Acrylamide derivatives for the treatment of diseases associated with pathogenic bacteria in the gastrointestinal system

Abstract

The present invention relates to compounds exhibiting antibiotic properties and uses thereof for the treatment of gastrointestinal disorders. Pharmaceutical compositions and kits comprising these compounds are also provided.

Description

[0001] HE 272866 Antibacterial compounds and their use for IBD Technical Field The present invention relates to compounds exhibiting antibiotic properties and uses thereof for the treatment of gastrointestinal disorders. Pharmaceutical compositions and kits comprising these compounds are also provided. Related Application The present application claims priority of European patent application 24179311.6 filed on May 31, 2024. The disclosure of this application is incorporated herein in its entirety. Background A well-known drawback of treating infections with antibacterial agents is the risk of disturbing the microbiome, causing disbiosys. Inflammatory bowel syndrome (IBD) and related conditions such as Crohn’s disease and ulcerative colitis are frequently linked to a disbalance of the microbiome involvingovergrowth of pathogenic bacteria such as Adherent invasive E.coli (AIEC) and colibactin-producing E.coli. Such infections are difficult to treat with conventional antibiotics. Theabove-mentioned general risk of disturbing the microbiome may even aggravate the patient’s condition. For example, E.coli NC101 is linked to aggressive forms of bowel disease and makes colibactin, a protein that damages DNA, which could lead to the causeor progression of cancer, such as colorectal cancer, see Callaway, E. E. coli strain linked tocancer in mice, Nature (2012).Some antibiotic agents, such as Afabicin, are known to be microbiota-sparing, see J. Nowakowska et al. in J. Antimicrob. Chemother.2023; 78: 1900–1908, https: / / doi.org / 10.1093 / jac / dkad181 A. HE 272866 However, an effective treatment of IBD and related conditions requires compounds that do not only spare the good commensal flora of the microbiome, but which additionally have established activity against the very specific pathogenic bacteria like AIEC, that are linked to IBD and related conditions. Moreover, having toxicity and side effects in mind, it is furthermore desirable to provide such therapeutic agents, which can be orally administered and which exhibit luminal restriction with minimized systemic exposure. At present, there is no information on any antibiotic compound that exhibits all these desired characteristics. There is, therefore, still a need for effective treatments of IBD and related conditions. Summary In view of the above, the present invention has the objective of providing antibiotic compounds that can be used for treating IBD and related conditions by selectively attacking pathogenic bacteria and especially AIEC in the gastrointestinal tract to thereby re-model the gastrointestinal microbiome by shifting the balance from pathogenic to beneficial bacteria. It has the further objective to provide such compounds, which can be orally administered and which exhibit luminal restriction with minimized systemic exposure. The present invention further aims to provide pharmaceutical compositions and kits containing these antibiotic compounds, that allow convenient treatment. Yet another objective is to provide methods for manufacturing the compounds of the invention. The above objectives are accomplished by the compounds, compounds for use, pharmaceutical compositions, and methods of treatments disclosed herein and as specified in the appended claims. Detailed Description HE 272866 Description of FiguresFigure 1(A) shows the Citrobacter rodentium CFUs in fecal pellets at day 14 of the firstexperiment of Pharmacological Example 2.Figure 1(B) shows the Citrobacter rodentium CFUs in colon at day 14 of the first experimentof Pharmacological Example 2.Figure 1(C) shows the Citrobacter rodentium CFUs in cecum at day 14 of the firstexperiment of Pharmacological Example 2. Figure 2 shows the inflammation score results of the second experiment of Pharmacological Example 2.Figure 3(A) shows the exposure level of compound 3 in plasma according toPharmacological Example 3.Figure 3(B) shows the exposure level of compound 3 in colon content according toPharmacological Example 3.Figure 3(C) shows the exposure level of compound 3 in ileum content according toPharmacological Example 3. Definitions The following definitions are provided to assist the reader. Unless otherwise defined, all terms of art, notations, and other scientific or medical terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the chemical and medical arts. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein HE 272866 should not be construed as representing a substantial difference over the definition of the term as generally understood in the art. The term "and / or" as used herein in a phrase such as "A and / or B" herein is intended to include both "A and B," "A or B," "A," and "B." Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). In some embodiments, the term “about” refers to a deviation of ± 10 % from the recited value. When the word “about” is used herein in reference to a number, it should be understood that still another embodiment of the invention includes that number not modified by the presence of the word “about”“Administering” or “administration of” a drug to a patient (and grammatical equivalentsof this phrase) refers to direct administration, which may be administration to a patient by a medical professional or may be self-administration, and / or indirect administration, which may be the act of prescribing a drug. E.g., a physician who instructs a patient to self- administer a drug or provides a patient with a prescription for a drug is administering the drug to the patient.“Dose” and “dosage” refer to a specific amount of active or therapeutic agents foradministration. Such amounts are included in a “dosage form,” which refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active agent calculated to produce the desired onset, tolerability, and therapeutic effects, in association with one or more suitable pharmaceutical excipients such as carriers. The terms “treatment” and “therapy”, as used in the present application, refer to a set of hygienic, pharmacological, surgical and / or physical means used with the intent to cure HE 272866 and / or alleviate a disease and / or symptoms with the goal of remediating the health problem. The terms “treatment” and “therapy” include preventive and curative methods, since both are directed to the maintenance and / or reestablishment of the health of an individual or animal. Regardless of the origin of the symptoms, disease and disability, the administration of a suitable medicament to alleviate and / or cure a health problem should be interpreted as a form of treatment or therapy within the context of this application. "Unit dosage form" as used herein refers to a physically discrete unit of therapeutic formulation appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active agent employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and / or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably. The term “comprising” is used to have the same meaning as “including”. The term “consisting of” is used to indicate that the listed element(s) is / are present but no other unmentioned elements. The term “comprising” is used to include the meaning of “consisting of” as a preferred embodiment. HE 272866 The term “FabI” is art-recognized and refers to the bacterial enzyme believed to function as an enoyl-acyl carrier protein (ACP) reductase in the final step of the four reactions involved in each cycle of bacterial fatty acid biosynthesis. This enzyme is believed to be widely distributed in bacteria and plants. The term “enzyme inhibitor” refers to any compound that prevents an enzyme from effectively carrying out its respective biochemical roles. Therefore a “FabI inhibitor” is any compound that inhibits FabI from carrying out its biochemical role. The amount of inhibition of the enzyme by any such compound will vary and is described herein and elsewhere. The term “antibiotic agent” or “antibacterial agent” shall mean any drug that is useful in treating, preventing, or otherwise reducing the severity of any bacterial disorder, or any complications thereof, including any of the conditions, disease, or complications arising therefrom and / or described herein. Antibiotic agents include, for example, cephalosporins, quinolones and fluoroquinolones, penicillins and beta lactamase inhibitors, carbapenems, monobactams, macrolides and lincosamides, glycopeptides, rifampin, oxazolidinones, tetracyclines, aminoglycosides, streptogramins, sulfonamides, and the like. Other antibiotic or antibacterial agents are disclosed herein, and are known to those of skill in the art. In certain embodiments, the term “antibiotic agent” does not include an agent that is a FabI inhibitor, so that the combinations of the present invention in certain instances will include one agent that is a FabI inhibitor and another agent that is not.The term “drug” as used herein refers to any substance falling within at least one of thedefinitions given in Article 1, Items 2(a), 2(b) or 3a. of Directive 2001 / 83 / EC of November 6, 2001 in the version of November 16, 2012 or in Article 1, Items 2(a) or 2(b) of Directive 2001 / 82 / EC of November 6, 2001 in the version of August 7, 2009 and in Article 2 of Regulation (EC) No.726 / 2004 of March 31, 2004. HE 272866 The term “disease” as used herein refers to any disease, illness or condition caused by or related to infection by an organism. The term “bacterial disease” as used herein refers to any disease, illness or condition caused by or related to infection by bacteria. The term “cis” is art-recognized and refers to the arrangement of two atoms or groups around a double bond such that the atoms or groups are on the same side of the double bond. Cis configurations are often labeled as (Z) configurations. The term “trans” is art-recognized and refers to the arrangement of two atoms or groups around a double bond such that the atoms or groups are on the opposite sides of a double bond. Trans configurations are often labeled as (E) configurations. The term “therapeutic effect” is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The term thus means any measurable effect in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and / or conditions in an animal or human. In the context of the present invention, the term “therapeutic effect” may especially be understood as any effect of reducing the amount or concentration of any one or more pathogenic bacteria in any part of the gastrointestinal system and / or any measurable effect in associated signs or symptoms of the infection with pathogenic bacteria and the related disease or condition, including, for instance, inflammation of the gastrointestinal tract. The phrase “therapeutically-effective amount” means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit / risk ratio applicable to any treatment. The therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. For example, the HE 272866 compounds and pharmaceutical compositions of the present invention may be administered in a sufficient amount to produce a at a reasonable benefit / risk ratio applicable to such treatment. The term “chiral” is art-recognized and refers to molecules which have the property of non- superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. A “prochiral molecule” is a molecule which has the potential to be converted to a chiral molecule in a particular process. The compounds of the disclosure may contain one or more chiral centers and / or double bonds and, therefore, exist as geometric isomers, enantiomers or diastereomers. The enantiomer and diastereomers may be designated by the symbols “(+)”, “(-)”, “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote one or more chiral centers implicitly. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. Geometric isomers, resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a cycloalkyl or heterocyclic ring, can also exist in the compounds of the present invention. In chemical structures, specific enantiomeric or diastereomeric forms are characterized using conventional signs, i.e. a solid triangle to indicate a substituent being located above the plane of the chiral center and a dashed triangle to indicate a substituent being located below the plane of the chiral center. If no such information on stereochemistry is provided, the present disclosure is to be understood as disclosing all stereoisomers encompassed by the formula as well as any mixture thereof including especially the racemate. The same applies if there should be a discrepancy between formula and chemical name. The symbol double or triple bond as described herein. HE 272866 Substituents around a carbon-carbon double bond are designated as being in the “Z” or “E” configuration wherein the terms “Z” and “E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “E” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond. The arrangement of substituents around a carbocyclic ring can also be designated as “cis” or “trans.” The term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans” or “Z / E.” The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Conformational isomers and rotamers of disclosed compounds are also contemplated. The term “MIC” is art-recognised and refers to the Minimum Inhibitory Concentration, that is the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism following overnight incubation, usually reported as mg / L or µg / mL. The term “antimicrobial” is art-recognized and refers to the ability of the compounds disclosed herein to prevent, inhibit or destroy the growth of microbes such as bacteria, fungi, protozoa and viruses. The term “antibacterial” is art-recognized and refers to the ability of the compounds disclosed herein to prevent, inhibit or destroy the growth of microbes of bacteria. HE 272866 The term “microbe” is art-recognized and refers to a microscopic organism. In certain embodiments the term microbe is applied to bacteria. In other embodiments the term refers to pathogenic forms of a microscopic organism. The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-8 or 1-6 carbon atoms referred to herein as C1- C8alkyl, or C1-C6alkyl, respectively. The term “lower alkyl” as used herein specifically refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-4 or 13 carbon atoms, referred to herein as C1-C4alkyl, and C1-C3alkyl, respectively. Exemplary alkyl groups and lower alkyl grous include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1- butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4- methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl. Moreover, the term “alkyl” (or “lower alkyl”) includes also divalent saturated straight or branched hydrocarbon groups, which are sometimes referred to as alkanediyl groups or alkylene groups. The term “alkyl” not only covers unsubstituted groups but also “substituted alkyls”, i.e. it should be understood as optionally carrying one or more substituents at one or more positions. That is, it refers also to alkyl moieties having one or more (e.g. two, three, four, five, six, etc.) substituents, each replacing a hydrogen on a carbon of the hydrocarbon backbone.Unless specified otherwise or the context dictates otherwise, substituents may include, forexample, a hydroxyl, a carbonyl group (wherein the carbonyl group carries a hydrogen atom, an alkyl group or another group as defined in this paragraph, such as to yield a carboxyl, an alkoxycarbonyl, a formyl, or an acyl group), a thiocarbonyl-containing group (wherein the carbonyl group carries a hydrogen atom, an alkyl group or another group as defined in this paragraph, such as to yield a thioester, a thioacetate, or a thioformate), an HE 272866 alkoxyl, a phosphoryl, a phosphonate, a phosphinate, a phosphate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, a cycloalkyl, a heterocycle or an aromatic or heteroaromatic moiety. In all instances, wherein the above-mentioned groups have more than one valency, the further free valency can be saturated by a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group. It will further be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain may themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate, phosphinate and phosphate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), nitrile and isonitrile. For the avoidance of doubt, an alkyl group carrying another alkyl group should not be regarded as an alkyl group substituted with another alkyl group, but as a single branched alkyl group. The term “alkylene” is art-recognized and refers to a group corresponding to the alkyl group defined above, but having two free valencies. The alkylene group is sometimes also referred to as alkanediyl group. The term “alkenyl” is art-recognized and refers to a group corresponding to the alkyl group defined above, but carrying one or more carbon-carbon double bonds. Of course, the total number of double bonds is restricted by the number of carbon atoms in the alkenyl group and in order to allow for at least one double bond, the alkenyl group must have at least two carbon atoms. Except for this difference, the definitions and characterizations given for the alkyl group above apply equally to the alkenyl group. The term “alkynyl” is art-recognized and refers to a group corresponding to the alkyl group defined above, but carrying one or more carbon-carbon triple bonds. Of course, the total number of double bonds is restricted by the number of carbon atoms in the alkenyl group HE 272866 and in order to allow for at least one triple bond, the alkynyl group must have at least two carbon atoms. Except for this difference, the definitions and characterizations given for the alkyl group above apply equally to the alkynyl group. The term “aryl” is art-recognized and refers to 5- or 6-membered single-ring aromatic groups that can be pure aromatic carbocycles or may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as “heteroaryl” or “heteroaromatics.” The aromatic ring may be unsubstituted or substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, phosphate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic as defined above, while there is no particular restriction regarding the fused further ring or rings, which may for instance be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and / or heterocyclyls. The term “aralkyl” or “arylalkyl” is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group). “Cyclic groups” include carbocyclic groups as defined herein or heterocyclic groups as defined herein. The term “carbocycle” is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon. HE 272866 The term “cycloalkyl” as used herein refers to a monocyclic saturated or partically unsatured alkyl or alkenyl group of for example 3-6, or 4-6 carbons, referred to herein, e.g., as "C3-6cycloalkyl" or “C4-6cycloalkyl," and derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, cyclobutane, cyclopropane or cyclopentene. Said cycloalkyl group may be unsubstituted or substituted at one or more positions with one or more substituents as described above. The terms “halogen” as used herein refer to F, Cl, Br, or I. “Halide” designates the corresponding anion of the halogens. The term “amino” as used herein refers to any group of the general structure -NRaRb, wherein, unless specified otherwise, Ra and Rb are independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic groups, as well as any other substituent group listed above with respect to the scope of substituted alkyl groups, with the exception of carbonyl groups, thiocarbonyl groups, imine groups, and substituent groups in which attachment to the remaining molecule is via a heteroatom selected from N, O, S and P. Alternatively, Raand Rbmay represent hydrocarbon groups that are linked to form a heterocycle together with the nitrogen atom to which they are attached. The term “heteroaryl” as used herein refers to a monocyclic aromatic 5-6 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, which may be the same or different, such as nitrogen, oxygen, and sulfur. Where possible, said heteroaryl ring may be linked to the adjacent radical through carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, benzofuran, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, and pyrimidine. Said heteroaryl group may be unsubstituted or substituted with one or more substituents as described for the aryl group above. The term “heteroaryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons or heteroatoms are common to two adjoining rings (the rings are “fused rings”) wherein at HE 272866 least one of the rings is a heteroaryl as defined above whereas the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aromatic rings and / or saturated, unsaturated or aromatic heterocycles. The term “heterocycle” as used herein refers to a monocyclic ring containing one or more heteroatoms, for example 1, 2, 3 or 4 atoms are heteroatoms. Preferably the heteroatoms are independently selected from O, N, S and P, more preferably O, N and S and most preferably O and N. The remaining ring members are formed by carbon atoms. The heterocycle typically has 3 to 10 ring members, such as 4 to 8 ring members and preferably 5 or 6 ring members. Unless specified otherwise, a heterocycle may be aromatic, partially or fully saturated. Unless specified otherwise, it may or may not contain permissible substituents as specified herein. Unless specified otherwise, it may optionally be substituted or be condensed with a further cyclic group selected from carbocyclic groups and heterocyclic groups to result in a bicyclic group with 8 to 10 ring members. Said further cyclic group may also be saturated, partially unsaturated or aromatic. The term “heterocyclic spiro” as used herein refers to a spirocyclic ring structure e.g. a bicyclic structure containing one or more heteroatoms, for example one to three heteroatoms, which may be the same or different, such as nitrogen, oxygen, and sulfur. The remaining ring members are formed by carbon atoms. The heterocyclic spiro typically has 7 to 11 ring members and preferably 7 or 9 ring members. Unless specified otherwise, a heterocyclic spiro may be partially or fully saturated. Unless specified otherwise, it may or may not contain permissible substituents as specified herein. The terms “hydroxy” and “hydroxyl” as used herein refer to the radical -OH. The term “nitro” is art-recognized and refers to -NO2; the term “sulfhydryl” is art- recognized and refers to -SH; the term “sulfonyl” is art-recognized and refers to -SO2-. The definition of each expression, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. HE 272866 The terms “triflyl”, “tosyl”, “mesyl”, and “nonaflyl” are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate, p-toluenesulfonate, methanesulfonate, and nonafluorobutanesulfonate functional groups and molecules that contain said groups, respectively.The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl,trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. Unless specified otherwise or the context dictates otherwise, these meanings are also applicable to the present disclosure. The term “prodrug” refers to a derivative of an active compound (drug) that undergoes a transformation under the conditions of use, such as within the body, to release the active drug. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. The term “substituted” is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those HE 272866 described herein above, e.g. in connection with substituted alkyls. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. In this context, the term “permissible substituents” means any substituent that can be bonded to the core molecule without contravening general principles of chemical bond formation such as the maximum number of valence electrons for an atom of interest, and without making the compound so toxic for the patient that inacceptable toxicity is found even at the minimum dosage required for achieving a therapeutic effect. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Also for purposes of the disclosure, the term “hydrocarbon” is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds that may be substituted or unsubstituted. The term “pharmaceutically-acceptable salts” is art-recognized and refers to the relatively non-toxic, inorganic and organic acid addition salts, or inorganic or organic base addition salts of compounds, including, for example, those contained in compositions of the present invention, and including those present in other approved drugs (wherein approval may be by any competent authority in the EU, USA, CA, JP, CN or KR at date up to the effective date of the present application). The term “treating” includes any significant effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like. HE 272866 The term “prophylactic” or “therapeutic” treatment is art-recognized and refers to administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate or maintain the existing unwanted condition or side effects therefrom). Prophylactic treatment is typically administered to a patient in need thereof, which means a patient who is at risk of developing a disease or condition as specified herein. Such an estimation of the patient being at risk of developing such a disease or condition may for instance be based on observation of early indicators, or based on known exposition to pathogenic bacteria, or based on pre-determined genetic disposition. In preferred embodiments, the compounds and / or compositions of the invention are used for therapeutic treatment. A “patient,” “subject” or “host” to be treated by the subject method may mean either a human or non-human animal. Non-human animals include companion animals (e.g. cats, dogs) and animals raised for consumption (i.e. food animals), such as cows, pigs, chickens. Non-human animals are preferably mammals. The term “mammal” is known in the art, and exemplary mammals include humans, primates, bovines, porcines, canines, felines, and rodents (e.g., mice and rats). The term “bioavailable” is art-recognized and refers to a form of the subject disclosure that allows for it, or a portion of the amount administered, to be absorbed by, incorporated to, or otherwise physiologically available to a subject or patient to whom it is administered. The term “pharmaceutically acceptable carrier” is art-recognized and refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting HE 272866 any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as dextrose, lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch as well as starch derivatives such as cyclodextrins and modified cyclodextrins including preferably (2-hydroxypropyl)-β-cyclodextrin and sulfobutylether-β-cyclodextrin; (3) cellulose, and its derivatives, such as microcrystalline cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose (HPMC), and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) matrix-forming polymeric excipients such as polyvinyl pyrrolidine (PVP), e.g. PVP K30, acrylic polymers and co-polymers such as the different grades of Eudragit and preferably Eurdragit L100, hydroxypropylmethyl cellulose acetate succinate (HPMCAS), other copolymers such as polyethylene glycol-based copolymers like Soluplus; (9) excipients, such as cocoa butter and suppository waxes; (10) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (11) glycols, such as propylene glycol; (12) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (13) esters, such as ethyl oleate, glyceryl behenate and ethyl laurate; (14) agar; (15) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (16) alginic acid; (17) pyrogen-free water; (18) isotonic saline; (19) Ringer’s solution; (20) ethyl alcohol; (21) phosphate buffer solutions; and (22) other non-toxic compatible substances employed in pharmaceutical formulations. The disclosed excipients may serve more than one function. For example, fillers or binders may also be disintegrants, glidants, anti-adherents, lubricants, sweeteners and the like. The term “solvent” is used herein to mean a liquid chemical substance that is capable of dissolving a significant quantity of another substance of interest, the “solute”, to thereby generate a clear homogeneous solution. The term “significant quantity” is determined by the intended use of the solution in such a manner that the intended use must be possible by the dissolved quantity of the solute. For instance, if it is intended to administer a HE 272866 compound of the present invention in the form of a solution by injection, the solvent must be capable of dissolving the compound in such amounts, to make administration of a therapeutic dose possible. The terms “acid” and “base” are used to have their conventional meanings as proton donators and proton acceptors, respectively (i.e. Broensted acids and bases). A “strong base” is meant to be any base having a basicity of t-BuOK in THF or stronger. A “mild acid” is meant to be any acid having acidity of 1M H2SO4or weaker. Unless specified otherwise, all reactions described herein are carried out at reaction temperatures that yield the desired target compound and that provide a reasonable compromise between reaction rate and selectivity. Typical reaction temperatures for Pd- based coupling reactions and Fe-based cyclization reactions are 80°C to 90°C while removal of protecting groups is typically accomplished at a temperature of from 0°C to room temperature (25°C). Unless specified otherwise, all indications in dependent claims that variable groups are the same as specified for the compound of formula I and its specific embodiments of formulae Ia and Ib, are to be understood such that the more specific meanings described for these variable groups in other dependent claims, are also possible and even preferred. The same applies to the description of meanings of variable groups in the general description. It is particularly preferred to rely on a combination of meanings for the different variable groups, wherein two, three or more and ideally all of these meanings are individually described as being preferred. Unless specified otherwise, the term “protective group” is used herein to characterize a group that is bonded to a functional group to prevent this functional group from participating in a contemplated chemical reaction. The protective group must be inert under the conditions of the contemplated chemical reaction, but it must be possible to remove the protetive group from the compound such that no further transformations take HE 272866 place in other parts of the molecule. Suitable protective groups are described for each functional group in “Greene’s Protective Groups in Organic Synthesis”, Peter G. M. Wuts, Theodora W. Greene, John Wiley & Sons, 20 Dec 2012. The present invention provides novel antibiotic compounds and it also provides novel uses of known antibiotic compounds. Thus, strictly speaking, some of the compounds disclosed herein may either be labeled “compounds of the invention” while other compounds should be labeled as “compound for use of the invention”. For the sake of simplicity, unless specified otherwise or the context dictates otherwise, the indication “compounds of the invention” is used to characterize all antibiotic compounds disclosed herein, i.e., the compounds of both groups of compounds.The expression “colibactin-producing E.coli” is used herein to specify Escherichia colistrains that possess and express the polyketide synthase (pks) genomic island encoding the biosynthetic machinery necessary for the production of colibactin, a genotoxic secondary metabolite linked to colorectal cancer development. These strains are capable of synthesizing colibactin or colibactin-related precursors that induce DNA damage, such as interstrand cross-links or double-strand breaks, in eukaryotic cells. The term encompassesboth naturally occurring and genetically modified E. coli strains that produce colibactin orfunctionally equivalent genotoxins via expression of the pks island or homologous biosynthetic gene clusters. A representative of colibactin-producing E.coli bacteria is E.coli NC101 as mentioned above. All definitions provided herein are to be understood as not encompassing unstable or toxic groups that would make the compounds containing the same unsuitable for pharmaceutical use. The documents cited herein are all incorporated by reference in their entirety. HE 272866 If a dependent claim specifies only the meaning of one or a limited number of variable groups, the remaining variable groups can have any of the meanings specified in the preceding claim or claims, to which the dependent claim of interest refers. Likewise, if the disclosure of a specific aspect or embodiment characterizes only one or a limited number of variable groups, the remaining variable groups can have any of the meanings specified in the preceding disclosure. Overview Surprisingly, it has been found that the compounds of the present invention are suitable for the treatment of diseases that are associated with pathogenic bacteria in the gastrointestinal system such as ulcerative colitis and Crohn’s disease. More specifically, it has been found that the compounds of the invention exhibit therapeutic efficacy that isselective against pathogenic bacteria, such as Enterobacteriaceae including AIEC,Acinetobacter and / or Citrobacter species, most preferably AIEC, in the gastrointestinalsystem while not affecting bacteria such as Enterococci, Firmicutes or Bacteriodetes,forming part of a healthy microbiome in the gastrointestinal system. Thus, in short, the present invention provides compounds, pharmaceutical compositions, kits and therapeutic methods for treating the above-mentioned diseases and especially IBD associated with AIEC. To accomplish this objective, the present invention relies on a novel approach in which the compounds of the present invention are used to “remodel” the microbiome in the gastrointestinal tract such that a healthier balance of desirable commensal bacteria to pathogenic bacteria is established. Another important aspect is that the compounds of the invention exhibit a degree of luminal restriction when orally administered, which minimizes systemic exposure. This, in turn, minimizes side effects. The compounds of the invention are furthermore capable of reducing inflammation of affected tissue in the gastrointestinal tract. Compounds of the invention HE 272866 Compounds for use in the present invention The compounds that may be used in accordance with the present invention are characterized by the following formula I I or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein LHS is selected from LHSa and LHSb as shown below wherein the asterisk (*) marks the point of attachment of the remainder of the molecule, whereinV represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group HE 272866 having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents NH or CH2;if W is CH2, X is NH or CR7R8,if W is NH, X is CR7R8R7represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R8represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R7 and R8 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R9represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R10represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R9 and R10 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; HE 272866 R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CO, CH2, CH(CH3), C(CH3)2.In some embodiments, the compound is characterized by V representing O. Thecompounds of these embodiments are characterized by the following formulae I-1 and I-2: In some embodiments, W is NH and X is CR7R8. The corresponding compounds arecharacterized by the following formulae I-a, I-1-a, I-2-a: HE 272866 In other embodiments, W is CH2 and X is CR7R8. The corresponding compounds arecharacterized by the following formulae I-b, I-1-b, I-2-b: HE 272866In further embodiments Z is CO, which means that the above formulae can be written asthe following formulae I-aa, I-1-aa, and I-2-aa as well as I-ba, I-1-ba and I-1-ba: HE 272866 I-2-baIn other embodiments, W is CH2 and X is NH and Z is CH2. The compounds of theseembodiments are thus characterized by the following structural formulae I-c, I-1-c and I-2- In further embodiments in connection with the above formulae I to I-2-c, one or more of the following further characteristics is preferably fulfilled: R3represents H or F, preferably H. R4represents H, F, Cl, ORa, NRaRb. HE 272866 R7represents H or F, preferably H; R8represents H or F, preferably H; orR7 and R8 together form a cyclic group having 4 to 6 ring members formed by methylenegroups and optionally an oxygen atom or NRa; or R9represents a group selected from H, C1-4-alkyl, CN. The compounds of the invention or pharmaceutically acceptable prodrugs, salts and / or solvates thereof include especially those selected from the following group of compounds: (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3- methylbenzofuran-2-yl)methyl)acrylamide, (S,E)-3-(3-hydroxy-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)- N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (S,E)-3-(3-amino-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl- N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (E)-3-((2R,3S)-3-amino-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin- 8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (R,E)-3-(3-Cyano-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)- N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((2- methylbenzofuran-3-yl)methyl)acrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3- methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide, and pharmaceutically acceptable prodrugs, salts and / or solvates thereof. Novel compounds of the invention HE 272866 The present invention further relates to novel antibiotic compounds within the scope of the above formula I. In a first compound embodiment, these compounds selected from compounds characterized by formula I, preferably one or more of formulae I-1 and I-2, more preferably one or more of formulae I-c, I-1-c and I-2-c, or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein LHS is selected from LHSa and LHSb as shown hereinabove and below, wherein the asterisk (*) marks the point of attachment of the remainder of the molecule, and wherein the variable groups of the compound of formula I, I-c, I-1-c and I-2-c, or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, are as follows:V represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated HE 272866 and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents CH2;X is NH R7represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R8represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R7 and R8 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R9represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R10represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, , C1-4-alkylene-NRaRb, ;or R9 and R10 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CH2, CH(CH3), C(CH3)2.In some aspects of the first compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, are characterized bya variable group R10 that represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa,C1-4-alkylene- OPO3R112. In more specific aspects of the first compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof arefurther characterized by a variable group R1 that represents an atom or a group selected HE 272866 from CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1- 4-alkylene-NR5Ra, C1-4-alkylene-OR5. In furthermore specific aspects of the first compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof arefurther characterized by a variable R2 that represents an atom or a group selected from CN,C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene- NR5Ra, C1-4-alkylene-OR5. In further more specific aspects of the first compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof are further characterized by 1, 2, 3, 4, 5, 6, 7 or 8 of the following variable groups having the meanings specified under items (a) to (h) below: (a) LHS is selected to be LHSa,(b) V is O,(c) Z is CH2,(d) R1 represents C1-4-alkylene-NR5Ra and R2 is H, or R1 is H and R2 is OR5,(e) R9 and R10 is each H,(f) R3 and R4 is each H(g) Ra is H(h) R5 is a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatomsindependently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, such as an unsubstituted pyridyl group. In further more specific aspects of the first compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, arecharacterized by a structure of the formula I-1-c wherein R9 and R10 is each H. In even morespecific aspects, one of R1 and R2 is a substituent other than H and the remaining variable HE 272866groups of R1, R2, R3 and R4 is each H, even more specifically, R1, R2, R3 and R4 have themeanings specified under items (d) and (f) of the preceding paragraph. In further more specific aspects of the first compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, are characterized by a structure of the compound that is selected from In a second compound embodiment, the present invention relates to compounds selected from compounds characterized by formula I, preferably one or more of formulae I-1, I-2, I- a, I-1-a and I-2-a, more preferably one or more of formulae I-aa, I-1-aa and I-2-aa, or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein LHS is selected from LHSa and LHSb as shown hereinabove and below, wherein the asterisk (*) marks the point of attachment of the remainder of the molecule, and wherein the variable groups of the compound of formula I or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, are as follows:V represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which HE 272866 may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents NH;X is CR7R8R7represents a group selected from F, C1-4-alkyl, C3-6-cycloalkyl; R8represents H, F, C1-4-alkylene-NRaRb, NRaRb; R9represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R10represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb;or R9 and R10 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CO, CH2, CH(CH3), C(CH3)2.In a third compound embodiment, the present invention further relates to compounds selected from compounds characterized by formula I, preferably one or more of formulae I-1, I-2, I-a, I-1-a and I-2-a, more preferably one or more of formulae I-aa, I-1-aa and I-2-aa, or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein HE 272866 LHS is selected from LHSa and LHSb as shown hereinabove and below, wherein the asterisk (*) marks the point of attachment of the remainder of the molecule, and wherein the variable groups of the compound of formula I or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, are as follows:V represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents NH;X is CR7R8 HE 272866 R7represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R8represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R7 and R8 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R9represents a group selected from H, F, C3-6-cycloalkyl; R10represents a group selected from F, ORa, C1-4-alkylene-NRaRb; R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CO, CH2, CH(CH3), C(CH3)2.In some aspects of the second or third compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof are are characterized in that R7represents a group selected from C1-4-alkyl; R8represents H; R9represents H; and R10represents ORa. In more specific aspects of the second or third compound embodiment, the above- mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvatesthereof are characterized in that R1 represents a group selected from NR5Ra and C1-4-alkylene-NR5Ra. In further more specific aspects of the second or third compound embodiment, the above- mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof are characterized in that 1, 2, 3, 4, 5 or 6 of the following features (a) to (f) is fulfilled: (a) LHS is selected to be LHSa,(b) V is O, HE 272866 (c) Z represents CO,(d) R2 to R4 is each H,(e) Ra is H(f) R5 is a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatomsindependently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, such as an unsubstituted pyridyl group. In further more specific aspects of the second and third compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / orsolvates thereof, are characterized by a structure of the formula I-1-aa wherein one of R7and R8 is methyl and the other is H, and one of R9 and R10 is hydroxyl and the other is H. Ineven more specific aspects, the methyl and hydroxyl groups are on the same side of the 7- membered ring plane, more preferably both below the 7-membered ring plane. In evenmore specific aspects, R1 is a substituent other than H and the remaining variable groupsR2, R3 and R4 are all H, even more specifically, R1 represents a group selected from NR5Raand C1-4-alkylene-NR5Ra, wherein Ra is H and R5 is a heterocycle, especially pyridine, e.g.,pyridin-3-yl. In further more specific aspects of the second or third compound embodiment, the above- mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof are characterized by a structure of the compound that is selected from In a fourth compound embodiment, the present invention further relates to compounds selected from compounds characterized by formula I, preferably one or more of formulae HE 272866 I-1, I-2, I-a, I-1-a and I-2-a, more preferably one or more of formulae I-aa, I-1-aa and I-2-aa, or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein LHS is selected from LHSa and LHSb as shown hereinabove and below, wherein the asterisk (*) marks the point of attachment of the remainder of the molecule, and wherein the variable groups of the compound of formula I or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, are as follows:V represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb;with the proviso that at least one of R1 to R4 is not H;R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa; HE 272866Ra and Rb is independently selected from H or CH3;W represents NH;X is CR7R8R7represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R8represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R7 and R8 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R9represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R10represents a group selected from F, C1-4-alkylene- OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R9 and R10 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CO, CH2, CH(CH3), C(CH3)2.In some aspects of the fourth compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, are characterizedin that R2 represents an atom or a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4- alkylene-OR5. In some more specific aspects of the fourth compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof arecharacterized in that R2 represents an atom or a group selected from OR5, O-C1-4-alkylene-R5, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5. In some more specific aspects of the fourth compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof arecharacterized in that R2 represents a group selected from OR5. HE 272866 In some more specific aspects of the fourth compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof are characterized in that R5represents an atom or a group selected from phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6. In some more specific aspects of the fourth compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof are characterized in that 1, 2, 3, 4, 5, 6, 7 or 8 of the following features (a) to (h) is fulfilled: (a) LHS is selected to be LHSa,(b) V is O,(c) R7 and R8 is each H,(d) R9 is H,(e) R10 is NRaRb,(f) R1 , R3 and R4 is each H(g) R6 represents a group selected from C1-4-alkylene-NRaRb, and(h) Ra and Rb is each H.In further more specific aspects of the fourth compound embodiment, the above- mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvatesthereof, are characterized by a structure of the formula I-1-aa wherein each of R7 and R8 isH, and one of R9 and R10 is NRaRb, and the other is H, wherein Ra and Rb is preferably eachH. In even more specific aspects, the amino group is below the 7-membered ring plane. In HE 272866even more specific aspects, R2 is a substituent other than H and the remaining variablegroups R1, R3 and R4 are all H, even more specifically, R2 represents a group selected fromOR5, wherein R5 represents a phenyl group which may optionally be substituted by 1, 2 or3 substituents independently selected from R6, wherein, preferably, R6 represents a groupselected from C1-4-alkylene-NRaRb, and, more perferably, Ra and Rb is each H.In some more specific aspects of the fourth compound embodiment, the above-mentioned compounds or pharmaceutically acceptable prodrugs, salts and / or solvates thereof are characterized in the compound having the following formula: . All the compounds, pharmaceutically acceptable prodrugs, salts and / or solvates thereof of the first, second, third and fourth compound embodiment are suitable for the therapeutic applications described herein. Hence, the present invention provides, as further embodiments, these compounds, pharmaceutically acceptable prodrugs, salts and / or solvates thereof for use in the therapeutic applications of the present invention, as well as pharmaceutical compositions, kits and methods of treatment, as described hereinabove or below, with these compounds, pharmaceutically acceptable prodrugs, salts and / or solvates thereof. Isomers and Isotopes Unless expressly specified otherwise, the present disclosure contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)- isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. However, the carbon-carbon double bond between the HE 272866 pyridine ring and the amide group in the center of the molecule must be in trans configuration, as shown in the above formulae. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. If, for instance, a particular enantiomer of a compound disclosed herein is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Moreover, individual enantiomers and diastereomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase gas chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses HE 272866 encompass both enantio- and diastereoselective transformations. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009. The invention also embraces isotopically labeled compounds of the invention which are as recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine,such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. For example, acompound of the invention may have one or more H atom replaced with deuterium.Certain isotopically-labeled disclosed compounds (e.g., those labeled with 3H and 14C) areuseful in compound and / or substrate tissue distribution assays. Tritiated (i.e., 3H) andcarbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) mayafford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the e.g., Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Pharmaceutically acceptable Salts, Solvates, Prodrugs, and Polymorphs The compounds of the present invention may be used in the free form or, alternatively, in the form of pharmaceutically acceptable salts. Acid addition salts are particularly suitable. Pharmaceutically acceptable salts that can be used in the present invention are well-known to the skilled person and are disclosed, for instance, in S. M. Berge et al., J. Pharm. Sci., 1977, 66, 1, 1-19; R. J. Bastin, et al., Org. Proc. Res. Dev., 2000, 4, 427-435; and P. H. Stahl, C. G. Wermuth, Eds. “Pharmaceutical Salts: Properties, Selection, and Use”, 2ndEd. Wiley- HE 272866 VCH, 2011. Particularly effective salts may be hydrochloride salts e.g. hydrochloride or dihydrochloride salts, or fluoroacetate salts e.g. trifluoroacetate salts. The prodrugs of the present invention may also be provided in the free form or in the form of pharmaceutically acceptable salts. Suitable are pharmaceutically acceptable salts well- known to the skilled person, e.g. as described in the literature cited above. The prodrugs of the present invention contain at least one prodrug moiety, i.e. a moiety that is cleaved under physiologic conditions to thereby release the active species. Such prodrug moieties may be attached to the compounds of the present invention in all positions showing sufficient reactivity such as the nitrogen of the 6-membered part of the bicyclic ring system. Such prodrug moieties are described for instance by Rautio et al. in Nat Rev Drug Discov.2018 Aug;17(8):559-587. doi: 10.1038 / nrd.2018.46. As used herein when referring to the compound of formula (I), the expression “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic or organic acids. For example, acceptable salts derived from acids such as quaternary salt, acetate, carbonate, carbamate, sulfonate, strong inorganic acids and the like. In general, pharmaceutically acceptable salts may be used for modifying the solubility or hydrolysis characteristics of a compound, or in sustained release formulations. It will be understood that, as used herein, references to the compound of formula (I) are meant to also include the pharmaceutically acceptable salts unless stated otherwise. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4 salts as well as the olamine (HO-CH2CH2- NH3+) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine HE 272866 cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. The compounds of the invention can exist in unsolvated forms as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. The compounds of the invention may exist in single or multiple crystalline forms or polymorphs. In one embodiment, the compound is amorphous. In one embodiment, the compound is a single polymorph. In another embodiment, the compound is a mixture of polymorphs. In another embodiment, the compound is in a crystalline form. Pharmaceutical Compositions and Kits Compounds of the present invention may be comprised in pharmaceutical compositions. Said pharmaceutical compositions of the disclosure may be administered by various means and may take any appropriate form of formulation, depending on their intended use, as is well known in the art. For example, if compositions of the disclosure are to be administered orally, they may be formulated as tablets, capsules, granules, powders or syrups. Alternatively, compositions disclosed herein may be administered parenterally and formulated as injections / injectables (intravenous, intramuscular, intraperitoneal or subcutaneous), drop infusion preparations or suppositories. For application by the ophthalmic mucous membrane route, the compositions disclosed herein may be formulated as eye drops or eye ointments. The compositions may comprise any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be comprised in the compositions. HE 272866 In the compositions of the invention, additives may serve more than one function. For example, fillers or binders may also be disintegrants, glidants, anti-adherents, lubricants, sweeteners and the like. The compositions may be prepared by any conventional means, which may depend on the type of formulation in question e.g. tablet, injection etc. The composition may comprise any conventional excipient and / or additive e.g. one or more of those set out above. The compositions may be formulated to be suitable for oral, nasal (e.g. by inhalation by formulating a dry powder formulation or a nebulized formulation), rectal, vaginal, aerosol and / or parenteral (e.g., by injection, for example, intravenous, intraperitoneal, intramuscular, or subcutaneous injection) administration. Compositions for oral administration are preferred. Said compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of a compound disclosed herein that may be combined with an excipient e.g. carrier material to produce a single dose may vary depending upon the identity of the compound, the subject being treated, and the particular mode of administration. The compositions of the invention may be prepared by any conventional means, said conventional means may depend on the desired form of the composition e.g. tablet, injection / injectable. Methods of preparing the compositions of the invention may include the step of bringing into association a composition of the disclosure with a carrier and, optionally, one or more additional additive ingredient. In general, the compositions are prepared by uniformly and intimately bringing into association compound of the invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Composition for the invention formulated to be suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose HE 272866 and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a subject composition thereof as an active ingredient. Compositions of the disclosure may also be administered as a bolus, electuary, or paste. In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition may be mixed with one or more pharmaceutically acceptable excipients selected from: (1) fillers or extenders, such as starches, dextrose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, celluloses (e.g., microcrystalline cellulose, methyl cellulose, hydroxypropylmethyl cellulose (HPMC) and carboxymethylcellulose), alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as croscarmellose sodium, sodium carboxymethyl starch (sodium starch glycolate), crosslinked polyvinylpyrrolidone (crospovidone), gellan gum, xanthan gum, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid and sodium alginate, certain silicates and especially calcium silicate, and sodium carbonate; (5) dissolution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) coloring agents; (11) complexing agents such as cyclodextrins and modified cyclodextrins including preferably (2-hydroxypropyl)-β- cyclodextrin and sulfobutylether-β-cyclodextrin; (12) matrix-forming polymeric excipients such as polyvinyl pyrrolidone (PVP), e.g. PVP K30, acrylic polymers and co-polymers such as the different grades of Eudragit and preferably Eudragit L100, hydroxypropylmethyl cellulose acetate succinate (HPMCAS), other copolymers such as polyethylene glycol-based copolymers like Soluplus; and (13) carriers, such as sodium citrate or dicalcium phosphate. In the case of capsules, tablets and pills, the compositions may also comprise buffering HE 272866 agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. The disclosed excipients may serve more than one function. For example, fillers or binders may also be disintegrants, glidants, anti-adherents, lubricants, sweeteners and the like. It is possible in accordance with the present invention to use two or more excipients, wherein said two or more excipients may belong to the same and / or different categories. There is no restriction in this respect. Composition of the invention formulated for parenteral administration, including intravenous, intramuscular, intraperitoneal or subcutaneous administration, may be provided in solid form in vials such that they can be diluted in a suitable solvent (e.g. oil, or water, aqueous NaCl solution e.g. 0.9 wt.% NaCl solution, aqueous glucose solution, dextrose solution). The solid form may comprise, a compound of formula (I) mixed with one or more of an excipient and / or an additional ingredient for example a buffer such as sodium citrate, a solubilizer (co-solvent) e.g. ethanol, a complexing agent (such as cyclodextrins and modified cyclodextrins including preferably (2-hydroxypropyl)-β- cyclodextrin and sulfobutylether-β-cyclodextrin), a stabilizer e.g. cellulose, 2- hydroxypropyl ether, Polyethylene Glycol 4000 crosslinked polyvinylpyrrolidone (crospovidone) and / or polyethylene glycols, an osmotic agent e.g. glucose or sodium chloride, a surfactant e.g. Polyoxyethylene 20 sorbitan monooleate, polyoxyl castor oil and / or sodium lauryl sulfate, a preservative or bacteriostat e.g. sodium citrate, benzyl alcohol and / or viscosity modifier as benzyl alcohol or carboxymethylcellulose. Other pharmaceutically acceptable excipients may also be suitable for inclusion in said solid forms e.g. one or more of the pharmaceutically acceptable excipients set out hereinabove as being suitable for inclusion in compositions formulated for oral administration. It is well within the purview of the skilled person to select appropriate excipients depending on the desired properties of the solid form. A composition formulated for parenteral administration may also be provided in liquid form, e.g. in an infusion bag or in a prefilled syringe. In this case, the same components as listed above may be present in the liquid formulation. The liquid formulation may be an aqueous formulation, aqueous NaCl HE 272866 solution, e.g.0.9 wt.% NaCl solution, aqueous glucose solution, or dextrose solution, the liquid formulation may also be an oil formulation e.g. a stabilized oil in water emulsion, comprising medium chain triglycerides and long chain triglycerides, stabilized by phospholipids. The pharmaceutical compositions of the present invention may be characterized by the presence of the compound of the invention in a well-defined unit dose per dosage form. For oral administration, typical unit dosages may range from 50 mg to 3000 mg. Further details on suitable excipients and formulations may be derived from WO 2020 / 099341 A, WO 2021 / 123372 A, and WO 2022 / 268890 A. The present invention further provides kits comprising the compounds, pharmaceutically acceptable prodrugs, salts and / or solvates thereof of the present invention or pharmaceutic compositions comprising the same provided in a container, optionally together with instructions for use. Said instructions for use may for instance be provided in the form of a paper leaflet or a label on the container or a label on the packaging of the container. Medical Indication, Therapeutic Uses and Methods of Treatment The compounds and compositions of the present invention may be used for treating diseases or conditions associated with pathogenic bacteria in the gastrointestinal system. Treatable, pathogenic bacteria include any bacteria that are FabI-dependant and are linkedto gastrointestinal disease. Said pathogenic bacteria may include Enterobacteriaceaespecies, especially adherent invasive E.coli (AIEC) and colibactin-producing E.coli,Acinetobacter and Citrobacter species as well as any combination thereof. The diseases orconditions associated with such bacteria include especially inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease or cancer, such as colorectal cancer. In the case of cancer, such as colorectal cancer, the treatment is preferably a prevention treatment HE 272866directed against the causative pathogenic bacteria such as colibactin-producing E.coli evenbefore the cancer develops. Preferably, the compounds and compositions of the present invention are used for treating IBD associated with AIEC. If the subject to be treated is an animal other than a human, preferably a mammal, gastrointestinal diseases and conditions may be linked to other pathogenic bacteria. The compounds of the invention may also beused against such other pathogenic bacteria such as Citrobacter rodentium.Patients in need thereof may be treated by administering the compounds and compositions of the present invention by any administration type. The administration frequency is not particularly restricted and may include single or multiple (2, 3, or 4) administrations per day. Total daily dosages may range from 50 mg to 3000 mg. The duration of the administration is also not particularly restricted. It may be suitably selected depending on the patient’s condition and response to the treatment. Typical administration durations may range from one week to three months. Methods of Manufacture The compounds of the invention may be prepared using experimental procedures described in the literature, for instance in WO 2020 / 099341 A, WO 2021 / 123372 A, WO 2022 / 268890 A and WO 2022 / 187329 A. Furthermore, the compounds of the present invention can be prepared using established organic chemistry synthetic methods and procedures and / or information described hereinbelow. Starting materials may either be purchased (if commercially available) or synthesized using established organic chemistry synthetic methods and procedures and / or information described hereinbelow. Numbered Embodiments The present invention specifically pertains to the subject-matter characterized in the following numbered embodiments: HE 2728661. A compound for use in the treatment of diseases associated with pathogenicbacteria in the gastrointestinal system, wherein the compound is selected from compounds characterized by the following formula I I or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein LHS is selected from LHSa and LHSb as shown below wherein the asterisk (*) marks the point of attachment of the remainder of the molecule, whereinV represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O HE 272866 and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents NH or CH2;if W is CH2, X is NH or CR7R8,if W is NH, X is CR7R8R7represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R8represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R7 and R8 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom and NRa; R9represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R10represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R9 and R10 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom and NRa; HE 272866 R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CO, CH2, CH(CH3), C(CH3)2.2. The compound for use according to embodiment 1 or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein the compound is characterized by 1, 2, 3, 4, 5 or 6 of the following features with the proviso that features (d) and / or (e) are not simultaneously fulfilled with feature (f): (a) V is O;(b) R3 represents H or F, preferably H;(c) R4 represents H, F, Cl, ORa, NRaRb;(d) R7 represents H or F, preferably H;(e) R8 represents H or F, preferably H;(f) R7 and R8 together form a cyclic group having 4 to 6 ring members formed bymethylene groups and optionally an oxygen atom or NRa; or (g) R9 represents a group selected from H, C1-4-alkyl, CN.3. The compound for use according to embodiment 1 or 2 or pharmaceuticallyacceptable prodrugs, salts and / or solvates thereof, wherein R1represents H, OR51, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents H; HE 272866 R3represents H; R4represents H; R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R51represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally besubstituted by 1, 2 or 3 substituents independently selected from R6, wherein R51 preferablyrepresents an atom or a group selected from H and C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6.4. The compound for use according to embodiment 1 or 2 or pharmaceuticallyacceptable prodrugs, salts and / or solvates thereof, wherein R1represents H; HE 272866 R2represents H, OR5, O-C1-4-alkylene-R5, or C1-4-alkylene-OR5; R3represents H; R4represents H; R5represents an atom or a group selected from C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selectedfrom R6; R5 preferably representing an atom or a group selected from C3-6-cycloalkyl whichmay optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selectedfrom R6; and R5 more preferably representing a heterocyclic group having 5 or 6 ringmembers and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated, preferably aromatic, and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6. HE 2728665. The compound for use according to any one of embodiments 1 to 4, orpharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein the compound is characterized by 1, 2, 3, 4 or 5 of the following features: (1) W represents NH;(2) V represents O;(3) R7 and R8 both represent H;(4) R9, Ra and Rb all represent H; and(5) R1 to R4 all represent H.6. The compound for use according to embodiment 5, or pharmaceutically acceptableprodrugs, salts and / or solvates thereof, wherein features (1) and (2) are simultaneously fulfilled, or wherein features (1) and (3) are simultaneously fulfilled, or wherein features (1) and (4) are simultaneously fulfilled, or wherein features (1) and (5) are simultaneously fulfilled, or wherein features (2) and (3) are simultaneously fulfilled, or wherein features (2) and (4) are simultaneously fulfilled, or wherein features (2) and (5) are simultaneously fulfilled, or wherein features (3) and (4) are simultaneously fulfilled, or wherein features (3) and (5) are simultaneously fulfilled, or wherein features (4) and (5) are simultaneously fulfilled.7. The compound for use according to embodiment 5, or pharmaceutically acceptableprodrugs, salts and / or solvates thereof, wherein features (1), (2) and (3) are simultaneously fulfilled, or wherein features (1), (2) and (4) are simultaneously fulfilled, or wherein features (1), (2) and (5) are simultaneously fulfilled, or wherein features (1), (3) and (4) are simultaneously fulfilled, or wherein features (1), (3) and (5) are simultaneously fulfilled, or wherein features (1), (4) and (5) are simultaneously fulfilled, or wherein features (2), (3) and (4) are simultaneously fulfilled, or wherein features (2), (3) and (5) are simultaneously HE 272866 fulfilled, or wherein features (2), (4) and (5) are simultaneously fulfilled, or wherein features (3), (4) and (5) are simultaneously fulfilled.8. The compound for use according to embodiment 5, or pharmaceutically acceptableprodrugs, salts and / or solvates thereof, wherein features (1), (2), (3) and (4) are simultaneously fulfilled, or features (1), (2), (3) and (5) are simultaneously fulfilled, or features (1), (2), (4) and (5) are simultaneously fulfilled, or features (1), (3), (4) and (5) are simultaneously fulfilled, or features (2), (3), (4) and (5) are simultaneously fulfilled.9. The compound for use according to embodiment 5, or pharmaceutically acceptableprodrugs, salts and / or solvates thereof, wherein all features (1), (2), (3), (4) and (5) are simultaneously fulfilled. 10. The compound for use according to any one of embodiments 1 to 4, wherein the compound is selected from the following group of compounds: (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3- methylbenzofuran-2-yl)methyl)acrylamide, (S,E)-3-(3-hydroxy-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)- N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (S,E)-3-(3-amino-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl- N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (E)-3-((2R,3S)-3-amino-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin- 8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (R,E)-3-(3-Cyano-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)- N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((2- methylbenzofuran-3-yl)methyl)acrylamide, (2E)-N-methyl-N-{[3-methyl-5-(pyridin-4-yloxy)-1-benzofuran-2-yl]methyl}-3- {1H,2H,3H,4H,5H-pyrido[2,3-e][1,4]diazepin-7-yl}prop-2-enamide, HE 272866 (E)-3-((2R,3S)-3-hydroxy-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3- b][1,4]diazepin-8-yl)-N-methyl-N-((3-methyl-4-(pyridin-3-ylamino)benzofuran-2- yl)methyl)acrylamide, (E)-N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)-3- (2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3- methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide, (E)-3-((2R,3S)-3-hydroxy-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3- b][1,4]diazepin-8-yl)-N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2- yl)methyl)acrylamide, (S,E)-3-(3-amino-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-((5-(4- (aminomethyl)phenoxy)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide and pharmaceutically acceptable prodrugs, salts and / or solvates thereof.11. A compound that is selected from compounds characterized by the followingformula I I or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein LHS is selected from LHSa and LHSb as shown below HE 272866 wherein the asterisk (*) marks the point of attachment of the remainder of the molecule, wherein the variable groups of the compound of formula I or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, are selected from the following options (A) to (D): (A) the variable groups areV represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents CH2;X is NH HE 272866 R7represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R8represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R7 and R8 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R9represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R10represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, , C1-4-alkylene-NRaRb, ;or R9 and R10 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CH2, CH(CH3), C(CH3)2;(B) the variable groups areV represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; HE 272866 R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents NH;X is CR7R8R7represents a group selected from F, C1-4-alkyl, C3-6-cycloalkyl; R8represents H, F, C1-4-alkylene-NRaRb, NRaRb; R9represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R10represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb;or R9 and R10 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; HE 272866 R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CO, CH2, CH(CH3), C(CH3)2;(C) the variable groups areV represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents NH;X is CR7R8 HE 272866 R7represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R8represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R7 and R8 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R9represents a group selected from H, F, C3-6-cycloalkyl; R10represents a group selected from F, ORa, C1-4-alkylene-NRaRb; R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CO, CH2, CH(CH3), C(CH3)2;(D) the variable groups areV represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb;with the proviso that at least one of R1 to R4 is not H;R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, HE 272866 phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents NH;X is CR7R8R7represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R8represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R7 and R8 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R9represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R10represents a group selected from F, C1-4-alkylene- OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R9 and R10 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; HE 272866 R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CO, CH2, CH(CH3), C(CH3)2.12. The compound of embodiment 11 (A), or pharmaceutically acceptable prodrugs,salts and / or solvates thereof, wherein the compound fulfils one or more of the following features:(a) R1 represents an atom or a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4- alkylene-OR5; (b) R2represents an atom or a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6- cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4- alkylene-OR5;(c) R9 represents a group selected from F, C1-4-alkyl, C3-6-cycloalkyl, CN; or a groupselected from H, F, C3-6-cycloalkyl, CN; preferably a group selected from F, C3-6-cycloalkyl, CN;(d) R10 represents a group selected from F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene-OPO3R112; or a group selected from H, F, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112; preferably a group selected from F, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112;(e) Z represents CO, CH(CH3), C(CH3)2; and / or(f) V represents O.13. The compound of embodiment 11 (B), or pharmaceutically acceptable prodrugs,salts and / or solvates thereof, wherein the compound fulfils one or more of the following features:(a) R1 represents an atom or a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4- alkylene-OR5; or an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6- cycloalkyl, OR5, O-C1-4-alkylene-R5, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene- HE 272866 OR5; preferably an atom or a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5;(b) R7 represents a group selected from F, C3-6-cycloalkyl;(c) R8 represents F, C1-4-alkylene-NRaRb, NRaRb;(d) R9 represents a group selected from F, C1-4-alkyl, C3-6-cycloalkyl, CN;(e) R10 represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene-OPO3R112, OPO3R112, C1-4-alkylene-NRaRb; or a group selected from F, C1-4-alkyl, C1-4- alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb; or preferably a group selected from F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, OPO3R112, C1-4- alkylene-NRaRb;Z represents CH2, CH(CH3), C(CH3)2.14. The compound of embodiment 11 (C), or pharmaceutically acceptable prodrugs,salts and / or solvates thereof, wherein the compound fulfils one or more of the following features:(a) R1 represents an atom or a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4- alkylene-OR5; or an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6- cycloalkyl, OR5, O-C1-4-alkylene-R5, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene- OR5; or preferably an atom or a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5;(b) R9 represents a group selected from F, C3-6-cycloalkyl;(c) R10 represents a group selected from F, C1-4-alkylene-NRaRb;(d) Z represents CH2, CH(CH3), C(CH3)2.15. The compound of embodiment 11 (A) or embodiment 12, or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein R10represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112. HE 27286616. The compound of embodiment 11 (A) or embodiments 12 or 15 or pharmaceuticallyacceptable prodrugs, salts and / or solvates thereof, wherein R1represents an atom or a group selected from CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4- alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5.17. The compound of embodiments 11 (A), 12, 15 or 16 or pharmaceutically acceptableprodrugs, salts and / or solvates thereof, wherein R2represents an atom or a group selected from CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4- alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5.18. The compound of embodiments 11 (A), 12, 15, 16 or 17 or pharmaceuticallyacceptable prodrugs, salts and / or solvates thereof, wherein 1, 2, 3, 4, 5, 6, 7 or 8 of the following features (a) to (h) is fulfilled: (a) LHS is selected to be LHSa,(b) V is O,(c) Z is CH2,(d) R1 represents C1-4-alkylene-NR5Ra and R2 is H, or R1 is H and R2 is OR5,(e) R9 and R10 is each H,(f) R3 and R4 is each H(g) Ra is H(h) R5 is a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatomsindependently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, such as an unsubstituted pyridyl group.19. The compound of embodiments 11 (A), 12, 15, 16, 17 or 18 or pharmaceuticallyacceptable prodrugs, salts and / or solvates thereof, wherein the compound is selected from HE 272866 20. The compound of embodiments 11 (B) or 11 (C), or embodiments 13 or 14, orpharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein R7represents a group selected from C1-4-alkyl; R8represents H; R9represents H; R10represents ORa,.21. The compound of embodiments 11 (B), 11 (C), 13, 14, or 20, or pharmaceuticallyacceptable prodrugs, salts and / or solvates thereof, wherein R1represents a group selected from NR5Raand C1-4-alkylene-NR5Ra.22. The compound of embodiments 11 (B), 11 (C), 13, 14, 20 or 21, or pharmaceuticallyacceptable prodrugs, salts and / or solvates thereof, wherein 1, 2, 3, 4, 5 or 6 of the following features (a) to (f) is fulfilled: (a) LHS is selected to be LHSa,(b) V is O,(c) Z represents CO,(d) R2 to R4 is each H,(e) Ra is H(f) R5 is a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatomsindependently selected from N, O and S, which may be aromatic, fully or partially HE 272866 saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, such as an unsubstituted pyridyl group.23. The compound of embodiments 11 (B), 11 (C), 13, 14, 20, 21 or 22, orpharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein the compound is selected from 24. The compound of embodiment 11 (D), or pharmaceutically acceptable prodrugs,salts and / or solvates thereof, wherein R2 represents an atom or a group selected from F,Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5.25. The compound of embodiment 24, or pharmaceutically acceptable prodrugs, saltsand / or solvates thereof, wherein R2 represents a group selected from OR5, O-C1-4-alkylene-R5, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5.26. The compound of embodiment 25, or pharmaceutically acceptable prodrugs, saltsand / or solvates thereof, wherein R2 represents a group selected from OR5.27. The compound of any one of embodiments 11 (D), 24, 25 or 26, or pharmaceuticallyacceptable prodrugs, salts and / or solvates thereof, wherein R5represents a group selected from phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo HE 272866 groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6.28. The compound of embodiment 11 (D), 24, 25, 26 or 27, or pharmaceuticallyacceptable prodrugs, salts and / or solvates thereof, wherein 1, 2, 3, 4, 5, 6, 7 or 8 of the following features (a) to (h) is fulfilled: (a) LHS is selected to be LHSa,(b) V is O,(c) R7 and R8 is each H,(d) R9 is H,(e) R10 is NRaRb,(f) R1 , R3 and R4 is each H(g) R6 represents a group selected from C1-4-alkylene-NRaRb, and(h) Ra and Rb is each H.29. The compound of any one of embodiments 11 (D), 24, 25, 26, 27 or 28, orpharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein the compound is characterized by the following formula: . HE 27286630. A compound according to any one of embodiments 11 to 29 or pharmaceuticallyacceptable prodrugs, salts and / or solvates thereof, for use in the treatment of diseases associated with pathogenic bacteria in the gastrointestinal system.31. The compound for use according to any one of embodiments 1 to 10 and 30, orpharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein the disease associated with pathogenic bacteria in the gastrointestinal system is inflammatory bowel disease or cancer, such as colorectal cancer, preferably ulcerative colitis, Crohn’s disease, irritable bowel syndrome, small intestinal bacterial overgrowth or functional dyspepsia, wherein, preferably, the treatment of cancer, such as colorectal cancer, is a prevention treatment.32. The compound for use according to any one of embodiments 1 to 10, 30 and 31, orpharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein the diseaseis associated with one or more selected from Acinetobacter, Enterobacteriaceae includingadherent invasive E.coli and colibactin-producing E.coli, and Citrobacter species.33. Pharmaceutical composition comprising the compound according to any one ofembodiments 11 to 29, or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, together with one or more pharmaceutically acceptable excipients.34. Method of treating a disease associated with pathogenic bacteria in thegastrointestinal system, the method comprising the steps of administering the compound of formula (I) or a pharmaceutically acceptable salt, prodrug, polymorph and / or solvate thereof, as defined in any one of embodiments 1 to 29, or pharmaceutical composition according to embodiment 33 to a patient in need thereof, wherein the method is preferably characterized by one or more of the features of any one of embodiments 31 and 32. 35. The compound for use according to any one of embodiments 1 to 10, 30, 31 and 32, or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, or the method HE 272866 according to embodiment 34, wherein the compound or pharmaceutically acceptable prodrug, salt and / or solvate thereof, is orally administered. 36. The pharmaceutical composition according to embodiment 33, wherein the pharmaceutical composition is adapted for oral administration. ExamplesExample 1. Synthesis of (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide hydrochloride(compound 1).The compound 1 of this example was prepared following the procedure for synthesizingcompound 71 as described in Example 7 of WO 2021 / 123372 A. Example 2. Synthesis of (S,E)-3-(3-hydroxy-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (compound 2). HE 272866The compound 2 of this example was prepared following the procedure as described inExample 8 of WO 2020 / 099341 A. HE 272866 Example 3. Synthesis of (S,E)-3-(3-amino-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide(compound 3).The compound 3 of this example was prepared following the procedure for synthesizingcompound 8 as described in Example 1 of WO 2021 / 123372 A.Example 4. Synthesis of (E)-3-((2R,3S)-3-amino-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (compound 4). HE 272866The compound 4 of this example was prepared following the procedure described forsynthesizing compound 52 as described in Example 5 of WO 2021 / 123372 A.Example 5. Synthesis of (R,E)-3-(3-Cyano-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (compound 16)General Synthetic Scheme. Step 1. Ethyl 2-cyano-3-hydroxy-2-methylpropanoate (compound 6). A mixture of ethyl 2-cyanopropanoate 5 (5.00 g, 39.3 mmol), paraformaldehyde (1.77 g, 59.0 mmol) andtriethylamine (6.5 mL, 47.2 mmol) in MeCN (100 mL) was heated to 50 °C for 3 h. The reaction mixture was allowed to cool to RT, concentrated in vacuo and the crude product was purified by chromatography (0-100% EtOAc / isohexane) to afford the desired product6 as a colourless oil (6.09 g, 89%). 1H NMR (500 MHz, DMSO-d6) δ 5.80 (t, J = 5.7 Hz, 1H),4.20 (q, J = 7.1 Hz, 2H), 3.74 (dd, J = 10.6, 5.7 Hz, 1H), 3.66 (dd, J = 10.6, 5.8 Hz, 1H), 1.44 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). HE 272866 Step 2. Ethyl 3-amino-2-(hydroxymethyl)-2-methylpropanoate hydrochloride (compound7). A mixture of ethyl 2-cyano-3-hydroxy-2-methylpropanoate 6 (1.00 g, 6.36 mmol),platinum oxide (0.14 g, 0.64 mmol) and HCl (3.18 mL, 12.7 mmol, 4M in 1,4-dioxane) in EtOH (12 mL) was stirred under H2(5 bar) for ~16 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The resulting residue was azeotroped withMeCN (30 mL) to give the desired product 7 as a colourless oil (1.33 g, 95%) which was usedin the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 3H),5.31 (s, 1H), 4.18 – 4.01 (m, 2H), 3.60 (d, J = 10.9 Hz, 1H), 3.46 (d, J = 11.0 Hz, 1H), 3.06 (d, J = 13.1 Hz, 1H), 2.94 (d, J = 13.1 Hz, 1H), 1.20 (t, J = 7.1 Hz, 3H), 1.12 (s, 3H). Step 3. Ethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-(hydroxymethyl)-2-methylpropanoate (compound 8). A mixture of ethyl 3-amino-2-(hydroxymethyl)-2-methylpropanoate hydrochloride 7 (1.07 g, 5.43 mmol), 5-bromo-3-fluoro-2-nitropyridine(1.00 g, 4.53 mmol) and TEA (2.52 mL, 18.1 mmol) in EtOH (40 mL) was stirred at reflux for 2 h. The reaction mixture was allowed to cool to RT, was concentrated in vacuo and the crude product was purified by chromatography (0-100% EtOAc / heptane) to afford thedesired product 8 as a bright yellow gum (1.55 g, 91%). m / z 362 / 364 (M+H)+ (ES+). 1H NMR(400 MHz, DMSO-d6) δ 8.23 (t, J = 6.0 Hz, 1H), 8.04 (d, J = 1.9 Hz, 1H), 7.86 (d, J = 1.8 Hz, 1H), 5.19 (t, J = 5.1 Hz, 1H), 4.12 – 4.03 (m, 2H), 3.67 – 3.57 (m, 3H), 3.54 (dd, J = 10.7, 5.1 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H), 1.13 (s, 3H). HE 272866 Step 4. Ethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-formyl-2-methylpropanoate(compound 9). To a stirred solution of ethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-(hydroxymethyl)-2-methylpropanoate 8 (0.23 g, 0.64 mmol) in DCM (10 mL) was addedsodium bicarbonate (160 mg, 1.91 mmol), followed by portion wise addition of Dess Martin Periodinane (350 mg, 0.83 mmol). The reaction mixture was stirred at RT for 2 h then was quenched by addition of 2M Na2SO3 solution (40 mL) and further diluted with sat. aq. NaHCO3 (20 mL) and H2O (20 mL). The aqueous material was extracted with DCM (3 x 40 mL) and concentrated in vacuo. The crude product was purified by chromatography (0-100% EtOAc / heptane) to afford the desired product 9 as a yellow oil (0.18 g, 77%).1H NMR(400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.13 (d, J = 1.9 Hz, 1H), 8.05 (t, J = 6.5 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 4.19 – 4.09 (m, 2H), 3.98 – 3.83 (m, 2H), 1.36 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H). Step 5. Ethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-((hydroxyimino)methyl)-2-methylpropanoate (compound 10). Hydroxylamine hydrochloride (0.68 g, 9.83 mmol),sodium acetate (0.81 g, 9.83 mmol) and water (30 mL) were added to a stirred solution ofethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-formyl-2-methylpropanoate 9 (1.18 g, 3.28mmol) in EtOH (45 mL) and the reaction mixture was heated to reflux for 2 h. The reaction mixture was allowed to cool to RT and was concentrated in vacuo. The resulting residue was partitioned between EtOAc (25 mL) and water (25 ml). The aqueous material was extracted with EtOAc (25 mL), the combined organic layers were washed with brine (30 mL), dried using a phase separation cartridge and concentrated in vacuo. The crude product was purified by chromatography (0-100% EtOAc / isohexane) to afford the desired product10 as a yellow solid (0.83 g, 65%). m / z 375 / 377 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) HE 272866 δ 11.07 (s, 1H), 8.15 (t, J = 6.3 Hz, 1H), 8.10 (d, J = 1.9 Hz, 1H), 7.89 (d, J = 1.8 Hz, 1H), 7.47 (s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.86 (dd, J = 13.8, 6.6 Hz, 1H), 3.79 (dd, J = 13.8, 6.2 Hz, 1H), 1.37 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H).Step 6. Ethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-cyano-2-methylpropanoate(compound 11). Burgess reagent (0.48 g, 2.00 mmol) was added to a stirred solution ofethyl (E)-3-((5-bromo-2-nitropyridin-3-yl)amino)-2-((hydroxyimino)methyl)-2-methylpropanoate 10 (0.50 g, 1.33 mmol) in THF (25 mL) and the reaction mixture washeated to 50 °C for ~16 h. The reaction mixture was allowed to cool to RT and was concentrated in vacuo. The resulting residue was taken up in DCM (100 mL) and washed with water (2 x 50 mL) and brine (50 mL), dried using a phase separation cartridge and concentrated in vacuo. The crude product was purified by chromatography (0-50%EtOAc / isohexane) to afford the desired product 11 as a yellow oil (0.38 g, 75%). m / z357 / 359 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 1.9 Hz, 1H), 8.06 (t, J =7.0 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 4.23 – 4.16 (m, 2H), 4.15 – 4.02 (m, 2H), 1.62 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). Step 7. Ethyl 3-((2-amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropanoate(compound 12). A suspension of ethyl 3-((5-bromo-2-nitropyridin-3-yl)amino)-2-cyano-2-methylpropanoate 11 (0.38 g, 1.06 mmol), iron powder (0.48 g, 8.47 mmol) and ammoniumchloride (0.23 g, 4.23 mmol) in a mixture of EtOH (16 mL) and water (4 mL) was heated to 90 °C and stirred for 30 min. The reaction mixture was cooled to RT, dry loaded on Celite HE 272866 and purified by chromatography (0-50% EtOAc / cyclohexane) to afford the desired product12 as a red-brown oil (0.25 g, 67%). m / z 327 / 329 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J = 2.0 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 5.79 (s, 2H), 5.35 (t, J = 6.7 Hz, 1H), 4.22 – 4.09 (m, 2H), 3.77 – 3.60 (m, 2H), 1.59 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). Step 8. Ethyl (R)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropanoate(compound 13). Enantiomers 12 were separated by chiral SFC on a Waters prep 15 with UVdetection by DAD (210 – 400 nm) at 40 °C and 120 bar on a Phenomenex Lux C4 Column (10 x 250 mm, 5 µm particle size). The flow rate was 15 mL / min using 20 % of EtOH (neutral). Chirality was arbitrarily assigned. The products were analysed by analytical SFC (Waters UPC2, 5 µm Phenomenex Lux C4 Column 250 x 4.6 mm column flow rate 4 mL / min) eluting 20% of EtOH with 0.3% of 7N methanolic ammonia solution:Ethyl (S)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropanoate (Firsteluting enantiomer): Rt2.74 min.Ethyl (R)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropanoate 13(Second eluting enantiomer): Rt 3.98 min. AB-277 Step 1Second eluting enantiomerStep 9. (R)-3-((2-Amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropanoic acid,Lithium salt (compound 14). A solution of LiOH (15 mg, 611 µmol) in Water (1 mL) was HE 272866 added to a stirred solution of ethyl (R)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropanoate 13 (0.10 g, 306 µmol) in a mixture of THF (4 mL) and MeOH (1 mL) andthe reaction was stirred at RT for 1 h. The solvent was removed in vacuo and the solidazeotroped with MeCN (10 mL). The resulting brown solid 14 (0.12 g, Quant) was used inthe next step without further purification. m / z 299 / 301 (M+H)+ (ES+). 1H NMR (400 MHz,DMSO-d6) δ 7.31 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 2.1 Hz, 1H), 5.62 (s, 2H), 5.33 (t, J = 6.0 Hz, 1H), 3.29 – 3.26 (m, 1H), 3.22 (dd, J = 12.8, 6.5 Hz, 1H), 1.36 (s, 3H). Step 10. (R)-8-Bromo-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepine-3-carbonitrile (compound 15). DIPEA (160 µL, 916 µmol) was added to a stirred solution of(R)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-cyano-2-methylpropanoic acid, Lithium salt14 (120 mg, 305 µmol) in DMF (2 mL) and the reaction mixture was stirred for 5 mins at RT.HATU (139 mg, 367 µmol) was then added and the reaction mixture was stirred for a further 1 h. The reaction was quenched with water (30 mL) and the resulting precipitate was collected. The precipitate was azeotroped with MeCN (2 x 10 mL) to give the desiredproduct 15 as a pale brown solid (62 mg, 71%), which was used in the next step withoutfurther purification. m / z 281 / 283 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ 10.51 (s,1H), 7.79 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 6.83 (dd, J = 5.8, 3.6 Hz, 1H), 3.62 (dd, J = 13.7, 5.9 Hz, 1H), 3.42 (dd, J = 13.8, 3.6 Hz, 1H), 1.54 (s, 3H). Step 11. (R,E)-3-(3-Cyano-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide(compound 16). A mixture of N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide HE 272866 prepared as in WO200767416 (27 mg, 0.12 mmol), (R)-8-bromo-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepine-3-carbonitrile 15 (30 mg, 0.11 mmol) and Pd-116 (6 mg, 11 µmol) was evacuated and backfilled with nitrogen three times, then 1,4- Dioxane (2 mL) and DIPEA (37 µL, 0.21 mmol) were added and the reaction was heated to 90 °C for 1 h. The reaction mixture was allowed to cool to RT, was diluted with water (20 mL) and the aqueous mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL), dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography (0-10% MeOH) / DCM) to afford thedesired product 16 as a yellow solid (16 mg, 34%). m / z 430 (M+H)+ (ES+).1H NMR (400 MHz,DMSO-d6, 363K) δ 9.94 (s, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.60 – 7.51 (m, 1H), 7.51 – 7.38 (m, 3H), 7.33 – 7.21 (m, 2H), 7.15 (d, J = 15.6 Hz, 1H), 6.37 (t, J = 3.9 Hz, 1H), 4.84 (s, 2H), 3.62 (dd, J = 13.8, 5.7 Hz, 1H), 3.42 (dd, J = 13.8, 3.9 Hz, 1H), 3.10 (s, 3H), 2.27 (s, 3H), 1.59 (s, 3H).Example 6. Synthesis of Synthesis of (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((2-methylbenzofuran-3-yl)methyl)acrylamide(compound 17).The compound 17 of this example was prepared following the procedure described forsynthesizing compound 200 as described in Example 31 of WO 2021 / 123372 A.Example 7. Synthesis of (2E)-N-methyl-N-{[3-methyl-5-(pyridin-4-yloxy)-1-benzofuran-2-yl]methyl}-3-{1H,2H,3H,4H,5H-pyrido[2,3-e][1,4]diazepin-7-yl}prop-2-enamide(compound 27) HE 272866 Step 1. 1-[5-(Benzyloxy)-2-hydroxyphenyl]ethan-1-one (compound 19). To a solution of2',5'-dihydroxyacetophenone 18 (1 eq., 50 g, 328 mmol) in MeCN (499 mL) is added at roomtemperature potassium carbonate (1.5 eq., 68.1 g, 492 mmol). Benzyl bromide (1.1 eq., 61.8 g, 43.2 mL, 361 mmol) is then added dropwise and the reaction mixture is stirred at RT for 18 hours. The crude reaction mixture is filtered on Büchner and the mother liquors are evaporated to dryness. The residue is dissolved in EtOAc (300 mL). The organic layer is washed with water (300 mL), brine (300 mL), dried over sodium sulfate, filtered and evaporated to dryness. Four successive triturations from diethyl ether afford the titlecompound 19 (58.7 g, 74 %) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 2.63(t, 3H, J = 1.6 Hz), 5.1 (s, 2H), 6.91 (d, 1H, J = 9.0 Hz), 7.25 (d, 1H, J = 8.8 Hz, 2.8 Hz), 7.4 (m, 6H), 11.46 (s, 1H). HE 272866Step 2. 5-(Benzyloxy)-3-methyl-1-benzofuran-2-carbaldehyde (compound 20). To asolution of 1-[5-(benzyloxy)-2-hydroxyphenyl]ethan-1-one 19 (1 eq., 30 g, 123 mmol) inTHF (442 mL) are added successively at 0°C t-BuOK (3.8 eq., 52.8 g, 470 mmol) followed by 1,1-dichloroethylene (1.4 eq., 16.8 g, 13.8 mL, 173 mmol) dropwise. The reaction mixture is allowed to warm to RT and stirred for 3 hours. The reaction is quenched with aqueous 1 M sulfuric acid (100 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were concentrated to dryness. The residue is dissolved in DCM (300 mL) and aq. 1 M H2SO4sulfuric acid (70 mL) is added at room temperature. The reaction mixture is then stirred at 50 °C for 18 hours. The reaction mixture is diluted with water (100 mL) and extracted with DCM (3 × 100 mL). The combined organic layers are washed with brine (150 mL), dried over sodium sulfate, filtered and evaporated to dryness. The residue is diluted with Et2O (300 mL) and filtered on a short pad of silica. The solvent isevaporated to dryness to afford the title compound 20 (33 g, 100 %) as a yellow solid. Theproduct is contaminated with various amount of an unknown impurity but engaged as suchin the next step. 1H NMR 400 MHz, CDCl3): δ (ppm) 2.58 (s, 3H), 5.12 (s, 2H), 7.13 (s, 1H),7.21 (d, 1H, J = 8.8 Hz), 7.38 (m, 6H), 9.99 (s, 1H). Step 3. {[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]methyl}(methyl)amine (compound21). Methylamine (33% in EtOH; 4 eq., 46.7 g, 61.7 mL, 495 mmol) is added to a solution of5-(benzyloxy)-3-methyl-1-benzofuran-2-carbaldehyde 20 (1 eq., 33 g, 123 mmol) in DCM (247 mL). The reaction mixture is stirred at RT overnight and concentrated to dryness. The residue is taken up in a mixture DCM (302 mL) and MeOH (75.6 mL), cooled to 0°C and sodium borohydride (3 eq., 14.1 g, 371 mmol) is added. The reaction mixture was stirred at RT for 5 hours. The reaction mixture is diluted with DCM (100 mL). The organic layer is washed with saturated aqueous NaHCO3 (200 mL), brine (200 mL), dried (Na2SO4), filtered and evaporated to dryness. The crude is purified by chromatography (SiO2 pretreated with HE 272866Et3N; DCM / MeOH, 100 / 0 to 95 / 5 V / V) to afford the title compound 21 (14.0 g, 40 %) as ayellow oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 2.19 (s, 3H), 2.44 (s, 3H), 3.84 (s, 2H), 5.1 (s,2H), 6.93 (dd, 1H, J = 8.9 Hz, 2.6 Hz), 7.01 (d, 1H, J = 2.6 Hz), 7.3 (d, 1H, J = 8.7 Hz), 7.34 (d, 1H, J = 6.8 Hz), 7.4 (t, 2H, J = 7.6 Hz), 7.47 (m, 2H). Step 4. 3-Methyl-2-[(methylamino)methyl]-1-benzofuran-5-ol (compound 22). A solutionof {[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl]methyl}(methyl)amine 21 (1 eq., 10.7 g,37.9 mmol) in a mixture of MeOH (99 mL) and THF (99 mL) is purged and backfilled with argon (operation repeated twice).10% Palladium on carbon (10% w / w, 1.07 g) is added. The mixture is purged and backfilled with argon (operation repeated twice) and stirred at RT for 18 hours. The reaction mixture is filtered through Clarcel, rinsed with THF / MeOH(1 / 1 V / V; 150 mL), concentrated and dried under vacuum to afford the title compound 22(7.26 g, 100 %) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 2.1 (s, 3H), 2.24 (s,3H), 3.72 (s, 2H), 6.71 (d, 1H, J = 8.7 Hz), 6.82 (s, 1H), 7.23 (d, 1H, J = 8.7 Hz). Step 5. Benzyl N-[(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]-N-methylcarbamate(compound 23). NaOH (3 M, 44.4 mL) was added to a suspension of 3-methyl-2-[(methylamino)methyl]-1-benzofuran-5-ol 22(1 eq., 7.26 g, 38 mmol) in THF (49.4 mL). Thereaction mixture was cooled to 0°C and benzyl chloroformate (50%wt. in toluene; 2.1 eq., 27.2 g, 26.9 mL, 79.7 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 30 minutes. Water (200 mL) and brine (100 mL) were added and the mixture was HE 272866 extrated with EtOAc (3 × 150 mL). The combined organics were dried (Na2SO4), filtered and concentrated to give an orange-brown oil (19.5 g). The residue was dissolved in THF (75 mL) and NaOH (3 M, 75 mL) was added at RT. The reaction mixture was stirred at RT for 18 hrs. Water (300 mL) was added and the mixture was extracted with EtOAc (3 × 150 mL). The combined organics were dried (Na2SO4) filtered and concentrated to dryness. The residue was purified by flash chromatography (C18 SiO2, gradient H2O / ACN, 98 / 2 to 0 / 100V / V, 90 min). ACN was evaporated and the product was extracted with EtOAc (3 × 50 mL). The organic layer was dried over sodium sulfate, filtered and solvents were evaporated toafford the title compound 23 (7.38 g, 98%) as a brown oil. 1H NMR (400 MHz, DMSO-d6): δ(ppm) 2.05 (s, 1.5H), 2.15 (s, 1.5H), 2.88 (s, 3H), 4.56 (s, 2H), 5.15 (s, 2H), 6.72 (d, 1H, J = 8.7 Hz), 6.82 (s, 1H), 7.26 (d, 1H, J = 8.7 Hz), 7.37 (m, 5H), 9.13 (s, 1H). HE 272866Step 6. N-methyl-N-{[3-methyl-5-(pyridin-4-yloxy)-1-benzofuran-2-yl]methyl}carbamate(compound 24). Copper (10%, 3.91 mg, 0.0615 mmol) was added to a degassed solution ofbenzyl N-[(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl]-N-methylcarbamate (23) (1 eq., 200 mg, 0.615 mmol), 4-iodopyridine (1.5 eq., 189 mg, 0.922 mmol) and Cs2CO3 (4 eq., 801 mg, 2.46 mmol) in DMF (1.2 mL) at RT. The reaction mixture was stirred at 100 °C for 18 h and diluted with EtOAc (20 mL). The organic layer was washed with NaHCO3 sat. (20 mL), brine (20 mL), dried over Na2SO4, filtered and evaporated to dryness. The residue waspurified by flash chromatography (SiO2, DCM / EtOAc, 10 / 0 to 0 / 10 V / V) to give the titlecompound (121 mg, 49%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 2.03 (s, 1.6H), 2.23(s, 1.4H), 3.03 (s, 3H), 4.59 (d, 2H, J = 20.5 Hz), 5.18 (s, 2H), 6.81 (d, 2H, J = 4.9 Hz), 6.99 (d,1H, J = 8.6 Hz), 7.17 (m, 1H), 7.36 (m, 6H), 8.44 (d, 2H, J = 5.0 Hz). Step 7. Methyl({[3-methyl-5-(pyridin-4-yloxy)-1-benzofuran-2-yl]methyl})amine(compound 25). A solution of N-methyl-N-{[3-methyl-5-(pyridin-4-yloxy)-1-benzofuran-2-yl]methyl}carbamate (24) (1 eq., 127 mg, 0.291 mmol) in MeOH (4.5 mL) was purged and backfilled with argon (operation repeated twice).10% Pd / C (10.8%, 33.6 mg, 0.0316 mmol) was added. The mixture was purged and backfilled with argon (operation repeated twice) then purged and backfilled with hydrogen (operation repeated twice) and stirred at RT for 6 h. The reaction mixture was filtered through Clarcel, rinsed with MeOH (15 mL), concentrated and dried under vacuum to give the title compound (75 mg, 96%) as acolorless oil. The crude was engaged in the next step without purification. 1H NMR (400MHz, CDCl3): δ 2.22 (s, 3H), 2.52 (s, 3H), 3.54 (br s, 1H), 3.97 (s, 2H), 6.80 (d, 2H, J = 5.1 Hz),7.0 (dd, 1H, J = 8.8 Hz, 1.8 Hz), 7.18 (m, 1H), 7.44 (d, 1H, J = 8.8 Hz), 8.43 (d, 2H, J = 4.7 Hz). HE 272866 Step 8. tert-Butyl 7-{3-hydroxy-3-[methyl({[3-methyl-5-(piperidin-4-yloxy)-octahydro-1-benzofuran-2-yl]methyl})amino]propyl}-decahydro-1H-pyrido[2,3-e][1,4]diazepine-4-carboxylate (compound 26). DIPEA (3 eq., 82.6 mg, 0.106 mL, 0.639 mmol) and T3P (50 %in AcOEt, 1.5 eq., 0.19 mL, 0.319 mmol) were added at RT to a solution of (2E)-3-{4-[(tert- butoxy)carbonyl]-1H,2H,3H,4H,5H-pyrido[2,3-e][1,4]diazepin-7-yl}prop-2-enoic acid (prepared as in WO2008009122) (1 eq., 68 mg, 0.213 mmol) and methyl({[3-methyl-5- (pyridin-4-yloxy)-1-benzofuran-2-yl]methyl})amine (25) (1.21 eq., 69 mg, 0.257 mmol) in DCM (2.5 mL). The reaction mixture was stirred at RT for 16 h, diluted with DCM (10 mL) and hydrolyzed with H2O (5 mL). The mixture was diluted with an aq. sat. solution of NaHCO3 (10 mL) and the layers were separated. The aqueous layer was extracted with DCM (2 × 10 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by chromatography (SiO2, DCM / MeOH,98 / 2 to 94 / 6 V / V) to give the title compound (113 mg, 93%) as a colorless oil. 1H NMR (400MHz, CDCl3): δ 1.41 (m, 9H), 2.28 (m, 3H), 3.27 (s, 2H), 3.37 (m, 2H), 3.69 (m, 2H), 4.35 (s,1H), 4.46 (s, 1H), 4.74 (m, 0.5H), 4.83 (s, 1.5H), 5.1 (m, 1H), 6.75 (m, 0.4H), 6.80 (d, 2.4H, J= 5.0 Hz), 7.01 (m, 1.3H), 7.20 (s, 1H), 7.45 (m, 1.4H), 7.67 (s, 1.5H), 8.15 (m, 1H), 8.44 (d,2H, J = 4.6 Hz) (rotamers). Step 9. (2E)-N-Methyl-N-{[3-methyl-5-(pyridin-4-yloxy)-1-benzofuran-2-yl]methyl}-3-{1H,2H,3H,4H,5H-pyrido[2,3-e][1,4]diazepin-7-yl}prop-2-enamide (compound 27).4 M HCl HE 272866 in dioxane (42.2 eq., 2 mL, 8 mmol) was added to a solution of tert-butyl 7-{3-hydroxy-3- [methyl({[3-methyl-5-(piperidin-4-yloxy)-octahydro-1-benzofuran-2- yl]methyl})amino]propyl}-decahydro-1H-pyrido[2,3-e][1,4]diazepine-4-carboxylate (26) (1 eq., 108 mg, 0.19 mmol) in DCM (1 mL). The reaction mixture was stirred at RT for 1 h, thenconcentrated, the residue was dissolved in a mixture of H2O / EtOH (5 mL, 1 / 0.1 V / V) andthen lyophilized to give the title compound (87 mg, 91%) as a pale yellow solid HCl salt. 1HNMR (400 MHz, DMSO-d6): δ 2.26 (s, 3H), 2.93 (s, 1H), 3.22 (s, 2H), 3.39 (m, 2H), 3.64 (m,2H), 4.34 (m, 2H), 4.82 (s, 1.2H), 5.03 (s, 0.8H), 7.15 (d, 0.6H, J = 15.3 Hz), 7.24 (d, 1.1H, J =8.9 Hz), 7.46 (m, 3.5H), 7.60 (s, 1.1H), 7.71 (d, 1.7H, J = 8.5 Hz), 8.34 (m, 2H), 8.77 (d, 2H, J= 6.1Hz, 1.7 Hz), 9.90 (s, 2H) (rotamers). MS: 470.25.Example 8. Synthesis of (E)-3-((2R,3S)-3-hydroxy-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methyl-4-(pyridin-3-ylamino)benzofuran-2-yl)methyl)acrylamide (compound 32)General Synthetic Scheme. HE 272866Step 1. tert-butyl N-[(4-amino-3-methyl-benzofuran-2-yl)methyl]-N-methyl-carbamate;2,2,2-trifluoroacetic acid (compound 29). To a suspension of 4-amino-N,3-dimethyl-benzofuran-2-carboxamide (28) prepared as in WO2020099341 (2.00 g, 8.81 mmol, 1.0 eq.) in dry THF (8.8 mL) at 0 °C was slowly added Borane-dimethyl sulfide (2.09 mL, 22.0 mmol, 2.5 eq.). The resulting mixture was stirred at 80°C for 16 hours.The reaction mixture was quenched with a sat. sol. of NaHCO3 (150nL) and extracted twice with EtOAc (2 x 150 mL). The combined organic layers were dried over Na2SO4 and concentrated to dryness. The residue was taken up with DCM (20mL), basified with N- ethyl-N-isopropylpropan-2-amine (5.86 mL, 35.3 mmol, 4.0 eq.), treated with di-tert-butyl dicarbonate (1.94 g, 8.81 mmol, 1.0 eq.) and stirred at rt for 2h. The reaction mixture was concentrated to dryness, was purified on silicagel with the eluent Heptane / EtOAc 10 / 0 to 0 / 10 then on RP C18 with the eluent ACN / Water (+0.1%TFA) 0 / 10 to 6 / 4 and lyophilised to afford the desiredproduct 29 (240 mg, 0.594 mmol, 6.7 % yield) as a white solid TFA salt. 1H NMR (400 MHz, DMSO-d6): δ 1.42 (s, 9H), 2.38 (s, 3H), 2.80 (s, 3H), 4.47 (s, 2H), 6.63 (d, 1H, J = 8.0 Hz), 6.92 (d, 1H, J = 8.0Hz), 7.04 (t, 1H, J = 8.0 Hz), +NH3 observed in the peak of water. Step 2. tert-butyl N-methyl-N-[[3-methyl-4-(3-pyridylamino)benzofuran-2-yl]methyl]carbamate(compound 30). To a solution of tert-butyl N-[(4-amino-3-methyl-benzofuran-2-yl)methyl]-N-methyl-carbamate;2,2,2-trifluoroacetic acid (29) (240. mg, 0.59 mmol, 1.0 eq.) in 1,4-Dioxane (6.0 mL) was added 3-bromopyridine (113 mg, 0.71 mmol, 1.2 eq.), cesium carbonate (580 mg, 1.78 mmol, 3.0 eq.), dicyclohexyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphane (66.4 mg, 0.12 mmol, 0.20 eq.) and Tris(dibenzylideneacetone)dipalladium(0) (57.2 mg, 0.06 mmol, 0.10 eq.) . The reaction mixture was flushed with N2 and stirred at 100°C for 16h.The reaction mixture was concentrated to dryness and purified on silicagel with the eluent heptane / EtOAc 5 / 5to 0 / 10 to afford the desired product 30 (215 mg, 0.585 mmol, 98.6 % yield) as a pink solid.1H NMR(400 MHz, DMSO-d6): δ 1.41 (s, 9H), 2.33 (s, 3H), 2.82 (s, 3H), 4.49 (s, 2H), 7.00 (d, 1H, J = 8.0 Hz), 7.09-7.18 (m, 2H), 7.20-7.28 (m, 2H), 7.96(dd, 1H, J = 8.0 Hz, 4.0 Hz), 7.99 (s, 1H). HE 272866 Step 3. N-[3-methyl-2-(methylaminomethyl)benzofuran-4-yl]pyridin-3-amine;2,2,2-trifluoroaceticacid (compound 31). To a solution of tert-butyl N-methyl-N-[[3-methyl-4-(3-pyridylamino)benzofuran-2-yl]methyl]carbamate 30 (215 mg, 0.59 mmol, 1.0 eq.) in DCM (20mL) was added Trifluoroacetic acid (20 mL). The reaction mixture was stirred at rt for 2h,concentrated to dryness and coevaporated twice with toluene (2 x 50mL) to afford the desiredproduct 31 (290 mg, 0.585 mmol, quantitative) as a yellow oil, TFA salt 1H NMR (400 MHz, DMSO-d6): δ 2.26 (s, 3H), 2.62 (t, 3H, J = 8.0 Hz), 4.38 (t, 2H, J = 8.0 Hz), 7.16-7.23 (m, 1H), 7.41 (t, 1H, J = 8.0 Hz), 7.47 (d, 1H, J = 8.0 Hz), 7.67 (d, 2H, J = 4.0 Hz), 8.18 (t, 1H, J = 4.0 Hz), 8.22 (d, 1H, J = 4.0 Hz), 8.92 (s, 1H), 9.07 (s, 2H). Step 4. (E)-3-((2R,3S)-3-hydroxy-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methyl-4-(pyridin-3-ylamino)benzofuran-2-yl)methyl)acrylamide (compound 32). To a solution of N-[3-methyl-2-(methylaminomethyl)benzofuran-4-yl]pyridin-3-amine;2,2,2-trifluoroacetic acid 31 (80.0 mg, 0.162mmol, 1.0 eq.) in DMF (1.6 mL) was added (E)-3-((2R,3S)-3-hydroxy-2-methyl-4-oxo-2,3,4,5- tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)acrylic acid--2,2,2-trifluoroacetic acid (1 / 2) prepared as in WO2020099341 (83.3 mg, 0.17 mmol, 1.05 eq.), triethylamine (0.23 mL, 1.61 mmol, 10 eq.) and N,N,N',N'-tetramethyl-1-(3-oxidotriazolo[4,5-b]pyridine-1,3-diium-1- ylidene)methanediamine;hexafluorophosphate (75.2 mg, 0.19 mmol, 1.2 eq.). The solution was stirred at rt for 16h. The reaction mixture was diluted with water (50mL) and EtOAc (50mL). the aqueous layer was extracted once with EtOAc (50mL). The combined organic layers were washed once with a sat. sol. of NH4Cl (50mL) and then NaHCO3(50mL), dried over Na2SO4and concentrated to dryness. The residue was purified on silicagel with the eluent DCM / MeOH 10 / 0 to HE 2728669 / 1 and freeze dried to afford the desired product 32 (44.5 mg, 0.0868 mmol, 53.8 % yield) as ayellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.09 (d, 3H, J = 8.0Hz), 2.27 (s, 3H), 2.94,3.21 (s,rotamers, 3H), 3.70-3.79 (m, 1H), 4.19 (s, 1H), 4.76-4.92 (s, rotamers, 2H), 5.13 (s, 1H), 6.12 (t, 1H, J = 8.0 Hz), 7.02 (d, 1H, J = 8.0 Hz), 7.06-7.37 (m, 5H), 7.39 (s, 1H), 7.41-7.45 (s, rotamers, 1H), 7.98(s, 1H), 8.04 (d, 1H, J = 12.0 Hz), 8.08 (s, 1H), 8.21 (s, 1H), 10.28 (s, 1H). MS (+H+): 513.3Example 9. Synthesis of (E)-N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)-3-(2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide dihydrochloride (compound 50). HE 272866 Step 1. 3-Bromophenyl diethylcarbamate (compound 34). To a stirred solution of K2CO3(23.9 g, 0.173 mol, 1.5 eq) in ACN (200 mL) was added 3-bromophenol 33 (20.0 g, 0.115mol, 1 eq). To this solution, diethyl carbamyl chloride (18.7g, 0.138 mol, 1.2 eq) was added and the reaction mixture was stirred overnight at 80 °C for 16 h. After the completion of the reaction, it was diluted with cold H2O (350 mL) and extracted with EtOAc (300 mL), dried (Na2SO4), filtered and evaporated to afford the crude product which was furtherpurified by CC (silica gel, n-Hexane / EtOAc, 99:1V / V). The title compound 34 (31.0 g, 0.113mol, 98%) as a colourless oil was synthesized. m / z 274.12 [M + 2H].+ HE 272866Step 2. 2-Acetyl-3-bromophenyl diethylcarbamate (compound 35). To a cooled (−78 °C)solution of 3-bromophenyl diethylcarbamate 34 (10.0 g, 0.036 mol) in THF (100 mL) wasadded LDA (2 M in THF) (7.86 g, 0.073 mol, 2.0 eq) dropwise. The reaction mixture wasstirred at −78 °C for 45 minutes. AceƟc anhydride (7.49 g, 0.073 mol, 2.0 eq) was addeddropwise to the reaction mixture. Note: Same reaction was performed with 20.0 g scale of starting (3-bromophenyl diethylcarbamate) and both batches were mixed together for the work up and purification. The reaction mixture was quenched with sat. NH4Cl solution (200 mL), extracted with EtOAc (500 mL), dried (Na2SO4), filtered and evaporated. The crude product which was furtherpurified by CC (silica gel, n-Hexane / EtOAc, 90:10V / V) gave the title compound 35 (22.0 g,0.07 mol, 63.58%) as a yellow oil. m / z 316.00 [M + 2H].+Note: used as such for the next step without further purification.Step 3. 1-(2-Bromo-6-hydroxyphenyl)ethan-1-one (compound 36). To a cooled (0 °C)solution of 2-acetyl-3-bromophenyl diethylcarbamate 35 (11.0 g, 0.035 mol) in DCM (150mL) was added TiCl4(1 M in DCM) (33.19 g, 0.175 mol, 5.0 eq) dropwise. The reaction mixture was stirred at 0 °C to RT overnight. Note : Same reaction was performed with 11.0 g scale of starting (2-acetyl-3-bromophenyl diethylcarbamate) and both batches were mixed together for the work up and purification. The reaction mixture was quenched with ice water (500 mL), extracted with DCM (500 mL), dried (Na2SO4), filtered and evaporated to afford the crude product which was furtherpurified by CC (silica gel, n-Hexane / EtOAc, 90:10V / V). The title compound 36 (14.0 g, 0.065mol, 92.9%) as a yellow solid was obtained. m / z 212.90 [M - 2H].+Step 4. 4-Bromo-3-methylbenzofuran-2-carbonitrile (compound 37). To a stirred solutionof K2CO3(29.8 g, 0.21 mol, 3.0 eq) in dry DMF (150 mL) was added 1-(2-bromo-6-hydroxyphenyl)ethan-1-one 36 (15.5 g, 0.072 mol, 1 eq). To this solution, chloroacetonitrile(8.15 g, 0.108 mol, 1.5 eq) was then added over 5 minutes and the reaction mixture was stirred at 100 °C for 16 h. After the completion of the reaction, it was diluted with cold H2O (1.0 L) and extracted with EtOAc (500 mL), dried (Na2SO4), filtered and evaporated to afford the crude product which was further purified by CC (silica gel, n-Hexane / EtOAc, 90:10V / V). HE 272866The expected compound 37 (15.8 g, 0.066 mol, 92.9%) as a yellow oil was obtained.1H NMR(CDCl3, 400 MHz): δ (ppm) 7.49-7.44 (m, 1H), 7.34-7.30 (t, J = 8 Hz, 1H), 2.65 (s, 3H).Step 5. 4-Bromo-3-methylbenzofuran-2-carboxylic acid (compound 38). To a stirredsolution of 4-bromo-3-methylbenzofuran-2-carbonitrile 37 (15.7 g, 0.115 mol, 1eq) in 200mL (H2O) and 100 mL (MeOH) was added NaOH (13.8 g, 0.346 mol, 3.0 eq). The reaction was heated at 100 °C for 72 h. The resulting mixture was cooled to 10 °C, pH adjusted to ~2 with 1 N HCI (50 mL), extracted with EtOAc (250 mL), dried (Na2SO4), filtered andevaporated to afford the title compound 38 (15.0 g, 0.058 mol, 88%) as an off white solid.m / z: 252.98 [M - 2H].+Step 6. (4-Bromo-3-methylbenzofuran-2-yl)methanol (compound 39). To a solution of 4-bromo-3-methylbenzofuran-2-carboxylic acid 38 (10.0 g, 0.039 mol) in dry THF (100 mL) at 0 °C was added borane-methyl sulfide complex (5.88 g, 0.078 mol, 2.0 eq). The reaction was stirred at RT overnight. The reaction mixture was cooled to 0 °C, quenched with MeOH (50 mL) and evaporated under reduced pressure. The crude product was dissolved in EtOAc (200 mL), washed with water (100 mL), dried (Na2SO4), filtered and evaporated to affordthe title compound 39 (10.0 g, crude) as an off-white solid. m / z 222.90 [M - OH].+Step 7. 4-Bromo-3-methylbenzofuran-2-carbaldehyde (compound 40). To a solution of (4-bromo-3-methylbenzofuran-2-yl)methanol 39 (9.94 g, 0.0414 mol) in dry DCM (100 mL) at0 °C was added Dess-Martin periodinate (26.3 g, 0.0622 mol, 1.5 eq). The reaction was stirred at 0 °C to RT for 24 h. The reaction mixture was filtered through a celite bed, washed with DCM (200 mL). The filtarate was washed with 1 N NaHCO3(200 mL), dried (Na2SO4),filtered and evaporated to afford the title compound 40 (10.0 g, crude) as an off-whitesolid. m / z: 241.04 [M + H].+Step 8. 1-(4-Bromo-3-methylbenzofuran-2-yl)-N-methylmethanamine (compound 41). Toa solution of 4-bromo-3-methylbenzofuran-2-carbaldehyde 40 (1.0 g, 0.042 mol) in EtOH(100 mL) was added 40% aq. MeNH2 solution (100 mL). The reaction was stirred at RT overnight. The solution was concentrated under reduced pressure. The resulting dark yellow oil was solvated in EtOH (100 mL) under N2. To the solution was added NaBH4 (3.2 g, 0.84 mol, 2.0 equiv.) and the mixture allowed to stir at the same temperature for 2 h. The solution was concentrated under reduced pressure. The resulting residue was diluted HE 272866 with EtOAc (200 mL), washed with water (100 mL), dried (Na2SO4), filtered and evaporated. The crude product was further purified by CC (silica gel, DCM / MeOH, 95:5V / V) to yield theexpected molecule 41 (6.5 g, 0.0255 mol, 60.6%) as a brown oil. m / z: 253.8 [M - H].̶Step 9. 3-Methyl-2-((methylamino)methyl)benzofuran-4-carbonitrile (compound 42). A 20mL vial flask was successively charged with 1-(4-bromo-3-methylbenzofuran-2-yl)-N-methylmethanamine 41 (2.0 g, 0.0078 mol, 1.0 eq), Zn(CN)2 (1.09 g, 0.0094 mol, 1.2 eq), Zndust (0.51 g, 0.0078 mol, 1.0 eq) and DMA (20 mL). Nitrogen was bubbled into the reaction mixture for 10 min. Pd2(dba)3(0.72 g, 0.00078 mol, 0.1 eq) and dppf (0.21 g, 0.00039 mol, 0.05 eq) was added to the reaction mixture and nitrogen was bubbled into it for an additional 5 min. The reaction vial was sealed and heated at 130 °C overnight. The reaction mixture was cooled to RT, filtered through the celite bed and rinsed with EtOAc (200 mL) and the filtrate was washed with water (100 mL), dried (Na2SO4), filtered and evaporated to afford the crude product which was further purified by CC (silica gel, DCM / MeOH, 95:5V / V) gave the title compound 42 (1.1 g, 0.0055 mol, 70%) as a brown oil. m / z: 201.12 [M +H].+Step 10. Benzyl ((4-cyano-3-methylbenzofuran-2-yl)methyl)(methyl)carbamate(compound 43). To a solution of 3-methyl-2-((methylamino)methyl)benzofuran-4-carbonitrile 42 (0.5 g, 0.0025 mol) in DCM (10 mL) at 0 °C was added TEA (0.75 g, 0.0075mol, 3.0 eq). Benzyl chloroformate (Cbz chloride; 0.63 g, 0.0037 mol, 1.5 eq) was added dropwise and allowed to stir at 0 °C to RT for 2 h. Note: The same reaction was performed on a 1.45 g of starting (3-methyl-2-((methylamino)methyl)benzofuran-4-carbonitrile) 42 and both batches were mixedtogether while work up and the purification. After the completion of the reaction, the reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc (200 mL), dried (Na2SO4), filtered and evaporated to afford thecrude product which was further purified by CC (eluent: n-Hexane / EtOAc, 90 / 10 V / V) gavethe title compound 43 (2.5 g, 0.0074 mol, 76%) as a colourless oil. m / z: 335.27 [M + H].+Step 11. Benzyl ((4-(((tert-butoxycarbonyl)amino)methyl)-3-methylbenzofuran-2-yl)methyl)(methyl)carbamate (compound 44). To a cooled (0 °C) solution of benzyl ((4-cyano-3-methylbenzofuran-2-yl)methyl)(methyl)carbamate 43 (0.4 g, 0.0011 mol) in MeOH HE 272866 (10 mL) at 0 °C was added Boc2O (0.65 g, 0.0029 mol, 2.5 eq) and NiCl2.6H2O (0.28 g, 0.0011 mol, 1.0 eq). NaBH4 (0.091 g, 0.0023 mol, 2.0 eq) was added in portions to the reaction mixture. The reaction mixture was stirred at 0 °C to RT for 2 h. Note: The same reaction was performed on a 2.1 g of starting (benzyl ((4-cyano-3-methylbenzofuran-2-yl)methyl)(methyl)carbamate) 43 and both batches were mixedtogether for further work-up and purification. After the completion of the reaction (TLC monitoring), the reaction mass was quenched with water, filtered through a Celite bed, washed with EtOAc (100 mL) and concentrated under reduced pressure. The residue was dissolved in EtOAc (150 mL), washed with H2O (100 mL), brine (50 mL), dried (Na2SO4) and evaporated under reduced pressure to afford the crude product. The crude material was purified by CC (eluent: n-Hexane / EtOAc, 90 / 10V / V) to afford the title compound 344 (2.5 g, 0.0057 mol,72.4%) as a colourless oil. m / z:456.2 [M +18].+Step 12. tert-Butyl ((3-methyl-2-((methylamino)methyl)benzofuran-4-yl)methyl)carbamate (compound 45). To a stirred solution of benzyl ((4-(((tert-butoxycarbonyl)amino)methyl)-3-methylbenzofuran-2-yl)methyl)(methyl)carbamate 44(0.7 g, 0.0015 mol) in MeOH (20 mL) was added 10% Pd / C (50% wet) (0.35 g). The reaction mixture was stirred at RT under hydrogen atmosphere for 2 h. The reaction mixture was filtered through a Celite bed, washed with MeOH (100 mL) and the filtrate wasconcentrated under reduced pressure to give the title compound 45 (0.5 g, 0.0016 mol,quantitative) as an off white solid. m / z: 305.28 [M + H]+.Step 13. tert-Butyl ((3-methyl-2-((N-methylacrylamido)methyl)benzofuran-4-yl)methyl)carbamate (compound 46). To a solution of tert-butyl ((3-methyl-2-((methylamino)methyl)benzofuran-4-yl)methyl)carbamate 45 (0.5 g, 0.0016 mol) in DCM(10 mL) at 0 °C was added TEA (0.49 g, 0.0049 mol, 3.0 eq). Acryloyl chloride (0.22g, 0.0024 mol, 1.5 eq) was added dropwise and allowed to stir at 0 °C for 1 h. The reaction mass was diluted with H2O (100 mL), extracted with EtOAc (100 mL), dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by CC (silica gel, DCM / MeOH, 98:2V / V) to yield the title compound 46 (0.3 g, 0.00083 mol, 66%) as an off white solid. m / z:359.35 [M + H].+ HE 272866Step 14. N-((4-(Aminomethyl)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamidehydrochloride (compound 47). To a stirring solution of tert-butyl ((3-methyl-2-((N-methylacrylamido)methyl)benzofuran-4-yl)methyl)carbamate 46 (0.3 g, 0.000836 mol, 1.0eq) in DCM (5 mL), 4 M HCl in dioxane (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred from 0 °C to RT over 2 h and then concentrated under reduced pressureto afford the crude product 47 (0.23 g, a mixture of A and B in a ratio of ca 3:2) as an offwhite solid. m / z 259.15 [M + H].+Note: the crude material was in the next step without further purification (inseparablemixture of desired salt A and adduct B).Step 15. N-Methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide (compound 48). A 20 mL sealed tube was charged with a mixture ofN-((4-(aminomethyl)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamidehydrochloride 47 (A and B) (0.01 g, 0.0000339 mol, 1.0 eq), 3-iodopyridine (0.008 g,0.00004 mol, 1.2 eq), Cs2CO3(0.066 g, 0.0002 mol, 6.0 eq) and DMF (0.5 mL). The reactionmixture was purged with nitrogen for 10 min and 1,1-binaphthol (0.002 g, 0.0000067 mol,1.0 eq), Cu (0.00021 g, 0.00000339 mol, 0.1 eq) and CuI (0.0006 g, 0.00000339 mol, 0.1 eq) were added sequentially and the nitrogen was bubbled through the resulting mixture for an additional 5 min. The reaction vial was sealed and stirred at 100 °C for 16 h. Note: The same reaction was performed on a 0.2 g scale of N-((4-(aminomethyl)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide hydrochloride (A and B) and bothbatches were mixed together (work up and purification). The reaction mixture was cooled to RT, filtered through a celite bed, the filtrate was diluted with H2O (50 mL), extracted with EtOAc (2 × 50 mL), the organic phase was dried (Na2SO4), filtered and evaporated. The crude material was purified by CC (silica gel, DCM / MeOH,95:5V / V) to give the title intermediate 48 (0.155 g, inseparable mixture of products) as abrown oil. m / z 336.39 [M + H].+Note: the isolated mixture was used in the next step without further purification.Step 16. tert-Butyl (E)-7-(3-(methyl((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-1,2,3,5-tetrahydro-4H-pyrido[2,3-e][1,4]diazepine-4-carboxylate (compound 49). A 20 mL vial flask was charged with a HE 272866 mixture of N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2- yl)methyl)acrylamide 48 (0.155 g, 0.000462 mol, 1.0 eq), tert-butyl 7-bromo-1,2,3,5-tetrahydro-4H-pyrido[2,3-e][1,4]diazepine-4-carboxylate (prepared as described inWO2008009122) (0.075 g, 0.000231 mol, 0.5 eq), DIPEA (0.476 g, 0.003696 mol, 8.0 eq)and CH3CH2CN:DMF mixture (4:1 V / V) (5 mL). The nitrogen was bubbled into the reactionmixture for 10 min. Pd(OAc)2 (0.01 g, 0.0000462 mol, 0.1 eq) and tri(o-tolyl)phosphine (0.028 g, 0.0000924 mol, 0.2 eq) were added and the nitrogen was bubbled into the resulting brown mixture for an additional 5 min. The reaction vial was sealed and stirred overnight at 100 °C. The reaction mixture was cooled to RT, diluted with water (25 mL) and extracted with EtOAc (2 × 25 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford the crude product which was furtherpurified by CC (eluent: DCM / MeOH, 95 / 5 V / V). The desired compound 49 (0.03 g, 0.0000515mol, 53%) as an off white solid was obtained. m / z 583.39 [M + H].+Step 17. (E)-N-Methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)-3-(2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamidedihydrochloride (compound 50). To a stirred solution of tert-butyl (E)-7-(3-(methyl((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-1,2,3,5-tetrahydro-4H-pyrido[2,3-e][1,4]diazepine-4-carboxylate 49 (0.03 g, 0.0000515mol, 1.0 eq) in DCM (1 mL), 2 M HCl in Et2O (0.2 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C to RT for 2 h and then concentrated under reduced pressure. The product was triturated with Et2O (2 × 5 mL), the solid was isolated andlyophilized to afford the desired molecule 50 (0.015 g, 0.000027 mol, 52.6%) as a brown.LCMS m / z 483.33 [M + H].+ 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 9.54 (bs, 1H), 8.38-8.33 (m, 1H), 8.14-8.06 (m, 3H), 7.76-7.75 (m, 2H), 7.57 (bs, 1H), 7.49-7.45 (bs, 2H), 7.26-7.21 (m, 4H), 4.97-4.74 (m, 4H), 4.27 (s, 2H), 3.53 (bs, 2H), 3.34 (bs, 2H), 3.19-2.91 (3H), 2.40 (s, 3H). Example 10. Synthesis of (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3- b]azepin-3-yl)-N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide dihydrochloride (compound 51). HE 272866The compound 51 of this example was prepared following the procedure for snthesizingcompound 167 as described in Example 20 of WO 2021 / 123372 A.Example 11. Synthesis of (E)-3-((2R,3S)-3-hydroxy-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide (compound 61)General Synthetic Scheme. HE 272866Step 1. tert-butyl (2S,3R)-3-((5-bromo-2-nitropyridin-3-yl)amino)-2-hydroxybutanoate(compound 54). To a solution of 5-Bromo-3-fluoro-2-nitropyridine 52 (60.0 g, 272 mmol, 1.0 eq.)in Ethanol (1.0 L) was added triethylamine (114 mL, 815 mmol, 3.0 eq.) and tert-butyl (2S,3R)-3-amino-2-hydroxy-butanoate 53 (56.5 g, 322 mmol, 1.2 eq.). The yellow solution was stirred at refluxfor 2h, was concentrated to dryness, was taken up with EtOAc (300ml), was washed with water (300mL), with NH4Cl (300mL), with brine (300 mL) and was dried over Na2SO4to afford the desiredproduct 54 (100 g, 266 mmol, 98 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 1.24 (d,3H, J = 8.0 Hz), 1.27 (s, 9H), 4.11 (dd, 1H, J = 4.0 Hz, J = 8.0 Hz), 4.28-4.38 (m, 1H), 5.93 (d, 1H, J = 4.0 Hz), 7.87 (d, 1H, J = 4.0 Hz), 7.94 (d, 1H, J = 8.0 Hz), 8.08 (d, 1H, J = 4.0 Hz) Step 2. methyl (2S,3R)-3-((5-bromo-2-nitropyridin-3-yl)amino)-2-hydroxybutanoate (compound55). To a solution of tert-butyl (2S,3R)-3-[(5-bromo-2-nitro-3-pyridyl)amino]-2-hydroxy-butanoate 54 (100 g, 266 mmol, 1.0 eq.) in Methanol (912 mL) was added at 0°C sulfurous dichloride (26.3 mL, 359 mmol, 1.35 eq.). the reaction mixture was stirred at 0°C for 15 min then at reflux for 2h. Thereaction mixture was concentrated to dryness to afford the desired product 55 (88.9 g, 266 mmol,quantitative) as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 1.24 (d, 3H, J = 8.0 Hz), 3.60 (s, 3H), 4.27 (d, 1H, J = 4.0 Hz), 4.29-4.37 (m, 1H), 6.18 (broad s, 1H), 7.88 (d, 1H, J = 4.0 Hz), 7.97 (d, 1H, J = 8.0 Hz), 8.02 (d, 1H, J = 4.0 Hz) Step 3. methyl (2S,3R)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-hydroxybutanoate(compound 56). To a solution of methyl (2S,3R)-3-[(5-bromo-2-nitro-3-pyridyl)amino]-2-hydroxy-butanoate 55 (22.3 g, 66.6 mmol, 1.0 eq.) in Methanol (262 mL) was added iron (18.6 g, 333 mmol, HE 2728665.0 eq.) and Acetic acid (131 mL). The yellow solution was stirred at 65°C for 1h, were filteredthrought celite then the filtrated was concentrated to dryness. The residue was taken up with EtOAc (500mL) and basified with NaHCO3 (1L) until pH=7. Layers were separated and the aqueous layer was extracted 3 times with EtOAc (3 x 200 mL). The combined organic layers were washed once with NaHCO3 (500 mL), once with brine (500 mL), were dried over Na2SO4 and concentrated todryness. The crude was purified on flash chromatography silicagel with the eluent Heptane / EtOAc2 / 8 to 0 / 10 and then EtOAc / MeOH 95 / 5 to afford the desired product 56 (16.5 g, 54.1 mmol,78.2 % yield) as a beige NMR (400 MHz, DMSO-d6): δ 1.15 (dw, 3H, J = 8.0 Hz), 3.59 (s, 3H), 3.75-3.84 (m, 1H), 4.14 (dd, 1H, J = 8.0 Hz, 4.0 Hz), 4.65 (d, 1H, J = 12.0 Hz), 5.54 (d, 1H, J = 8.0 Hz), 5.73 (s, 2H), 6.71 (d, 1H, J = 4.0 Hz), 7.28 (d, 1H, J = 4.0 Hz). Step 4. methyl (2S,3R)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-((tert-butoxycarbonyl)oxy)butanoate (compound 57). To a solution of methyl (2S,3R)-3-[(2-amino-5-bromo-3-pyridyl)amino]-2-hydroxy-butanoate 56 (66.5 g, 219 mmol, 1.0 eq.) in DCM (400 mL)and THF (40 mL) was added 4-(Dimethylamino)pyridine (540 mg, 4.37 mmol, 0.02 eq.), N-ethyl-N- isopropylpropan-2-amine (38.3 mL, 219 mmol, 1.0 eq.) and di-tert-butyl dicarbonate (51.1 mg, 230 mmol, 1.05 eq.). The brown solution was stirred at rt for 16h, was concentrated to dryness and waspurified with the eluent Heptane / EtOAc 6 / 4 to 6 / 4 to afford the desired compound 57 (88.4 g, 219mmol, quantitative) as a brown oil. 1H NMR (400 MHz, DMSO-d6): δ 1.20 (dd, 3H, J = 8.0 Hz), 1.42(s, 9H), 3.60 (s, 3H), 4.06-4.12 (m, 1H), 4.88 (d, 1H, J = 4.0 Hz), 4.90 (d, 1H, J = 12.0 Hz), 5.82 (s, 2H), 6.77 (d, 1H, J = 4.0 Hz), 7.30 (d, 1H, J = 4.0 Hz). HE 272866Step 5. lithium (2S,3R)-3-((2-amino-5-bromopyridin-3-yl)amino)-2-((tert-butoxycarbonyl)oxy)butanoate (compound 58). To a suspension of methyl (2S,3R)-3-[(2-amino-5-bromo-3-pyridyl)amino]-2-tert-butoxycarbonyloxy-butanoate (88.4 g, 218 mmol, 1.0 eq.) 57in THF(565 mL) and Water (565 mL) was added Lithium hydroxide monohydrate (10.0 g, 239 mmol, 1.1 eq.) at 0°C. The reaction mixture was stirred at rt for 1h30,THF was evaporated and the residue wasfreeze dried to afford the desired product 58 (91.7 g, 218 mmol, quantitative) as a brown solid.1HNMR (400 MHz, DMSO-d6): δ 1.07 (d, 3H, J = 4.0 Hz), 1.40 (s, 9H), 3.61-3.71 (m, 1H), 4.47 (d, 1H, J = 4.0 Hz), 5.22 (d, 1H, J = 8.0 Hz), 5.67 (s, 2H), 6.85 (d, 1H, J = 4.0 Hz), 7.31 (d, 1H, J = 4.0 Hz). Step 6. (2R,3S)-8-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl tert-butyl carbonate (compound 59). To a solution of lithium (2S,3R)-3-[(2-amino-5-bromo-3-pyridyl)amino]-2-tert-butoxycarbonyloxy-butanoate 58 (15.1g, 38.1 mmol, 1.0 eq.) in DMF (400 mL) was added DIEA (13.6 mL, 76.2 mmol, 2.0 eq.) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (15.5 g, 40.0 mmol, 1.05 eq.). The brown solution was stirred at rt for 1h, was diluted with EtOAc (300 mL) and a sat. sol. of Na2CO3 (300 mL). After extraction the phases were separated. The aq. layer was re-extracted 2 times with EtOAc (200 mL each). The combined organic layers were washed with brine (2 x 200 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by CC on a silica gel (20-40-60% of AcOEt / n-hexane) to afford the desired product 59 (12.5 g, 32.2 mmol, 83.4% yield)as an off-white foam. 1H NMR (400 MHz, DMSO-d6): δ 1.12 (d, 3H, J = 4.0 Hz), 1.40 (s, 9H),3.97-4.03 (m, 1H), 4.96 (d, 1H, J = 4.0 Hz), 6.42 (d, 1H, J = 4.0 Hz), 7.38 (d, 1H, J = 4.0 Hz), 7.84 (d, 1H, J = 4.0 Hz), 10.44 (s, 1H). HE 272866 Step 7. tert-butyl ((2R,3S)-2-methyl-8-((E)-3-(methyl((3-methyl-4-((pyridin-3- ylamino)methyl)benzofuran-2-yl)methyl)amino)-3-oxoprop-1-en-1-yl)-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl) carbonate (compound 60).(2R,3S)-8-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl tert-butylcarbonate 59 (92.8 mg, 0.25 mmol, 1.1 eq.) was solubilized in 1,4-Dioxane (1.8mL) and chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (12.2 mg, 0.02 mmol, 0.1 eq.), DIPEA(0.12 mL, 0.68 mmol, 3.0 eq.), N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide (80.0 mg, 0.23 mmol, 1.0 eq.) and tetrabutylammonium chloride (12.6 mg, 0.05 mmol, 0.2 eq.) were added. The reaction mixture was flushed with N2, was stirred at 90°C for 16h, was diluted with a sat. sol. of Na2CO3 (50mL) and extracted twice with EtOAc (2x50mL). The combined organic layers were washed once with water, dried over Na2SO4 and concentrated todryness to afford the desired product 60 which was engaged as such in the next step. Step 8. (E)-3-((2R,3S)-3-hydroxy-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin- 8-yl)-N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide(compound 61). tert-butyl [(2R,3S)-2-methyl-8-[(E)-3-[methyl-[[3-methyl-4-[(3-pyridylamino)methyl]benzofuran-2-yl]methyl]amino]-3-oxo-prop-1-enyl]-4-oxo-1,2,3,5-tetrahydropyrido[2,3-b][1,4]diazepin-3-yl] carbonate 60 (142 mg, 0.23 mmol, 1.0 eq.) wassolubilized in DCM (25 mL) then trifluoroacetic acid (25 mL) was added and the reaction mixture was stirred at rt for 1h. The reaction mixture was concentrated to dryness, diluted with a sat. sol. of Na2CO3 (50mL) and extracted twice with EtOAc (2x50mL). The combined organic layers were washed once with water, dried over NA2SO4 and concentrated to dryness.The residue was purified on silicagel with the eluent DCM / MeOH 10 / 0 to 7 / 3 and freeze dried to afford the desired product61 (32.0 mg, 0.0608 mmol, 26.8 % yield) as a yellow solid. NMR (400 MHz, DMSO-d6): δ 1.08 (d, HE 272866 3H, J = 4.0 Hz), 2.42 (s, 3H), 2.95-3.18 (s, 3H, rotamers), 3.69-3.79 (m, 1H), 4.16-4.21 (m, 1H), 4.61 (d, 2H, J = 8.0 Hz), 4.80-4.95 (s, 2H, rotamers), 5.13 (d, 1H, J = 4.0 Hz), 6.08-6.15 (m, 1H), 6.35 (t, 1H, J = 8.0 Hz), 6.97 (d, 1H, J = 8.0 Hz), 7.04-7.48 (m, 7H), 7.79 (d, 1H, J = 4 Hz), 8.02-8.09 (m, 2H), 10.28 (s, 1H).Example 12. Synthesis of (S,E)-3-(3-amino-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-((5-(4-(aminomethyl)phenoxy)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide hydrochloride (compound 70) Step 1. tert-butyl (S,E)-3-(3-((tert-butoxycarbonyl)amino)-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)acrylate (compound 63). To a solution of tert-butyl (S)-(8-bromo-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-3-yl)carbamate 62 prepared as inWO2021 / 123372 (2.00 g, 5.32 mmol, 1.0 eq.) in 1,4-Dioxane (53.2 mL) was added tert-butyl acrylate (1.56 mL, 10.6 mmol, 2.0 eq.), N-ethyl-N-isopropylpropan-2-amine (2.06 g, 16.0 mmol, 3.0 eq.), tetrabutylammonium chloride (221 mg, 0.800 mmol, 0.15 eq.) and chloro(crotyl)(tri-tert- butylphosphine)palladium(II) (128 mg, 0.320 mmol, 0.06 eq.). The reaction mixture was flushed with N2, was stirred at 90°C for 3h, was concentrated to dryness, was diluted with DCM / MeOH 95 / 5, filtered over celite and concentrated to dryness. The residue was triturated with DCM (20mL)to afford the desired product 63 (1.21 g, 2.98 mmol, 56.1 % yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6): δ 1.39 (s, 9H), 1.49 (s, 9H), 2.50-2.55 (m, 1H), 3.41-3.52 (m, 1H), 4.09-4.17 (m, 1H), HE 272866 6.02 (d, 1H, J = 8.0 Hz), 6.39 (d, 1H, J = 12.0 Hz), 7.00 (d, 1H, J = 8.0 Hz), 7.42 (s, 1H), 7.46 (d, 1H, J = 12.0 Hz), 8.07 (s, 1H), 10.21 (s, 1H). Step 2. (S,E)-3-(3-((tert-butoxycarbonyl)amino)-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)acrylic acid (compound 64). To a solution of tert-butyl (E)-3-[(3S)-3-(tert-butoxycarbonylamino)-4-oxo-1,2,3,5-tetrahydropyrido[2,3-b][1,4]diazepin-8-yl]prop-2-enoate 63(1.74 g, 4.29 mmol, 1.0 eq.) in DCM (50 mL) was added Trifluoroacetic acid (50 mL). The reaction mixture was stirred at rt for 2h, was concentrated to dryness and was coevaporated twice with toluene. The residue was taken up with a mixture of 1,4-Dioxane (50 mL) and DMF (50 mL). N- ethyl-N-isopropylpropan-2-amine (2.85 mL, 17.2 mmol, 4.0 eq.) and di-tert-butyl dicarbonate (1.42 g, 6.43 mmol, 1.5 eq.) were added. then the reaction mixture was stirred at rt for 16h, was diluted with a sat. sol. of NaHCO3 (500mL) and EtOAc (500mL). The aqueous layer was extracted once with EtOAc (500mL). The combined orgnaic layers were washed once with brine, were dried over Na2SO4 and concentrated to dryness. The residue was triturated with Et2O (50mL) to affordthe desired product 64 (1.32 g, 3.79 mmol, 88.3 % yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 1.39 (s, 9H), 2.50-2.55 (m, 1H), 3.41-3.52 (m, 1H), 4.13-4.19 (m, 1H), 6.05 (d, 1H, J = 8.0 Hz), 6.39 (d, 1H, J = 12.0 Hz), 7.00 (d, 1H, J = 8.0 Hz), 7.42 (s, 1H), 7.48 (d, 1H, J = 12.0 Hz), 8.07 (s, 1H), 10.21 (s, 1H). General Synthetic Scheme. HE 272866 Step 3. Benzyl ((5-(4-cyanophenoxy)-3-methylbenzofuran-2-yl)methyl)(methyl)carbamate(compound 66). To a solution of 4-fluorobenzonitrile 65 (2.50 g, 20.6 mmol, 5.7 eq.) in DMF (36 mL)in a sealed tube was added benzyl ((5-hydroxy-3-methylbenzofuran-2-yl)methyl)(methyl)carbamate (1.25 g, 3.65 mmol, 1.0 eq.) 23 and potassium carbonate (2.57 g, 18.3mmol, 5 eq.). The reaction mixture was stirred at 120°C for 1h, was diluted with a sat. sol. of Na2CO3 (100mL) and EtOAC (100mL). The aqueous layer was extracted once with EtOAc (100mL). The combined organic layers were washed once with water (200mL), dried over NA2SO4 and concentrated to dryness. The residue was purified on silicagel with the eluent Heptane / EtOAc 10 / 0to 7 / 3 to afford the desired product 66 (1.55g, 3.63 mmol, 99.6% yield) as a colorless gum.1H NMR(400 MHz, DMSO-d6): δ 2.09-2.20 (s, 3H, rotamers), 2.93 (s, 3H), 4.63 (s, 2H), 5.13 (s, 2H), 7.04 (d, 2H, J = 8.0 Hz), 7.10 (dd, 1H, J = 8.0 Hz, 4.0 Hz), 7.29-7.42 (m, 6H), 7.56-7.63 (m, 1H), 7.81 (d, 2H, J = 8.0 Hz), HE 272866 Step 4. benzyl ((5-(4-(((tert-butoxycarbonyl)amino)methyl)phenoxy)-3-methylbenzofuran-2-yl)methyl)(methyl)carbamate (compound 67). To a solution of benzyl N-[[5-(4-cyanophenoxy)-3-methyl-benzofuran-2-yl]methyl]-N-methyl-carbamate (778. mg, 1.82 mmol, 1.0 eq.) 66 in Methanol(6.2 mL) was added di-tert-butyl dicarbonate (1.01 g, 4.56 mmol, 2.5 eq.), Nickel(II) chloride hexahydrate (867 mg, 3.65 mmol, 2.0 eq.) and sodium tetrahydroborate (176 mg, 4.56 mmol, 2.5 eq.). The black mixture was stirred at 0°C for 1h then at rt for 16h. The reaction mixture was concentrated to dryness (Diboc formation), then was taken up with DCM (50mL) and 50mL of TFA was added and the reaction mixture was stirred at rt for 1h, concentrated to dryness, worked up with EtOAc (50mL) and Na2CO3(50mL). The residue was taken up with DCM (6.5 mL), basified with N-ethyl-N-isopropylpropan-2-amine (0.32 mL, 1.95 mmol, 3.0 eq.) and treated with di-tert-butyl dicarbonate (157 mg, 0.72 mmol, 1.1 eq.). The reaction mixture was stirred at rt for 16h, was concentrated to dryness and purified on silicagel with the eluent Heptane / EtOAc 10 / 0 to 0 / 10 toafford the desired product 67 (230 mg, 0.434 mmol, 66.6% yield) as a colorless oil.1H NMR (400MHz, DMSO-d6): δ 1.39 (s, 9H), 2.05-2.16 (s, 3H, rotamers), 2.91 (s, 3H), 4.08 (d, 2H, J = 4.0 Hz), 4.61 (s, 2H), 5.12 (s, 2H), 6.90 (d, 2H, J = 12.0 Hz), 6.97 (dd, 1H, J = 8.0 Hz, 4.0 Hz), 7.13-7.20 (m, 1H), 7.20 (d, 2H, J = 12.0 Hz), 7.32-7.44 (m, 6H), 7.46-7.54 (m, 1H). Step 5. Tert-butyl (4-((3-methyl-2-((methylamino)methyl)benzofuran-5-yl)oxy)benzyl)carbamate(compound 68). A solution of benzyl N-[[5-[4-[(tert-butoxycarbonylamino)methyl]phenoxy]-3-methyl-benzofuran-2-yl]methyl]-N-methyl-carbamate (1.31 g, 2.47 mmol, 1.0 eq.) in Methanol (8.4 mL) was flushed with N2, palladium 10% / C (131 mg, 10% w / w.) was added, then the reaction mixture was flushed with N2, with H2 and was stirred at rt for 3h under H2 atmospher (Patm). The HE 272866 reaction mixture was filtered over celite and concentrated to dryness to afford the desiredcompound 68 (970 mg, 2.45 mmol, 99.1% yield) as a beige oil.1H NMR (400 MHz, DMSO-d6):δ 1.39 (s, 9H), 2.03 (s, 1H), 2.13 (s, 3H), 2.25 (s, 3H), 3.74 (d, 2H, J = 4.0 Hz), 4.08 (d, 2H, J = 8.0 Hz), 6.90-6.96 (m, 3H), 7.16 (s, 1H), 7.21 (d, 2H, J = 8.0 Hz), 7.36 (t, 1H, J = 4.0 Hz), 7.48 (d, 1H, J = 8.0 Hz). Step 6. tert-butyl (S,E)-(4-((2-((3-(3-((tert-butoxycarbonyl)amino)-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methylacrylamido)methyl)-3-methylbenzofuran-5-yl)oxy)benzyl)carbamate (compound 69). To a solution of tert-butyl (4-((3-methyl-2-((methylamino)methyl)benzofuran-5-yl)oxy)benzyl)carbamate 68 (100 mg, 0.252 mmol, 1.2 eq.)in DMF (2.5 mL) was added tert-butyl (S,E)-3-(3-((tert-butoxycarbonyl)amino)-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)acrylate 64 (96.7 mg, 0.28 mmol, 1.1 eq.),triethylamine (0.140 mL, 1.01 mmol, 4.0 eq.) and N,N,N',N'-tetramethyl-1-(3-oxidotriazolo[4,5-b]pyridine-1,3-diium-1-ylidene)methanediamine;hexafluorophosphate (117 mg, 0.30 mmol, 1.2 eq.). The solution was stirred at rt for 3h, was diluted with water (50mL) and EtOAc (50mL). the aqueous layer was extracted once with EtOAc (50mL). The combined organic layers were washed once with NH4Cl (50mL) and once with NaHCO3(50mL), dried over Na2SO4 and concentrated to dryness. The residue was purified on silicagel with the eluent DCM / MeOH 10 / 0 to9 / 1 to afford the desired compound 69 (105 mg, 0.145 mmol, 57.3 % yield) as a yellow solid. 1HNMR (400 MHz, DMSO-d6): δ 1.38 (s, 18H), 2.23 (s, 3H), 2.93-3.19 (s, 3H, rotamers), 3.44-3.51 (m, 1H), 4.08 (d, 2H, J = 8.0 Hz), 4.08-4.19 (m, 1H), 4.79-4.96 (s, 3H), 5.92-6.07 (m, 1H), 6.91 (d, 2H, J = 8.0 Hz), 6.99 (t, 2H, J = 8.0 Hz), 7.10-7.41 (m, 5H), 7.46 (t, 2H, J = 8.0 Hz), 7.52 (d, 1H, J = 8.0 Hz), 8.13 (d, 1H, J = 8.0 Hz), 10.17 (s, 1H). HE 272866 Step 7. (S,E)-3-(3-amino-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-((5-(4- (aminomethyl)phenoxy)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide hydrochloride(compound 70). tert-butyl N-[(3S)-8-[(E)-3-[[5-[4-[(tert-butoxycarbonylamino)methyl]phenoxy]-3-methyl-benzofuran-2-yl]methyl-methyl-amino]-3-oxo-prop-1-enyl]-4-oxo-1,2,3,5-tetrahydropyrido[2,3-b][1,4]diazepin-3-yl]carbamate 69 (120. mg, 0.17 mmol, 1.0 eq.) was treatedwith hydrogen chloride 4N dioxane (6.02 mg, 0.17 mmol, 1.0 eq.). This suspension was stirred at rt for 1h, was concentrated to dryness and was freeze dried to afford the desired compound70 (96.8 mg, 0.162 mmol, 97.8 % yield) as a yellow solid . 1H NMR (400 MHz, DMSO-d6): δ2.22 (s, 3H), 2.96-3.20 (s, 3H, rotamers), 3.40-3.45 (m, 1H), 4.00 (dd, 2H, J = 12.0 Hz, 8.0 Hz), 4.19- 4.26 (m, 1H), 4.80-4.98 (s, 2H), 6.36-6.46 (m, 1H), 6.94-7.04 (m, 3H), 7.13-7.49 (m, 5H), 7.25 (s, 1H), 7.56 (d, 1H, J = 12.0 Hz), 8.10-8.24 (m, 4H), 8.45 (s, 3H), 10.71 (s, 1H). MS (+H+): 527.3 Pharmacological ExamplesPharmacological Example 1: Antibacterial activity and luminal restriction of examplecompoundsAntibacterial activity was determined for the example compounds against pathogenic E.coli and AIEC bacteria as well as beneficial E. faecalis and B. fragilis bacteria. Additionally,luminal restriction was determined in a MDCK-MDR1 bi-directional permeability assay. Minimal Inhibitory Concentration (MIC):The antibacterial activity of FabI inhibitors against facultative anaerobes including E. coliand E. faecalis was tested using the broth microdilution Minimal Inhibitory Concentration(MIC) assay following CLSI guidelines for insoluble compounds. All bacterial strains weresourced from the American Type Culture Collection (ATCC) except for E. coli NC101 which is HE 272866a previously published AIEC strain isolated from a mouse according to S.C. Kim et al.,Gastroenterology, volume 128, issue 4, 2005, 891-906. Test articles were serially diluted 2- fold in 100% dimethyl sulfoxide (DMSO) and then diluted 100-fold into cation adjusted Mueller-Hinton broth (CA-MHB) to achieve a 10-point test concentration range in 1% DMSO. Final compound concentrations were 0.06 – 32 µg / ml. MIC test plates were then prepared by transferring 100 µl of the final assay medium (test article in CA-MHB, 1% DMSO) into the appropriate wells of a sterile, low binding 96-well polystyrene plate. Direct colony suspension inoculums of the test strains were freshly prepared per CLSI guidelines, and the appropriate test wells were inoculated to achieve a final bacterial cell density of 5 x 105CFU / ml. Growth control (no test article) and negative control (no bacterial inoculum) wells were also included. Exposure to light was minimized during all stages of assay preparation. MIC test plates were incubated at 35-37 °C for 20 hours. For obligate anaerobes, MICs were tested in supplemented Brucella broth (SBB) with hemin, vitamin K1 and laked horse blood. Anaerobic panels were pre-reduced in an anaerobic chamber prior to inoculation. Anaerobic MICs were read following 48 hours of incubation at 35-37° C. Bacterial growth was then determined by measuring the optical density at 600 nm (OD600) using a SpectraMax Plus plate-reader spectrophotometer. MIC values were assigned, following assessment of both OD600values and visual inspection of wells, as the lowest test article concentration that resulted in no visible bacterial growth. MDCK-MDR1 Bi-directional permeability assay: MDCK-MDR1 overexpressing human P-gp cells were cultured 4 days to form a monolayer on 24-well PET inserts. Integrity of the monolayer was confirmed with TEER > 750Ωcm2 (preassay) and lucifer yellow analysis (post assay). Test compound at 10 µM (final concentration of 0.1% DMSO in water) was added to apical well under gentle orbital agitation and transport was determined by measuring concentration in the basolateral well at 2h (A to B). At the same time as A to B incubation, a parallel incubation was also performed where the test compound was added to a basolateral well under similar conditions and then measured in the apical well (B to A) at 2h. All donor wells contain lucifer yellow. After the 2h incubation, aliquots were removed from all apical and basolateral wells HE 272866 for analysis by LC-MSMS analysis with internal standard against a standard curve. A second set of aliquots were analyzed by UV / vis absorbance against a lucifer yellow standard curve to measure monolayer integrity at the end of the assay. Propranolol & quinidine (P-gp) were used as controls in each assay run. TEER readings were taken prior to the experiment, lucifer yellow permeability was used in donor wells and measured at the end of the experiment in the receiver wells to show membrane integrity. Exposure to light was minimized during all stages of assay preparation. The efflux ratio was then calculated by comparing the rates of transport in both directions (B to A / A to B) to determine if the test compound is an efflux transporter substrate. The results of these experiments are summarized in the following table.

[0002] HE 272866 Example No. Compound E.coli E.coli AIEC E. faecalis B. fragilis MDCK MDR1 No. ATCC25922 NC101 MIC ATCC 29212 ATCC 25285 PappA-B MIC (µg / mL) (µg / mL) MIC (µg / mL) MIC (µg / mL) (nm / s) 11 ≤ 4 ≤ 4 ≥ 64 ≥ 64 ≤ 1002 2 ≤ 4 ≤ 4 ≥ 64 ≥ 64 ≤ 1003 3 ≤ 4 ≤ 4 ≥ 64 ≥ 64 ≤ 1004 4 ≤ 4 ≤ 4 ≥ 64 ≥ 64 ≤ 1005 16 ≤ 4 ≤ 4 ≥ 64 ≥ 64 ≤ 1006 17 ≤ 4 ≤ 4 ≥ 64 ≥ 64 ≤ 1007 27 ≤ 4 ≤ 4 ≥ 64 ≥ 64 ≤ 1008 32 ≤ 4 ≤ 4 ≥ 64 ≥ 64 ≤ 1009 50 ≤ 4 ≤ 4 ≥ 64 ≥ 64 ≤ 10010 51 ≤ 4 ≤ 4 ≥ 64 ≥ 64 ≤ 10011 61 ≤ 4 ≤ 4 ≥ 64 ≥ 64 ≤ 10012 70 ≤ 4 ≤ 4 ≥ 64 ≥ 64 ≤ 100It is demonstrated by the above results that the tested example compounds of the invention exhibit high antibacterial activity against pathogenic bacteria while showing insignificant antibacterial activity against beneficial bacteria. The experiments further demonstrate a high level of luminal restriction, which suggests the possibility of effective HE 272866 treatments in the gastrointestinal tract with minimum systemic exposure and risk of side effects.Pharmacological Example 2: Effect of invention compound on Citrobacter rodentium-induced colitis Citrobacter rodentium-induced colitis was investigated as a mouse model for human gastrointestinal disease associated with infection by pathogenic bacteria. In a firstexperiment, antibacterial efficacy against Citrobacter rodentium was determined forcompound 50 of Example 9.Seventy-five C57BL / 6 female mice (JAX) were either uninfected or administered a murinepathobiont with 2 x109 CFU of Citrobacter rodentium (ATCC 51459) (Day 0) followed by oraltreatment (starting Day 6) with either PBS, vehicle (10% DMSO, 40% captisol, 50% saline),varying doses of test article compound 50, or the reference compound ciprofloxacin. Micewere sacrificed on Day 14, see Experimental Design below, and formalin-fixed colons (arranged in Swiss rolls were routinely processed and embedded in paraffin blocks. One slide per block was sectioned and stained with hematoxylin and eosin (H&E). Glass slides were evaluated by a board-certified veterinary pathologist using light microscopy.

[0003] HE 272866 Experimental Design Group Infection Treatment DoseDosing DosingR Dosing N Status (mg / kg) Frequency oute Volume( ml / kg) Group 1Naïve -- -- -- -- 5Group 2UninfectedVehicle -- QD PO -- 8Group 3 Vehicle + Cpd 50 100 QD PO 10 8Group 4PBS -- QD PO -- 7Group 5 Vehicle -- QD PO -- 8Group 6 Infection30 QD PO 10 8Group 7(C.50 QD PO 10 8oup 8rode Compound 50 Grntium)100 QD PO 10 7Group 9 50 BID PO 5 8Group 10 Ciprofloxacin 1 QD PO 10 8N values in parentheses indicate the number of samples evaluatedAt Day 14, Citrobacter rodentium CFUs were assessed in fecal pellets, colon and cecum.Compound 50 was found to reduce in a dose-dependent manner Citrobacter rodentiumCFUs burden in fecal pellets, colon and cecum content. The results are shown in Figures 1(A), 1(B) and 1(C).In a second experiment, the inflammatory status of the mice was investigated after 14 daysof treatment. Collected glass slides in the distal colon at Day 14 were assessed for inflammation according to the following score: The extent of neutrophil, lymphocyte, plasma cell, and / or macrophage infiltrate was assigned severity scores according to the following criteria: HE 272866 0 = Normal 0.5 = Very Minimal, one or 2 small foci, mononuclear inflammatory cells (MNIC) 1 =Minimal, larger focal area with MNIC and neutrophils or minimal diffuse, no separation of glands, may be mostly in areas of submucosal edema or mesentery, affecting up to 10% of the mucosa 2 = Mild, diffuse mild, or multifocal affecting 11-25% of mucosa with minor focal or multifocal gland separation, no separation in most areas 3 = Moderate, 26-50% of mucosa affected with minimal to mild focal or multifocal separation of glands by inflammatory cell infiltrate, milder in remaining areas of mucosa with some areas having no gland separation by inflammation 4 = Marked, 51-75% of mucosa affected with mild to moderate separation of glands by inflammatory cell infiltrate, minimal to mild in remaining areas of mucosa but all glands have some separation by infiltrate 5 = Severe, 76-100% of mucosa affected with moderate to marked areas of gland separation by inflammatory cell infiltrate, mild to moderate in remaining areas of mucosaThe results are shown in Figure 2. Compound 50 at all doses exhibited strong reductions incolitis inflammation, similar to the reference compound Ciprofloxacin.Pharmacological Example 3: Pharmacokinetic effect of invention compound prepared in astandard formulationA formulation comprising compound 3 and carboxymethyl cellulose (CMC) was preparedin a following manner: compound 3 in free base form was added to a 0.5% (w / w) CMCsolution in Milli-Q water at room temperature. The solution was stirred overnight (minimum 12 hours) until complete dissolution of the CMC. No pH adjustment was made;the pH was approximately 6.5. The solution was then mixed with compound 3 (free base) HE 272866according to the study dose to obtain a suspension with homogeneous distribution ofparticles, which is referred to as formulation 1.Pharmacokinetics of compound 3 were assessed in female BALB / C mice following singleoral administration using formulation 1. Animal were fed ad libithum. Whole blood (about50 μL for serial collection about 100 μL for terminal collection) was collected via saphenous or portal vein 0.25, 0.5, 1, 2, 4, 8 and 24h post-dose, and transferred into prechilled K2EDTA tubes and placed on wet ice, centrifuged at approximately 4°C, 3200g for 10 min within 30 min after collection. Plasma samples were stored in polypropylene tubes protected from light, quick frozen over dry ice and kept at -70±10 °C until LC-MS / MS analysis. Colon and ileum were harvested at 2, 4, 8 and 24h post-dose. Colon and ileum contents were collected and homogenized in PBS 10 mM and kept at -70°C until LC-MS / MS analysis. Lower limits of quantitation were 1 ng / mL in plasma and 1 or 2 ng / g in tissues content. PK parameters were assessed by noncompartmental analysis with Phoenix WinNonlin software (version 8.3.5, Certara) using the linear / log trapezoidal method.Results: Following a single oral administration of compound 3 in formulation 1 at 50^mg / kgin female BALB / C mice, the exposures (AUC0-last) of compound 3 were 6856592^ng·h / g incolon content, 5443190^ng·h / g in ileum content and 11511^ng·h / mL in plasma. The tissue content versus plasma AUC0-lastratios were 596 for colon content and 473 for ileum contentshowing high GI tract compound 3 levels compared to plasma following oral administration.Therefore, compound 3 shows excellent GI tract exposure compared to systemic exposure,demonstrating the excellent luminal restriction properties of the compounds of the presentinvention in vivo.

Claims

HE 272866 Claims1. A compound for use in the treatment of diseases associated with pathogenicbacteria in the gastrointestinal system, wherein the compound is selected from compounds characterized by the following formula II or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein LHS is selected from LHSa and LHSb as shown belowwherein the asterisk (*) marks the point of attachment of the remainder of the molecule, whereinV represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independentlyHE 272866 selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents NH or CH2;if W is CH2, X is NH or CR7R8,if W is NH, X is CR7R8R7represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R8represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R7 and R8 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom and NRa; R9represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R10represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R9 and R10 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom and NRa;HE 272866 R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CO, CH2, CH(CH3), C(CH3)2.

2. The compound for use according to claim 1 or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein the compound is characterized by 1, 2, 3, 4, 5 or 6 of the following features with the proviso that features (d) and / or (e) are not simultaneously fulfilled with feature (f): (a) V is O;(b) R3 represents H or F, preferably H;(c) R4 represents H, F, Cl, ORa, NRaRb;(d) R7 represents H or F, preferably H;(e) R8 represents H or F, preferably H;(f) R7 and R8 together form a cyclic group having 4 to 6 ring members formed bymethylene groups and optionally an oxygen atom or NRa; or (g) R9 represents a group selected from H, C1-4-alkyl, CN.

3. The compound for use according to claim 1 or 2 or pharmaceutically acceptableprodrugs, salts and / or solvates thereof, wherein R1represents H, OR51, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5;HE 272866 R2represents H; R3represents H; R4represents H; R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R51represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally besubstituted by 1, 2 or 3 substituents independently selected from R6, wherein R51 preferablyrepresents an atom or a group selected from H and C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6.

4. The compound for use according to claim 1 or 2 or pharmaceutically acceptableprodrugs, salts and / or solvates thereof, whereinHE 272866 R1represents H; R2represents H, OR5, O-C1-4-alkylene-R5, or C1-4-alkylene-OR5; R3represents H; R4represents H; R5represents an atom or a group selected from C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selectedfrom R6; R5 preferably representing an atom or a group selected from C3-6-cycloalkyl whichmay optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selectedfrom R6; and R5 more preferably representing a heterocyclic group having 5 or 6 ringmembers and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated, preferably aromatic, and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6.HE 2728665. The compound for use according to any one of claims 1 to 4, or pharmaceuticallyacceptable prodrugs, salts and / or solvates thereof, wherein the compound is characterized by 1, 2, 3, 4 or 5 of the following features: (1) W represents NH;(2) V represents O;(3) R7 and R8 both represent H;(4) R9, Ra and Rb all represent H; and(5) R1 to R4 all represent H.

6. The compound for use according to claim 5, or pharmaceutically acceptableprodrugs, salts and / or solvates thereof, wherein features (1) and (2) are simultaneously fulfilled, or wherein features (1) and (3) are simultaneously fulfilled, or wherein features (1) and (4) are simultaneously fulfilled, or wherein features (1) and (5) are simultaneously fulfilled, or wherein features (2) and (3) are simultaneously fulfilled, or wherein features (2) and (4) are simultaneously fulfilled, or wherein features (2) and (5) are simultaneously fulfilled, or wherein features (3) and (4) are simultaneously fulfilled, or wherein features (3) and (5) are simultaneously fulfilled, or wherein features (4) and (5) are simultaneously fulfilled.

7. The compound for use according to claim 5, or pharmaceutically acceptableprodrugs, salts and / or solvates thereof, wherein features (1), (2) and (3) are simultaneously fulfilled, or wherein features (1), (2) and (4) are simultaneously fulfilled, or wherein features (1), (2) and (5) are simultaneously fulfilled, or wherein features (1), (3) and (4) are simultaneously fulfilled, or wherein features (1), (3) and (5) are simultaneously fulfilled, or wherein features (1), (4) and (5) are simultaneously fulfilled, or wherein features (2), (3) and (4) are simultaneously fulfilled, or wherein features (2), (3) and (5) are simultaneouslyHE 272866 fulfilled, or wherein features (2), (4) and (5) are simultaneously fulfilled, or wherein features (3), (4) and (5) are simultaneously fulfilled.

8. The compound for use according to claim 5, or pharmaceutically acceptableprodrugs, salts and / or solvates thereof, wherein features (1), (2), (3) and (4) are simultaneously fulfilled, or features (1), (2), (3) and (5) are simultaneously fulfilled, or features (1), (2), (4) and (5) are simultaneously fulfilled, or features (1), (3), (4) and (5) are simultaneously fulfilled, or features (2), (3), (4) and (5) are simultaneously fulfilled.

9. The compound for use according to claim 5, or pharmaceutically acceptableprodrugs, salts and / or solvates thereof, wherein all features (1), (2), (3), (4) and (5) are simultaneously fulfilled.

10. The compound for use according to any one of claims 1 to 4, wherein the compound is selected from the following group of compounds: (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3- methylbenzofuran-2-yl)methyl)acrylamide, (S,E)-3-(3-hydroxy-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)- N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (S,E)-3-(3-amino-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-methyl- N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (E)-3-((2R,3S)-3-amino-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin- 8-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (R,E)-3-(3-Cyano-3-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)- N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((2- methylbenzofuran-3-yl)methyl)acrylamide, (2E)-N-methyl-N-{[3-methyl-5-(pyridin-4-yloxy)-1-benzofuran-2-yl]methyl}-3- {1H,2H,3H,4H,5H-pyrido[2,3-e][1,4]diazepin-7-yl}prop-2-enamide,HE 272866 (E)-3-((2R,3S)-3-hydroxy-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3- b][1,4]diazepin-8-yl)-N-methyl-N-((3-methyl-4-(pyridin-3-ylamino)benzofuran-2- yl)methyl)acrylamide, (E)-N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)-3- (2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylamide, (S,E)-3-(7-amino-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-3-yl)-N-methyl-N-((3- methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2-yl)methyl)acrylamide, (E)-3-((2R,3S)-3-hydroxy-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3- b][1,4]diazepin-8-yl)-N-methyl-N-((3-methyl-4-((pyridin-3-ylamino)methyl)benzofuran-2- yl)methyl)acrylamide, (S,E)-3-(3-amino-4-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-8-yl)-N-((5-(4- (aminomethyl)phenoxy)-3-methylbenzofuran-2-yl)methyl)-N-methylacrylamide and pharmaceutically acceptable prodrugs, salts and / or solvates thereof.

11. A compound that is selected from compounds characterized by the followingformula II or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein LHS is selected from LHSa and LHSb as shown belowHE 272866 wherein the asterisk (*) marks the point of attachment of the remainder of the molecule, wherein the variable groups of the compound of formula I or pharmaceutically acceptable prodrugs, salts and / or solvates thereof, are selected from the following options (A) to (D): (A) the variable groups areV represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents CH2;X is NHHE 272866 R7represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R8represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R7 and R8 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R9represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R10represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, , C1-4-alkylene-NRaRb, ;or R9 and R10 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CH2, CH(CH3), C(CH3)2;(B) the variable groups areV represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb;HE 272866 R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents NH;X is CR7R8R7represents a group selected from F, C1-4-alkyl, C3-6-cycloalkyl; R8represents H, F, C1-4-alkylene-NRaRb, NRaRb; R9represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R10represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb;or R9 and R10 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa;HE 272866 R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CO, CH2, CH(CH3), C(CH3)2;(C) the variable groups areV represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents NH;X is CR7R8HE 272866 R7represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R8represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R7 and R8 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R9represents a group selected from H, F, C3-6-cycloalkyl; R10represents a group selected from F, ORa, C1-4-alkylene-NRaRb; R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CO, CH2, CH(CH3), C(CH3)2;(D) the variable groups areV represents an atom selected from O or S;R1represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R2represents an atom or a group selected from H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, OR5, O-C1-4-alkylene-R5, NR5Ra, NRa-C1-4-alkylene-R5, C1-4-alkylene-NR5Ra, C1-4-alkylene-OR5; R3represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb; R4represents H, F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb;with the proviso that at least one of R1 to R4 is not H;R5represents an atom or a group selected from H, C1-4-alkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, C3-6-cycloalkyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6,HE 272866 phenyl which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6, a bicyclic group in which a phenyl is condensed with a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6or wherein a sulfur atom in the heterocycle may be substituted with two oxo groups, a heterocyclic group having 5 or 6 ring members and 1, 2 or 3 heteroatoms independently selected from N, O and S, which may be aromatic, fully or partially saturated and which may optionally be substituted by 1, 2 or 3 substituents independently selected from R6; R6represents a group selected from F, Cl, Br, I, CN, C1-4-alkyl, C3-6-cycloalkyl, ORa, S-CH3, NRaRb, C1-4-alkylene-NRaRb, C1-4-alkylene-ORa;Ra and Rb is independently selected from H or CH3;W represents NH;X is CR7R8R7represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R8represents a group selected from H, F, C1-4-alkyl, C1-4-alkylene-ORa, C1-4-alkylene- OPO3R112, ORa, OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R7 and R8 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa; R9represents a group selected from H, F, C1-4-alkyl, C3-6-cycloalkyl, CN; R10represents a group selected from F, C1-4-alkylene- OPO3R112, C1-4-alkylene-NRaRb, NRaRb;or R9 and R10 together form a saturated cyclic group having 4 to 6 ring members formed bymethylene groups and optionally a heteroatom selected from oxygen atom an NRa;HE 272866 R11represents a hydrogen atom or a cation suitable for forming a pharmaceutically acceptable salt; andZ represents CO, CH2, CH(CH3), C(CH3)2.

12. A compound according to claim 11, or pharmaceutically acceptable prodrugs, saltsand / or solvates thereof, for use in the treatment of diseases associated with pathogenic bacteria in the gastrointestinal system.

13. The compound for use according to any one of claims 1 to 10 and 12, orpharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein the disease associated with pathogenic bacteria in the gastrointestinal system is inflammatory bowel disease or cancer, such as colorectal cancer, preferably ulcerative colitis, Crohn’s disease, irritable bowel syndrome, small intestinal bacterial overgrowth or functional dyspepsia, wherein, preferably, the treatment of cancer, such as colorectal cancer, is a prevention treatment.

14. The compound for use according to any one of claims 1 to 10, 12 and 13, orpharmaceutically acceptable prodrugs, salts and / or solvates thereof, wherein the diseaseis associated with one or more selected from Acinetobacter, Enterobacteriaceae includingadherent invasive E.coli and colibactin-producing E.coli, and Citrobacter species.

15. Pharmaceutical composition comprising the compound according to claim 11, orpharmaceutically acceptable prodrugs, salts and / or solvates thereof, together with one or more pharmaceutically acceptable excipients.

16. Method of treating a disease associated with pathogenic bacteria in thegastrointestinal system, the method comprising the steps of administering the compound of formula (I) or a pharmaceutically acceptable salt, prodrug, polymorph and / or solvateHE 272866 thereof, as defined in any one of claims 1 to 11, or pharmaceutical composition according to claim 15 to a patient in need thereof, wherein the method is preferably characterized by one or more of the features of any one of claims 13 and 14.

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