;13C NMR (151 MHz; CDCI3) 6 175.2, 160.1 , 151.1 , 142.9, 140.1 , 139.3, 138.4, 136.3, 130.0, 126.5, 126.1 , 125.1 , 122.8, 120.0, 119.9, 118.1 , 116.6, 115.7, 113.2, 112.5, 84.3, 55.5, 52.3, 46.2, 28.6, 19.2; m / z [HRMS, ES+] found [M]+459.2037, C28H29NO5 requires

[0298] 459.2040. tert-Butyl 2-(1-methoxy-1-oxopropan-2-yl)-6-(2-methoxyphenyl)-9H-carbazole-9- carboxylate (7) A solution of tert-butyl 3-chloro-6-(1-methoxy-1-oxopropan-2-yl)-9H-carbazole-9-carboxylate (250 mg, 0.64 mmol), 2-methoxyphenylboronic acid (147 mg, 0.97 mmol), palladium acetate (7.2 mg, 5.0 mol%), XPhos (30 mg, 10 mol%), and potassium fluoride (112 mg, 1.93 mmol) in anhydrous dioxane (3 ml) was heated at reflux for 24 h. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (2- 20% EtOAc in n-hexane) to afford the product as a colourless oil (129 mg, 44%). IR (neat, Vmax / crn-1): 2977, 1722, 1152, 1132;1H NMR (600 MHz; CDCh) 6 8.35-8.25 (2H, m, 1-ArH & 8-ArH), 8.09 (1 H, s, 5-ArH), 7.93 (1 H, d, J = 8.0 Hz, 4-ArH), 7.63 (1 H, d, J = 8.7 Hz, 7- ArH), 7.42 (1 H, d, J = 7.4 Hz, 6’-ArH), 7.35 (1 H, app t, J = 7.8 Hz, 4’-ArH), 7.30 (1 H, d, J = 8.0 Hz, 3-ArH), 7.08 (1 H, app t, J = 7.4 Hz, 5’-ArH), 7.03 (1 H, d, J = 8.3 Hz, 3’-ArH), 3.91 (1 H, q, J = 7.2 Hz, CHCH3), 3.84 (3H, s, ArOCH3), 3.69 (3H, s, CO2CH3), 1.78 (9H, s, C(CH3)3) 1.61 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (151 MHz; CDCh) 6 175.3, 156.7, 151.2, 139.8, 139.2, 137.9, 133.6, 131.3, 130.8, 128.8, 128.7, 125.6, 125.2, 122.6, 121.0, 120.6, 119.9, 115.8, 115.7, 111.4, 84.1 , 55.8, 52.3, 46.1 , 28.5, 19.1 ; m / z [ES+] 458 ([M - H]-, 8%); 358 ([M - H - Boc]-, 100%); m / z [HRMS, ES+] found [M]+459.2037, C28H29NO5 requires 459.2040. tert-Butyl 2-(1-methoxy-1-oxopropan-2-yl)-6-(piperidin-1-yl)-9H-carbazole-9- carboxylate (8)

[0299] A solution of tert-butyl 3-chloro-6-(1-methoxy-1-oxopropan-2-yl)-9 / 7-carbazole-9-carboxylate (250 mg, 0.64 mmol), piperidine (82.0 mg, 0.97 mmol), palladium acetate (7.2 mg, 5.0 mol%), XPhos (30 mg, 10 mol%) and CS2CO3 (273 mg, 0.84 mmol) in anhydrous toluene (5 ml) was heated at reflux for 48 h under an argon atmosphere. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (5-20% EtOAc in petroleum ether) to afford the product as a colourless glassy solid (130 mg, 46%). Mp 121-124 °C; IR (neat, vmax / cm-1): 2948, 2791 , 1718, 1152, 1122;1H NMR (600 MHz; CDCI3) 6 8.27 (1 H, s, 1-ArH), 8.13 (1 H, d, J = 9.2 Hz, 8-ArH), 7.86 (1 H, d, J = 8.0 Hz, 4-ArH), 7.47 (1 H, d, J = 2.4 Hz, 5-ArH), 7.27 (1 H, dd, J = 8.0, 1.6 Hz, 3-ArH), 7.13 (1 H, dd, J = 9.2, 2.4 Hz, 7-ArH), 3.89 (1 H, q, J = 7.2 Hz, CHCH3), 3.68 (3H, s, CO2CH3), 3.23-3.18 (4H, m, 2’-H), 1.76 (13H, m, 3’-H & C(CH3)3), 1.61-1.57 (5H, m, CHCH3& 4’-H);13C NMR (151 MHz; CDCI3) 6 175.3, 151.2, 149.2, 139.5, 139.3, 133.0, 126.2, 125.3, 122.3, 119.6, 118.2, 116.7, 115.6, 107.2, 83.7, 52.3, 52.2, 46.1 , 28.5, 26.2, 24.4, 19.1 ; m / z [ES+] 436 ([M]+, 100%); m / z [HRMS, ES+] found [M + H]+437.2435, C26H33N2O4 requires 437.2435. tert-Butyl 2-(1-methoxy-1-oxopropan-2-yl)-6-morpholino-9H-carbazole-9-carboxylate

[0300] (9)

[0301] A solution of tert-butyl 3-chloro-6-(1-methoxy-1-oxopropan-2-yl)-9H-carbazole-9-carboxylate (200 mg, 0.51 mmol), morpholine (67.0 mg, 0.77 mmol), palladium acetate (6 mg, 5 mol%), XPhos (25 mg, 10 mol%) and CS2CO3 (273 mg, 0.84 mmol) in anhydrous toluene (8 ml) was heated at reflux for 48 h under an argon atmosphere. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (5- 20% EtOAc in n-hexane) to afford the product as a brown solid (33 mg, 12%). Mp 153- 156 °C; IR (neat, Vmax / cnr1): 2979, 2859, 1719;1H NMR (600 MHz; CDCI3) 6 8.26 (1 H, s, 1- ArH), 8.17 (1 H, app br s, 8-ArH), 7.87 (1 H, d, J = 7.9 Hz, 4-ArH), 7.45 (1 H, s, 5-ArH), 7.28 (1 H, d, J = 7.9 Hz, 3-ArH), 7.10 (1 H, d, J = 7.9 Hz, 7-ArH), 4.00-3.86 (5H, m, CHCH3& 1’- H), 3.67 (3H, s, CO2CH3) 3.24 (4H, t, J = 4.8 Hz, 2’-H), 1 .76 (9H, s, C(CH3)3), 1.59 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (151 MHz; CDCI3) 6 175.2, 151.1 , 148.0, 139.8, 139.3, 133.4, 126.4, 125.1 , 122.4, 119.7, 117.1 , 117.0, 115.7, 106.4, 83.9, 67.2, 52.3, 50.9, 46.1 , 28.5, 19.1 ; m / z [ES+] 439 ([M + H]+, 100%); m / z [HRMS, ES+] found [M +H]+439.2227, C25H31N2O5 requires 439.2227.

[0302] 2-(6-Phenyl-9H-carbazol-2-yl)propanoic acid (10)

[0303] To a solution of tert-butyl 2-(1 -methoxy- 1-oxopropan-2-yl)-6-phenyl-9H-carbazole-9- carboxylate (125 mg, 0.29 mmol) in CH2CI2 (2 ml) was added TFA (2 ml). The reaction mixture was stirred at RT for 1 h before the solvent was removed under reduced pressure. The crude product was then dissolved in CH2CI2 (4 ml) and methanolic NaOH (2 M, 2 ml, 4 mmol) and stirred at RT for 18 h. The solvent was removed under reduced pressure and the crude product was dissolved in water (10 ml) and washed with EtOAc (3 x 10 ml). The aqueous layer was acidified with HCI<aq) (1 M) and then extracted with EtOAc (3 x 10 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford the product as a solid (45 mg, 49%). Mp 188-192 °C; IR (neat, Vmax / crn-1): 3420, 2934, 1695;1H NMR (600 MHz; CD3OD) 5 8.26 (1 H , d, J = 1.9 Hz, 5- ArH), 8.06 (1 H, d, J = 8.2 Hz, 4-ArH), 7.70 (2H, dd, J = 8.0, 1.3 Hz, 2’-ArH), 7.64 (1 H, dd, J = 8.4, 1.9 Hz, 7-ArH), 7.49 (1 H, d, J = 8.4 Hz, 8-ArH), 7.46-7.41 (3H, m, 1-ArH & 3’-ArH), 7.29 (1 H, tt, J = 7.2, 1.3 Hz, 4’-ArH), 7.15 (1 H, dd, J = 8.2, 1.6 Hz, 3-ArH), 3.87 (1 H, q, J = 7.2 Hz, CHCH3), 1.55 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (151 MHz; CD3OD) 5 178.8, 143.7, 142.3, 141.3, 140.3, 133.5, 129.8, 128.1 , 127.3, 125.9, 124.7, 123.5, 121.1 , 119.7, 119.2, 112.0, 110.7, 47.2, 19.5; m / z [ES+] 316 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+316.1330, C21H18NO2 requires 316.1332.

[0304] 2-(6-(p-Tolyl)-9H-carbazol-2-yl)propanoic acid (11) ,

[0305] To a solution of terf-butyl 2-(1 -methoxy- 1-oxopropan-2-yl)-6-(p-tolyl)-9 / 7-carbazole- 9- carboxylate (150 mg, 0.34 mmol) in CH2CI2 (2 ml) was added TFA (2.0 ml, 26 mmol). The reaction mixture was stirred at RT for 1 h before the solvent was removed under reduced pressure. The crude product was then dissolved in CH2CI2 (4 ml) and methanolic NaOH (2 M, 2 ml, 4 mmol) before being stirred at RT for 18 h. The solvent was removed under reduced pressure and the crude product dissolved in water (10 ml) and washed with EtOAc (3 x 10 ml). The aqueous layer was acidified with HCI(aq) (1 M) and then extracted with EtOAc (3 x 10 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford the product as a white solid (58 mg, 52%). Mp 214-219 °C; IR (neat, Vmax / crrn1): 3414, 2923, 2543, 1694;1H NMR (600 MHz; CD3OD) 5 8.23 (1 H, d, J = 1.9 Hz, 5-ArH), 8.04 (1 H, d, J = 8.0 Hz, 4-ArH), 7.61 (1 H, dd, J = 8.4, 1.9 Hz, 7-ArH), 7.58 (2H, d, J = 8.3 Hz, 2’-ArH), 7.47 (1 H, d, J = 8.4 Hz, 8-ArH), 7.41 (1 H, d, J = 1.6 Hz 1-ArH), 7.25 (2H, d, J = 8.3 Hz, 3’-ArH), 7.14 (1 H, dd, J = 8.0, 1.6 Hz, 3-ArH), 3.86 (1 H, q, J = 7.2 Hz, CHCH3), 2.38 (3H, s, ArCH3), 1.55 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (151 MHz; CD3OD) 5 178.7, 142.3, 141.1 , 140.8, 140.2, 137.0, 133.5, 130.4, 127.9, 125.8, 124.7, 123.5, 121.1 , 119.6, 119.0, 111.9, 110.6, 47.1 , 21.1 , 19.5; m / z [ES+] 330 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+330.1481 , C22 H 20 NO2requires 330.1489.

[0306] 2-(6-(4-Methoxyphenyl)-9H-carbazol-2-yl)propanoic acid (12)

[0307] To a solution of terf-butyl 2-(1-methoxy-1-oxopropan-2-yl)-6-(4-methoxyphenyl)-9 / 7- carbazole-9-carboxylate (150 mg, 0.33 mmol) in CH2CI2 (2 ml) was added TFA (2.0 ml, 26 mmol). The reaction mixture was stirred at RT for 1 h before the solvent was removed under reduced pressure. The crude product was then dissolved in CH2CI2 (4 ml) and methanolic NaOH (2 M, 2 ml, 4 mmol) before being stirred at RT for 18 h. The solvent was removed under reduced pressure and crude product dissolved in water (10 ml) and washed with EtOAc (3 x 10 ml). The aqueous layer was acidified with HCIfaq) (1 M) and then extracted with EtOAc (3 x 10 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford the product as a solid (71 mg, 63%). Mp 185-187 °C; IR (neat, vmax / cm-1): 3405, 2975, 1695;1H NMR (600 MHz; CD3OD) 5 8.19 (1 H, d, J = 1.8 Hz, 5-ArH), 8.03 (1 H, d, J = 8.1 Hz, 4-ArH), 7.61 (2H, d, J = 8.8 Hz, 2’-ArH), 7.58 (1 H, dd, J = 8.4, 1.8 Hz, 7-ArH), 7.45 (1 H, d, J = 8.4 Hz, 8-ArH), 7.41 (1 H, s, 1-ArH), 7.13 (1 H, dd, J = 8.1 , 1.6 Hz, 3-ArH), 7.00 (2H, d, J = 8.8 Hz, 3’-ArH), 3.86 (1 H, q, J = 7.2 Hz, CHCH3), 3.83 (3H, s, ArOCH3), 1.54 (3H, d, J = 7.2 Hz, CHCH3);13C NMR

[0308] (151 MHz; CD3OD) 5 178.8, 160.0, 142.3, 140.9, 140.2, 136.2, 133.3, 129.0, 125.6, 124.7, 123.5, 121.1 , 119.6, 118.7, 115.2, 111.9, 110.6, 55.7, 47.2, 19.5; m / z [ES+] 346 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+346.1433, C22 H 20 NO3requires 346.1438.

[0309] 2-(6-(3-Methoxyphenyl)-9H-carbazol-2-yl)propanoic acid (13) ,

[0310] To a solution of terf-butyl 2-(1-methoxy-1-oxopropan-2-yl)-6-(3-methoxyphenyl)-9 / 7- carbazole-9-carboxylate (150 mg, 0.33 mmol) in CH2CI2 (2 ml) was added TFA (2.0 ml, 26 mmol). The reaction mixture was stirred at RT for 1 h before the solvent was removed under reduced pressure. The crude product was then dissolved in CH2CI2 (4 ml) and methanolic NaOH (2 M, 2 ml, 4 mmol) before being stirred at RT for 18 h. The solvent was removed under reduced pressure and the crude product dissolved in water (10 ml) and washed with EtOAc (3 x 10 ml). The aqueous layer was acidified with HCI<aq) (1 M) and then extracted with EtOAc (3 x 10 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude product was then recrystallised (Et20 and pentane) to afford the product as a brown solid (18 mg, 16%). Mp 159-164 °C; IR (neat, vmax / crn-1): 3443, 2943 br, 2555, 1710;1H NMR (600 MHz; CD3OD) 5 8.24 (1 H, d, J = 1.9 Hz, 5-ArH), 8.03 (1 H, d, J = 8.1 Hz, 4-ArH), 7.61 (1 H, dd, J = 8.4, 1.9 Hz, 7-ArH), 7.46 (1 H, d, J = 8.4 Hz, 8-ArH), 7.41 (1 H, d, J = 1.6 Hz, 1-ArH), 7.32 (1 H, t, J = 7.8 Hz, 5’-ArH), 7.25 (1 H, dt, J = 7.8, 1.4 Hz, 6’-ArH), 7.24-7.21 (1 H, m, 2’-ArH), 7.13 (1 H, dd, J = 8.1 , 1.6 Hz, 3-ArH), 6.85 (1 H, dd, J = 7.8, 2.6 Hz, 4’-ArH), 3.85 (4H, m, CHCH3& ArOCH3), 1.54 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (151 MHz; CD3OD) 5 178.7, 161.5, 145.1 , 142.2, 141.3, 140.3, 133.4, 130.7, 125.9, 124.7, 123.5, 121.2, 120.6, 119.7, 119.3, 113.7, 112.6, 111.9, 110.6, 55.7, 47.1 , 19.5; m / z [ES+] 346 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+346.1432, C22H20NO3 requires 346.1438.

[0311] 2-(6-(2-Methoxyphenyl)-9H-carbazol-2-yl)propanoic acid (14) ,

[0312] To a solution of terf-butyl 2-(1-methoxy-1-oxopropan-2-yl)-6-(2-methoxyphenyl)-9 / 7- carbazole-9-carboxylate (100 mg, 0.22 mmol) in CH2CI2 (2 ml) was added TFA (2.0 ml, 26 mmol). The reaction mixture was stirred at RT for 1 h before the solvent was removed under reduced pressure. The crude product was then dissolved in CH2CI2 (4 ml) and methanolic NaOH (2 M, 2 ml, 4 mmol) before being stirred at RT for 18 h. The solvent was removed under reduced pressure and the crude product was dissolved in water (10 ml) and washed with EtOAc (3 x 10 ml). The aqueous layer was acidified with HCI(aq) (1 M) and then extracted with EtOAc (3 x 10 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to afford the product as an oil (53 mg, 35%). IR (neat, Vmax / cnr1): 3404, 2978 br, 1703;1H NMR (600 MHz; CD3OD) 5 8.10 (1 H, d, J = 1.8 Hz, 5-ArH), 7.98 (1 H, d, J = 8.0 Hz, 4-ArH), 7.49 (1 H, dd, J = 8.4, 1.8 Hz, 7-ArH), 7.44-7.40 (2H, m, 1-ArH & 8-ArH), 7.36 (1 H, dd, J = 7.4, 1.7 Hz, 6’-ArH), 7.29 (1 H, ddd, J = 8.3, 7.4, 1.7 Hz, 4’-ArH), 7.12 (1 H, dd, J = 8.0, 1.6 Hz, 3-ArH), 7.07 (1 H, dd, J = 8.3, 1.2 Hz, 3’-ArH), 7.02 (1 H, app td, J = 7.4, 1.2 Hz, 5’-ArH), 3.86 (1 H, q, J = 7.1 Hz, CHCH3), 3.80 (3H, s, ArOCHj), 1.54 (3H, d, J = 7.1 Hz, CHCH3);13C NMR (151 MHz; CD3OD) 5 178.8, 158.1 , 142.1 , 140.8, 140.0, 133.2, 132.1 , 130.8, 129.0, 128.5, 124.0, 123.5, 121.9, 121.7, 121.0, 119.5, 112.6, 111.0, 110.6, 56.1 , 47.1 , 19.5; m / z [ES+] 346 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+346.1438, C22H20NO3 requires 346.1438.

[0313] 2-(6-(Piperidin-1-yl)-9H-carbazol-2-yl)propanoic acid (15)

[0314] To a solution of terf-butyl 2-(1-methoxy-1-oxopropan-2-yl)-6-(piperidin-1-yl)-9 / 7-carbazole-9- carboxylate (75.0 mg, 0.17 mmol) in CH2CI2 (2 ml) was added TFA (2.0 ml, 26 mmol). The reaction mixture was stirred at RT for 1 h before the solvent was removed under reduced pressure. The crude product was then dissolved in CH2CI2 (4 ml) and methanolic NaOH (2 M, 2 ml, 4 mmol) before being stirred at RT for 18 h. The solvent was removed under reduced pressure and the crude product dissolved in water (10 ml) and washed with EtOAc (3 x 10 ml). The aqueous layer was acidified with HCI(aq) (1 M) and then extracted with EtOAc (3 x 10 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude product was then recrystallised (Et20 and pentane) to afford the product as a white solid (4.8 mg, 6%). IR (neat, vmax / cnr1): 3221 br, 2868 br, 1666;1H NMR (600 MHz; CD3OD) 5 8.12 (1 H, d, = 2.4 Hz, 5-ArH), 8.00 (1 H, d, J = 8.1 Hz, 4-ArH), 7.49 (1 H, d, J = 8.8 Hz, 8-ArH), 7.44 (2H, m, 1-ArH & 7-ArH), 7.17 (1 H, dd, J = 8.1 , 1.6 Hz, 3-ArH), 3.86 (1 H, q, J = 7.2 Hz, CHCH3), 3.50 (4H, t, J = 5.6 Hz, 2’-H), 1.98 (4H, app quint, J = 6.0 Hz 3’-H), 1.74 (2H, pentet, J = 6.0 Hz, 4’-H), 1.53 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (151 MHz; CD3OD) 5 178.9, 142.7, 141.5, 140.4, 139.0, 124.6, 122.8, 121.3, 120.2, 119.2, 112.8, 112.5, 111.0, 57.9, 47.5, 25.8, 23.1 , 19.5; m / z [ES+] 323 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+323.1753, C20H23N2O2 requires 323.1754.

[0315] 2-(6-Morpholino-9H-carbazol-2-yl)propanoic acid (16)

[0316] To a solution of terf-butyl 2-(1-methoxy-1-oxopropan-2-yl)-6-morpholino-9 / 7-carbazole-9- carboxylate (50 mg, 0.11 mmol) in CH2CI2 (2 ml) was added TFA (2 ml). The reaction mixture was stirred at RT for 1 h before the solvent was removed under reduced pressure. The crude product was then dissolved in CH2CI2 (4 ml) and methanolic NaOH (2 M, 2 ml, 4 mmol) before being stirred at RT for 18 h. The solvent was removed and the crude product dissolved in water (10 ml) and washed with EtOAc (3 x 10 ml). The aqueous layer was acidified with HCI(aq) (1 M) and then extracted with EtOAc (3 x 10 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude product was then recrystallised (Et20 and pentane) to afford the product as a white solid (3.7 mg, 10%). Mp 229-234 °C; IR (neat, Vmax / cnT1): 3249 br, 2923 br, 1707;1H NMR (600 MHz; CD3OD) 5 7.95 (1 H, d, J = 8.1 Hz, 4-ArH), 7.65 (1 H, d, J = 2.4 Hz, 5-ArH), 7.36 (1 H, s, 1-ArH), 7.34 (1 H, d, J = 8.7 Hz, 8-ArH), 7.13 (1H, dd, J = 8.7, 2.4 Hz, 7-ArH), 7.09 (1H, dd, J = 8.1, 1.6 Hz, 3-ArH), 3.89-3.81 (5H, m, CHCH3& 3’-H), 3.13 (4H, t, J = 4.8 Hz, 2’-H), 1.52 (3H, d, J = 7.2 Hz, CHCH3);13C NMR (151 MHz; CD3OD) 5 178.8, 145.7, 142.4, 140.0, 137.7, 124.5, 123.4, 121.0, 119.3, 119.1 , 112.3, 110.6, 109.1 , 68.0, 53.6, 47.1 , 19.5; m / z [ES+] 325 ([M + H]+, 100%); m / z [HRMS, ES+] found [M + H]+325.1544, C19H21N2O3 requires 325.1547.

[0317] Antimycobacterial potency

[0318] Compounds according to the invention were evaluated for their antimycobacterial potency and selectivity according to literature assays referenced herein11. All of the compounds tested had a clear selectivity for toxicity to the slow-growing M. bovis BCG (ATCC35734) over the fast-growing M. smegmatis mc2155 (ATCC700084). This was consistent with the selectivity previously observed for carprofen.11 46

[0319] Compounds 12 and 13 were identified as particularly interesting compounds, having MIC values of 7.8 pg / ml (24 pM) in the HT-SPOTi assay and SI values of 8, based on this data. However, both performed less impressively in the REMA assay, with MICs of 31.3 pg / ml and 62.5 pg / ml, respectively, resulting in reduced SI values of 2 and 1. This represented a significant increase in activity compared to carprofen, with some small gains in selectivity. All of the C-6 aryl-substituted carbazoles in this series maintained significant antitubercular activity in both assays.

[0320] Of the other compounds tested, the presence of a methyl ester in place of a carboxylic acid was generally beneficial. Moreover, C-3 substitution was found to confer the most desirable activity to the carboxylic acid-bearing carbazoles, with 30 displaying increased antimycobacterial potency and selectivity compared to 32. However, for methyl esters the reverse was true, as C-2 substituted carbazole 28 displayed increased potency and selectivity compared to 26.

[0321] Evaluation of C-3 subsituted carbazoles for activity against M. smegmatis, M. bovis BCG and THP-1 cells identified the C-6 trifluoromethyl-substituted carbazole 42 as the most potent and selective carprofen analogue, with an MIC of 3.9 pg / ml (12 pM) in the HT-SPOTi assay against M. bovis BCG and an SI of 64. In the context of C-3 subsituted carbazoles, it was also established that the methyl ester analogues were in all cases more potent and selective than their carboxylic acid counterparts. Carprofen and compound 42 were tested against Mycobacterium tuberculosis H37Rv (Mtb) in vitro. Compound 42 was found to be 8 times more potent in killing Mtb than Carprofen (Compound 42 MIC = 3.91 - 15.63 pg / mL; Carprofen MIC = 62.5 - 125 pg / mL; see

[0322] Figure 1). Compound 42 was also found to be less cytotoxic compared to carprofen against eukaryotic cells (RAW264.7 / THP-1) at 250 pg / mL. For these experiments the minimum inhibitory concentration (MIC) was determined by measuring the relative growth.

[0323] Various modifications and variations of the described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention which are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.

[0324]

[0325]

[0326]

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Claims

CLAIMS1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein: one of R2 and R3 is H, and the other is (CRaRb)nY;Y is selected from CC Rc, CN and CONReRf;R4 is selected from H, halo, CN, alkyl and alkoxy;Re is selected from H, F, Br, I, COOH, CN, CORd, CO2Rd, alkyl, haloalkyl, alkoxy, haloalkoxy, nitro, OH, SRd, SORd, SO2Rd, SO2NRdRd, NHSO2Rd, an aryl group and a heteroaryl group, wherein said aryl or heteroaryl group is optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy;R7is selected from H, halo, alkyl, and alkoxy;Rg is selected from H, CORd, alkyl, haloalkyl, aryl, CO-aryl, CO-haloaryl, aralkyl and haloaralkyl;R1, R5and R8are H; each Ra, Rb, Rc, Rd, Re and Rf is independently selected from H, alkyl and haloalkyl; n is 1 to 6; for use in the treatment or prevention of a mycobacterial infection.

2. A compound for use according to claim 1, wherein Y is CO2RC.

3. A compound for use according to claim 1 or claim 2, wherein: one of R2 and R3 is H, and the other is (CRaRb)nCO2Rc;Re is selected from H, F, Br, alkyl, haloalkyl, alkoxy, an aryl group and a heteroaryl group, wherein said aryl or heteroaryl group is optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy;Ri, R4, Rs, R7 and R8and R9are H; andRa, b, Rcand Rdare each independently selected from H, alkyl and haloalkyl.

4. A compound for use according to any preceding claim, wherein R3is H and R2is (CRaRb)nCO2Rc5. A compound for use according to any preceding claim, wherein n is 1 to 3, more preferably 1 .

6. A compound for use according to any preceding claim, wherein R3is H and R2is CH(Me)CO2H or CH(Me)CO2Me, more preferably, CH(Me)CO2H.

7. A compound for use according to any preceding claim, wherein Re is an aryl group which is optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy.

8. A compound for use according to any preceding claim, wherein Re is a phenyl group optionally substituted by one or more substituents selected from Ci-6-alkyl and Ci-e- alkoxy.

9. A compound for use according to any one of claims 1 to 3, wherein R2is H and R3iS (CRaRb)nCO2Rc.

10. A compound for use according to claim 9, wherein R2is H and R3is CH2CO2H or CH2CO2Me.

11. A compound according to claim 9 or claim 10 wherein:R6is selected from H, F, Br, I, Ci-e-alkyl, Ci-6-haloalkyl, Ci-6-alkoxy; andR1, R4, R5, R7, Rs and R9are all H.

12. A compound for use in the treatment or prevention of a mycobacterial infection, wherein said compound is selected from the following:and pharmaceutically acceptable salts and hydrates thereof.

13. A compound for use according to any one of claims 1 to 12 wherein the mycobacterial infection is M. tuberculosis.

14. A compound for use according to claim 13 wherein the mycobacterial infection is a drug resistant strain of M. tuberculosis.

15. A compound for use according to claim 14 wherein the mycobacterial infection is a rifampicin-resistant strain of M. tuberculosis.

16. A compound for use according to claim 15 wherein the mycobacterial infection is a multidrug resistant strain of M. tuberculosis.

17. A compound of formula (la), or a pharmaceutically acceptable salt or solvate thereof,wherein: one of R2 and R3 is (CRaRb)nY and the other is H;R4 is selected from H, halo, CN, alkyl and alkoxy;Y is selected from CC Rc, CN and CONReRf; each Ra, Rb, Rc, Re and Rf is independently selected from H and alkyl; n is 1 to 6; andRe is selected from an aryl group and a heteroaryl group, wherein said aryl or heteroaryl group is which is optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxyl.

18. A compound according to claim 17, wherein Y is CO2RC.

19. A compound according to claim 17 or claim 18, wherein R3is H and R2 is (CRaRb)nCO2Rc20. A compound according to any one of claims 17 to 19, wherein n is 1 to 3, more preferably 1.

21. A compound according to any one of claims 17 to 20, wherein R3is H and R2is CH(Me)CO2H or CH(Me)CO2Me, more preferably, CH(Me)CO2H.

22. A compound according to any one of claims 17 to 21 , wherein R6is a phenyl group optionally substituted by one or more substituents selected from Ci-6-alkyl and Ci-6-alkoxy.

23. A compound according to any one of claims 17 to 22, which is selected from the following:

24. A pharmaceutical composition comprising a compound according to any of claims 17 to 23, and a pharmaceutically acceptable diluent, excipient, or carrier.

25. A compound according to any one of claims 17 to 23, for use as a medicament.

26. A method of treating a mycobacterial infection in a subject, said method comprising administering to the subject a compound as defined in any of claims 1 to 23.

27. A compound as defined in any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing a mycobacterial infection.

28. Use of a compound as defined in any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating or preventing a mycobacterial infection in a subject.

29. A method according to claim 26, or a compound according to claim 27, or a use according to claim 28, wherein the mycobacterial infection is M. tuberculosis.

30. A compound according to any one of claims 1 to 23 for use in treating a respiratory disease.

31. A compound for use according to claim 30, wherein the respiratory disease is tuberculosis, or a tuberculosis-like disease.

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