NZ620212B2 - Antibacterial cyclopenta[c]pyrrole substituted 3,4-dihydro-1h-[1,8]naphthyridinones - Google Patents

Abstract

The present disclosure is related to novel compounds of formula (I) that inhibit the activity of the FabI enzyme which are therefore useful in the treatment of bacterial infections. It further relates to pharmaceutical compositions comprising these compounds, and chemical processes for preparing these compounds. se compounds.

Description

ANTIBACTERIAL CYCLOPENTA[C]PYRROLE SUBSTITUTED 3 ,4-DIHYDRO- l H-[ l HTHYRIDINONES The present invention is related to novel compounds of formula (I) that inhibit the ty of the FabI enzyme which are ore useful in the treatment of ial infections. It further relates to pharmaceutical compositions comprising these compounds, and chemical processes for preparing these nds.

The compounds of the present invention are antibacterial compounds that inhibit the FabI protein, a NADH-dependent enoyl-acyl carrier protein (ACP) reductase enzyme in the fatty acid bio synthesis pathway. Fatty acid synthase (FAS) is involved in the overall bio synthetic pathway of ted fatty acids in all organisms, but the structural organization of FAS varies considerably among them. The ctive characteristics of FAS of vertebrates and yeasts are that all enzymatic actiVities are encoded on one or two polypeptide chains, and that the acyl carrier protein (ACP) exists in the form of a complex. In contrast, in bacterial FAS, each of synthetic steps is catalyzed by a distinct, mono-fianctional enzyme and the ACP is a discrete protein. Therefore, it is possible to selectively inhibit bacterial FAS by blocking one of the synthetic steps using an inhibitory agent. NADH-dependent enoyl-ACP reductase (Fab 1) is involved in the last step of the four reaction steps involved in each cycle of bacterial fatty acid biosynthesis. Thus, the FabI enzyme is the biosynthetic enzyme in the overall synthetic pathway ofbacterial fatty acid bio synthesis.

The FabI enzyme has been shown to constitute an essential target in major pathogens such as E. Coli (Heath et al. J. Biol. Chem. 1995, 270, 26538; Bergler et al. Eur. J.

Biochem. 2000, 275, 4654). Hence, compounds that inhibit FabI may be useful as cterials.

Compounds having FabI enzyme inhibitory ty have been sed in WO-Ol/26652, WO-Ol/26654, and WO-Ol/27103. Substituted naphthyridinone compounds having FabI inhibitory activity have been disclosed in WO-03/088897, 7/043835 and WO-2008/098374. International patent application discloses various compounds for potential use as FabI inhibitors.

International patent application also discloses various nds for ial use as FabI inhibitors. However, none of these documents disclose a fusedbicyclic moiety that is directly attached to a carbonyl moiety that is or to an alkene.

The present invention relates to a compound of formula (I) wherein A represents —CEC— or V\ R . the—------ bond represents a single bond or a double bond, X represents carbon or nitrogen, and when X represents nitrogen then the — bond represents a single bond; 21 represents CH or N; R1 is hydrogen, C1_4alkyl or halo; R2 is hydrogen, C1_4alkyl or halo; R3 is en, C1_6alkyl, hydroxy or halo; R4 is hydrogen; halo; C1_6alkyl; C2_6alkenyl; C2_6alkynyl; C1_6alkyloxy; C1_4alkyloxycarbonyl; carbonyl; mono- or di(C1_4alkyl)- an1inocarbonyl; aryl; aryloxy; arylcarbonyl; arylsulfonyl; heteroaryl; C1_6alkyl tuted with cyano; C1_6alkyl substituted with aryl or aryloxy; or C1_6alkyl substituted with heteroaryl; aryl is phenyl; phenyl substituted with one, two or three tuents each indiVidually ed from halo, hydroxy, C1_4alkyl, C1_4alkyloxy, polyhaloC1_4alkyl, polyhaloC1_4alkyloxy, cyano, nitro, and amino; aryl is furanyl, enyl, pyrrolyl, pyrazolyl, in1idazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, isothiazolyl, azolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzo[l,3]dioxolyl, benzofuranyl, benzothiazolyl, indolyl, 2,3-dihydro-lH-indolyl, tetrahydrothiophenyl, or quinolinyl, wherein each heteroaryl may be substituted with one or two substituents each independently selected from halo, cyano, C1_4alkyl, C1_4alkyloxy, C1_4alkylcarbonyl, or phenyl; or a pharmaceutically acceptable acid on salt thereof.

As used in the foregoing def1nitions : - halo is generic to fluoro, chloro, bromo and iodo; - C1_4alkyl defines straight and branched chain saturated arbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, l-methyl- ethyl, 2-methylpropyl and the like; - C1_6alkyl is meant to include C1_4alkyl and the higher homo logues f having 5 or 6 carbon atoms, such as, for e, 2-methylbutyl, pentyl, hexyl and the like; - polyhaloC1_4alkyl is defined as polyhalo substituted C1_4alkyl (as hereinabove defined) substituted with 2 to 6 halogen atoms such as omethyl, trifluoromethyl, trifluoroethyl, and the like.

As used in the description, whenever the term "compound of formula (1)" is used, it is meant to include also the pharmaceutically addition salts the compounds of formula (I) are able to form and the solvates the compounds of formula (I) or the pharmaceutically acceptable acid addition salts of compounds of formula (I) are able to form.

The definition of "compounds of formula (1)" inherently includes all stereoisomers of the compound of formula (I) either as a pure stereoisomer or as a e of two or more stereoisomers. omers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture. Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, z'.e. they are not related as mirror images. If a compound contains a disubstituted lkyl group, the substituents may be in the cis or trans configuration.

Therefore, the invention includes enantiomers, diastereomers, racemates, cis s, trans isomers and mixtures thereof The absolute configuration is specified ing to the Cahn-Ingold-Prelog system.

The configuration at an asymmetric atom is specified by either R or S. Resolved compounds whose absolute configuration is not known can be designated by (+) or (-) ing on the direction in which they rotate plane polarized light. When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, z'.e. associated with less than 50%, preferably less than 20%, more preferably less than %, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other isomers. Thus, when a nd of formula (I) is for ce specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is for instance specified as E, this means that the compound is substantially free of the Z ; when a compound of formula (I) is for instance specified as cis, this means that the compound is substantially fiee of the trans isomer.

The terms "stereoisomers" or "stereochemically isomeric forms" hereinbefore or hereinafter are used interchangeably.

The absolute stereochemical configuration of the compounds of a (I) and of the intermediates used in their ation may easily be determined by those skilled in the art while using well-known methods such as, for example, X-ray diffraction.

Some ofthe compounds of a (I) may also exist in their tautomeric form. Such forms although not explicitly ted in the above formula are intended to be included within the scope of the present invention.

Furthermore, some compounds of formula (I) and some of the ediates used in their preparation may exhibit polymorphism. It is to be understood that the present invention encompasses any rphic forms possessing properties useful in the treatment of the conditions noted hereinabove.

The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are able to form. These pharmaceutically acceptable acid addition salts can conveniently be obtained by ng the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e. g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i. e. ethanedioic), malonic, succinic (i. e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

The nds of formula (I) may exist in both unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular ation comprising a compound of the invention and one or more ceutically acceptable solvent molecules, e.g. water or ethanol. The term ‘hydrate’ is used when said solvent is water.

The term "FabI" is art-recognized and refers to the bacterial enzyme ed to fianction as an enoyl-acyl r 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.

Compounds of formula (I) that may be mentioned include those in which: (i) 21 represents CH, and hence the nd of formula I represents the following: NEll—{GM wherein X\’\R]:/\NCA\/NH (ii) when R1 or R2 represent halo, then they are preferably F or Cl; (iii) R1 ents hydrogen or C1_4alkyl; and/or (iv) R2 represents hydrogen or C1_4alkyl.

Preferred compounds of formula (I) e those in which A represents a double bond (and not a triple bond), i.e. it is preferred that: A represents \2\ Interesting compounds of formula (I) are those compounds of a (I) wherein one or more of the following restrictions apply: a) R1 and R2 represent hydrogen; or b) R3 represents en; or c) R3 represents hydrogen, halo or hydroxy; or d) R4 ents hydrogen or halo; or e) R4 represents aryl; or f) R4 represents C1_6alkyl; or g) R4 represents aryloxy, or arylsulfonyl; or h) R4 represents C1_6alkyl substituted with aryl; or i) R4 represents heteroaryl; or j) R4 represents C1_6alkyl substituted with heteroaryl; or k) heteroaryl represents furanyl, thiophenyl, pyrazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, or pyrimidinyl; or 1) X represents ; or m) X represents nitrogen and the ------ bond represents a single bond. 2012/065733 A first group of compounds are the compounds of formula (I) NEll—{GM wherein X\’\R]:/\NCA\/NH A ents —CEC— or V\ the—------ bond represents a single bond or a double bond, X represents carbon or nitrogen, and when X represents nitrogen then the — bond represents a single bond; R1 is hydrogen; R2 is hydrogen; R3 is hydrogen, hydroxy or halo; R4 is hydrogen; halo; C1_6alkyl; C1_6alkyloxy; C1_4alkyloxycarbonyl; aminocarbonyl; mono- or di(C1_4alkyl)-aminocarbonyl; aryl; aryloxy; arylsulfonyl; aryl; C1_6alkyl substituted with cyano; kyl substituted with aryl; or C1_6alkyl substituted with heteroaryl; aryl is phenyl; phenyl substituted with one substituent selected from halo, C1_4alkyl, C1_4alkyloxy, and cyano; heteroaryl is furanyl, thiophenyl, lyl, olyl, thiazolyl, triazolyl, olyl, thiadiazolyl, pyridinyl, or pyrimidinyl; wherein each heteroaryl may be substituted with one substituent selected from halo, cyano, C1_4alkyl, kyloxy, or C1_4alkylcarbonyl; or a pharmaceutically acceptable acid addition salt thereof.

A second group of compounds of formula (I) are those compounds of formula (I) wherein A represents —CEC—.

A third group of compounds of formula (I) are those compounds of formula (I) wherein A represents V\ .

Compounds of formula (I) that are preferred include those in which the X-containing ring ents one of the following: E N% 3 3 R H R H CiS single enantiomer (cis) single enantiomer (cis) i.e. bicycles containing a cis-relationship at the ring junction (a trans-relationship would cause ring tension), which may be c or single enantiomers. As explained hereinafter, if for single enantiomers the absolute stereochemistry is/was not known, the chiral carbons at the ring junction may be depicted by bold or hashed lines r than as wedges).

More preferred compounds of formula (I) include those in which the fused bicyclic X- containing ring represents one of the following: wherein in the above-mentioned fused bicycles, the compounds may be racemic or single enantiomers (if there is no nt symmetry, and enantiomers are possible), as ed hereinbefore.

In compounds of formula (I), it is preferred that: (i) There is at least one R3 or R4 substituent present that does not represent en; (ii) One of R3 and R4 (e. g. R3) represent hydrogen, hydroxy or halo (e.g. fluoro) and the other one of R3 and R4 (e.g. R4) represents a substituent other than hydrogen; (iii) R3 represents hydrogen, hydroxy or halo (e.g. fluoro) and most preferably represents hydrogen (i.e. R3 is essentially not present); 2012/065733 (iv) R4 represents a substituent other than hydrogen (i.e. there is an R4 substituent that is t, and does not represent hydrogen); (V) R4 represents a substituent other than hydrogen, which is attached to X, in which any of the above can be taken together or in combination. For instance, (iii), (iv) and/or (V) may be taken in combination to provide the particularly preferred compounds of formula (1) below: wee wee mm in which R4 ents a substituent other than hydrogen. Particularly preferred substituents that R4 (here and elsewhere) may represent e: (i) optionally substituted aryl; (ii) optionally substituted heteroaryl (iii) C1_6alkyl substituted by aryl or heteroaryl (which latter two aryl and heteroaryl groups are themselves optionally substituted as defined herein); (iv) aryloxy (in which the aryl moiety is optionally substituted as defined (v) arylsulfonyl (in which the aryl moiety is ally substituted as defined herein); (vi) C1_6alkyl, which is unsubstituted (e.g. ethyl, methyl, isopropyl); (Vii) di(C1_4alkyl)aminocarbonyl (e.g. -C(O)N(CH3)2); (viii) aminocarbonyl (-C(O)NH2); (ix) C1_4alkyloxycarbonyl (e.g. -C(O)O-CH2CH3); (x) halo (e. g. fiuoro); (xi) C2_6alkynyl (e.g. -CEC); (xii) C1_6alkoxy (e. g. -OCH3).

It is particularly preferred that the R4 group contains an aromatic moiety, and hence (i), (ii), (iii), (iv) and (v) above are particularly red).

In the case when R4 represents (i) above, then the aryl group is preferably phenyl, which group may be unsubstituted or substituted by one or two (e.g. one) substituent ed fiom C1_4alkyloxy, halo, C1_4alkyl or cyano (e.g. -OCH3, chloro, fluoro, methyl or cyano).

In the case where R4 represents (ii) above, then the heteroaryl group is a monocyclic - or 6-membered ring containing one to four heteroatoms, for instance thienyl (e.g. 2- or 3-thienyl), l (e. g. 4-pyridyl or 3-pyridyl), pyrazolyl (e. g. 5-pyrazolyl, 4-pyrazolyl or l-pyrazolyl), furanyl (e.g. 2- or 3-fi1ranyl), thiazolyl (e. g. 2-thiazolyl), isoxazolyl (e.g. 4-isoxazolyl), pyrrolyl (e.g. l-pyrrolyl), triazolyl (e. g. l,2,3-triazol—lyl , triazol—2-yl or l,2,4-triazol—2-yl), azolyl (e.g. l,3,4-thiadiazol—2-yl), pyrimidinyl (e.g. 5-pyrimidinyl), tetrazolyl (e.g. l,2,3,4-tetrazol—2-yl, l,2,3,4-tetrazol— l-yl), imidazolyl (e.g. 2-imidazolyl). Such aryl groups may be unsubstituted or substituted with one or two (e.g. two or, preferably, one) tuent(s) selected from halo, cyano, C1_4alkyl (e.g. C1_2alkyl), C1_4alkyloxy (e.g. C1_2alkyloxy) and C1_4alkyl- carbonyl (e.g. C1_2alkylcarbonyl), e.g. -OCH3, methyl, halo (e.g. chloro), cyano, and -C(O)-CH3.

In the case where R4 represents (iii) above, then preferably the C1_6alkyl group is methyl, i.e. -CH3 substituted with aryl (e.g. phenyl, such as unsubstituted phenyl) or heteroaryl (e.g. a 5- or 6-membered monocyclic heteroaryl group ning one or two (e.g. one) atom(s), so forming e.g. a thienyl group such as a 2-thienyl group; and such a heteroaryl group is ably unsubstituted).

In the case where R4 represents (iv) or (V) above, aryl is preferably unsubstituted phenyl, and hence the R4 group is -O-phenyl or -S(O)2-phenyl.

Most ably, the R4 group represents (i) or (ii) above, i.e. aryl or heteroaryl. Even more preferably the R4 group represents (i) above, ally unsubstituted phenyl.

The most red compounds of formula (I) include those in which the X-containing fused bicyclic moiety represents: Ram emu4 4 in which R4 is as defined herein. Such compounds which contain either a N(R4) moiety or a C(R4) moiety adjacent a double bond may be beneficial. This is because the shape ofthe nitrogen atom (e.g. being more planar in nature, as compared to a CR4 moiety that is not adjacent a double bond) or the presence of the double bond in the X-containing ring may help to orient the R4 group (if present) such that the compound WO 21054 overall (e.g. in view of the R4 substituent’s orientation) displays better/improved binding properties to the FabI ial enzyme. Hence, these compounds ofthe invention may be advantageous in the sense that the presence of the double bond may lead to improved binding to/inhibition of the FabI enzyme. Consequently the compounds of the invention may be advantageous nds (e.g. compared to known compounds) by virtue of these properties which may consequentially lead to better potency, cy, etc.

Compounds of formula (I) can generally be prepared by reacting an ediate of formula (II) with an intermediate of formula (III), in at least one reaction-inert solvent and optionally in the presence of at least one le coupling t and/or a suitable base, the said process fiarther optionally comprising converting a compound of formula (1) into an addition salt thereof, and/or preparing stereochemically isomeric forms thereof X\’\]:>NHif E? 21— O + HO—C—A—<\_/ NH —> (I) (II) (III) It may be convenient to activate the carboxylic acid of formula (III) by adding an effective amount of a reaction promoter. Non-limiting examples of such reaction promoters include carbonyldiimidazole, N,N’-dicyclohexyl-carbodiimide or l-(3-dimethylaminopropyl)ethylcarbodiimide, hydroxybenzotriazole, benzotriazolyl-oxytris (dimethylamino)-phosphonium hexafluorophosphate, tetrapyrrolidino-phosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluoro-phosphate, or a fianctional derivative f Compounds of formula (I) can also be prepared by reacting an intermediate of formula (II) with an intermediate of formula (IV) wherein Y represents hydroxy or halo. The reaction can be med in a reaction-inert solvent such as, for example, dichloromethane or dimethylformamide and optionally in the presence of a suitable base such as, for example, ropylethyl-amine (DIPEA). )<’\]:>NH/‘/ l? Z1- 0 + Y—C—A—<\_N/ NH —> (I) (I I) (IV) Compounds of formula (I) in which A represents =C(R1)- can also be prepared by reacting an intermediate of formula (V) with an ediate of formula (VI), O 21— O )\,\R3f/]:>N + X \ / NH —> a1 (I) / R2 N (V) H (VI) wherein Xal represents a suitable leaving group such as a suitable halo group (e.g. chloro, iodo and, especially, bromo) and the other integers are as hereinbefore defined, under reaction suitable reaction ions, for example under metal catalyst coupling reaction conditions (e.g. precious metal coupling reaction conditions, wherein the precious metal is e.g. palladium-based), in particular under Heck reaction conditions using preferably a palladium-based catalyst such as palladium acetate, tetrakis(triphenylphosphione)palladium(0), iphenylphosphine)palladium(II) dichloride, [l ,l ’-bis(diphenylphosphino)ferrocene]palladium(II) dichloride or the like (preferably, the catalyst is palladium acetate), for instance optionally in the presence of a suitable solvent (e. g. acetonitrile or the like), base (e.g. an amine base such as N,N—diispropylamine or the like), and a ligand (e.g. triphenylphosphine, tri-O-tolylphosphine or the like). The reaction may be performed in a sealed tube and/or in a microwave.

The ng materials and some of the intermediates are known compounds and are commercially available or may be prepared ing to conventional on procedures generally known in the art.

For the compounds in which 21 represents CH, intermediates (IV) and (VI) may be prepared as described herein, or according to conventional reaction ures generally known in the art. For the corresponding intermediates in which 21 represents N, this may also be the case. However, such compounds may also be prepared in ance with the following scheme: _ 12 _ N COOEt \ Br N\ COOEt Br b N\ Br a OH N\ I Br / —> | —> | _> | 2 N NH2 N NH2 N NH2 CAS 162986 A Br COOMe N d N\ e N\ f A —> I —> I —> I 01% \ N N/ H O N N H O O O H Conditions : a) NBS, ACN, reflux, 3 h, 70% ; b) LiAlH4 lM in THF, THF, 5°C to RT, on, 20%; c) PBI‘3, DCM, RT, on, 90%; f) dimethyl malonate, NaOMe in MeOH, MeOH, RT, on, % ; g) NaOH, MeOH, reflux, 4h, HCl, reflux, o.n. ; h) DIEA, Pd(OAc)2, tri-O- tolylphosphine, ACN, DMF, uw, 180°C, 25 min.

The compounds of formula (I) as ed in the above described processes may be synthesized in the form of racemic es of enantiomers which can be separated from one another following art-known resolution procedures. Those compounds of a (I) that are obtained in racemic form may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said reomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the omeric forms of the compounds of formula (1) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a c stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

The compounds described herein are inhibitors of the FabI enzyme, as demonstrated by the examples below (including in Pharmacological Example 1). In view of these FabI enzyme inhibiting properties the nds described herein are useful for treating bacterial infections. For instance, these compounds are useful for the ent of ial infections, such as, for example, infections of upper respiratory tract (e.g. otitis media, bacterial itis, acute epiglottitis, thyroiditis), lower respiratory (e. g. empyema, lung abscess), cardiac (e.g. infective endocarditis), gastrointestinal (e. g. secretory diarrhoea, splenic abscess, retroperitoneal s), CNS (e.g. cerebral abscess), eye (e. g. blepharitis, conjunctivitis, keratitis, endophthalmitis, preseptal and orbital cellulitis, darcryocystitis), kidney and urinary tract (e.g. epididymitis, enal and phric abscess, toxic shock syndrome), skin (e.g. impetigo, folliculitis, cutaneous abscesses, cellulitis, wound infection, ial myositis), and bone and joint (e.g. septic arthritis, yelitis). Additionally, the nds may be useful in combination with known antibiotics.

Therefore the present invention also relates to compounds of formula (I) for use as a medicine especially for use in treating bacterial infections, in particular bacterial infections caused by a bacterium that expresses a FabI enzyme. Subsequently the present compounds may be used for the manufacture of a medicine for treatment of bacterial infections, in particular bacterial infections caused by a bacterium that expresses a FabI enzyme. r, the present invention provides a method of treating ial infections which comprises administering to a subject in need thereof a FabI enzyme inhibiting compound of formula (I).

A subject in need oftreatment has a bacterial infection or has been exposed to an infectious bacterium, the symptoms of which may be alleviated by administering a therapeutically effective amount of the compounds of the present invention. For example, a subject in need of treatment can have an infection for which the compounds of formula (I) can be administered as a treatment. In another example, a subject in need oftreatment can have an open wound or burn injury, for which the compounds of formula (I) can be administered as a prophylactic. Typically a subject will be treated for an ng bacterial infection.

A subject can have a bacterial infection caused by Bacillus cis, Citrobacter sp., Escherichia coli, Francisella tularensis, Haemophilus influenza, Listeria mono- cytogenes, Moraxella catarrhalis, Mycobacterium ulosis, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Salmonella sp., Serratia sp., Shigella sp., Stenotrophomonas maltophilia, Staphylococcus aureus, or Staphylococcus epidermidis.

Preferably, the t is treated (prophylactically or therapeutically) for a ial infection caused by a bacterium that expresses a FabI enzyme.

The term "treating" and ment', as used herein, refers to curative, tive and prophylactic treatment, including reversing, alleviating, inhibiting the progress of, or preventing the e, disorder or ion to which such term applies, or one or more 2012/065733 symptoms of such disease, disorder or condition.

A "therapeutically effective amount" of a compound of the present invention is the quantity which, when stered to a subject in need of ent, improves the sis ofthe subject, e.g. delays the onset of and/or reduces the severity of one or more ofthe subject’s symptoms associated with a bacterial infection. The amount of the disclosed compound to be administered to a subject will depend on the particular disease, the mode of administration, and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight and tolerance to drugs.

The skilled person will be able to determine appropriate dosages depending on these and other factors.

The compounds may be tested in one of several biological assays to determine the concentration of nd which is required to have a given cological effect.

Additionally the present ion provides pharmaceutical itions comprising at least one ceutically acceptable carrier and a therapeutically ive amount of a compound of formula (I).

In order to prepare the ceutical compositions of this invention, an effective amount of the ular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with at least one pharmaceutically acceptable carrier, which r may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for oral administration, rectal administration, percutaneous administration or parenteral injection.

For example in preparing the compositions in oral dosage form, any of the usual liquid pharmaceutical carriers may be employed, such as for instance water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid pharmaceutical carriers such as starches, , kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and s. Because of their easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral injection itions, the pharmaceutical carrier will mainly comprise sterile water, although other ingredients may be included in order to improve solubility of the active ingredient.

Inj ectable solutions may be prepared for instance by using a pharmaceutical carrier comprising a saline solution, a glucose solution or a mixture of both. Injectable suspensions may also be prepared by using appropriate liquid carriers, suspending agents and the like. In compositions suitable for percutaneous administration, the pharmaceutical carrier may optionally comprise a penetration enhancing agent and/or a le wetting agent, optionally combined with minor proportions of suitable additives which do not cause a significant deleterious effect to the skin. Said additives may be selected in order to tate administration of the active ingredient to the skin and/or be helpful for preparing the desired compositions. These l compositions may be stered in various ways, e.g., as a ermal patch, a n or an ointment. Addition salts of the compounds of formula (1), due to their increased water lity over the corresponding base form, are sly more suitable in the preparation of aqueous compositions.

It is especially advantageous to ate the ceutical compositions of the invention in dosage unit form for ease of administration and uniformity of dosage.

"Dosage unit form" as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired eutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, inj ectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

For oral administration, the ceutical compositions ofthe present invention may take the form of solid dose forms, for example, tablets (both wable and chewable forms), capsules or gelcaps, prepared by conventional means with pharmaceutically acceptable excipients and carriers such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like), fillers (e. g. lactose, microcrystalline cellulose, calcium phosphate and the like), lubricants (e.g. magnesium stearate, talc, silica and the like), disintegrating agents (e. g. potato starch, sodium starch glycollate and the like), wetting agents (e.g. sodium laurylsulphate) and the like. Such tablets may also be coated by methods well known in the art.

Liquid preparations for oral administration may take the form of e.g. solutions, syrups or suspensions, or they may be ated as a dry product for admixture with water and/or another suitable liquid carrier before use. Such liquid ations may be prepared by conventional means, optionally with other pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous carriers (e. g. almond oil, oily esters or ethyl alcohol), -l6- sweeteners, flavours, masking agents and preservatives (e. g. methyl or propyl p-hydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners useful in the pharmaceutical compositions of the invention comprise preferably at least one e ner such as aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose (4,l',6'-trichloro-4,l',6'-trideoxygalactosucrose) or, ably, saccharin, sodium or calcium saccharin, and optionally at least one bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, l, l or honey. Intense ners are conveniently used in low concentrations. For example, in the case of sodium saccharin, the said concentration may range from about 0.04% to 0.1% (weight/volume) of the final ation. The bulk sweetener can effectively be used in larger concentrations ranging from about 10% to about 35%, preferably from about 10% to 15% (weight/volume).

The pharmaceutically acceptable flavours which can mask the bitter tasting ingredients in the low-dosage formulations are preferably fruit flavours such as cherry, raspberry, black currant or strawberry flavour. A ation of two flavours may yield very good results. In the high-dosage formulations, stronger pharmaceutically acceptable flavours may be required such as Caramel Chocolate, Mint Cool, Fantasy and the like.

Each flavour may be t in the final composition in a concentration ranging from about 0.05% to l% (weight/volume). ations of said strong flavours are advantageously used. Preferably a flavour is used that does not undergo any change or loss of taste and/or color under the circumstances of the formulation.

The compounds of formula (I) may be formulated for parenteral administration by injection, conveniently intravenous, muscular or subcutaneous injection, for example by bolus injection or continuous intravenous on. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or multi-dose containers, including an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as isotonizing, suspending, stabilizing and/or dispersing agents. Alternatively, the active ient may be t in powder form for mixing with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such WO 21054 as cocoa butter and/or other glycerides.

Those of skill in the treatment of antibacterial diseases linked to the inhibition of the FabI enzyme will easily determine the therapeutically effective amount of a nd of formula (I) from the test results presented hereinafter. In general it is contemplated that a therapeutically ive dose will be from about 0.001 mg/kg to about 50 mg/kg ofbody weight, more preferably from about 0.01 mg/kg to about 10 mg/kg of body weight ofthe patient to be d. It may be riate to administer the eutically ive dose in the form of two or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example each containing from about 0.1 mg to about 1000 mg, more particularly from about 1 to about 500 mg, of the active ingredient per unit dosage form.

The exact dosage and frequency of stration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical ion of the particular patient as well as the other medication, the patient may be taking, as is well known to those skilled in the art. Furthermore, said "therapeutically effective amount" may be lowered or increased depending on the response of the treated patient and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.

Compounds of formula (I) may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic e (e. g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise. The compounds may also exhibit such advantages in View of the presence of the NR4 moiety or CR4 moiety that is adjacent a double bond in the X-containing ring.

For instance, compounds of a (I) may have the advantage that they have a good or an improved thermodynamic solubility (e.g. compared to nds known in the prior art; and for instance as determined by a known method and/or a method described herein). Compounds of formula (I) may also have the advantage that they have a broad spectrum of actiVity against antibacterials (e.g. a broader spectrum of antibacterial actiVity compared to compounds known in the prior art; and for instance as determined by known tests and/or tests bed herein). Compounds of formula (I) may also WO 21054 have the advantage that they have good or improved in viva pharmacokinetics and oral bioavailabilty. They may also have the advantage that they have good or improved in viva efficacy. For instance, the compounds of the invention may adaptable for intravenous formulation/dosing and hence may exhibit an improved in viva efficacy when stered intravenously. The compounds may also exhibit such advantages in view of the presence of the NR4 moiety or CR4 moiety that is adjacent a double bond in the aining ring.

Experimental part Abbreviations "DMF" is defined as N,N—dimethylformamide, "DCM" or "CHzClz" is defined as dichloromethane, "MeOH" is defined as methanol, "EtOH" is defined as ethanol, "MgSO4" is defined as magnesium e, and "THF" is defined as tetrahydrofuran, " or "EtOAc" is defined as ethyl acetate, "DIPEA" is defined as diisopropyl- ethylamine, "EDCI" is defined as N'-(ethylcarbonimidoyl)-N,N-dimethyl-l,3-propane- diamine monohydrochloride, "HOBT" is defined as l-hydroxy-lH—benzotriazole, "DIPA" is defined as diisopropylamine, "K2C03" is defined as potassium carbonate, "TFA" is defined as trifluoroacetic acid, "NH4OH" is defined as ammonium hydroxide, "NaHC03" is defined as carbonic acid monosodium salt, "EtzO" is defined as diethyl ether, "NaZSO4" is defined as sulfuric acid disodium salt, "CH3CN" is defined as acetonitrile, "NaOH" is defined as sodium hydroxide, "n—BuLi" is defined as n-Butyllithium, "i—PrOH" is defined as panol, "Pd(OAc)2" is defined as palladium acetate, "DMA" is defined as ylacetamide, "Et3N" is defined as triethylamine.

Stereochemical representation The compounds of formula (I) have at least two asymmetric carbon atoms as illustrated below wherein the asymmetric carbon atoms are identified by a * : R4 * , fi? Z1— 0 (I) R3Big—C}>l< H Due to ring tension in the system of two annulated five membered rings, only the ‘cis’ forms can be prepared and not the ‘trans’ forms.

WO 21054 Compounds of formula (I) wherein the system of two annulated five membered rings has the configuration "IIIBMEO 3000 0:02&2ZflogZI I "<35’}, Each of the above depicted "cis" compounds consists of a racemic mixture of two enantiomers and bold bonds or hashed bonds have been used to indicate this relative stereochemical configuration.

In case such a "cis" nd was separated into its two individual enantiomers, the stereochemical configuration of the single enantiomer was than designated as R* or S* indicating a relative stereochemistry. Accordingly a single enantiomer designated as (R*,S*) can either have the absolute (R,S) configuation or the (S,R) ration. If the absolute stereochemistry of a specific chiral carbon atom in a single enantiomer was known the bold and hashed bonds were replaced by wedged bonds to indicate the compound is a single enantiomer having a known absolute stereochemistry.

A. Synthesis ofthe intermediates Example A.l >k O Om/ \ a) Preparatlon of_ ed1ate (l). .

N N O A on of 6-bromo-3,4-dihydro-lH—[l,8]naphthyridinone (l .0 g, 4.4 mmol), tert- butyl acrylate (2.56 ml, 17.62 mmol) and N,N—diisopropylethylamine (l .46 ml, 8.81 mmol) in acetonitrile (20 ml) and DMF (7 ml) was d and degassed with nitrogen gas for 10 minutes. Tri-o-tolylphosphine (0.27 g, 0.88 mmol) and palladium (II) acetate (47% on Pd) (0.099 g, 0.44 mol) were added and the resulting mixture was aved (1600 W, 180°C, 35 minutes). The reaction mixture was evaporated till dryness, taken up in a mixture of DCM/methanol (8/2) (50 ml), filtered through a short pad of celite and washed with DCM. The organic layer was washed with water, dried (MgSO4), filtered and evaporated to dryness. The residue was taken up in cold ethanol (10 ml) and stirred at 5°C for 5 minutes, the precipitate was filtered off, washed with cold ethanol (3 ml) and dried under vacuum to yield 950 mg intermediate (1).

HO / \ b) Preparat10n of. .CF3COOH intermediate (2) N/ H 0 Intermediate (1) (4.1 g, 14.95 mmol) was dissolved in a mixture of trifluoroacetic acid (23.2 ml) in DCM (41 ml). The reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under d pressure. The ing solid was triturated with diethyl ether, filtered off and dried under vacuum to yield 3.97 g of intermediate (2). c) Preparation of | HQ intermediate (3) Intermediate (2) was ated overnight in a mixture of HCl in dioxane (4 M, 48 ml), the solid was filtered off, washed with diethyl ether and dried under vacuum to give 3.7 g of intermediate (3).

Example A2 a) Preparation of Om—g—O—é intermediate (4) A solution of propynyl-carbamic acid tert-butyl ester (CAS 1475289, 45 g, 0.23 mol), cobalt carbonyl (17.5 g, 46.1 mmol) and 3-tetramethylthiourea (36.6 g, 0.277 mol) in toluene (1.8 L) was stirred and heated at 70°C for 5 hours in an autoclave under CO pressure (2-3 bar). The resulting mixture was filtered through a short pad of celite and evaporated till dryness. The residue was taken up in DCM and filtered through a short pad of celite in order to obtain a clear solution. It was evaporated till dryness to give 85.7 g of crude residue. It was d by preparative liquid chromatrography on (silicagel 20-45 um, 1000 g, mobile phase (gradient DCM/AcOEt from 95/5 to 80/20). Pure fractions were collected and the t was evaporated to give 36.5 g of intermediate (4). b) Preparat10n of "Pew—é (C's) 1ntermed1ate (5) A mixture of intermediate (4) (37.6 g, 0.168 mol) and palladium 10% on charcoal (7.5 g) in ethyl acetate (750 ml) was hydrogenated at room temperature for 30 minutes at 3 bars in a closed vessel r. The resulting mixture was filtered h a short pad of celite and evaporated till dryness to give 38.2 g of intermediate (5).

F3C‘fi_0_<:’:>N_C_OO 0 || || < (C's). c) Preparation of intermediate (6) n-BuLi 1.6M in hexane (64 ml, 0.102 mol) was added drop wise at -20°C, under a N2 atmosphere, to a solution of diisopropylamine (14.3 ml, 0.102 mol) in dry THF (140 mL) then the mixture was stirred at -20°C for 20 minutes. A solution of intermediate (5) (19.1 g, 84.8 mmol) in dry THF (190 mL) was then added at -78°C and the resulting mixture was stirred for 1 hour at -78°C. A solution ofN—phenyl- trifluoromethane sulfonimide (36.4 g, 0.102 mol) in dry THF (110 mL) was added at -78°C then the mixture was allowed to reach room ature and stirred ght.

The mixture was evaporated till dryness. The residue was taken in DCM, washed with an aqueous NaHC03 solution, dried (MgSO4) and evaporated till dryness to give 27.7 g of intermediate (6). d) Preparation of mN—(HZ—O—é (Cis) intermediate (7) A solution of intermediate (6) (9.3 g, 26.0 mmol) and phenyl boronic acid (3.81 g, 31.2 mmol) in a on of potassium carbonate 2 M (26 ml) and ethylene glycol dimethyl ether (93 ml) was purged with N2 for 10 minutes then tetrakistriphenyl- phosphine-palladium (3.0 g, 2.6 mmol) was added. The closed reactor was heated at 80°C using one multimode cavity microwave CEM Mars system with a power output g from 0 to 400W for 30 minutes. The resulting on was cooled down to room ature, water and EtOAc were added, the organic layer was separated, washed with water then brine, dried (MgSO4) and evaporated till dryness. Purification ofthe residue was carried out by flash chromatography over silica gel (330g, 15-40um, heptane/EtOAc from 100/0 to 80/20). The pure fractions were collected and evaporated to dryness to afford 4.3 g of ediate (7). e) Preparation of mm (Cis) intermediate (8) Trifluoroacetic acid (44 ml) was added drop wise to a solution of intermediate (7) (14.5 g, 50.8 mmol) in CHzClz (44 ml). The resulting solution was stirred at room temperature for 30 min then the mixture was cooled to 5°C. NaOH 3N was added slowly until the mixture was basic, it was extracted twice with CHzClz. The combined organic layer were washed with NaOH 3N then water, dried over MgSO4 and ated to give 8.8 g ofracemic compound of intermediate (8). f) Preparation of WW intermediate (9) and 8O R N" intermediate (10) Intermediate (8) was purified and resolved by chiral SFC on (CHIRALPAK AD-H um 250x20 mm). Mobile phase (0.3% isopropylamine, 73% C02, 27% iPrOH). Pure fractions were collected and the solvent was removed to give 3.9 g of intermediate (10) (R*,S*)([01]D20 = 53.190 (589 nm, c 0.3365 w/v %, DMF, 20°C)) and 4 g of intermediate (9) (S*,R*) ([011])20 = +386 0 (589 nm, c 0.285 w/v %, DMF, .

Intermediate 1 9 2 1H NMR (400MHz 8 (ppm) 7.43 (d, J: 7.6 Hz, 2 H), 7.32 (t, J: 7.6 Hz, 2 , DMSO-d6) H), 7.20 - 7.26 (m, l H), 6.07 (d, J: 2.0 Hz, 1 H), 3.30 - 3.39 (m, l H), 2.77 - 2.94 (m, 4 H), 2.66 (dd, J: 3.0, 11.1 Hz, 1 H), 2.58 (dd, J: 3.0, 11.1 Hz, 1 H), 2.46 (d, J: 15.7 Hz, 1 H). ediate 1 10) 1H -NMR z 5 (ppm) 7.43 (d, J: 7.6 Hz, 2 H), 7.32 (t, J: 7.6 Hz, , DMSO-d6) 2 H), 7.20 — 7.26 (m, 1 H), 6.07 (d, .1: 2.0 Hz, 1 H), 3.30 — 3.39 (m, 1 H), 2.77 — 2.94 (m, 4 H), 2.66 (dd, .1: 3.0, 11.1 Hz, 1 H), 2.58 (dd, .1: 3.0, 11.1 Hz, 1 H), 2.46 (d, .1: .7 Hz, 1 H). e A.3 a) Preparation of WHO—é (Cis) intermediate (ll) A solution of intermediate (6) (44.4 g, lll.82 mmol) and 3-thiopheneboronic acid (l7. 17 g, l34.l9 mmol) in potassium carbonate 2M (1 12 ml) and ethylene glycol dimethyl ether (444 ml), in an open vessel, was purged with N2 for 10 minutes then tetrakistriphenylphosphinepalladium (12.92 g, 223.65 mmol) was added. The solution was heated at 78°C using one multimode cavity ave CEM MARS system with a power output g from 0 to 400 W for 1 hour. The solution was cooled to room temperature, water and EtOAc were added. The mixture was filtered through a pad of celite. The organic layer was separated, washed with water then brine, dried over MgSO4 and evaporated till dryness. The residue was purified by preparative liquid tography on (silicagel 20-45 um ,1000 g, mobile phase (80% heptane, 20% AcOEt)). The pure fractions were collected and concentrated to give 16 g of intermediate (1 1). b) Preparation of WW (Cis) intermediate (12) Trifluoroacetic acid (14.37 ml, 186.47 mmol) was added to a solution of intermediate (11) (5.72 g, 18.65 mmol) in CHzClz (57 ml). The reaction e was stirred at room temperature for 3 hours. K2C03 (10% aqueous solution, 50 ml) and then K2C03 solid were added at 0°C to basify the solution. The organic layer was separated, washed with water, dried ) and evaporated till dryness. The residue was purified by preparative liquid chromatography on (silicagel 20-45um, 1000 g, mobile phase (1% NH4OH, 93% DCM, 7% MeOH)). The pure fractions were collected and concentrated to give 12 g of of intermediate (12). c) Preparation of SN" intermediate (13) IIIIII and 79 NH U) \ intermediate (14) Illlll Intermediate (12) was purified and resolved by chiral SFC on (CHIRALPAK AD-H 5 um 250x20 mm). Mobile phase (0.3% isopropylamine, 80% C02, 20% methanol).

Pure fractions were collected and the solvent was removed to give 5.8 g of intermediate (14) (R*,S*) ([01],)20 = —12.4° (589 nm, c 0.5 w/v %, DCM, 20°C)) and 5.6 g of intermediate (13) ) )20 = +9.43 0 (589 nm, c 0.35 w/v %, DCM, 20°C)).

Intermediate 1 13) 1H NMR (500MHz ,DMSO-d6) 5 (ppm) 7.49 (dd, J: 2.5, 5.0 Hz, 1 H), 7.31 (d, J: 5.0 Hz, 1 H), 7.29 (d, .1: 2.5 Hz, 1 H), 5.88 (d, .1: 1.9 Hz, 1 H), 3.28 — 3.33 (br.s., 1 H), 2.75 — 2.87 (m, 4 H), 2.61 (dd, .1: 2.8, 10.7 Hz, 1 H), 2.54 (dd, .1: 3.3, 10.9 Hz, 1 H), 2.40-2.15(m, 2 H).

Intermediate 1 14) 1H NMR (500MHz ,DMSO-d6) 5 (ppm) 7.49 (dd, J: 2.5, 5.0 Hz, 1 H), 7.31 (d, J: 5.0 Hz, 1 H), 7.29 (d, .1: 2.5 Hz, 1 H), 5.88 (d, .1: 1.9 Hz, 1 H), 3.28 — 3.33 (br.s., 1 H), 2.75 — 2.87 (m, 4 H), 2.61 (dd, .1: 2.8, 10.7 Hz, 1 H), 2.54 (dd, .1: 3.3, 10.9 Hz, 1 H), 2.40-2.15(m, 2 H).

Example A.4 a) ation of "MN—(H)o/ < (C's). intermediate (15) A solution of intermediate (6) (108 g, 0.302 mol) and pyridineboronic acid (49.5 g, 0.363 mol) in aqueous potassium ate 2M (302 ml, 0.604 mol) and ethylene glycol dimethyl ether (1.1 L) was purged with N2 for 5 minutes then tetrakistriphenyl— phosphinepalladium (34.9 g, 0.030 mol) was added, the e was heated at 78°C using a ode microwave (CEM Mars 5) with a power output ranging from 0 to 800 W for 1hour, cooled to room temperature, water and EtOAc were added, the organic layer was separated, washed with water then brine, dried over MgSO4 and evaporated till dryness. The residue was purified by preparative liquid chromatography on (silicagel 15-40um, 300g, mobile phase (0.1% NH4OH, 97% DCM, 3% iPrOH).

Pure fractions were collected and the solvent was removed to obtain 47.6 g of intermediate (15).

* II b) ation of "MN—C"O/ < intermediate (17) IIIII O / * II and "MN—C"< intermediate (18) Illlll Intermediate (16) was purified and resolved by chromatography on pak AD (20um, 2000g, 110 mm) with a flow rate of 750 ml/min. The mobile phase was methanol 100%. The pure fractions were collected and evaporated to dryness to give 18.7 g ofintermediate (18) (R*,S*) (([d1D20 = +5575 0 (589 nm, c 0.339 w/v %, DMF, 20 °C)) and 20.7 g ofintermediate (17) (S*,R*) (([d1D20 = -68.38 0 (589 nm, c 0.253 w/v %, DMF, 20 C’C)).

Intermediate 1 17) 1H NMR (500MHz ,DMSO-d6) 5 (ppm) 8.52 (d, J: 6.0 Hz, 2 H), 7.41 (d, J: 6.0 Hz, 2 H), 6.50 (s, 1 H), 3.36 — 3.61 (m, 4 H), 2.81 — 3.02 (m, 3 H), 2.61-2.53 (m, 1 H), 1.36 (s, 9 H) Intermediate 118) 1 1H NMR (500MHz ,DMSO-d6) 5 (ppm) 8.52 (d, J: 6.0 Hz, 2 H), 7.41 (d, J: 6.0 Hz, 2 H), 6.50 (s, 1 H), 3.36 — 3.61 (m, 4 H), 2.81 — 3.02 (m, 3 H), 2.61-2.53 (m, 1 H), 1.36 (s, 9 H) Example A.5 IIIIIII Z / 79 Preparation of I .HCI intermediate (19) Illlll Intermediate (18) (24.8 g, 86.6 mmol) was added to HCl in dioxane (4 M, 108 ml) at °C then the mixture was stirred at room temperature for 90 minutes. The precipitate was filtered off, washed with EtzO and dried under vacuum at 70°C 21.1 g of ediate (19).

Preparation of NW"/ 'HC' intermediate (20) Intermediate (20) was prepared analogously starting from intermediate (17).

Example A.6 a) Preparation of 0’3 \ intermediate (21) on done on 4 batches of 0.5g of 6-bromo-3,4-dihydro-1H-[1,8]naphthyridin one each. A solution of 6-bromo-3,4-dihydro-1H-[1,8]naphthyridinone (0.5 g, 2.20mmol), bis(pinacolato)diboron (0.67 g, 2.64 mmol) and potassium acetate (0.648 g, 6.61 mmol) in DMF (5 ml) and CH3CN (10 ml) was stirred and degassed with nitrogen for 10 minutes. 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.161 g, 0.22mmol) was added and the resulting mixture was heated at 120°C using a microwave (Biotage tor 60) with a power output ranging from 0 to 400 W for 40 minutes. The mixture was evaporated till dryness, the e was taken up in DCM and water, filtered through a short pad of . The organic layer of the filtrate was WO 21054 ted, washed with water, dried (MgSO4) and evaporated till dryness. The residue was taken up in EtOH, filtered off and dried to give 0.36 g of intermediate (21). >L O . § b) Preparation of \ ed1ate (22). .

N/ M 0 Intermediate (21) (1.0 g, 3.65 mmol), tert—butyl propiolate (0.426 ml, 3.04 mmol), silver(I)oxide (1.06 g, 4.56 mmol) and K2C03 (0.84 g, 6.08 mmol) in CH3CN (10 ml) and DMF (5ml) was purged with N2 then palladium(II)acetate (47% Pd) (0.034 g, 0.152 mmol) was added and the mixture heated at 100°C using a monomode ave ge initiator 60) with a power output ranging fiom 0 to 400W for 20 minutes. Water and EtOAc were added, the e was filtered through a short pad of celite, the organic layer was separated, washed with water then brine, dried (MgSO4) and evaporated till dryness. The obtained residue was purified by flash chromatography over silica gel (15-40um, cartridge 30g, from CHzClz to CHzClz/CHgOH/NH4OH: 98.5/1 .5/0. 1) The pure fractions were collected and evaporated to dryness, yielding 0.037g of intermediate (22). c) Preparation of \ intermediate (23) Intermediate (22) (0.053 g, 0.195 mmol) was dissolved in a solution of TFA/DCM (0.37 ml /0.5 ml). The reaction mixture was stirred at room temperature for 30 minutes.

The reaction mixture was concentrated under reduced pressure. The resulting solid was triturated with EtZO, filtered off and dried under vacuum (80°C) to give 0.032 g of intermediate (23).

Example A.7 a) Preparation of. OSt: — A solution of bromobenzene ml, 2.64mmol), cistert—butyloxy-carbonyl- hexahydropyrrolo[3.4]pyrrole (0.6 g, 2.82 mmol) and sodium tert—butoxide (0.624 g, 6.5 mmol) in toluene (extra dry with molecular sieves) (15 ml) was stirred and 2012/065733 _ 27 _ degassed with nitrogen for 10 minutes. ibenzylideneacetone) dipalladium(0) (0.198 g, 0.216 mrnol) and 2-(di-tert—butylphosphino)biphenyl (0.065 g, 0.216 mmol) were added and the resulting mixture was ated following the microwave conditions above. Water and EtOAc were addded, the organic layer was separated and then dried (MgSO4), filtered off and concentrated. The obtained residue was purified by flash tography over silica gel (l5-40u, 40 g, heptane/EtOAc 80/20). Pure fractions were collected and concentrated, yielding ediate (24). b) Preparation of intermediate (25) TFA (4.54 ml, 58.95 mmol) was added to a solution of intermediate (24) (l .7 g, 5.9 mmol) in DCM (15 ml). The reaction mixture was stirred at room temperature for 2 hours, water and DCM were added, K2C03 (10% aqueous solution) was added to basify and the organic layer was ted, washed with water, dried (MgSO4) and evaporated till dryness yielding intermediate (25) as an oil.

The following compounds were made using the same procedure as Example A.7 whereby bromobenzene was ed by 2-bromothiophene, 2-bromoanisole, 2-bromol-methylbenzene , 2-bromo- l -chlorobenzene, 3-bromopyridine, 2-bromothiazole, 4-bromo- l -chlorobenzene, or 3-bromo- l -chlorobenzene respectively.

H \O H s wow H QN<$NH H intermediate (26) intermediate (27) intermediate (28) CI H H H ._ [EHQISNH H H H intermediate (29) intermediate (30) intermediate (3 1) H Cl H ONNH H H intermediate (32) intermediate (33) Example A8 E? S? a) Preparation of F3C—fi— N—C—04é (cis) intermediate (34) Reaction under N2. n-BuLi (1.6M in hexane) (3.33 ml, 5.33 mmol) was added dropwise at -20°C to a solution of DIPA (0.749 ml, 5.33 mmol) in THF (8 ml) then the mixture was stirred at -20°C for 20 minutes . A solution of intermediate (4) (1.0 g, 4.44 mmol) in THF (10 ml) was then added at -78°C and the resulting mixture was stirred for 30 minutes at -78°C. A solution enyltrifluoro-methanesulfonimide (1.74 g, 4.88 mmol) in THF (6 ml) was added at -78°C then the mixture was allowed to reach room temperature and was stirred ght. The mixture was concentrated and the residue was purified by flash chromatography over silica gel (40 g, 15-40 um, heptane/EtOAc 70/30) The pure fractions were ted and evaporated to dryness, yielding intermediate (34). b) Preparation of. l \ "—0‘0 < (C's)- ediate (35). .

Reaction under nitrogen. Microwave conditions : Biotage initiator 60, 80°C, minutes. A solution of intermediate (34) (0.42g, 0.881mmol) and thiophene boronic acid (0.135 g, 1.06 mmol) in K2C03 (2 M, 0.88 ml) and ethylene glycol dimethyl ether (4 ml) was purged with N2 for 10 minutes then tetrakis(triphenylphosphine )palladium(0) (0.102 g, 0.088 mmol) was added. The mixture was irradiated following the microwave conditions above, cooled to room temperature, water and EtOAc were added, the organic layer was separated, washed with water then brine, dried (MgSO4) and ated till dryness. The residue was purified by flash chromatography over silica gel (10 g, m, heptane 100 to heptane/EtOAc 80/20).

The pure fractions were collected and evaporated to dryness, yielding ediate (35). c) Preparation of I s\ N" (05) intermediate (36) A mixture of intermediate (35) (0.226 g, 0.776 mmol) in TFA (0.7 ml) and DCM (4ml) was d at room temperature for 1 hour then the reaction mixture was poured out into K2C03 (10% aqueous solution) and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4) and evaporated till dryness, yielding intermediate (36).

The following compounds were made using the same procedure as Example A.8b/A.8c whereby thiopheneboronic acid was replaced by 2-methoxyphenyl-boronic acid, or formic acid respectively. mm (Cis) (cis) Ct)" intermediate (42) intermediate (43) e A.9 a) ation of >_N\/;IE>N__N\/;IE>NH intermediate (38) TFA (0.62 ml, 8.02 mmol) was added to a solution of intermediate (37) (0.204 g, 0.8 mmol) in DCM (2 ml). The reaction mixture was stirred at room temperature for 3 hours, water and DCM were added, K2C03 10% was added to basify, NaCl solid was added to saturate, and the organic layer was separated, washed with water, dried (MgSO4) and evaporated till dryness ng intermediate (38) as an oil.

The following compounds were made using the same procedure as Example A.9 whereby 2-bromopropane was replaced by propargyl bromide, benzenesulfonyl chloride, or 2-thienylmethyl methanesulfonate respectively. in) R NSRNH O—fi—NSRNH NS NH / O H H \S intermediate (39) intermediate (40) intermediate (41) Example A.10 sjgcpN O HO II a) ation of < (0'5). intermediate (44) Reaction under N2. BuLi (1.6M in hexane) (4.8 ml, 7.70 mmol) was added dropwise at -78°C to a solution of thiazole (0.5 ml, 7.05 mmol) in EtZO (5 ml) then the mixture was stirred for 30 minutes. A solution of intermediate (5) (1.44 g, 6.41mmol) in EtzO (7 ml) was added then the mixture d and allowed to reach room temperature for 2 hours.

Water and EtOAc were added, the organic layer was separated, washed with water then brine, dried (MgSO4) and evaporated till dryness. The obtained residue was purified by flash chromatography over silica gel (50 g, 15-40um, heptane/EtOAc 80/20 to e/EtOAc 50/50 ). The pure fractions were ted and evaporated to dryness, yielding intermediate (44). b) Preparation of [Q—CpNH (Cis) intermediate (45) A mixture of intermediate (44) (1.05 g, 3.38 mmol) in HCl (37% in H20) (7ml) in a sealed tube was heated at 140°C using a single mode microwave ge Initiator EXP 60) with a power output ranging from 0 to 400 W for 1 hour. The reaction mixture was poured into K2C03 (10% s solution), the organic layer was separated, dried (MgSO4) and evaporated till dryness, yielding 0.23g of residue (1). The aqueous layer was evaporated till dryness, the solid was suspended in DCM and stirred for 10 minutes. The sion was filtered and the filtrate was evaporated till dryness, yielding 0.29 g of residue (2). Residues (1) and (2) were combined for purification, it was carried out by flash chromatography over silica gel (15-40um, 30 g,from CHzClz to /CHgOH/NH4OH: 90/10/ 1). The pure fractions were collected and evaporated to dryness, yielding 0.42 g of intermediate (45). e A.11 a) Preparation of >C.:>N_C‘O+ (Cis) intermediate (46) Diethylaminosulfur trifiuoride (1.24 ml, 10.12 mmol) was added se to a solution ofintermediate (5) (0.570 g, 2.53 mmol) in DCM (6 ml) cooled in a ice bath at 5°C, the mixture was stirred 1 hour at 5°C and then overnight at room temperature. The mixture was cooled down at 0°C and NaHC03 saturated was added. The organic layer was extracted with CH2C12, dried (MgSO4), d and concentrated affording intermediate (46). b) Preparation of >Ci:>NH (05) intermediate (47) TFA (0.39 ml, 5.12 mmol) was added to a on of intermediate (46) (0.146 g, 0.51 mmol) in DCM (1.5 ml). The reaction mixture was stirred at room temperature for 3 hours, water and DCM were added, K2C03 (10% aqueous solution) was added to basify and the organic layer was separated, washed with water, dried (MgSO4) and evaporated till dryness yielding ediate (47) as an oil.

Example A. 12 a) Preparation of N—C—O—é (C's) intermediate (48) A mixture of intermediate (7) (0.3g, 1.05mmol) and Pd/C 10% dry (0.06 g) in MeOH (15 ml) was hydrogenated at room temperature and heric pressure for 2 hours.

The on e was filtered through a short pad of , washed with DCM and the filtrate was evaporated till s, yielding intermediate (48). b) Preparation of MN" (Cis) intermediate (49) A mixture of intermediate (48) (0.286 g, 0.995 mmol) and TFA (0.9 ml) in DCM (6ml) was stirred at room temperature for 30 minutes then the reaction mixture was poured out into K2C03 (10% aqueous solution) and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4) and evaporated till dryness, yielding intermediate (49).

Example A. 13 on H a) Preparation of mN—g—O‘é (CiS) intermediate (50) Reaction under N2. Microwave conditions: Biotage initiator 60, 80°C, 20 minutes.

A solution of intermediate (38) (0.45g 1.26 mmol) and 2-chlorophenylboronic acid (0.236g, 1.51mmol) in K2C03 (2 M, 1.26 ml) and ethylene glycol dimethyl ether (5 ml) was purged with N2 for 10 minutes then tetrakis(triphenylphosphine)palladium(0) (0.146 g, 0.126 mmol) was added. The mixture was irradiated following the conditions above, cooled to room temperature, water and DCM were added, the organic layer was separated, washed with water, dried (MgSO4) and ated till dryness. The e was purified by preparative liquid chromatography on (silicagel 5 um, 150 x 30.0 mm).

Mobile phase (100% DCM). The desired fractions were collected and the solvent was ated, yielding of intermediate (50).

CI H b) Preparation of mm (ciS) intermediate (51) A mixture of intermediate (50) (0.3 g, 0.938 mmol) and TFA (0.9 ml) in DCM (6 ml) was stirred at room ature for 30 minutes then the reaction mixture was poured out into K2C03 (10% aqueous solution) and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4) and evaporated till dryness, yielding intermediate (5 l).

The following nds were made using the same procedure as Example A. 13 whereby 2-chlorophenylboronic acid was replaced by 2-methylphenylboronic acid, l-methyl-lH-pyrazole-S-boronic pinacol ester, furanboronic acid, 2-fluorophenyl— boronic acid, fiaran—3-boronic acid, 2-cyanophenylboronic acid, 5-dimethylisoxazole boronic acid, pyridineboronic acid, l-methyl(4,4,5,5-tetramethyl-l,3,2- dioxaborolanyl)-lH-pyrazole, benzylzinc bromide, 2-chloropyridineboronic acid, pyrimidyl-S-boronic acid pinacolate, l-boc-pyrazoleboronic acid pinacol ester, 5- methylfuranboronic acid, or 4-methoxypyridinylboronic acid respectively.

H H H ‘N O H \ H H intermediate (52) intermediate (53) intermediate (54) F H H CN H WNH (cis) WNH (CiS) WNH (cis) H H H intermediate (55) ediate (56) intermediate (57) 3%:H H H (as) MW (at) 3W3 (as) H H H intermediate (58) intermediate (59) intermediate (60) _ 33 _ , _ H H C . N NH (cus) (cis) (/WNH (cis) O "_ H Q—djNH "— CI H H intermediate (61) intermediate (62) ediate (63) , , H H HEW: N (as) mm (as) ’_\ NH H H 0— intermediate (64) intermediate (65) intermediate (66) Example A. 14 C") . rs .

/ (C's). a) Preparation of N 1ntermed1ate (67).

Intermedaite (34) (2.798 mmol), palladium(II)acetate (47% Pd) (0.14 mmol), K2C03 (4.198 mmol), trimethylacetic acid (0.84 mmol) and tricyclohexylphosphonium tetrafluoroborate (0.196 mmol) were purged with N2 in a sealed tube. Thiazole (4.198 mmol) and DMA (10 ml) were added and the reaction mixture was heated at 100°C overnight. Water and EtOAc were added, the organic layer was separated, washed with water and brine, dried (MgSO4) and evaporated till s. The obtained residue was purified by flash chromatography over silica gel (cartridge 30g, 15-40um, heptane/EtOAc 80/20 to heptane/EtOAc 60/40 ) The pure fractions were collected and evaporated to dryness, yielding intermediate (67). b) Preparation of WW (Cis) intermediate (68) A solution of intermediate (67) (0.24 g, 0.821 mmol) in TFA (0.8 ml) and DCM (5 ml) was stirred at room temperature for 30 s then the reaction mixture was poured out into K2C03 (10% aqueous solution) and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4) and evaporated till dryness, yielding 0.1 g of ediate (68).

Example A.15 a) Preparation of \—o 9 (Cis) intermediate (69) )2 (1.3 mg, 0.0056 mmol) was added to a solution of intermediate (34) (0.1 g, 0.28 mmol), 1,3-bis(diphenylphosphino)propane (4.6 mg, 0.011 mmol) and potassium acetate (0.041 g, 0.42 mmol) in EtOH (0.25 ml) and THF (2 ml) under nitrogen atmosphere. The mixture was stirred under 5 bars of carbon monoxyde at 100°C for 18 hours in a stainless steel autoclave, yielding intermediate (69). b) Preparation of \_O>_<:‘:>NHO (Cis) ediate (70) A solution of intermediate (69) (0.2 g, 0.711 mmol) in HCl (4M in dioxane) (2 ml) was stirred at room temperature for 30 minutes then it was evaporated till dryness, ng 0.13 g of intermediate (70).

Example A.16 "W0 || a) Preparation of' N—C—O < (c's) ‘ ' ' 1ntermed1ate (71) Pd(OAc)2 (25 mg, 0.112 mmol) was added to a solution of intermediate (34) (2.0 g, 5.6 mmol), 1,3-bis(diphenylphosphino)propane (92 mg, 0.22 mmol) and potassium e (0.82 g, 8.4 mmol) in EtOH (5 ml) and THF (40 ml) under nitrogen atmosphere then the mixture was stirred under 5 bars of carbon monoxyde at 100°C for 18 hours in a stainless steel autoclave. The reaction mixture was poured into water and EtOAc, the organic layer was washed with water then brine, dried (MgSO4), filtered and evaporated till dryness. The obtained residue was purified by flash chromatography over silica gel (15-40um, 40g, Heptane/EtOAc 90/10 to Heptane/EtOAc 70/30). The pure fractions were collected and evaporated to dryness, ng 0.61 g of intermediate (71). _ _ _"_ ' b) Preparation of- _WNC O < (C's) 1ntermed1ate (72)u u A mixture of intermediate (71) (0.3 g, 1.18 mmol), dimethylamine in THF (2 M, 1.18 ml, 2.37 mmol), EDCI (0.27 g, 1.42 mmol), HOBt (0.19 g, 6.21 mmol) and triethylamine (0.25 ml, 1.78 mmol) in DCM (3 ml) and THF (3 ml) was stirred overnight at room temperature. Water and DCM were added, the organic layer was separated, dried (MgSO4) and evaporated till s, ng 0.37 g of intermediate (72). _ _ c) Preparation of _N>_<:’:>NH (01$) intermediate (73) A solution of intermediate (72) (0.37 g, 1.32 mmol) in HCl (4M in dioxane) (4 ml) was d at room temperature for 30 minutes then the reaction mixture was poured out into K2C03 (10% s solution) and extracted with DCM. The c layer was separated, washed with water, dried (MgSO4) and evaporated till s, ng intermediate (73).

Example A17 0 O a) Preparation of. (C's) intermediate (74). .

H N5—dj/Nfl‘O—é2 A mixture of intermediate (71) (0.3 g, 1.18 mmol), 1,1,1,3,3,3-hexamethyldisilazane (0.23 g, 1.42 mmol), EDCI (0.27 g, 1.42 mmol), HOBt (0.19 g, 6.21 mmol) and triethylamine (0.25 ml, 1.78 mmol) in DCM (3 ml) and THF (3 ml) was stirred overnight at room temperature. Water and DCM were added, the organic layer was separated, dried (MgSO4) and evaporated till dryness. The obtained residue was purified by flash chromatography over silica gel (15-40um, 10 g, from CH2C12 to CHzClz/CHgOH/NH4OH: 94/6/01) The pure fractions were collected and evaporated to dryness, ng 0.16g of intermediate (74). b) Preparation of (Cis) intermediate (75) H "Ii—Ck)"2 A on of intermediate (74) (0.16 g, 0.634 mmol) in HCl (4M in dioxane) (2 ml) was stirred at room temperature for 30 minutes then it was evaporated till dryness, yielding 0.1 g of intermediate (75).

Example A. 1 8 io’BACpN—Cfl—eH0\ 8 a) Preparation of (C's) ediate (76) A solution of intermediate (34) (0.2g 0.56 mmol), bis(pinacolato)diboron (0.171 , g, 0.67mmol) and potassium acetate (0.165 g, 1.68 mmol) in 1,4-dioxane (2 ml) was stirred and degassed with N2 for 10 minutes. is(diphenylphosphino)ferrocene- dichloropalladium(II) (0.041 g, 0.056 mmol) was added and the reaction mixture was heated at 100°C using a single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 20 minutes. Water and EtOAc were added, the organic layer was separated, washed with water then brine, dried (MgSO4) and evaporated till dryness. The obtained residue was purified by flash chromatography over silica gel (10g, 15-40um, heptane/EtOAc 85/15 to heptane/EtOAc 70/30). The pure fractions were collected and evaporated to dryness, yielding intermediate (76).

S 9 b) Preparation of \[NmN—C‘O—é (C's) intermediate (77) A on of intermediate (76) (0.45 g, 1.34 mmol) and 2-bromomethyl-1,3,4- thiadiazole (0.288 g, 1.61 mmol) in K2C03 (2 M, 1.34 mL, 2.69 mmol) and ethylene glycol dimethyl ether (5ml) was stirred and degassed with N2 for 10 minutes.

Tetrakis(triphenylphosphine)palladium(0) (0.155 g, 0.134 mmol) was added and the reaction mixture was heated at 150°C using a single mode ave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400W for 5 minutes. Water and EtOAc were added, the organic layer was separated, washed with brine, dried (MgSO4) and evaporated till dryness. The obtained residue was purified by flash tography over silica gel (cartridge 30 g, 15-40um, DCM to DCM/MeOH/NH4OH : 98/2/01) The pure fractions were ted and evaporated to dryness, yielding ediate (77). \rs"L / (C's)_ c) Preparation of NH intermediate (78) A on of intermediate (77) (0.14 g, 0.455 mmol) in HCl (4M in dioxane) (2 ml) was stirred at room ature for 30 minutes then the reaction mixture was poured out into K2C03 10% aqueous and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4) and evaporated till dryness, yielding 81 mg of intermediate (78).

Example A.19 H g .

N_C_ (C's) a) Preparation of N_ intermediate (79) BuLi (1.6M in ) (4.2 ml, 6.66 mmol) was added dropwise to a solution of 1-methylimidazole (0.53 ml, 6.66 mmol) in THF (5 ml) under nitrogen at -78°C then the resulting mixture was stirred for 1 hour at 0°C. The on mixture was cooled down to -78°C, a solution of intermediate (5) (1.0 g, 4.44 mmol) in THF (10 ml) was added. The mixture was stirred at -78°C for 2 hours then d to reach room temperature and stirred overnight. Water and EtOAc were added, the organic layer was separated, washed with water and brine, dried (MgSO4) and evaporated till dryness.

The obtained residue was purified by flash chromatography over silica gel (15-40um, g, from CH2C12 to CHzClz/CHgOH/NH4OH: 95/5/01). The pure fractions were collected and evaporated to dryness, yielding 0.54 g of intermediate (79). b) Preparation of [WW (Cis) ediate (80) \ H A mixture of intermediate (79) (0.54 g, 1.76 mmol) in HCl (37% in H20) (5 ml) in a sealed tube was heated at 140°C using a single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400W for 1 hour. The reaction mixture was ated till dryness, yielding 0.47 g of intermediate (80).

Example A.20 a) ation of F3C‘fi_0_d:/\N_ MN_ The mixture was purged with argon and tetrakis(triphenylphosphine)palladium (0) (0.032 g, 0.028 mmol) was added. Then, the mixture was heated at 80°C overnight.

The mixture was cooled to room temperature and then water (10 ml) and ethyl acetate (10 ml) were added. The organic layer was separated washed with water (10 ml) and with brine (10 ml), dried (sodium sulfate), filtered and ated until dryness under vacuum. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/ ethyl acetate 8/2). The desired fractions were collected and the solvent was ated, yielding 0.076 g of intermediate (82). c) Preparation of | / NH (cis) intermediate (83) The on was performed in anhydrous conditions under argon atmosphere and monitored by TLC (silica gel, dichloromethane/ methanol 9/ 1, UV). Hydrogen chloride, 4M in dioxane (3.33ml, l3.3mmol) was added to a solution of intermediate (82) (0.444 g, l.33mmol) in dioxane (9 ml). The reaction mixture was stirred at room ature for 70 hours and then concentrated until dryness, yielding 0.370 g of intermediate (83).

The following compounds were made using the same procedure as Example A.20b/ A.20c whereby ylthienylboronic acid was replaced by 4-methylthiophene boronic acid, 2-chlorothiopheneboronic acid, 4-methylthiophene-boronic acid, 2-acetylthiopheneboronic acid, 5-cyanothiopheneboronic acid, 5-chlorothiopheneboronic acid, 5-methylthiopheneboronic acid pinacol ester, 3-methylthiopheneboronic acid pinacol ester, or 3-methoxythiopheneboronic acid l ester respectively.

H C' H mm H (cis) WW (NS, WW (cis) H H H intermediate (84) ediate (85) intermediate (86) H H H N CI s \ NH (cis) WNH (cis) Wm (cis) ediate (87) intermediate (88) intermediate (89) _ 39 _ V L H H H WNHs s (cis) (cis) H WNHs WNH (cis) H o— H , , intermediate (90) intermediate (91) intermediate (92) _ , Example A.21 a) Preparation of Adslhé)O < (Gig) intermediate (93) The reaction was performed in anhydrous conditions under argon atmosphere and monitored by TLC a gel, eluent: petroleum ether/ethyl acetate 9/ 1, PMA).

Methyllithium 1.6M in diethyl ether (3.29 ml, 5.26 mmol) was added to a sion of Copper(I) iodide (0.794 g, 4.17 mmol) in THF (5.0 ml) at 0°C. After 1 hour, a solution ofintermediate (81) (0.355 g, 0.993 mmol) in THF (2.1 ml) was added at 0°C by cannula, rinsing with THF (2.1 ml). The mixture was stirred at room temperature overnight. The mixture was quenched with an aqueous saturated solution ofNH4Cl (14 ml) and evaporated to dryness. The residue was purified by column chromatography over silica gel (eluent: pentane/ethyl acetate 95/5). The product fractions were collected and the solvent was evaporated, yielding 0.180 g of ediate (93). b) Preparation of ‘djNH (Cis) intermediate (94) The reaction was med in anhydrous conditions under argon here and monitored by TLC (silica gel, eluent: petroleum ether/ethyl acetate 9/ 1, PMA).

Hydrogen de 4M in dioxane (2.02 ml, 8.06 mmol) was added to a solution of intermediate (93) (0.180 g, 0.806 mmol) in 1,4-dioxane (4.3 ml), the solution was stirred at room temperature for 65 hours and was then trated to dryness, ng 0.141 g ofintermediate (94) .

Example A.22 1’ - a) Preparation of. @prc‘o‘é (C's) 1ntermed1ate (95). .

The hydrogenation was performed in anhydrous conditions and monitored by TLC (silica gel, petroleum ether/ ethyl acetate 50/50, developer: UV/PMA. A solution of intermediate (4) (6.93 g, 31.0 mmol) in THF (180 ml) was hydrogenated at room temperature (atmospheric pressure) with Palladium on carbon, 10wt% loading (1.65 g) as catalyst for 15 hours. The st was filtered off on clarcel, the filter cake was rinsed with dichloromethane (50 ml) and the combined filtrates were trated under d pressure to dryness. The obtained residue (7.26 g) was purified by column chromatography over silica gel (eluent: petroleum ether / ethyl acetate 80/20 to 50/50). The product fractions were ted and the solvent was evaporated, yielding 6.70 g of intermediate (95). b) Preparation of "Pew—éa? (C's). intermediate (96) The reaction was performed in anhydrous conditions under argon atmosphere and monitored by TLC (silica gel, eluent: petroleum ether/ethyl acetate 6/4, DCIP).

Lanthanium trichloride m complex 0.6M in THF (3.70 ml, 2.22 mmol) was added to a solution of intermediate (95) (0.500 g, 2.22 mmol) in THF (15 ml). The e was stirred at room temperature for 1 hour, then cooled to 0°C. Ethylmagnesium bromide solution, 1.0M in THF (2.66 ml, 2.66 mmol) was added dropwise and the reaction mixture was allowed to warm to room ature and was stirred for 18 hours. The mixture was quenched by addition of saturated aqueous NH4Cl (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were dried 4), filtered and concentrated. The obtained residue (0.635 g) was d by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 9/1 to 7/3). The product fractions were collected and the solvent was evaporated. The obtained e (0.410 g) was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 8/2). The product fractions were collected and the solvent was evaporated, yielding 0.235 g of intermediate (96). c) Preparation of /_<:’:>NH (Cis) intermediate (97) The reaction was med in anhydrous conditions under argon here and monitored by 1H NMR. HCl in dioxane (4 M, 2.30 ml, 9.20 mmol) was added to a solution of intermediate (96) (0.235 g, 0.920 mmol) in dioxane (2 ml). The reaction mixture was stirred at 60°C for 18 hours. After g down to room temperature, the precipitate was filtered off on a glass frit and washed with diethyl ether (20 ml), yielding 0.126 g of solid. The filtrate was concentrated to dryness, yielding 0.077 g of residue. The solid and residue were ed and dissolved in dioxane (2 ml). 4M HCl in dioxane (2.30 ml, 9.20 mmol) was added and the mixture was stirred at 60°C for 24 hours, then at 100°C for 72 hours. The reaction mixture was concentrated to s, ng 0.158 g of intermediate (97).

Example A.23 || . a) Preparation of HO_<:’:>N_C_O < (C's) intermediate (98) The reaction was performed in anhydrous conditions under argon atmosphere and monitored by TLC (silica gel, eluent: petroleum ether/ethyl acetate 1/ 1, PMA). Sodium borohydride (0.893 g, 23.6 mmol) was added portionwise over a period of 30 minutes to a solution of intermediate (95) (2.66 g, 11.8 mmol) in MeOH (60 ml) at 0°C. The on mixture was stirred at 0°C for 1 hour and then concentrated to dryness. The residue was diluted with ethyl acetate (200 ml) and washed with water (100 ml), 1M aqueous hydrochloric acid (100 ml) and brine (100 ml). The organic layer was dried (Na2S04), filtered and concentrated, yielding 2.27 g of intermediate (98). _E_O’C‘:>N_C‘Oo o || || . b) Preparation of. é (C's) intermediate (99). .

The reaction was performed in anhydrous conditions under argon atmosphere and monitored by TLC (silica gel, eluent: petroleum ether/ethyl e 1/ 1, PMA). esulfonyl de (0.930 ml, 11.9 mmol) was added se to a solution of intermediate (98) (2.27 g, 9.98 mmol) and triethylamine (4.17 ml, 29.9 mmol) in DCM (50 ml) at 0°C. The reaction mixture was stirred at room temperature for 1 hour and concentrated to dryness. The e was diluted in ethyl acetate (200 ml) and washed with water (100 ml), brine (100 ml), 1M aqueous hydrochloric acid (100 ml) and brine (100 ml) again. The organic layer was dried (Na2S04), filtered and concentrated. The obtained residue (2.52 g) was purified by column chromatography over silica gel (eluent: petroleum ethyl acetate, 8/2 to 5/5). The product fractions were collected and the solvent was evaporated, yielding 2.39 g of intermediate (99). c) Preparation of QN’CpWE‘O—€ (Cis) intermediate (100) The reaction was performed in anhydrous conditions under argon atmosphere and monitored by TLC a gel, eluent: petroleum ether/ethyl e, 8/2, ninhydrine/PMA). Intermediate (99) (0.300 g, 0.982 mmol) was dissolved in DMF (3 ml) and the mixture was cooled to 0°C. Pyrrole (0.102 ml, 1.47 mmol) and sodium hydride, 60% dispersion in mineral oil (0.0589 g, 1.47 mmol) were added and the on mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (2 x 50 ml), then with brine (3 x 50 ml). The organic layer was dried (Na2S04), filtered and concentrated. The ed residue (0.290 g) was purified by column tography over silica gel (eluent: petroleum ether/ethyl acetate, 98/2 to 95/5, then 90/ 10). The product fractions were collected and the solvent was evaporated, yielding 0.175 g of intermediate (100). d) ation of H (015) intermediate (1 0 1) The reaction was performed in anhydrous conditions under argon atmosphere and monitored by TLC (silica gel, eluent: petroleum ether/ethyl acetate, 6/4, PMA). 4M HCl in dioxane (1.58 ml, 6.33 mmol) was added to a solution of intermediate (100) (0.175 g, 0.633 mmol) in dioxane (3 ml). The reaction mixture was stirred at 50°C for 2 hours and concentrated to dryness, yielding 0.135 g of intermediate (101).

The following compounds were made using the same procedure as Example A.23c/ A.23d y e was replaced by tetrazole, pyrazole, 1,2,4-triazole, 1,2,3-triazole or phenol respectively.

H H N/N4C’:>NHN /N N Z\\ \ N’ \ / . \ .

CIS) NH (Cls) (cuS ) / N§/N| \ NmNH H H H intermediate (102) intermediate (103) ediate (104) H H H ®N4Ct>NH / gN (cis) E::N4<:’:>NH (cis) N\ \N4C’:>NH (cis) H H H intermediate (105) intermediate (106) intermediate (107) 00%: (as) intermediate (108) Example A.24 a) Preparation of _O N—C—O—é (C's) 1ntermed1ate (109) The reaction was performed in anhydrous conditions under argon atmosphere and monitored by TLC (silica gel, : petroleum ether/ethyl acetate, 8/2, ninhydrine/ PMA). Sodium methoxide 25 wt% solution in methanol (0.449 ml, 1.96 mmol) was added to a solution of intermediate (99) (0.300 g, 0.982 mmol) in MeOH (4 ml). The mixture was stirred under reflux for 20 hours. The reaction mixture was concentrated to s. The residue was diluted with ethyl acetate (50 ml) and washed with water (50 ml), then with brine (50 ml). The c layer was dried (Na2S04), filtered and trated. The obtained residue was purified by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate, 100/0 to 97/3, then 1/1). The product fractions were ted and the solvent was evaporated, yielding 0.182 g of intermediate (109). b) Preparation of _O_<:‘:>NH (Cis) intermediate (110) The reaction was performed in anhydrous conditions under argon here and monitored by TLC (silica gel, : eum ether/ethyl acetate, 8/2, ninhydrine/PMA). 4M HCl in dioxane (1.88 ml, 7.54 mmol) was added to a solution of intermediate (109) (0.182 g, 0.754 mmol) in dioxane (4 ml). The on mixture was stirred at room temperature for 18 hours, then at 50°C for 2 hours. The reaction mixture was concentrated to dryness, yielding 0.139 g of intermediate (110).

Some intermediate compounds used in the preparation of the final compounds are commercially available such as.

B. Synthesis of the final compounds Example B.1 Preparation of [Q N’ N 0 compound (14) H H A mixture of intermediate (3) (9.4 g, 36.9 mmol), intermediate (9) (8.2 g, 44.3 mmol), EDCI (8.5 g, 44.3 mmol), hydroxybenzotriazole (6.0 g, 44.3 mmol) and triethylamine (15.4 ml, 0.111 mmol) in CHzClz (160 ml) and THF (160 ml) was stirred overnight at room temperature. Water (175 ml) was added, the precipitate was filtered off, washed with water/EtOH (50 ml). The solid was suspended in EtOH (50 ml) and d for minutes. The resulting suspension was filtered off and dried under vacuum at 70°C to give 7.3 g of compound (14) as a white powder (mp = 266°C), ([0t]D20 = -105.10 (589 nm, c 0.1275 w/v %, CHzClz, 20 0C). 1H NMR (500MHz 5 (ppm) 10.64 (d, .1: 7.6 Hz, 1 H), 8.33 (dd, .1: 1.7, , DMSO-d6) 9.6 Hz, 1 H), 8.04 (d, .1: 17.3 Hz, 1 H), 7.48 (d, .1: 7.6 Hz, 2 H), 7.31 — 7.42 (m, 3 H), 7.23 — 7.28 (m, 1 H), 6.99 (t, .1: 15.0 Hz, 1 H), 6.20 (d, .1: 6.0 Hz, 1 H), 3.38 — 4.04 (m, 5 H), 3.09 — 3.21 (m, 1 H), 2.85 — 3.04 (m, 3 H), 2.55 — 2.67 (m, 3 H).

Example B.2 I—‘L/ N / \ R* I Preparation of ,, N’ N 0 compound (44) / "H I H A solution of intermediate (14) (5.8 g, 30.32 mmol), intermediate (3) (7.72 g, 30.32 mmol), oxybenzotriazole (4.92 g, 36.38 mmol), EDCI (6.97 g, 36.38 mmol) and triethylamine (14.71 mL, 106.12 mmol) in CH2C12 (100 ml) and THF (100 ml) was stirred overnight at room temperature. The mixture was poured out into water. The precipitate was filtered off and washed twice with EtOH and dried under vacuum at 65°C. This itate was crystallized from EtOH, d off and dried under vacuum at 62°C to give 9.02 g of nd (44) as a white powder, (mp = 264°C) ([0t]D20 = +170.12 ° (589 nm, c 0.2075 w/v %, CHzClz, 20°C)). 1H NMR (400MHz 8 (ppm) 10.63 (d, .1: 4.5 Hz, 1 H), 8.32 (d, .1: 5.1 Hz, , DMSO-d6) 1 H), 8.03 (d, .1: 10.6 Hz, 1 H), 7.52 (dd, .1: 2.8, 4.8 Hz, 1 H), 7.41 (br. s., 1 H), 7.36 (dd, .1: 4.8, 9.3 Hz, 2 H), 6.98 (dd, .1: 9.1, 15.7 Hz, 1 H), 6.01 (br. s., 1 H), 3.35 — 4.03 (m, 5 H), 2.94 _ 3.21 (m, 2 H), 2.90 (q, .1: 7.9 Hz, 3 H), 2.52 _ 2.62 (m, 2 H).

Example B.3 Ha N / \ R* I Preparation of 5,4 N/ N 0 compound (40) N' / H H A solution ofintermediate (19) (21.1 g, 81.4 mmol), intermediate (3) (17.3 g, 67.8 mmol), 1-hydroxybenzotriazole (11.0 g, 81.4 mmol), EDCI (15.6 g, 81.4 mmol) and triethylamine (47 ml, 0.339 mol) in CH2C12 (350 ml) and THF (350 ml) was stirred overnight at room temperature. Water was added to the mixture. The precipitate was filtered off, washed with water/EtOH then EtOH and dried at 70°C under vacuum to give 12.7g ofcompound (40) as a white powder (mp = 271°C) ([0t]D20 = +116.08 ° (589 nm, c 0.2145 w/v %, CH2C12, 20°C)). 1H NMR (400MHz 8 (ppm) 10.63 (d, .1: 5.1 Hz, 1 H), 8.52 (d, .1: 5.6 Hz, , DMSO-d6) 2 H), 8.33 (d, .1: 6.1 Hz, 1 H), 8.03 (d, .1: 13.6 Hz, 1 H), 7.41 — 7.46 (d, .1: 15.7 Hz, 2 H), 7.38 (d, .1: 4.0 Hz, 1 H), 6.98 (dd, .1: 11.6, 15.7 Hz, 1 H), 6.53 (d, .1: 8.1 Hz, 1 H), 3.37 — 4.04 (m, 5 H), 2.86 — 3.22 (m, 5 H), 2.58 — 2.70 (m, 2 H). 0 compound (41) Compound (41) was prepared analogously by reacting intermediate (20) with intermediate (3) ing the same procedure. 1H NMR (500MHz 5 (ppm) 10.63 (d, .1: 5.1 Hz, 1 H), 8.52 (d, .1: 5.6 Hz, , DMSO-d6) 2 H), 8.33 (d, .1: 6.1 Hz, 1 H), 8.03 (d, .1: 13.6 Hz, 1 H), 7.41 — 7.46 (d, .1: 15.7 Hz, 2 H), 7.38 (d, .1: 4.0 Hz, 1 H), 6.98 (dd, .1: 11.6, 15.7 Hz, 1 H), 6.53 (d, .1: 8.1 Hz, 1 H), 3.37 — 4.04 (m, 5 H), 2.86 — 3.22 (m, 5 H), 2.58 — 2.70 (m, 2 H). ([61])20 = —115.85 0 (589 nm, c 0.183 w/v %, CH2C12, 20°C)). e B4 a) Preparation of Wm intermediate (1 1 1) N O O H E The reaction was performed under Ar-atmosphere and monitored by TLC (silica gel, CHzClg/methanol/triethylamine 95/5/01, UV/PMA). 1-(3-Dimethylaminopropyl) ethylcarbodiimide (.HCl) (1.70 g, 8.87 mmol) was added to a mixture of intermediate (3) (2.02 g, 7.39 mmol), crude cis hexahydro-cyclopenta[c]pyrrol—5(1H)one (1.85 g, maximal 8.89 mmol), 1-hydroxybenzotriazole drate (1.36 g, 8.87 mmol) and N—ethyldiisopropylamine (6.32 ml, 36.9 mmol) in DMF (75 ml). The e was stirred at room temperature overnight for 18 hours. The mixture was concentrated under reduced pressure, diluted with dichloromethane (150 ml) and washed with saturated aqueous NaHC03 (100 ml). The aqueous layer was extracted back with romethane (2 x 150 ml). The combined organic layers were washed with brine (400 ml), dried (Na2S04), filtered and concentrated under reduced pressure to dryness.

The obtained residue was purified by flash column chromatography over silica gel (eluent : dichloromethane/methanol 100/0 to 94/6). The product fractions were collected and the t was evaporated. The basic aqueous layers were extracted again with dichloromethane (3 x 300 ml). The combined c layers were washed with brine (900 ml), dried (Na2S04), d and concentrated under reduced pressure to dryness. The obtained residue was purified by flash column chromatography over silica gel (eluent: dichloromethane/methanol 100/0 to 94/6). The product fractions were collected and the solvent was evaporated. The desired residues were combined, yielding 1.58 g of intermediate (111). b) Preparation of N/ compound (71) N 0 H H The reaction was performed in anhydrous conditions under argon atmosphere and monitored by TLC (silica gel, romethane/methanol 95/5, UV/PMA). Lanthanum trichloride lithium chloride complex 0.6M THF (2.38 ml, 1.43 mmol) was added to a suspension of ediate (111) (0.464 g, 1.43 mmol) in THF (18 ml). The mixture was stirred at room temperature for 1 hour, then cooled to 0°C. Phenylmagnesium bromide solution 1.0 M in THF (3.57 ml, 3.57 mmol) was added dropwise. The reaction mixture was stirred and allowed to warm back to room temperature for 3 days.

Additional magnesium e on 1.0 M in THF (2.85 ml, 2.85 mmol, 2 equivalents) was added dropwise. The mixture was stirred at room temperature additional 2 days. The mixture was quenched by addition of saturated s ammonium chloride (30 ml) and extracted with EtOAc (3 x 30 ml). The combined c layers were dried (Na2S04), filtered and trated under reduced pressure to dryness. The obtained residue (0.801 g) was purified by flash column chromatography over silica gel (eluent: CHzClz/MeOH 100/0 to 95/5). The solvent of the collected product fractions was evaporated. The residue was triturated with diethyl ether (2 x 3 ml), and then dried under vacuum, yielding 0.077 g of compound (71).

Example B.5 Preparation of compound (73) A e of intermediate (23) (0.032 g, 0.097 mmol), intermediate (8) (0.032 g, 0.145 mmol), EDCI (0.022 g, 0.0116 mmol), HOBT (0.016 g, 0.116 mmol) and triethylamine (0.049 ml, 0.349 mmol) in DCM (1 ml) and THF (1 ml) was stirred overnight at room temperature. Water was added, the mixture was extracted with DCM, the organic layer was separated, washed with water, dried (MgSO4) and ated till dryness. The residue was crystallized from EtOH, the solid was filtered off, washed with EtOH, and dried (vacuum 70°C), yielding 0.015 g of compound (73).

W0 2013/021054 _ 47 _ Table F-1 lists the compounds that were ed according to one of the above Examples.

TableF-1 O O N N o O ON N N o H H H H (cis) Co. No.1; EX. B.1 Co. No.2; EX. B.1 / WWII/ NNO NR NNO H C5\ H H Co Co. No.4; EX. B.1 H NW / \ N8 N/NO NO H H Co. Co. No.6; EX. B.1 I: \o 69% N N o 6N3 N N o H H H Co. Co. No.8; EX. B.1 / Wl/ NNO NNO H W H S (cis) Co. No.9; EX. B.1 Co. No.10; EX. B.1 O O N M o G/fig N M o (cis) (cis) Co. No.11; EX. B.1 Co. No.12; Ex. B.1 O O N M 0 EH N M o Co. No.13; EX. B.1; MD" = +104.17° (589 C0. No.14; EX. B.1 WO 21054 nm, c = 0.096 W/V %, CHZCIZ, 20°C) N’N\ (cis) \r Co. No.15; EX. B.1 Co. No.16; EX. B.1 O O 6NS N/ S N o N N/ N o H H H H Co. No.17; EX. B.1 Co. No.18; EX. B.1 O O N/ S o N/ o H H (j/N H H (cis) N/ Co. No.19; EX. B.1 Co. No.20; EX. B.1 O 0 DH N H 0 (EM N n O (cis) O (cis) Co. No.21; EX. B.1 Co. No.22; Ex. B.1 O O O N 0 H H STN H fl (cis) §/N Co. No.23; EX. B.1 Co. No.24; Ex. B.1 O O H H N / \ N / \ | | / / N\// o N o H H |\ H H O (cis) N/ (cis) Co. No.25; EX. B.1 Co. No.26; EX. B.1 O O N O N O ‘N\ H M / N H M \N’ Q (cis) (cis) Co. No.27; EX. B.1 Co. No.28; EX. B.1 WO 21054 O O N\ N/ N o / <5, N N N 0 / N H H H H (cis) // Co. No.29; EX. B.1 Co. No.30; EX. B.1 H / \ N/ N\ H O \ N o H O H H (ciS) <\’3 (cis) Co. No.31; EX. B.1 Co. No.32; EX. B.1 O\\/N N/ N o 569 N/ N o S\\o H H g H H (cis) Co. No.33; EX. B.1 Co. No.34; EX. B.1 aan H H N / \ N / \ .659R ' N 0 N N/ O H M H H CI ; Co. No.35; EX. B.1 Co. No.36; EX. B.1 H53?" / \ N N/ N O O

Claims (20)

Claims

1. A compound of formula (I) O Z1 O (I) X N C A NH 5 R3 wherein A represents –C≡ C– or the bond represents a single bond or a double bond, 10 X represents carbon or nitrogen, and when X represents nitrogen then the bond represents a single bond; Z1 ents CH or N; R1 is hydrogen, kyl or halo; R2 is hydrogen, C1-4alkyl or halo; 15 R3 is en, C1-6alkyl, hydroxy or halo; R4 is hydrogen; halo; C1-6alkyl; C2-6alkenyl; C2-6alkynyl; C1-6alkyloxy; C1-4alkyloxycarbonyl; aminocarbonyl; mono- or di(C1-4alkyl)- aminocarbonyl; aryl; y; arylcarbonyl; arylsulfonyl; heteroaryl; C1-6alkyl substituted with cyano; C1-6alkyl substituted with aryl or 20 aryloxy; or C1-6alkyl tuted with heteroaryl; aryl is phenyl; phenyl substituted with one, two or three substituents each individually selected from halo, hydroxy, C1-4alkyl, C1-4alkyloxy, polyhaloC1-4alkyl, polyhaloC1-4alkyloxy, cyano, nitro, and amino; heteroaryl is furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, 25 thiazolyl, triazolyl, tetrazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzo[1,3]dioxolyl, benzofuranyl, benzothiazolyl, indolyl, 2,3-dihydro-1H-indolyl, tetrahydrothiophenyl, or inyl, wherein each aryl may be substituted with one or two substituents each 30 independently selected from halo, cyano, C1-4alkyl, C1-4alkyloxy, C1-4alkylcarbonyl, or phenyl; or a pharmaceutically acceptable acid on salt thereof.

2. The nd as claimed in claim 1 wherein: Z1 represents CH; R1 is hydrogen or C1-4alkyl; R2 is hydrogen or C1-4alkyl.

3. The nd as claimed in claim 1 or claim 2 wherein A represents –C≡ C– or the bond represents a single bond or a double bond, 10 X represents carbon or nitrogen, and when X represents nitrogen then the bond represents a single bond; R1 is hydrogen; R2 is hydrogen; R3 is hydrogen, hydroxy or halo; 15 R4 is hydrogen; halo; C1-6alkyl; C1-6alkyloxy; C1-4alkyloxycarbonyl; aminocarbonyl; mono- or di(C1-4alkyl)-aminocarbonyl; aryl; aryloxy; arylsulfonyl; heteroaryl; C1-6alkyl tuted with cyano; kyl substituted with aryl or aryloxy; or C1-6alkyl substituted with heteroaryl; 20 aryl is phenyl; phenyl substituted with one substituent selected from halo, C1-4alkyl, C1-4alkyloxy, and cyano; heteroaryl is furanyl, thiophenyl, pyrazolyl, isoxazolyl, lyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, or pyrimidinyl, wherein each heteroaryl may be substituted with one substituent selected from 25 halo, cyano, C1-4alkyl, kyloxy, or C1-4alkylcarbonyl; or a pharmaceutically acceptable acid addition salt thereof.

4. The compound as claimed in any one of claims 1 to 3 wherein R1 is hydrogen and R2 is hydrogen.

5. The compound as claimed in any one of claims 1 to 4 wherein R3 represents hydrogen.

6. The compound as claimed in any one of claims 1 to 5 wherein R4 is aryl.

7. The nd as claimed in any one of claims 1 to 5 wherein R4 is heteroaryl.

8. The compound as claimed in any one of claims 1 to 5 n R4 is C1-6alkyl substituted with aryl.

9. The compound as d in any one of claims 1 to 8 wherein X represents 5 nitrogen and the bond represents a single bond.

10. The compound as claimed in any one of claims 1 to 9 wherein

11. A represents . 10 11. The compound

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier 15 and a therapeutically active amount of a compound as claimed in any one of claims 1 to 11.

13. A process for preparing a pharmaceutical composition as claimed in claim 12 wherein a therapeutically active amount of a compound as claimed in any one of 20 claims 1 to 11 is intimately mixed with a pharmaceutically acceptable carrier.

14. nd of formula (I) as defined in any of claims 1 to 11 for use as a medicine.

15. A compound of formula (I) as defined in any of claims 1 to 11 for use in treating 25 bacterial infections.

16. A nd as claimed in claim 15 wherein the bacterial infection is caused by a bacterium that ses a FabI . 30

17. A process for preparing compounds of formula (I), as defined in claim 1: (i) by reacting an intermediate of formula (II) with an intermediate of formula (III), O Z1 O X NH + HO C A NH (I) (II) (III) (ii) for compounds of formula (I) in which A represents -C(R2)=C(R1)-, by reacting an intermediate of formula (V) with an intermediate of formula (VI), O Z1 O X N + Xa1 NH (I) R2 N (V) H (VI) wherein Xa1 represents a suitable leaving group and the other integers are as defined in Claim 1; or; if desired; a compound of formula (I) is converted into a pharmaceutically 10 acceptable acid addition salt, or sely, an acid addition salt of a compound of formula (I) is converted into a free base form with alkali.

18. The use of a nd as claimed in claim 1 or 11 in the manufacture of a medicament for the ent of bacterial infections.

19. The use as claimed in claim 18, wherein the bacterial infection is caused by a bacterium that expresses a FABI enzyme.

20. A compound according to claim 1 or 11, substantially as herein described with 20 reference to any one of the examples.