Pyrazolotriazinones for the treatment of bacterial infections

Abstract

The present invention relates to pyrazolotriazinone compounds of formula IA wherein the variables are defined as given in the description and claims including their tautomers and pharmaceutically acceptable salts useful for the treatment and / or prevention of bacterial infections in a mammal. This invention also provides pharmaceutical compositions comprising such compounds. The compounds and compositions may be used as a medicament, such as in the treatment and / or prevention of bacterial infection. Also provided are methods of using such compounds in the treatment and / or prevention of bacterial infection.

Description

[0001] 240946

[0002] 1

[0003] Pyrazolotriazinones for the treatment of bacterial infections

[0004] The present invention relates to pyrazolotriazinone compounds of formula IA defined below including their tautomers and pharmaceutically acceptable salts useful for the treatment and / or prevention of bacterial infections in a mammal. This invention also provides pharmaceutical compositions comprising such compounds. The compounds and compositions may be used as a medicament, such as in the treatment and / or prevention of bacterial infection. Also provided are methods of using such compounds in the treatment and / or prevention of bacterial infection.

[0005] The intensive use of antibiotics resulted in a selective evolutionary pressure on microorganisms to produce genetically based resistance mechanisms. Modem medicine and socio-economic behavior exacerbate the problem of resistance development by creating slow growth situations for pathogenic microbes, e.g. in artificial joints, and by supporting long-term host reservoirs, e.g. in immune-compromised patients. In hospital settings, an increasing number of strains of Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp., Enterobacteriaceae such as Escherichia coli, Klebsiella pneumonia, Acinetobacter baumannii and Pseudomonas aeruginosa are becoming multi-drug resistant and therefore difficult to treat. This is particularly the case for Gram-negative organisms where the situation is getting worrisome since no novel agents with a differentiated mechanism of action have been approved for decades. Therefore, there is an important medical need for new antibacterial compounds addressing Gram-negative resistant bacteria, in particular third generation cephalosporins- and carbapenem-resistant Enterobacteriaceae and multi-drug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii.

[0006] Antibacterial benzyl substituted pyrazolotriazinones have been described before (cf. Heterocycles (2009), 78(1), 71-91 ; DE 102005021963 A1), but the activity, especially on Gram-negative bacteria, was not sufficient.

[0007] Thus, it is an object of the present invention to compounds that are useful in the treatment of bacterial infections, in particular for the treatment of infections caused by Gram-negative bacteria. The compounds should also provide efficacious antimicrobial antibacterial activity against resistant strains of bactaeria. Further, the compounds should have have an increased antibacterial activity, thus allowing the use of a lower amount or dose of antibiotic while reducing the development of resistant bacterial strains.

[0008] These and further objectives are achieved by the compounds of formula IA defined below including their tautomers and pharmaceutically acceptable salts.

[0009] Accordingly, the present invention relates to a compound of the general formula IA 240946 wherein

[0010] R1is H, halogen, Ci-C6-alkyl, or C3-Cio-cycloalkyl;

[0011] R2is H, Ci-C6-alkylcarbonyl, or C6-Ci2-arylcarbonyl;

[0012] R3is H, halogen, Ci-C4-alkyl, or CN;

[0013] R4is H, halogen, Ci-C4-alkyl, or CN;

[0014] R5is H, Ci-C6-alkyl, formyl, Ci-C6-alkylcarbonyl, Ci-C6-haloalkylcarbonyl, or Ci-C6-alkoxycar- bonyl;

[0015] R6is H or Ci-C6-alkyl; or

[0016] R5and R6, together with the adjacent nitrogen atom, may form a 4-, 5-, 6- or 7-membered saturated ring wherein 1 or 2 ring carbon atoms may be replaced by O, NH or S;

[0017] R7is H or Ci-C6-alkyl;

[0018] R8is H or Ci-C6-alkyl; or, provided that R2is H, a tautomer thereof selected from a compound of the general formulae

[0019] IB and IC wherein, in each of the formulae IB and IC, R1, R3, R4, R5, R6, R7and R8have the same meanings as defined for formula IA; 240946

[0020] 3 or a pharmaceutically acceptable salt thereof.

[0021] The articles “a”, “an” and "the" each refer to one or more, unless otherwise indicated.

[0022] Depending on the kind of substituents, the compounds of formula lA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof may have one or more centers of chirality, in which case they may be present as mixtures of enantiomers or diastereomers but also in the form of the pure enantiomers or pure diastereomers. The invention provides both the pure enantiomers or pure diastereomers of the compounds of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof and their mixtures and the use according to the invention of the pure enantiomers or pure diastereomers of the compounds of formula I or their mixtures. Suitable compounds of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof also include all possible geometrical stereoisomers (cis / trans isomers) as a specific form of diastereomers and mixtures thereof. Cis / trans isomers may be present with respect to an alkene, carbon-nitrogen double-bond, nitrogen-sulfur double bond, amide group or a cyclic, non-aromatic moiety. The term "stereoisomer(s)" encompasses both optical isomers, such as enantiomers or diastereomers existing due to more than one stereo- genic center in the molecule, as well as geometrical isomers (cis / trans isomers).

[0023] If the compounds of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC have ionizable functional groups, they can also be employed in the form of their pharmaceutically acceptable salts.

[0024] By the term "pharmaceutically acceptable" is meant in the present invention compounds and compositions that do not produce adverse, allergic or other undesirable reactions when administered to an animal or human. The term "pharmaceutically acceptable salts" as used herein includes acid addition salts and base addition salts.

[0025] The term “pharmaceutically acceptable base addition salt” denotes those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-di- ethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, and polyamine resins. The term “A pharmaceutically active metabolite” denotes a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. After entry into the body, most drugs are substrates for chemical reactions that may change their physical properties and biologic effects. These metabolic conversions, which usually affect the polarity of the compounds of the invention, alter the way in which drugs are distributed in and excreted from 240946

[0026] 4 the body. However, in some cases, metabolism of a drug is required for therapeutic effect. The term “therapeutically effective amount” denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors. The term “pharmaceutical composition” denotes a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.

[0027] If the compounds of formula IA can form tautomers due to intramolecular proton transfer, these tautomers are also encompassed by the scope of this invention. Common examples of such interconversions i.a. are keto-enol- (H-O-C=C O=C-C-H) and amide-imidic acid- (H-N-C=O N=C-O-H) tautomerism. The amount in which the one or other tautomeric form is present depends on the complete molecular structure and even stronger on the surrounding conditions (presence or absence of solvent, type of solvent, pH, temperature etc.). For example, if R2is H, the compound IA can exist in several tautomeric forms which interconvert under physiological conditions: 240946

[0028] 5

[0029] The compound of formula IA has a ketone group and, if R2is H, can undergo a keto-enol tautomerization into the enol form as represented by the compound of formula IB. The pyrazole ring of the enol form of formula IB can also undergo tautomerization into another keto form as represented by the compound of formula IC.

[0030] If R2is H, and depending on the environmental conditions, the compounds according to the present invention can be in the form of the keto tautomer comprising a 4-oxo-5H-pyrazolo[4,3-d]tri- azin-3-yl moiety (compound of formula IA), in the form of the enol tautomer (compound of formula IB) or in the form of another keto tautomer comprising a 4-oxo-6H-pyrazolo[4,3-d]triazin-3- yl moiety (compound of formula IC), or can exist as an equilibrium mixture of the compounds of formulae IA, IB and IC, and their composition ratio widely varies depending on the conditions, such as solvent, temperature and the like. Such tautomers, i.e. the compounds of formulae IA, IB and IC, and mixtures of the compounds IA, IB and IC at all ratios are included in the present invention.

[0031] The organic moieties mentioned in the definitions of the variables (substituents) R1, R2R3, R4, R5, R6, R7and R8are - like the term halogen - collective terms for individual listings of the individual group members. The prefix Cn-Cmindicates in each case the possible number of carbon atoms in the group.

[0032] The term "halogen", as used herein, denotes fluorine, bromine, chlorine or iodine.

[0033] The term "alkyl", as used herein, denotes a straight-chain or branched saturated hydrocarbon group having usually 1 to 6 carbon atoms (Ci-C6-alkyl), more frequently 1 to 4 carbon atoms (Ci-C4-alkyl), especially 1 to 3 carbon atoms (Ci-C3-alkyl) or 1 or 2 carbon atoms (Ci-C2-alkyl). Examples of Ci-C6-alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl (= sec-butyl), isobutyl and tert-butyl, n-pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, n-hexyl, 1 ,1 -dimethylpropyl, 1 ,2-dimethylpropyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2- dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1 ,1 ,2- trimethylpropyl, 1 ,2,2-trimethylpropyl, 1-ethyl-1 -methylpropyl, 1-ethyl-2-methylpropyl and the like.

[0034] The term “cycloalkyl”, as used herein, denotes a mono- or bicyclic saturated hydrocarbon group having 3 to 10, in particular 3 to 6, carbon ring members, for example C3-C6-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Examples of bicyclic radicals comprise bicyclo[2.2.1]heptyl, bicyclo[3.1 .1 ]heptyl, bicyclo[2.2.2]octyl and bicyclo[3.2.1]octyl.

[0035] The term "haloalkyl", as used herein, denotes an alkyl group as defined above, wherein the hydrogen atoms are partially or fully replaced by halogen atoms. Examples of Ci-C6-haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, bromomethyl, 1 -fluoroethyl, 2-fluoro- ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 1 -chloroethyl, 2-chloroethyl, 2,2,- dichloroethyl, 2,2,2-trichloroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro- 240946

[0036] 6

[0037] 2-fluoroethyl, 1 -bromoethyl, 1 -fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, heptafluoropropyl, 1 , 1 , 1 -trifluoroprop-2-yl, 3-chloropropyl, and the like. The term "alkoxy" (O-alkyl), as used herein, denotes an alkyl group as defined above, which is bound to the remainder of the molecule via an oxygen atom. Examples of Ci-C6-alkoxy are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), butoxy, 1 -methylpropoxy (secbutoxy), 2-methylpropoxy (isobutoxy), 1 ,1 -dimethylethoxy (tert- butoxy), pentoxy, 1-methylbut- oxy, 2-methylbutoxy, 3-methylbutoxy, 1 ,1 -dimethylpropoxy, 1 ,2-dimethylpropoxy, 2,2-dime- thylpropoxy, 1 -ethylpropoxy, hexoxy, 1 -methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4- methylpentoxy, 1 ,1 -dimethylbutoxy, 1 ,2-dimethylbutoxy, 1 ,3-dimethylbutoxy, 2,2-dimethylbut- oxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1 -ethylbutoxy, 2-ethylbutoxy, 1 ,1 ,2-trime- thylpropoxy, 1 ,2,2-trimethylpropoxy, 1-ethyl-1 -methylpropoxy or 1-ethyl-2-methylpropoxy and the like.

[0038] The term “formyl,” as used herein, means a — C(O)H group.

[0039] The term “alkylcarbonyl”, as used herein, means an alkyl group, as defined herein, which is bound to the remainder of the molecule via a carbonyl group. Examples of Ci-C6-alkylcarbonyl are acetyl, 1 -oxopropyl, 2,2-dimethyl-1 -oxopropyl, 1 -oxobutyl and 1 -oxopentyl.

[0040] The term "aryl", as used herein, refers to an aromatic mono- or bicyclic monovalent ring having 6-12 ring carbon atoms, preferably 6-10 ring carbon atoms, which may be unsubstituted (preferably a phenyl or naphthyl (1- or 2-naphthyl) group) or may have at least one Ci-C6-alkyl, Ci-C6- alkoxy or halogen substituent. The number of substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, each substituent can be the same or different.

[0041] The term "arylcarbonyl", as used herein, refers to an aryl group, as defined herein, which is bound to the remainder of the molecule via a carbonyl group. Examples of C6-Ci2-arylcarbonyl (preferably C6-Cio-arylcarbonyl) include benzoyl, o-, m- or p-toluoyl, 1-naphthoyl, 2-naphthoyl, o-, m- or p-anisoyl, veratroyl, o-, m- or p-isopropylbenzoyl and 3,4,5-trimethoxybenzoyl, of which the benzoyl, toluoyl, 1-naphthoyl and 2-naphthoyl are preferred and the benzoyl and toluoyl are most preferred.

[0042] The term “alkoxycarbonyl”, as used herein, means an alkoxy group, as defined herein, which is bound to the remainder of the molecule via a carbonyl group. Examples of Ci-C6-alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.

[0043] The term “haloalkylcarbonyl”, as used herein, means an haloalkyl group, as defined herein, which is bound to the remainder of the molecule via a carbonyl group. Examples of Ci-C6- haloalkylcarbonyl include fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl, pentafluoroethylcarbonyl, heptafluoro-n-propylcarbonyl, 1 ,1 -difluoroethylcarbonyl, 2,2-difluoro- ethylcarbonyl, 2,2-dichloroethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, 2-fluoroethylcarbonyl, 1 ,1 ,1-trifluoro-2-propylcarbonyl, 3,3,3-trifluoro-n-propylcarbonyl, 4,4,4-trifluoro-n-butylcarbonyl.

[0044] The 4-, 5-, 6- or 7-membered saturated ring which may be formed by R5and R6, together with the adjacent nitrogen atom, and wherein 1 or 2 ring carbon atoms may be replaced by O, NH or 240946

[0045] 7

[0046] S includes, for example, an azetidine, pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane or diazepane ring.

[0047] The preferred embodiments of the invention mentioned herein below have to be understood as being preferred either independently from each other or in combination with one another.

[0048] According to a preferred embodiment of the invention, preference is also given to those compounds of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof, wherein the variables, either independently of one another or in combination with one another, have the following meanings:

[0049] Preferably, R1is H, halogen, Ci-C6-alkyl, or C3-C6-cycloalkyl, more preferably H, halogen, Ci- C4-alkyl, or C3-C6-cycloalkyl, even more preferably H, fluoro, chloro, bromo, methyl, ethyl, n-pro- pyl, isopropyl, or cyclopropyl, yet more preferably H, bromo, methyl, ethyl, isopropyl, or cyclopropyl and in particular H, bromo, methyl, ethyl, or cyclopropyl.

[0050] In another preferred embodiment, R1is H, Ci-C6-alkyl, or C3-C6-cycloalkyl, more preferably H, Ci-C4-alkyl, or C3-C6-cycloalkyl and even more preferably H, methyl, ethyl, n-propyl, isopropyl, or cyclopropyl.

[0051] Preferably, R2is H, Ci-C6-alkylcarbonyl, or C6-Cio-arylcarbonyl, more preferably H, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzoyl, toluoyl, 1 -naphthoyl or 2-naphthoyl. Most preferably, R2is H.

[0052] Preferably, R3is H or halogen. In another preferred embodiment, R3is H, fluoro, chloro, bromo, methyl, or CN, more preferably H or fluoro.

[0053] Preferably, R4is H or halogen. In another preferred embodiment, R4is H, fluoro, chloro, bromo, methyl, or CN, more preferably H, fluoro, chloro or bromo, even more preferably H or fluoro and most preferably H.

[0054] Preferably, R5is H, Ci-C4-alkyl, formyl, Ci-C4-alkylcarbonyl, Ci-C4-haloalkylcarbonyl, or Ci-C6- alkoxycarbonyl, more preferably H, methyl, ethyl, formyl, acetyl, chloroacetyl, trifluoroacetyl, or tert-butyloxycarbonyl and even more preferably H, methyl, formyl, acetyl, chloroacetyl, trifluoroacetyl, or tert-butyloxycarbonyl.

[0055] Preferably, R6is H or Ci-C4-alkyl, more preferably H, methyl, or ethyl, even more preferably H or methyl, and most preferably H.

[0056] Preferably, R5and R6, together with the adjacent nitrogen atom, may form a 5-membered saturated ring, or a 6-membered saturated ring wherein 1 ring carbon atom may be replaced by O, NH or S, preferably by O.

[0057] In one embodiment, R5and R6, together with the adjacent nitrogen atom, may form a 5-mem- bered saturated ring. 240946

[0058] 8

[0059] In another embodiment, R5and R6, together with the adjacent nitrogen atom, may form a 6- membered saturated ring wherein 1 ring carbon atom may be replaced by O, NH or S, preferably by O.

[0060] In another preferred embodiment, R5and R6, together with the adjacent nitrogen atom, form a pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine ring, preferably a pyrrolidine or morpholine ring and more preferably a morpholine ring.

[0061] Preferably, R7is H or Ci-C4-alkyl, more preferably H, methyl, or ethyl, even more preferably H or methyl, and most preferably H.

[0062] Preferably, R8is H or Ci-C4-alkyl, more preferably H, methyl, or ethyl, even more preferably H or methyl, and most preferably H.

[0063] In a preferred embodiment, the present invention relates to a compound of formula IA wherein R1is H, halogen, Ci-C6-alkyl, or C3-C6-cycloalkyl;

[0064] R2is H;

[0065] R3is H or halogen;

[0066] R4is H or halogen;

[0067] R5is H, Ci-C6-alkyl, formyl, Ci-C6-alkylcarbonyl, Ci-C6-haloalkylcarbonyl, or Ci-C6-alkoxycar- bonyl;

[0068] R6is H or Ci-C6-alkyl; or R5and R6, together with the adjacent nitrogen atom, may form a 5-membered saturated ring, or a 6-membered saturated ring wherein 1 ring carbon atom may be replaced by O, NH or S, preferably by O;

[0069] R7is H;

[0070] R8is H; or a tautomer thereof selected from a compound of formulae IB and IC, wherein, in each of the formulae IB and IC, R1, R3, R4, R5, R6, R7and R8have the same meanings as defined for formula IA, or a pharmaceutically acceptable salt thereof.

[0071] In a more preferred embodiment, the present invention relates to a compound of formula IA wherein

[0072] R1is H, halogen, Ci-C6-alkyl, or C3-C6-cycloalkyl;

[0073] R2is H;

[0074] R3is H or halogen;

[0075] R4is H or halogen;

[0076] R5is H, Ci-C6-alkyl, formyl, Ci-C6-alkylcarbonyl, Ci-C6-haloalkylcarbonyl, or Ci-C6-alkoxycar- bonyl;

[0077] R6is H or Ci-C6-alkyl; or R5and R6, together with the adjacent nitrogen atom, may form a 5-membered saturated ring, or a 6-membered saturated ring wherein 1 ring carbon atom may be replaced by O;

[0078] R7is H;

[0079] R8is H; 240946

[0080] 9 or a tautomer thereof selected from a compound of formulae IB and IC, wherein, in each of the formulae IB and IC, R1, R3, R4, R5, R6, R7and R8have the same meanings as defined for formula IA, or a pharmaceutically acceptable salt thereof.

[0081] In an even more preferred embodiment, the present invention relates to a compound of formula IA wherein

[0082] R1is H, bromo, methyl, ethyl, isopropyl, or cyclopropyl;

[0083] R2is H;

[0084] R3is H or fluoro;

[0085] R4is H, fluoro, chloro or bromo;

[0086] R5is H, methyl, ethyl, formyl, acetyl, chloroacetyl, trifluoroacetyl, or tert-butyloxycarbonyl;

[0087] R6is H, methyl, or ethyl; or R5and R6, together with the adjacent nitrogen atom, form a pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine ring;

[0088] R7is H;

[0089] R8is H; or a tautomer thereof selected from a compound of formulae IB and IC, wherein, in each of the formulae IB and IC, R1, R3, R4, R5, R6, R7and R8have the same meanings as defined for formula IA, or a pharmaceutically acceptable salt thereof.

[0090] In a yet more preferred embodiment, the present invention relates to a compound of formula IA wherein

[0091] R1is H, bromo, methyl, ethyl, or cyclopropyl;

[0092] R2is H;

[0093] R3is H or fluoro;

[0094] R4is H, fluoro, chloro or bromo;

[0095] R5is H, methyl, ethyl, formyl, acetyl, chloroacetyl, trifluoroacetyl, or tert-butyloxycarbonyl;

[0096] R6is H, methyl, or ethyl; or R5and R6, together with the adjacent nitrogen atom, form a pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine ring;

[0097] R7is H;

[0098] R8is H; or a tautomer thereof selected from a compound of formulae IB and IC, wherein, in each of the formulae IB and IC, R1, R3, R4, R5, R6, R7and R8have the same meanings as defined for formula IA, or a pharmaceutically acceptable salt thereof.

[0099] In an especially preferred embodiment, the present invention relates to a compound of formula IA wherein

[0100] R1is H, bromo, methyl, ethyl, or cyclopropyl;

[0101] R2is H;

[0102] R3is H or fluoro;

[0103] R4is H, fluoro, chloro or bromo;

[0104] R5is H, methyl, ethyl, formyl, acetyl, chloroacetyl, trifluoroacetyl, or tert-butyloxycarbonyl;

[0105] R6is H or methyl; 240946

[0106] 10 or R5and R6, together with the adjacent nitrogen atom, form a pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine ring;

[0107] R7is H;

[0108] R8is H; or a tautomer thereof selected from a compound of formulae IB and IC, wherein, in each of the formulae IB and IC, R1, R3, R4, R5, R6, R7and R8have the same meanings as defined for formula IA, or a pharmaceutically acceptable salt thereof.

[0109] In a particularly preferred embodiment, the present invention relates to a compound of formula IA wherein

[0110] R1is H, bromo, methyl, ethyl, or cyclopropyl;

[0111] R2is H;

[0112] R3is H or fluoro;

[0113] R4is H, fluoro, chloro or bromo;

[0114] R5is H, methyl, ethyl, formyl, acetyl, chloroacetyl, trifluoroacetyl, or tert-butyloxycarbonyl;

[0115] R6is H or methyl; or R5and R6, together with the adjacent nitrogen atom, form a pyrrolidine or morpholine ring;

[0116] R7is H;

[0117] R8is H; or a tautomer thereof selected from a compound of formulae IB and IC, wherein, in each of the formulae IB and IC, R1, R3, R4, R5, R6, R7and R8have the same meanings as defined for formula IA, or a pharmaceutically acceptable salt thereof.

[0118] Preference is also given to a compound of formula IA wherein

[0119] R1is H, halogen, Ci-C6-alkyl, or C3-C6-cycloalkyl;

[0120] R2is H;

[0121] R3is H or halogen;

[0122] R4is H or halogen;

[0123] R5is H, Ci-C6-alkyl, formyl, Ci-C6-alkylcarbonyl, Ci-C6-haloalkylcarbonyl, or Ci-C6-alkoxycar- bonyl;

[0124] R6is H or Ci-C6-alkyl;

[0125] R7is H;

[0126] R8is H; or a tautomer thereof selected from a compound of formulae IB and IC, wherein, in each of the formulae IB and IC, R1, R3, R4, R5, R6, R7and R8have the same meanings as defined for formula IA, or a pharmaceutically acceptable salt thereof.

[0127] Special preference is given to compounds of the formula IA wherein

[0128] R1is H, halogen, Ci-C6-alkyl, or C3-C6-cycloalkyl;

[0129] R2is H;

[0130] R3is H or halogen;

[0131] R4is H;

[0132] R5is H, Ci-C6-alkyl, formyl, Ci-C6-alkylcarbonyl, Ci-C6-haloalkylcarbonyl, or Ci-C6-alkoxycar- bonyl;

[0133] R6is H or Ci-C6-alkyl; 240946

[0134] R7is H;

[0135] R8is H; or a tautomer thereof selected from a compound of formulae IB and IC, wherein, in each of the formulae IB and IC, R1, R3, R4, R5, R6, R7and R8have the same meanings as defined for formula IA, or a pharmaceutically acceptable salt thereof.

[0136] Particular preference is given to compounds of the formula IA wherein

[0137] R1is H, bromo, methyl, ethyl, isopropyl, or cyclopropyl;

[0138] R2is H;

[0139] R3is H or fluoro;

[0140] R4is H;

[0141] R5is H, methyl, ethyl, formyl, acetyl, chloroacetyl, trifluoroacetyl, or tert-butyloxycarbonyl;

[0142] R6is H, methyl, or ethyl;

[0143] R7is H;

[0144] R8is H; or a tautomer thereof selected from a compound of formulae IB and IC, wherein, in each of the formulae IB and IC, R1, R3, R4, R5, R6, R7and R8have the same meanings as defined for formula IA, or a pharmaceutically acceptable salt thereof.

[0145] Very particular preference is given to compounds of the formula IA wherein

[0146] R1is H, bromo, methyl, ethyl, or cyclopropyl;

[0147] R2is H;

[0148] R3is H or fluoro;

[0149] R4is H;

[0150] R5is H, methyl, formyl, acetyl, chloroacetyl, trifluoroacetyl, or tert-butyloxycarbonyl;

[0151] R6is H or methyl;

[0152] R7is H;

[0153] R8is H; or a tautomer thereof selected from a compound of formulae IB and IC, wherein, in each of the formulae IB and IC, R1, R3, R4, R5, R6, R7and R8have the same meanings as defined for formula IA, or a pharmaceutically acceptable salt thereof.

[0154] In yet another preferred embodiment of the compounds of the formula IA, R2, R7and R8are each H. Accordingly, compounds of formula lAa 240946

[0155] 12 or a tautomer thereof selected from a compound of formulae IBa and ICa or a pharmaceutically acceptable salt thereof are preferred wherein, in each of the formulae lAa, IBa and ICa, the variables R1, R3, R4, R5and R6have the meanings defined at the outset and preferably those mentioned above.

[0156] In yet another preferred embodiment of the compounds of the formula IA, R2, R4, R7and R8are each H. Accordingly, compounds of formula lAb or a tautomer thereof selected from a compound of formulae IBb and ICb 240946

[0157] 13 or a pharmaceutically acceptable salt thereof are preferred wherein, in each of the formulae lAb, IBb and ICb, the variables R1, R3, R5and R6have the meanings defined at the outset and pref- erably those mentioned above.

[0158] Special preference is given to the compounds of the formulae IAa.1 to IAa.180 of Table A, where the definitions of the variables R1, R3, R4, R5and R5are of particular importance for the compounds according to the invention not only in combination with one another but in each case also on their own:

[0159] Table A

[0160] Compounds of the formula IA which correspond to the formula lAa as shown above 240946

[0161] 14 240946

[0162] 15 240946

[0163] 16 240946

[0164] 17 240946

[0165] 18

[0166] Table B

[0167] Compounds of the formula IB which correspond to the compounds of formula IBa as shown above, in particular compounds of formulae IBa.1 to IBa.180, wherein the combination of the variables R1, R3, R4, R5and R5for the individual compound corresponds in each case to the respective row of Table A.

[0168] Table C

[0169] Compounds of the formula IC which correspond to the compounds of formula ICa as shown above, in particular compounds of formulae ICa.1 to ICa.180, wherein the combination of the variables R1, R3, R4, R5and R5for the individual compound corresponds in each case to the respective row of Table A.

[0170] Preferred compounds according to the invention are selected from the group consisting of the compounds of formulae IA-1 , IB-1 , IA-2, IB-2, IA-3, IB-3, IA-4, IB-4, IA-5, IB-5, IA-6, IB-6, IA-7, IB-7, IA-8, IB-8, IA-9, IB-9, IA-10, IB-10, IA-11 , IB-11 , IA-12, IB-12, IA-13, IB-13, IA-14, IB-14,

[0171] IA-15, IB-15, IA-16, IB-16, IA-17, IB-17, IA-18, IB-18, IA-19, IB-19, IA-20, IB-20, IA-21 , IB-21 ,

[0172] IA-22, IB-22, IA-23, IB-23, IA-24, IB-24, IA-25, IB-25, IA-26, IB-26, IA-27, IB-27, IA-28, IB-28,

[0173] IA-29, IB-29, IA-30, IB-30, IA-31 , IB-31 , IA-32, IB-32, IA-33, IB-33, IA-34, IB-34, IA-35 and IB-35 as listed below:

[0174] - 3-[4-(aminomethyl)phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-1

[0175] - 3-[4-(aminomethyl)phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-1

[0176] - tert-butyl N-[[4-(4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carbamate of formula IA-2 240946

[0177] 19

[0178] - tert-butyl N-[[4-(4-hydroxypyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carbamate of formula IB-2

[0179] - tert-butyl N-[[4-(7-bromo-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carbamate of formula IA-3

[0180] - tert-butyl N-[[4-(7-bromo-4-hydroxy-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carbamate of formula IB-3 240946

[0181] 20

[0182] - 3-[4-(aminomethyl)phenyl]-7-bromo-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-4

[0183] - 3-[4-(aminomethyl)phenyl]-7-bromo-pyrazolo[4,3-d]triazin-4-ol of formula IB-4

[0184] - 3-[4-(aminomethyl)phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-5

[0185] - 3-[4-(aminomethyl)phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-5

[0186] - methyl N-[[4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carbamate of formula IA-6 240946

[0187] 21

[0188] - methyl N-[[4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carbamate of formula IB-6 - 3-[4-(aminomethyl)phenyl]-7-ethyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-7

[0189] - 3-[4-(aminomethyl)phenyl]-7-ethyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-7 - N-[[4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]formamide of formula IA-8 240946

[0190] 22

[0191] - N-[[4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]formamide of formula IB-

[0192] - N-[[4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]acetamide of formula IA-9

[0193] - N-[[4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]acetamide of formula IB-9 240946

[0194] 23

[0195] - 2,2,2-trifluoro-N-[[4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]acetamide of formula IA-10 - 2,2,2-trifluoro-N-[[4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]acetamide of formula IB-10

[0196] - 3-[4-(aminomethyl)phenyl]-7-cyclopropyl-5H-pyrazolo[4,3-d]triazin-4-one of formula I A- 11

[0197]

[0198] - 3-[4-(aminomethyl)phenyl]-7-cyclopropyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-11

[0199] - 2-chloro-N-[[4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]acetamide of for- mula IA-12

[0200] - 2-chloro-N-[[4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]acetamide of for- mula IB-12 25

[0201] - 3-[4-[(dimethylamino)methyl]phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-

[0202] - 3-[4-[(dimethylamino)methyl]phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-13

[0203] - tert-butyl N-[[4-(7-cyclopropyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)-2-fluoro-phenyl]me- thyl]carbamate of formula IA-14 - tert-butyl N-[[4-(7-cyclopropyl-4-hydroxy-pyrazolo[4,3-d]triazin-3-yl)-2-fluoro-phenyl]me- thyl]carbamate of formula IB-14

[0204] - tert-butyl N-methyl-N-[[4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carba- mate of formula IA-15 240946

[0205] 26

[0206] - tert-butyl N-[[4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]-N-methyl-car- bamate of formula IB-15

[0207] - 3-[4-(aminomethyl)-3-fluoro-phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-

[0208] - 3-[4-(aminomethyl)-3-fluoro-phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-16 - tert-butyl N-[[2-fluoro-4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carba- mate of formula IA-17 240946

[0209] 27

[0210] - tert-butyl N-[[2-fluoro-4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carba- mate of formula IB-17 - 3-[4-(aminomethyl)-3-fluoro-phenyl]-7-cyclopropyl-5H-pyrazolo[4,3-d]triazin-4-one of formula

[0211] I A- 18

[0212] - 3-[4-(aminomethyl)-3-fluoro-phenyl]-7-cyclopropyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-18 - 7-methyl-3-[4-(methylaminomethyl)phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-19 240946

[0213] 28

[0214] - 7-methyl-3-[4-(methylaminomethyl)phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-19 - 3-[4-[(dimethylamino)methyl]-3-fluoro-phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-20

[0215] - 3-[4-[(dimethylamino)methyl]-3-fluoro-phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-20

[0216] - tert-butyl N-[[2,6-difluoro-4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]car- bamate of formula IA-21 240946

[0217] 29

[0218] - tert-butyl N-[[2,6-difluoro-4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]car- bamate of formula IB-21 - 3-[3-fluoro-4-(morpholinomethyl)phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula

[0219] IA-22

[0220] - 3-[3-fluoro-4-(morpholinomethyl)phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-22 - 3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-23 240946

[0221] 30

[0222] - 3-[3-fluoro-4-(pyrrolidin-1 -ylmethyl)phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB- 23

[0223] - 3-[4-(aminomethyl)-3-fluoro-phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-24 - 3-[4-(aminomethyl)-3-fluoro-phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-24

[0224] - 3-[3-fluoro-4-(methylaminomethyl)phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of for- mula IA-25 240946

[0225] 31

[0226] - 3-[3-fluoro-4-(methylaminomethyl)phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB- 25

[0227] - 3-[4-(ethylaminomethyl)-3-fluoro-phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-26 - 3-[4-(ethylaminomethyl)-3-fluoro-phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-26

[0228] - 3-[4-(aminomethyl)-3-chloro-phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA- 27 240946

[0229] 32

[0230] - 3-[4-(aminomethyl)-3-chloro-phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-27

[0231] - 3-[4-[(dimethylamino)methyl]-3-fluoro-phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-

[0232] - 3-[4-[(dimethylamino)methyl]-3-fluoro-phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-28

[0233] - 3-[3-fluoro-4-(methylaminomethyl)phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-29 240946

[0234] 33

[0235] - 3-[3-fluoro-4-(methylaminomethyl)phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-29

[0236] - 3-[3-chloro-4-(methylaminomethyl)phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-30

[0237] - 3-[3-chloro-4-(methylaminomethyl)phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-30

[0238] - 3-[3-chloro-4-(methylaminomethyl)phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-31 240946

[0239] 34

[0240] - 3-[3-chloro-4-(methylaminomethyl)phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB- 31

[0241] - 3-[3-chloro-4-[(dimethylamino)methyl]phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-

[0242] - 3-[3-chloro-4-[(dimethylamino)methyl]phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-32

[0243] - 3-[3-chloro-4-[(dimethylamino)methyl]phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-33 - 3-[3-chloro-4-[(dimethylamino)methyl]phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula 240946

[0244] 35

[0245] - 3-[4-(aminomethyl)-3-chloro-phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-34

[0246] - 3-[4-(aminomethyl)-3-chloro-phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-34

[0247] - 3-[3-bromo-4-[(dimethylamino)methyl]phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-

[0248] - 3-[3-bromo-4-[(dimethylamino)methyl]phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-35 240946

[0249] 36

[0250] In another embodiment, the compounds according to the invention are selected from the group consisting of the compounds of formulae IA-1 , IB-1 , IA-2, IB-2, IA-3, IB-3, IA-4, IB-4, IA-5, IB-5, IA-6, IB-6, IA-7, IB-7, IA-8, IB-8, IA-9, IB-9, IA-10, IB-10, IA-11 , IB-11 , IA-12, IB-12, IA-13, IB-13, IA-14, IB-14, IA-15, IB-15, IA-16, IB-16, IA-17, IB-17, IA-18, IB-18, IA-19, IB-19, IA-20, IB-20, IA-21 , IB-21 , IA-22 and IB-22.

[0251] Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution. Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The "effective amount" of the compound to be administered will be governed by such considerations and is the minimum amount necessary to reduced bacterial load or improve host survival. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole. In one example, the pharmaceutically effective amount of the compounds of the invention administered parenterally per dose will be in the range of about 0.1 to 1000 mg / kg, alternatively about 1 to 100 mg / kg of patient body weight per day, with the typical initial range of compound used being 1 to 50 mg / kg / day. In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about 5 to about 5000 mg of the compound of the invention.

[0252] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0253] The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. A typical formulation is prepared by mixing a compound of the 240946

[0254] 37 present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifier suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0255] An example of a suitable oral dosage form is a tablet containing about 10 to 500 mg of the compound of the invention compounded with about 40 to 400mg anhydrous lactose, about 5 to 50 mg sodium croscarmellose, about 5 to 50 mg polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 5 to 1000 mg) of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.

[0256] An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof. In a further embodiment includes a pharmaceutical composition comprising a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

[0257] Another embodiment includes a pharmaceutical composition comprising a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of bacterial infections. The following composition A and B illustrate typical compositions of the present invention but serve merely as representative thereof.

[0258] Composition A

[0259] A compound of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

[0260] Per tablet

[0261] Active ingredient 200mg

[0262] Microcrystalline cellulose 155 mg Corn starch 25mg Tale 25mg 240946

[0263] 38

[0264] Hydroxypropylmethylcellulose 20mg 425mg

[0265] Composition B

[0266] A compound of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

[0267] Per capsule

[0268] Active ingredient 100.0 mg

[0269] Corn starch 20.0 mg

[0270] Lactose 95.0 mg

[0271] Tale 4.5 mg

[0272] Magnesium stearate 0.5 mg

[0273] 220.0 mg

[0274] The compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof can prevent bacterial growth of susceptible organisms and are useful for: preventing or treating a bacterial infection, preferably a Gram-negative bacterial infection (all claimed) e.g. nosocomial pneumonia, urinary tract infections, systemic infections (bacteremia and sepsis), skin and soft tissue infections, surgical infections, eye infections, intraabdominal infections, lung infections and diabetic foot infections caused by Gram-negative bacteria e.g. third generation cephalosporins- and carbapenem- resistant Enterobacteriaeceae (e.g. Klebsiella pneumoniae, Escherichia coli) and multi-drug-re- sistant Pseudomonas aeruginosa and Acinetobacter baumannii or Acinetobacter spp., e.g. Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylorus e.g. Bacteroides spp. e.g. Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides distasonis, Campylobacter jejuni, Campylobacter fetus or Campylobacter coil, Francisella tularensis and Providencia spp. e.g. Providencia stuartii, Providencia rettgeri or Providencia alcalifaciens and Pseudomonas spp., as well as Gram-positive bacterial infections caused by e.g. Clostridium difficile, Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp., Salmonella spp, Shigella spp., Mycobacterium spp.; and for cleaning purposes e.g. to remove pathogenic microbes and bacteria from surgical instruments, catheters and artificial implants or to make a room or an area aseptic. The products of the invention can be administered, for example, parenterally e.g. by injection, or administered orally, perorally, such as in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, or rectally, such as in the form of suppositories. Pharmaceutical compositions containing these compounds can be prepared using conventional procedures familiar to those skilled in the art, such as by combining the ingredients into a dosage form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, the usual pharmaceutical adjuvants. Lt is contemplated that the compounds are ultimately embodied into compositions of suitable oral, parenteral or topical dosage forms. The compositions of this invention can contain, as optional ingredients, any of the various adjuvants, which are used ordinarily in the production of pharmaceutical preparations. Thus, for example, in formulating the present compositions into the desired oral dosage forms, one may use, as optional ingredients, fillers, such as co-precipitated aluminum hydroxide-calcium carbonate, di-calcium phosphate or lactose; disintegrating agents such as maize starch; and lubricating agents, such as talc, calcium stearate, and the like. It 240946

[0275] 39 should be fully understood, however, that the optional ingredients herein named are given by way of example only and that the invention is not restricted to the use hereof. Other such adjuvants, which are well known in the art, can be employed in carrying out this invention. Suitable as such carrier materials are not only inorganic, but also organic carrier materials. Thus, for tablets, coated tablets, dragees and hard gelatin capsules there can be used, for example, lactose, maize starch or derivatives thereof, talc, stearic acid or its salts. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active substance; no carriers are, however, required in the case of soft gelatin capsules). Suitable carrier materials for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and glucose. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. As pharmaceutical adjuvants there are contemplated the usual preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, coating agents and antioxidants.

[0276] In another embodiment, the present invention relates to a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for use as therapeutically active substance.

[0277] In another embodiment, the present invention relates to a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for use as a medicament.

[0278] In another embodiment, the present invention relates to a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for use in therapy.

[0279] In another embodiment, the present invention relates to the use of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for the treatment or prophylaxis of bacterial infection, preferably bacterial infection caused by Gram-positive bacteria or Gram-negative bacteria and more preferably bacterial infection caused by Gram-negative bacteria.

[0280] In a preferred embodiment, the present invention relates to the use of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for the treatment or prophylaxis of bacterial infection caused by Gram-negative bacteria selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylorus, Acinetobacter bau- mannii and Pseudomonas aeruginosa.

[0281] In a more preferred embodiment, the present invention relates to the use of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for the treatment or prophylaxis of bacterial infection caused by Gram-negative bacteria selected from Enterobacteriaceae. In an even more preferred embodiment, the present invention relates to the use of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for the treatment or prophylaxis of bacterial infection caused by Gram-negative bacteria selected from Enterobacteriaceae which is Klebsiella pneumoniae or Escherichia coli.

[0282] In another embodiment, the present invention relates to the use of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for the preparation of a medicament for the treatment or prophylaxis of bacterial infection, preferably bacterial infection caused by Gram-positive bacteria or Gram-negative bacteria and more preferably bacterial infection caused by Gram-negative bacteria.

[0283] In a preferred embodiment, the present invention relates to the use of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for the preparation of a medicament for the treatment or prophylaxis of bacterial infection caused by Gram-negative bacteria selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylorus, Acinetobacter baumannii and Pseudomonas aeruginosa.

[0284] In a more preferred embodiment, the present invention relates to the use of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for the preparation of a medicament for the treatment or prophylaxis of bacterial infection caused by Gram-negative bacteria selected from Enterobacteriaceae.

[0285] In an even more preferred embodiment, the present invention relates to the use of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for the preparation of a medicament for the treatment or prophylaxis of bacterial infection caused by Gramnegative bacteria selected from Enterobacteriaceae which is Klebsiella pneumoniae or Escherichia coli.

[0286] In another embodiment, the present invention relates to a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for use in the treatment or prophylaxis of bacterial infection, preferably bacterial infection caused by Gram-positive bacteria or Gram-negative bacteria and more preferably bacterial infection caused by Gram-negative bacteria.

[0287] In a preferred embodiment, the present invention relates to a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for use in the treatment or prophylaxis of bacterial infection caused by Gram-negative bacteria selected from Enterobacteriaceae, 41

[0288] Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylorus, Acinetobacter bau- mannii and Pseudomonas aeruginosa.

[0289] In a more preferred embodiment, the present invention relates to a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for use in the treatment or prophylaxis of bacterial infection caused by Gram-negative bacteria selected from Enterobacteriaceae.

[0290] In an even more preferred embodiment, the present invention relates to a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein for use in the treatment or prophylaxis of bacterial infection caused by Gram-negative bacteria selected from Enterobacteriaceae which is Klebsiella pneumoniae or Escherichia coll.

[0291] In another embodiment, the present invention relates to a method for the treatment or prophylaxis of bacterial infection, preferably bacterial infection caused by Gram-positive bacteria or Gram-negative bacteria and more preferably bacterial infection caused by Gram-negative bacteria, which method comprises administering a therapeutically effective amount of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein.

[0292] In a preferred embodiment, the present invention relates to a method for the treatment or prophylaxis of bacterial infection caused by Gram-negative bacteria selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylorus, Acinetobacter baumannii and Pseudomonas aeruginosa, which method comprises administering a therapeutically effective amount of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein.

[0293] In a more preferred embodiment, the present invention relates to a method for the treatment or prophylaxis of bacterial infection caused by Gram-negative bacteria selected from Enterobacteriaceae, which method comprises administering a therapeutically effective amount of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein.

[0294] In an even more preferred embodiment, the present invention relates to a method for the treatment or prophylaxis of bacterial infection caused by Gram-negative bacteria selected from Enterobacteriaceae which is Klebsiella pneumoniae or Escherichia coll, which method comprises administering a therapeutically effective amount of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined herein.

[0295] The pyrazolotriazinone compounds of formula IA according to the invention can be prepared by standard processes of organic chemistry. Suitable processes for synthesizing the compounds of 240946

[0296] 42 formula IA as well as their starting materials are provided in the schemes below and in the synthesis examples. All substituents, in particular, R1to R8are defined above. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry. General synthetic routes for preparing the bicycle of compounds of formula IA have been described before (cf. Heterocycles (2009), 78(1), 71-91 ; DE 102005021963 A1) and are shown below.

[0297] The 4-nitro-1 H-pyrazole-3-carboxylic acids of formula II used as starting material in Schemes 1 and 2 below are either commercially available (e.g. CAS 5334-40-7, 5334-38-3, 215298-72-9, 141721-97-3, 76424-48-1 , 1384846-96-1 or 1159769-54-6) or can be prepared according to known procedures.

[0298] Likewise, the amines IV used in the synthesis of Schemes 1 and 2 below are either commercially available such as, for example, certain 4-aminobenzenemethaneamines (e.g. CAS 900174-92-7, 2579084-52-7, 94838-55-8, 6406-74-2, 1134541-61-9, 2354572-66-8, 225240-83-5, 51013-67-3, 503160-29-0 or 1340523-69-4) or can be prepared according to known procedures.

[0299] The 4-nitro-1 H-pyrazole-3-carboxylic acid of formula II can be converted into the corresponding 4-nitro-1 H-pyrazole-3-carboxylic acid chloride of formula III by reaction with a chlorinating agent such as, for example, thionyl chloride (SOCI2) in a solvent like toluene or methylene chloride, preferably without a solvent. The coupling of the 4-nitro-1 H-pyrazole-3-carboxylic acid chloride III with the amine IV to the nitropyrazole carboxamide of formula V can be done in a solvent like dichloromethane, tetrahydrofuran, toluene, water, together with a base, like triethylamine, N,N- diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate. The reduction of the nitro group of the nitropyrazole carboxamide V to the amino group of the aminopyrazole carboxamide of formula VI can be done with hydrogen and a catalyst, e.g. palladium on carbon in a solvent like tetrahydrofuran or ethanol. The cyclization of 240946

[0300] 43 the aminopyrazole carboxamide VI to the pyrazolotriazinone compound of formula IA with R2= H is done using a diazotating reagent like sodium nitrite or a nitric acid ester like isoamyl nitrite in a solvent like acetonitrile, tetrahydrofuran or water. The groups R2= Ci-C6-alkylcarbonyl or C6-Ci2-arylcarbonyl can be added to the pyrazolotriazinone compound of formula lA with R2= H by acylation reaction using the respective acyl chloride or anhydride of formula VII wherein R2ais Ci-C6-alkyl or C6-Ci2-aryl and X is Cl or RXCOO with Rxbeing Ci-C4-alkyl, preferably acetyl, as acylating agent in the presence of a Lewis acid catalyst like HCI, BF3-etherate or AICI3or a base like triethylamine or N,N-diisopropylethylamine. R2= C1-C6-alkylcarbonyl or C6-C12-arylcarbonyl

[0301] The 4-nitro-1 H-pyrazole-3-carboxylic acid of formula II can be converted into the corresponding 4-nitro-1 H-pyrazole-3-carboxylic acid ester of formula VIII by reaction with an alcohol, like methanol, in presence of a Lewis acid catalyst, like HCI. The reduction of the nitro group of the 4-ni- tro-1 H-pyrazole-3-carboxylic acid ester VIII to the amino group of the aminopyrazole acid ester of formula IX can be done with hydrogen and a catalyst, e.g. palladium on carbon in a solvent like tetrahydrofuran, methanol or ethanol. The generation of the dimethyl triazene acid of formula X is done using a diazotating reagent like sodium nitrite or a nitric acid ester like isoamyl nitrite in a solvent like acetonitrile, tetrahydrofuran or water. After addition of dimethylamine the ester group is cleaved with a hydroxide source like sodium hydroxide or potassium tert-butoxide and water to give the dimethyl triazene acid X. The pyrazolotriazinone compounds of formula IA with R2= H are formed under amide coupling conditions using, e.g. benzotriazol- 1 -yloxytripyrrol- idinophosphonium hexafluorophosphate, 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N'- Dicyclohexylcarbodiimid or a chlorocarbonate like methylchlorocarbonate in an organic solvent like dimethylformamide, tetrahydrofuran or acetonitrile, and an amine IV. 240946

[0302] 44

[0303] If required, the addition of the groups R2= Ci-C6-alkylcarbonyl or C6-Ci2-arylcarbonyl to the py- razolotriazinone compound of formula lA with R2= H can be accomplished by the acylation reaction as described above for Scheme 1 using the respective acyl chloride or anhydride of formula VII wherein R2ais Ci-C6-alkyl or C6-Ci2-aryl and X is Cl or RXCOO with Rxbeing Ci-C4-al- kyl, preferably acetyl, as acylating agent in the presence of a Lewis acid catalyst like like HCI, BF3-etherate or AICI3or a base like triethylamine or N,N-diisopropylethylamine.

[0304] An optional final deprotection of a BOC (tert-butyloxycarbonyl)-protected amine IV (in particular when R5and / or R6is H) can be done with an acid like HCI or trifluoroactic acid in a solvent like dichloromethane, water or dioxane.

[0305] A compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof when manufactured according to the above processes is also an object of the invention.

[0306] Examples

[0307] This invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.

[0308] Abbreviations used herein are as follows:

[0309] CFU: colony forming unit

[0310] DMSO: dimethyl sulfoxide

[0311] HPLC: high performance liquid chromatography

[0312] LSMS, LS-MS or LS / MS: liquid chromatography-mass spectometry TLC: thin layer chromatography

[0313] General experimental conditions:

[0314] Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SPI system and the Quad 12 / 25 Cartridge module, ii) ISCO combi-flash chromatography instrument. Silica gel brand and pore size: i) KP-SIL 60 A, particle size: 40-60 pm; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400.

[0315] Intermediates and final compounds were purified by preparative HPLC on reversed phase column using XBridge™ Prep-C18 (5 pm, OBDTM 30 x 100 mm) column, SunFire™ Prep-C18 (5 pm, OBD™ 30 x 100 mm) column, Phenomenex Synergi-C18 (10 pm, 25 x 150 mm) or Phe- nomenex Gemini-C18 (10 pm, 25 x 150 mm). Waters AutoP purification System (Sample Manager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, solvent system: acetonitrile and 0.1 % ammonium hydroxide in water; acetonitrile and 0.1 % formic acid in water or acetonitrile and 0.1 % trifluoroacetic acid in water). Or Gilson-281 purification System (Pump 322, Detector: UV 156, solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% formic acid in water; acetonitrile and 0.05% HCI in water; acetonitrile and 0.075% trifluoroacetic acid in water; or acetonitrile and water). 240946

[0316] 45

[0317] LC / MS spectra of compounds were obtained using a LC / MS (Waters™ Alliance 2795- Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ or Agilent Alliance 6110-Micromass ZQ).

[0318] Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion.

[0319] All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.

[0320] A. Synthesis examples

[0321] The preparation of compounds of formula IA is illustrated by the examples below; however, the subject matter of the present invention is not limited to the examples given.

[0322] With appropriate modification of the starting materials, the procedures given in the synthesis examples below were used to obtain further compounds IA. The compounds obtained in this manner are listed in the table I that follows, together with physical data.

[0323] The products shown below were characterized by NMR spectroscopy or the masses ([m / z]) determined by LC-MS spectrometry except for crude intermediates which were directly used in a subsequent step.

[0324] Example 1 : Synthesis of 3-[4-[(dimethylamino)methyl]phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin- 4-one of formula IA-13 (see Table I below)

[0325] Step 1 : Synthesis of 5-methyl-4-nitro-1 H-pyrazole-3-carboxylic acid chloride

[0326] To 5-methyl-4-nitro-1 H-pyrazole-3-carboxylic acid (CAS 5334-38-3) (3 g, 17.54 mmol) SOCI2(30 mL) was added. The mixture was stirred at 90 °C for 2 h. TLC (petroleum ether : ethyl acetate = 5:1) showed the reaction was completed. The reaction mixture was concentrated to give 5-methyl-4-nitro-1 H-pyrazole-3-carboxylic acid chloride (3.73 g, crude) as a yellow solid.

[0327] Step 2: Synthesis of N-[4-[(dimethylamino)methyl]phenyl]-3-methyl-4-nitro-1 H-pyrazole-5-car- boxamide To a solution of 5-methyl-4-nitro-1 H-pyrazole-3-carboxylic acid chloride (2.95 g, 19.73 mmol) in dichloromethane (37 mL) was added triethylamine (3.98 g, 39.47 mmol) and 4-amino-N,N-dime- thylbenzenemethanamine (CAS 6406-74-2) (3.73g, 19.73 mmol) at 0°C. The mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed. The reaction was quenched with H2O (50 mL), extracted with ethyl acetate (50 mL x 3), the combined organic was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the N-[4-[(dimethyla- mino)methyl]phenyl]-3-methyl-4-nitro-1 H-pyrazole-5-carboxamide (7.64 g, crude) as a yellow solid.

[0328] Step 3: Synthesis of 4-amino-N-[4-[(dimethylamino)methyl]phenyl]-3-methyl-1 H-pyrazole-5-car- boxamide

[0329] To a solution of N-[4-[(dimethylamino)methyl]phenyl]-3-methyl-4-nitro-1 H-pyrazole-5-carbox- amide (9 g, 29.7 mmol) in ethanol (270 mL) was added Pd / C (0.9 g) at 25 °C. The mixture was degassed under vacuum and purged with H2several times. The mixture was stirred at 50 °C, 50 Psi under H2for 16 h. LCMS showed the reaction was completed. The reaction was filtered, dried and concentrated to give the 4-amino-N-[4-[(dimethylamino)methyl]phenyl]-3-methyl-1 H- pyrazole-5-carboxamide(6.7 g, crude) as a yellow solid.

[0330] Step 4: Synthesis of 3-[4-[(dimethylamino)methyl]phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4- one of formula IA-13

[0331] To a solution of 4-amino-N-[4-[(dimethylamino)methyl]phenyl]-3-methyl-1 H-pyrazole-5-carbox- amide (409 mg, 1.5 mmol) in acetonitile (80 mL) was added isopentyl nitrite (351 mg, 3.0 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed the reaction was completed.

[0332] The reaction was concentrated and the crude was purified by preparative HPLC (NH4HCO3, Ac- etonitrile-water) to give the 3-[4-[(dimethylamino)methyl]phenyl]-7-methyl-5H-pyrazolo[4,3-d]tria- zin-4-one (0.18 g, 42 %) as a grey solid.

[0333] 1H NMR: (400 MHz, DMSO-d6): 5 = 7.55 - 7.51 (m, 2H), 7.49 - 7.46 (m, 2H), 3.49 (s, 2H), 3.37 (s, 1 H), 2.65 (s, 3H), 2.20 (s, 6H) 47

[0334] Example 2: Synthesis of tert-butyl N-[[2-fluoro-4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3- yl)phenyl]methyl]carbamate of formula IA-17 (see Table I below)

[0335] Step 1 : Synthesis of tert-butyl N-[[2-fluoro-4-[(3-methyl-4-nitro-1 H-pyrazole-5-car- bonyl)amino]phenyl]-methyl]carbamate

[0336] To a solution of 5-methyl-4-nitro-1 H-pyrazole-3-carboxylic acid chloride (3.80 g, 15.83 mmol) in dichloromethane (30 mL) was added triethylamine (3.20 g, 31.65 mmol) at 25 °C. The mixture was added dropwise 1 ,1-dimethylethyl-N-[(4-amino-2-fluorophenyl)methyl]carbamate (CAS900174-92-7) (3 g, 15.83 mmol) at 0 °C. Then the mixture solution was stirred for 16 h at 0 °C~25 °C. TLC (ethyl acetate) showed the reaction was completed. The mixture poured into H2O (90 mL) and extracted with dichloromethane (3 x 60 ml). The organic phase was washed with brine (60 mL) and dried over Na2SO4. Filtered, concentrated and purification by column (petroleum ether : ethyl acetate = 100% ~ 0%) to give tert-butyl-N-[[2-fluoro-4-[(3-methyl-4-nitro- 1 H-pyrazole-5-carbonyl)amino]phenyl]-methyl]carbamate (3.5 g, 56.22%) as yellow solid.

[0337] 1H NMR: (400 MHz, DMSO-d6): 5 = 14.03 (br s, 1 H), 10.79 (br s, 1 H), 7.60 (br d, J = 12.3 Hz, 1 H), 7.43 - 7.24 (m, 3H), 4.13 (br d, J = 5.6 Hz, 2H), 2.56 (s, 3H), 1.45 - 1.34 (m, 9H)

[0338] Step 2: Synthesis of tert-butyl N-[[4-[(4-amino-3-methyl-1 H-pyrazole-5-carbonyl)amino]-2-fluoro- phenyl]methyl]carbamate

[0339] To a solution of tert-butyl N-[[2-fluoro-4-[(3-methyl-4-nitro-1 H-pyrazole-5-carbonyl)amino]phe- nyl]-methyl]carbamate (3.50 g, 8.90 mmol) in ethanol (140 mL) was added Pd / C (9.47 g, 8.90 mmol) under N2. The mixture was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(30 psi) at 25 °C for 16 h. LCMS showed the reaction was completed. The mixture was filtered and concentrated to give tert-butyl N-[[4-[(4-amino-3-me- thyl-1 H-pyrazole-5-carbonyl)amino]-2-fluoro-phenyl]methyl]carbamate (3.3 g, crude) as yellow solid. 240946

[0340] 48

[0341] 1H NMR: (400 MHz, DMSO-d6): 5 = 12.62 (br s, 1 H), 9.90 (br s, 1 H), 7.72 (br d, J = 12.6 Hz, 1 H), 7.55 (br d, J = 3.5 Hz, 1 H), 7.35 - 7.16 (m, 2H), 4.49 (br s, 2H), 4.11 (br d, J = 5.4 Hz, 2H), 2.12 (s, 3H), 1.39 (s, 9H)

[0342] Step 3: Synthesis of tert-butyl N-[[2-fluoro-4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phe- nyl]methyl]carbamate of formula IA-17

[0343] (IA-17)

[0344] To a solution of tert-butyl N-[[4-[(4-amino-3-methyl-1 H-pyrazole-5-carbonyl)amino]-2-fluoro-phe- nyl]methyl]carbamate (3.3 g, 9.08 mmol) in acetonitrile (35 mL) was added iso-amylnitrate (2.13 g, 18.16 mmol). Then the mixture solution was stirred at 25°C for 16 h. LCMS showed the reaction was completed. The mixture was concentrated to give tert-butyl N-[[2-fluoro-4-(7-methyl-4- oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carbamate (3.5 g, crude) and 500 mg of the crude to purification by prep-HPLC (NH4HCO3, acetonitrile-water) to give ES4602X-65A (309 mg, 61 .8%) as yellow solid.

[0345] 1H NMR: (400 MHz, DMSO-d6): 5 = 7.54 - 7.36 (m, 4H), 4.25 (br d, J = 5.9 Hz, 2H), 2.62 (s, 3H), 1.41 (s, 9H)

[0346] Example 3: Synthesis of 3-[4-(aminomethyl)-3-fluoro-phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin- 4-one of formula IA-16 (see Table I below)

[0347] (IA-17) (IA-16)

[0348] To a solution of given tert-butyl N-[[2-fluoro-4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3- yl)phenyl]methyl]carbamate of formula IA-17 (3.5 g, 9.08 mmol) in dichloromethane (35 mL) was added trifluoroacetic acid (12 mL). Then the mixture solution was stirred at 25°C for 2 h. LCMS showed the reaction was completed. The mixture was concentrated and purification by preparative HPLC (NH4HCO3, acetontrile-water) to give 3-[4-(aminomethyl)-3-fluoro-phenyl]-7- methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-16 (570 mg, 22%) as yellow solid.

[0349] 1H NMR: (400 MHz, DMSO-d6): 5 = 7.67 (t, J = 8.3 Hz, 1 H), 7.51 - 7.39 (m, 2H), 3.88 (s, 2H), 2.63 (s, 3H) 240946

[0350] 49

[0351] Table I: Compounds of the formula lAa as shown above wherein the variables R1, R3, R4, R5and R6have the following meanings :

[0352] B. Biological examples

[0353] Minimal Inhibitory Concentration Protocol (MIC) Assay: 240946

[0354] 50

[0355] The in vitro potency of compounds IA according to the invention to inhibit E. coli (strain NCTC 13441) and S. aureus (strain NRS 384) growth was assessed by MIC (minimum inhibitory concentration) assay.

[0356] Susceptibility testing was performed based on Clinical and Laboratory Standards Institute (CLSI) guidelines M7-A11 . All bacterial strains were recovered from long-term storage (-80°C) and cultured on nutrient agar (NA). All strains were incubated at 37°C under aerobic conditions for approximately 20 h. Minimum inhibitory concentration (MIC) assays were performed in BD cation-adjusted Mueller-Hinton broth (caMHB). Assays were performed in 96-well flat-bottomed polystyrene plates (Corning #3370). A 6.4 mg / mL master stock of each test article was prepared in DMSO (100* stock). From the master stock, a 128 pg / mL stock was prepared in caMHB and transferred to a test plate. Serial 1 :1 dilutions were performed from wells 1 to 10 in caMHB + 2% DMSO. Well 11 served as a growth control (medium and organism only) and well 12 served as a negative control (medium only). A suspension of each bacterial strain was prepared in sterile phosphate-buffered saline (PBS) to a density equivalent of a 0.5 McFarland standard. These suspensions were then further diluted into caMHB and used to inoculate assay plates (columns 1 through 11) to provide a starting inoculum of ~ 2 to 8 x 105 CFU / mL and a final DMSO concentration of 1%. Assay plates were incubated at 37°C for 17 h under aerobic conditions. The MIC was defined as the lowest concentration resulting in no visible growth of organism compared to the growth control.

[0357] Table II: MIC values of compounds IA of this invention against E. coli and S aureus 240946

[0358] 51

Claims

1. 24094652Claims1. A compound of general formula IAwhereinR1is H, halogen, Ci-C6-alkyl, or C3-Cio-cycloalkyl;R2is H, Ci-C6-alkylcarbonyl, or C6-Ci2-arylcarbonyl;R3is H, halogen, Ci-C4-alkyl, or CN;R4is H, halogen, Ci-C4-alkyl, or CN;R5is H, Ci-C6-alkyl, formyl, Ci-C6-alkylcarbonyl, Ci-C6-haloalkylcarbonyl, or Ci-C6- alkoxycarbonyl;R6is H or Ci-C6-alkyl; orR5and R6, together with the adjacent nitrogen atom, may form a 4-, 5-, 6- or 7-membered saturated ring wherein 1 or 2 ring carbon atoms may be replaced by O, NH or S;R7is H or Ci-C6-alkyl;R8is H or Ci-C6-alkyl; or, provided that R2is H, a tautomer thereof selected from a compound of the general formulae IB and IC24094653 wherein, in each of the formulae IB and IC, R1, R3, R4, R5, R6, R7and R8have the same meanings as defined for formula IA; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R1is H, fluoro, chloro, bromo, methyl, ethyl, n- propyl, isopropyl, or cyclopropyl, preferably H, bromo, methyl, ethyl, isopropyl, or cyclopropyl and more preferably H, bromo, methyl, ethyl, or cyclopropyl.

3. The compound according to claim 1 or 2, wherein R2is H.

4. The compound according to any one of claims 1 to 3, wherein R3is H, fluoro, chloro, bromo, methyl, or CN, preferably H or fluoro.

5. The compound according to any one of claims 1 to 4, wherein R4is H, fluoro, chloro, bromo, methyl, or CN, preferably H, fluoro, chloro or bromo , more preferably H or fluoro and even more preferably H.

6. The compound according to any one of claims 1 to 5, wherein R5is H, methyl, ethyl, formyl, acetyl, chloroacetyl, trifluoroacetyl, or tert-butyloxycarbonyl, preferably H, methyl, formyl, acetyl, chloroacetyl, trifluoroacetyl, or tert-butyloxycarbonyl.

7. The compound according to any one of claims 1 to 6, wherein R6is H, methyl, or ethyl, preferably H or methyl, and more preferably H.

8. The compound according to any one of claims 1 to 5, wherein R5and R6, together with the adjacent nitrogen atom, may form a 5-membered saturated ring, or a 6-membered saturated ring wherein 1 ring carbon atom may be replaced by O, NH or S, preferably by O.

9. The compound according to any one of claims 1 to 5 and 8, wherein R5and R6, together with the adjacent nitrogen atom, form a pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine ring, preferably a pyrrolidine or morpholine ring and more preferably a morpholine ring.

10. The compound according to any one of claims 1 to 9, wherein R7is H.11 . The compound according to any one of claims 1 to 10, wherein R8is H.

12. The compound according to any one of claims 1 to 11 , whereinR1is H, halogen, Ci-C6-alkyl, or C3-C6-cycloalkyl;R2is H;R3is H or halogen;R4is H or halogen;R5is H, Ci-C6-alkyl, formyl, Ci-C6-alkylcarbonyl, Ci-C6-haloalkylcarbonyl, or Ci-C6- alkoxycarbonyl;24094654R6is H or Ci-C6-alkyl; or R5and R6, together with the adjacent nitrogen atom, may form a 5-membered saturated ring, or a 6-membered saturated ring wherein 1 ring carbon atom may be replaced by O, NH or S, preferably by O;R7is H; andR8is H.

13. The compound according to any one of claims claims 1 to 12, whereinR1is H, bromo, methyl, ethyl, or cyclopropyl;R2is H;R3is H or fluoro;R4is H, fluoro, chloro or bromo;R5is H, methyl, ethyl, formyl, acetyl, chloroacetyl, trifluoroacetyl, or tert-butyloxycar- bonyl;R6is H, methyl, or ethyl, preferably H or methyl; or R5and R6, together with the adjacent nitrogen atom, form a pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine ring, preferably a pyrrolidine or morpholine ring;R7is H; andR8is H.

14. The compound according to any one of claims 1 to 13, being selected from the group consisting of the compounds of formulae IA-1 , IB-1 , IA-2, IB-2, IA-3, IB-3, IA-4, IB-4, IA-5, IB-5, IA-6, IB-6, IA-7, IB-7, IA-8, IB-8, IA-9, IB-9, IA-10, IB-10, IA-11 , IB-11 , IA-12, IB-12, IA-13, IB-13, IA-14, IB-14, IA-15, IB-15, IA-16, IB-16, IA-17, IB-17, IA-18, IB-18, IA-19, IB-19, IA- 20, IB-20, IA-21 , IB-21 , IA-22, IB-22, IA-23, IB-23, IA-24, IB-24, IA-25, IB-25, IA-26, IB-26, IA-27, IB-27, IA-28, IB-28, IA-29, IB-29, IA-30, IB-30, IA-31 , IB-31 , IA-32, IB-32, IA-33, IB- 33, IA-34, IB-34, IA-35 and IB-35 as listed below:- 3-[4-(aminomethyl)phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-1- 3-[4-(aminomethyl)phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-124094655- tert-butyl N-[[4-(4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carbamate of formula- tert-butyl N-[[4-(4-hydroxypyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carbamate of formula IB-2- tert-butyl N-[[4-(7-bromo-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carbamate of formula IA-3tert-butyl N-[[4-(7-bromo-4-hydroxy-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carbamate of formula IB-324094656- 3-[4-(aminomethyl)phenyl]-7-bromo-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-4- 3-[4-(aminomethyl)phenyl]-7-bromo-pyrazolo[4,3-d]triazin-4-ol of formula IB-4- 3-[4-(aminomethyl)phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-53-[4-(aminomethyl)phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-524094657- methyl N-[[4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carbamate of formula IA-6- methyl N-[[4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]carbamate of formula IB-6- 3-[4-(aminomethyl)phenyl]-7-ethyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-724094658- 3-[4-(aminomethyl)phenyl]-7-ethyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-7- N-[[4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]formamide of formula- N-[[4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]formamide of formula IB-8- N-[[4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]acetamide of formulaIA-924094659- N-[[4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]acetamide of formula IB-9- 2,2,2-trifluoro-N-[[4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]acet- amide of formula IA-102,2,2-trifluoro-N-[[4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]acet- amide of formula IB-1024094660- 3-[4-(aminomethyl)phenyl]-7-cyclopropyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-- 3-[4-(aminomethyl)phenyl]-7-cyclopropyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-112-chloro-N-[[4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]acetamide of formula IA-12240946612-chloro-N-[[4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]acetamide- 3-[4-[(dimethylamino)methyl]phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formulaI A- 13- 3-[4-[(dimethylamino)methyl]phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-13- tert-butyl N-[[4-(7-cyclopropyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)-2-fluoro-phenyl]me- thyl]carbamate of formula IA-1424094662- tert-butyl N-[[4-(7-cyclopropyl-4-hydroxy-pyrazolo[4,3-d]triazin-3-yl)-2-fluoro-phenyl]me- thyl]carbamate of formula IB-14- tert-butyl N-methyl-N-[[4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]me- thyl]carbamate of formula IA-15- tert-butyl N-[[4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]-N-methyl- carbamate of formula IB-15- 3-[4-(aminomethyl)-3-fluoro-phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formulaI A- 163-[4-(aminomethyl)-3-fluoro-phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-1624094663- tert-butyl N-[[2-fluoro-4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]methyl]car- bamate of formula IA-17- tert-butyl N-[[2-fluoro-4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]me- thyl]carbamate of formula IB-17- 3-[4-(aminomethyl)-3-fluoro-phenyl]-7-cyclopropyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-18- 3-[4-(aminomethyl)-3-fluoro-phenyl]-7-cyclopropyl-pyrazolo[4,3-d]triazin-4-ol of formula IB- 18240946647-methyl-3-[4-(methylaminomethyl)phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-7-methyl-3-[4-(methylaminomethyl)phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-193-[4-[(dimethylamino)methyl]-3-fluoro-phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-203-[4-[(dimethylamino)methyl]-3-fluoro-phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-2024094665- tert-butyl N-[[2,6-difluoro-4-(7-methyl-4-oxo-5H-pyrazolo[4,3-d]triazin-3-yl)phenyl]me- thyl]carbamate of formula IA-21- tert-butyl N-[[2,6-difluoro-4-(4-hydroxy-7-methyl-pyrazolo[4,3-d]triazin-3-yl)phenyl]me- thyl]carbamate of formula IB-21- 3-[3-fluoro-4-(morpholinomethyl)phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-223-[3-fluoro-4-(morpholinomethyl)phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-2224094666- 3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-23- 3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formulaIB-23- 3-[4-(aminomethyl)-3-fluoro-phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-24- 3-[4-(aminomethyl)-3-fluoro-phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-2424094667- 3-[3-fluoro-4-(methylaminomethyl)phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-25- 3-[3-fluoro-4-(methylaminomethyl)phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formulaIB-25- 3-[4-(ethylaminomethyl)-3-fluoro-phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of for- mula IA-263-[4-(ethylaminomethyl)-3-fluoro-phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-2624094668- 3-[4-(aminomethyl)-3-chloro-phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-27- 3-[4-(aminomethyl)-3-chloro-phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-27- 3-[4-[(dimethylamino)methyl]-3-fluoro-phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-283-[4-[(dimethylamino)methyl]-3-fluoro-phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-2824094669- 3-[3-fluoro-4-(methylaminomethyl)phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-- 3-[3-fluoro-4-(methylaminomethyl)phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-29- 3-[3-chloro-4-(methylaminomethyl)phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-- 3-[3-chloro-4-(methylaminomethyl)phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-3024094670- 3-[3-chloro-4-(methylaminomethyl)phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-31- 3-[3-chloro-4-(methylaminomethyl)phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-31- 3-[3-chloro-4-[(dimethylamino)methyl]phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-32- 3-[3-chloro-4-[(dimethylamino)methyl]phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-323-[3-chloro-4-[(dimethylamino)methyl]phenyl]-7-methyl-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-3324094671- 3-[3-chloro-4-[(dimethylamino)methyl]phenyl]-7-methyl-pyrazolo[4,3-d]triazin-4-ol of formula IB-333-[4-(aminomethyl)-3-chloro-phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-34- 3-[4-(aminomethyl)-3-chloro-phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-34- 3-[3-bromo-4-[(dimethylamino)methyl]phenyl]-5H-pyrazolo[4,3-d]triazin-4-one of formula IA-3524094672- 3-[3-bromo-4-[(dimethylamino)methyl]phenyl]pyrazolo[4,3-d]triazin-4-ol of formula IB-3515. The compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 14 for use as therapeutically active substance.

16. A pharmaceutical composition comprising a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IA and IC, or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 14 and a therapeutically inert carrier.

17. The use of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 14 for the treatment or prophylaxis of bacterial infection, preferably bacterial infection caused by Gram-positive bacteria or Gram-negative bacteria and more preferably bacterial infection caused by Gram-negative bacteria.

18. The use of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 14 for the preparation of a medicament for the treatment or prophylaxis of bacterial infection, preferably bacterial infection caused by Gram-positive bacteria or Gram-negative bacteria and more preferably bacterial infection caused by Gramnegative bacteria.

19. The use according to claim 17 or 18, wherein the Gram-negative bacteria is selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylorus, Acinetobacter baumannii and Pseudomonas aeruginosa.

20. The use according to claim 19, wherein the Gram-negative bacteria is selected from Entero- bacte / 7'aceaewhich is Klebsiella pneumoniae or Escherichia coll.2409467321 . A compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 14 for use in the treatment or prophylaxis of bacterial infection, preferably bacterial infection caused by Gram-positive bacteria or Gram-negative bacteria and more preferably bacterial infection caused by Gram-negative bacteria.

22. A compound for use according to claim 21 , wherein the Gram-negative bacteria is selected from Enterobacteriaceae, Neisseria gonorrhoeae, Haemophilus influenzae, Helicobacter pylorus, Acinetobacter baumannii and Pseudomonas aeruginosa.

23. A compound for use according to claim 22, wherein the Gram-negative bacteria is selected from Enterobacteriaceaewhich is Klebsiella pneumoniae or Escherichia coll.

24. A method for the treatment or prophylaxis of bacterial infection, preferably bacterial infection caused by Gram-positive bacteria or Gram-negative bacteria and more preferably bacterial infection caused by Gram-negative bacteria, which method comprises administering a therapeutically effective amount of a compound of formula IA or, provided that R2is H, a tautomer thereof selected from a compound of formulae IB and IC, or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 14.

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